Modified-Release Minoxidil Compositions and Methods of Use

Abstract

The compositions and methods provided herein include oral pharmaceutical formulations containing a daily dose of a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof. Also provided herein are oral pharmaceutical formulations containing a daily dose of a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof and one or more additional active ingredients. Also provided herein are methods for treating hair loss by administering a daily dose of a sustained-release formulation of minoxidil or a pharmaceutically acceptable salt thereof to a subject in need thereof. Kits containing a sustained-release modified vehicle containing oral minoxidil or a pharmaceutically acceptable salt thereof are also provided.

Description

[Technical Field]

[0001] (Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 419,155, filed October 25, 2022, and U.S. Provisional Patent Application No. 63 / 433,203, filed December 16, 2022, which applications are incorporated herein by reference in their entireties. [Brief explanation of the drawings]

[0002] For a fuller understanding of the nature and advantages of the present embodiments, reference should be made to the following detailed description of the invention taken in conjunction with the accompanying drawings.

[0003] [Figure 1] Figure 1 shows the study design. There will be a washout period of at least 7 days between each investigational medicinal product administration, and sufficient time to allow for decision-making processes and product manufacturing. [Figure 2] Figure 2 shows the average dissolution profiles of pharmaceutical formulation prototype A under single-step dissolution conditions (pH 7.2 phosphate buffer, USP II, 75 rpm (+infinite spin)). Prototype A (batch number 300720-032, n=6) at T=0 day and T=7 day versus the reference batch (batch number 300720-017-02, n=3). [Figure 3] Figure 3 shows the average dissolution profiles of pharmaceutical formulation prototype B under single-step dissolution conditions (pH 7.2 phosphate buffer, USP II, 75 rpm (+infinite spin)). Prototype B (batch number 300720-034, n=6) at T=0 day and T=7 day versus the reference batch (batch number 300720-027-01, n=3). [Figure 4]Figure 4 shows the average dissolution profiles of pharmaceutical formulation prototype C under single-step dissolution conditions (pH 7.2 phosphate buffer, USP II, 75 rpm (+infinite spin)). Prototype C (batch number 300720-039, n=6) at T=0 day and T=7 day vs. the reference batch (batch number 300720-028-01, n=3). [Figure 5] Figure 5 shows the average dissolution profiles of pharmaceutical formulation prototype D under single-step dissolution conditions (pH 7.2 phosphate buffer, USP II, 75 rpm (+infinite spin)). Prototype D (batch number 300720-041, n=6) at T=0 day and T=7 day versus the reference batch (batch number 300720-029-01, n=3). [Figure 6] Figure 6 shows the dissolution of prototype batches containing 10 mg minoxidil versus 2.5 mg minoxidil. Summary of the Invention

[0004] In some aspects, the technology described herein relates to a pharmaceutical formulation for oral administration comprising a daily dose of minoxidil or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical formulation is a modified release formulation.

[0005] In some aspects, the technology described herein relates to pharmaceutical formulations comprising a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0006] In some aspects, the technology described herein relates to pharmaceutical formulations comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, the modified release formulation having a Tmax of about 30 minutes to about 360 minutes.

[0007] In some aspects, the technology described herein relates to pharmaceutical formulations comprising a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof, the modified-release formulation having a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0008] In some aspects, the technology described herein relates to methods for treating hair loss, comprising administering to a subject in need thereof a daily dosage of a composition comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof.

[0009] In some aspects, the technology described herein relates to a method of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0010] In some aspects, the technology described herein relates to a method of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Tmax of about 30 minutes to about 360 minutes.

[0011] In some aspects, the technology described herein relates to a method of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0012] In some aspects, the technology described herein relates to kits that include a slow modified release vehicle that includes oral minoxidil or a pharmaceutically acceptable salt thereof.

[0013] (Detailed Description of the Invention) This disclosure is not limited to the particular systems, devices, and methods described, as these may vary. The terminology used herein is for the purpose of describing particular versions or embodiments only and is not intended to limit the scope. These aspects of the disclosure may be embodied in many different forms, rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0014] The present disclosure is not limited to the specific embodiments described herein, which are intended to be illustrative of various aspects. It will be apparent to those skilled in the art that many modifications and variations are possible without departing from the spirit and scope of the present disclosure. In addition to the methods and devices described herein, functionally equivalent methods and devices within the scope of the present disclosure will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to be included within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is, of course, to be understood that the present disclosure is not limited to the particular methods, reagents, compounds, compositions, or biological systems that can be modified. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0015] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Nothing in this disclosure should be construed as an admission that the embodiments described in this disclosure antedate the present disclosure by virtue of prior invention. As used herein, the term "comprising" means "including, but not limited to."

[0016] Although various compositions, methods, and devices are described with terms "comprising" (which may be interpreted as "including, but not limited to") various components or steps, the compositions, methods, and devices may also "consist essentially of" or "consist of" the various components and steps, and such terms should be interpreted as defining an essentially closed group of members.

[0017] With respect to the use of virtually any plural and / or singular term herein, one of ordinary skill in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or disclosure. For clarity, various singular / plural permutations may be explicitly stated.

[0018] Those skilled in the art should understand that, in general, the terms used in this specification, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "including, but not limited to," etc.). Furthermore, those skilled in the art should understand that when a specific number is intended in an introduced claim recitation, such intention is explicitly set forth in the claim; in the absence of such recitation, such intention does not exist. For example, to aid in understanding, the appended claims below may use the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be interpreted as meaning that the introduction of a claim recitation with the indefinite article "a" or "an" limits a particular claim that includes such an introduced claim recitation to embodiments that include only one such recitation. The same is true when the same claim includes the introductory phrases "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted as "at least one" or "one or more"). The same is true for the use of definite articles used to introduce claim recitations. Moreover, even when a particular number is explicitly recited in an introduced claim recitation, those skilled in the art will recognize that such recitation should be interpreted as at least the recited number (e.g., the single recitation "two recitations" without any other modifier means at least two recitations, or more than two recitations).When notation similar to "at least one of A, B, or C, etc." is used, such an interpretation is generally intended in the sense that one of ordinary skill in the art would understand the notation (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, A alone, B alone, C alone, a system combining A and B, a system combining A and C, a system combining B and C, and / or a system combining A, B, and C, etc.). Furthermore, one of ordinary skill in the art will understand that almost all disjunctive words and / or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to intend the possibility of encompassing one of the terms, either term, or both terms. For example, the phrase "A or B" would be understood to include the possibilities of "A" or "B" or "A and B."

[0019] Furthermore, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also described in terms of either individual members or subgroups of members of the Markush group.

[0020] All percentages, parts, and ratios are based on the total weight of the composition and all measurements are measured at approximately 25°C unless otherwise specified.

[0021] As will be understood by those skilled in the art, for any and all purposes, such as providing descriptive criteria, all ranges disclosed herein also include any and all possible subranges and combinations of subranges. Any listed range can be readily divided into at least 2, 3, 4, 5, 10, etc., and the same range can be readily recognized as fully satisfying descriptive and enablement criteria. As a non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, upper third, etc. Furthermore, as will be understood by those skilled in the art, expressions such as "within," "at least," and similar terms refer to ranges that are inclusive of the recited numerical values ​​and can be subsequently divided into subranges, as previously described. Finally, as will be understood by those skilled in the art, ranges include individual members. Thus, for example, a group having 1 to 3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to groups having 1, 2, 3, 4, or 5 cells, etc.

[0022] When a range of values ​​is listed, the upper and lower limits of that range, and every other value or intervening value within that range, are intended to be included within the disclosed range. For example, if a range of 1 mm to 8 mm is listed, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, and 7 mm are also expressly disclosed, and ranges of values ​​greater than or equal to 1 mm and less than or equal to 8 mm are also intended to be disclosed.

[0023] The term "about" as used herein refers to variations in quantity that may occur, for example, through real-world measurement or handling operations, through inadvertent errors in these operations, through differences in the manufacture, source, or purity of compositions or reagents, and the like. Typically, the term "about" as used herein refers to a value that is less than or more than 1 / 10 of the stated value or range of values, e.g., ±10%. The term "about" also refers to variations that would be recognized as equivalents by those of ordinary skill in the art, unless such variations include known values ​​implemented by the prior art. Each value or range of values ​​preceded by the term "about" is also intended to include embodiments of the stated absolute value or range of values. The quantitative values ​​described in this disclosure, whether modified by the term "about," include equivalents of the stated value, e.g., variations in the quantity of such values ​​that may occur and would be recognized as equivalents by those of ordinary skill in the art. If the context of the disclosure indicates otherwise or contradicts such an interpretation, the above interpretation may be modified to the extent readily understandable to those of ordinary skill in the art. For example, in a list of numerical values ​​such as "about 49, about 50, about 55," "about 50" means less than half the interval between the preceding and following values, e.g., a range from greater than 49.5 to less than 52.5. Furthermore, the expressions "less than about (numerical value)" or "greater than about (numerical value)" should be understood in light of the definition of the term "about" provided herein.

[0024] As used herein, the terms "administer," "administering," and "administration" refer to the direct administration of a compound (also referred to as an agent of interest) or a pharmaceutically acceptable salt of the compound (agent of interest), or a composition, to a subject.

[0025] As used herein, the term "adverse effect" refers to an unwanted, harmful effect resulting from the administration of a pharmaceutical preparation. The adverse effect may be selected from peripheral edema, tachycardia, hypotension, dizziness, and hirsutism. The adverse effect may also be referred to as a side effect.

[0026] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.

[0027] As used herein, the term "cardiac condition" refers to any condition related to the heart or vascular system. Cardiac conditions may be selected from heart disease, hypotension (including orthostatic hypotension), chronic congestive heart failure, cardiomyopathy, tachyarrhythmias (including atrial fibrillation, premature beats, supraventricular tachycardia, ventricular fibrillation, etc.), renal disease, pre-existing pulmonary hypertension, and chronic congestive heart failure not secondary to hypertension.

[0028] As used herein, the term "cardiac effects" refers to any effect on the heart or vascular system that occurs as a result of administration of a pharmaceutical formulation. Cardiac effects can be hemodynamic changes in blood pressure. Cardiac effects can be selected from tachycardia, hypotension, premature beats, and other tachyarrhythmias.

[0029] As used herein, the term "clinical significance" or "clinically significant" refers to the practical importance of the therapeutic effect in everyday life.

[0030] As used herein, the term "composition" refers to a combination or mixture of two or more different ingredients, components, or substances.

[0031] As used herein, the term "daily" refers to administration within one day.

[0032] As used herein, the term "disease" refers to an abnormal condition of the human or animal body or part thereof that impairs the normal functioning, is usually manifested by characteristic signs and symptoms, and reduces the lifespan or quality of life of the human or animal. Unless otherwise specified, the term "disease" may be used interchangeably with the terms "illness," "symptom," or "pathology."

[0033] As used herein, the term "excipient" refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the delivery or transport of a pharmaceutical, cosmetic, or other agent through a tissue layer, such as the stratum corneum or spinous layer, and includes carriers and diluents.

[0034] As used herein, the term "first order release" refers to the rate of release of a drug, where the rate of release of the drug is proportional to the concentration of one of the reactants. For first order release, the rate equation is "Rate = k[A] (or B instead of A)", where k is in seconds. -1 This becomes:

[0035] The term " hair loss " used herein refers to excessive hair loss.Hair loss can be from scalp.Hair loss can be male pattern hair loss, female pattern hair loss, hereditary hair loss, telogen effluvium, anagen effluvium, alopecia areata, cicatricial alopecia (including central centrifugal cicatricial alopecia, lichen planus, frontal linear alopecia etc.) or traction alopecia.

[0036] As used herein, the term "hair regrowth" refers to the growth of hair to restore hair following hair loss. Hair regrowth can be measured by commonly accepted methods, including target area hair count (TAHC) and specific rating systems for pattern hair loss (e.g., Hamilton-Norwood, Sinclair, Ludwig, etc.).

[0037] As used herein, the term "improved" refers to a state that is better than another state.

[0038] The term "modified-release" as used herein refers to a pharmaceutical composition that does not immediately release the active ingredient, as opposed to an otherwise immediate, complete release. For example, the active ingredient may be released at a sustained or controlled rate over an extended period of time, after a delayed time after administration, or in any combination with an immediate-release composition. Modified release includes sustained, extended, controlled, and delayed release. The terms "sustained release" or "extended release" as used herein refer to a dosage form that makes the drug available for an extended period of time after administration compared to a dose administered in a completely immediate-release formulation. The term "delayed release" as used herein refers to a dosage form that releases the drug at a time other than immediately after administration. The terms "orally," "oral," and "oral administration" as used herein refer to routes of administration in which a substance is administered via the mouth.

[0039] As used herein, the term "pharmaceutical formulation" refers to a substance containing a combination of excipients and active pharmaceutical ingredients to produce a pharmaceutical product. As used herein, the term "drug" or "compound" refers to a chemical, biological, or chemical-biological combination administered to a human to treat, prevent, or control a disease or condition. The chemical or biological agent is preferably, but need not be, a low molecular weight compound and can be, for example, a larger compound of nucleic acid, amino acid, or carbohydrate oligomers, including, but not limited to, proteins, oligonucleotides, ribozymes, DNA enzymes, glycoproteins, siRNA, lipoproteins, aptamers, and modifications and combinations thereof.

[0040] As used herein, the term "pharmacokinetics" refers to the movement of a drug within the body and its elimination from the body. As used herein, the term "pharmacokinetic profile" refers to the measurement of the pharmacokinetic properties of a drug, compound, or formulation. A pharmacokinetic profile includes measurements of half-life, Cmax, Tmax, and area under the plasma concentration-time curve (AUC). As used herein, the term "half-life" refers to the time required for a drug, compound, or formulation to decrease to half of its initial amount. As used herein, the term "effective half-life" refers to the rate of accumulation or elimination of a biochemical or pharmacological substance in an individual and is analogous to the biological half-life when its kinetics are governed by multiple independent mechanisms. As used herein, the term "plasma concentration versus time" refers to the concentration of an active ingredient in plasma measured over time. As used herein, the term "Cmax" refers to the maximum serum concentration reached by a drug, compound, or formulation after a single administration. As used herein, the term "Tmax" refers to the time it takes for a drug, compound, or formulation to reach its maximum concentration after a single administration. As used herein, the term "AUC" refers to the total exposure of a drug in plasma over time.

[0041] As used herein, the term "pseudo-zero-order release" refers to a rate of drug release that appears to follow zero-order kinetics but is actually the result of a first-order reaction in which one of the reactants is in large excess. In a zero-order reaction, the reaction rate is independent of the concentration of the reactants.

[0042] As used herein, the term "pseudo-first-order release" refers to a drug release rate that is a second-order or bimolecular reaction that is made to behave like a first-order reaction. This reaction occurs when one reactant is present in large excess relative to the other or is maintained at a constant concentration.

[0043] As used herein, the term "second-order release" refers to a rate of release of a drug that is proportional to the square of the concentration of a single reactant or the product of the concentrations of two reactants. For second-order release, the rate equation is Rate = k[A] (or replace A with B, or multiply k by the product of the concentrations of A and B), and the rate constant has units of Msec.

[0044] As used herein, the term "skin" refers to the thin layer of tissue that forms the natural outer covering of the human or animal body. Skin is composed of the epidermis and the dermis. As used herein, the term "scalp" refers to the skin on a patient's head.

[0045] As used herein, the term "steady state" refers to a state in which the amount of drug excreted per unit time is equal to the amount of drug reaching the systemic circulation per unit time. As used herein, the term "steady state blood concentration" refers to a state in which the amount of drug in the blood is constant. This occurs when the amount of drug absorbed is equal to the amount of drug excreted from the body when the drug is repeatedly administered.

[0046] The terms "subject" and "patient" can be used interchangeably and can be taken to mean any organism that may be treated with a compound of the invention. Thus, the terms "patient" and "subject" include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, a "patient" or "subject" is a mammal such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. In some embodiments, a patient or subject is an adult, child, or infant. In some embodiments, a patient or subject is human.

[0047] The term "sub-therapeutic amount" or "sub-therapeutic amount" of a compound or composition refers to a dose or concentration of an agent that is lower than that normally prescribed to effectively treat a disease.

[0048] As used herein, the term "therapeutic" or "therapeutic agent" or "pharmaceutically active agent" or "active agent" means a drug used to cure, combat, alleviate, prevent, or ameliorate an undesirable symptom or disease in a patient.

[0049] A "therapeutically effective amount" or "effective amount" of a compound or composition is a predetermined amount calculated to achieve the desired effect, i.e., inhibition, prevention, or reversal of cell activation, migration, or proliferation. The activity contemplated by the present method includes both medical therapeutic and / or prophylactic treatment, if necessary. The specific dose of a compound administered in accordance with the present invention to achieve a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide range of doses. However, it should be understood that the effective amount to be administered should be determined by a physician depending on the relevant circumstances, including the condition to be treated, the choice of compound to be administered, and the selected route of administration, and therefore the above-mentioned dose ranges are not intended to limit the scope of the present invention in any way. A therapeutically effective amount of a compound of the present invention is typically an amount sufficient to achieve an effective systemic or local concentration in tissues when administered in a physiologically acceptable excipient composition.

[0050] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to reduce the frequency of or delay the onset of a medical condition in a subject compared to a subject not receiving the compound or composition, to improve the tissue texture, appearance, color, feel, or moisture content of the tissue in the intended tissue treatment area of ​​the subject's tissue surface, or to otherwise achieve a beneficial or desired clinical result. For purposes of this invention, a beneficial or desired clinical result includes, but is not limited to, a reversal, reduction, or alleviation of symptoms, whether detectable, undetectable, enhanced, or ameliorated; a reduction in the magnitude of a symptom, disease, or condition; a stabilization (i.e., no worsening) of the severity of a symptom, disease, or condition; a delay in the onset or slowing of the progression of a symptom, disease, or condition; or an improvement (whether partial or complete) remission of the symptom, disease, or condition, whether the symptom, disease, or condition is detectable, undetectable, enhanced, or ameliorated. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0051] As used herein, the term "zero-order release" refers to a drug release rate where the release of the drug is constant and independent of the concentration of the reactant. For zero-order release, the rate equation is "rate = k", where k has units of M / sec.

[0052] In some embodiments, the compounds and methods disclosed herein can be used with a subject "in need thereof," meaning that the compounds and methods disclosed herein can be used with a subject in need of such treatment. As used herein, "in need thereof" means that the subject has been identified as needing a particular method or treatment, and the treatment has been administered to the subject for that specific purpose.

[0053] Less than the entire disclosure may be claimed for any reason, with the provisos hereby reserving the right to exclude or exclude any individual member of any such group, including subranges or combinations of subranges within a group that may be claimed in a range or similar manner. Furthermore, less than the entire disclosure may be claimed for any reason, with the provisos hereby reserving the right to exclude or exclude any individual alternative, structure, or any member of the group or claimed group. Various patents, patent applications, and publications are referenced throughout this disclosure. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entireties into this disclosure in order to more fully describe the art as known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure governs.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Nothing in this disclosure should be construed as an admission that the embodiments described in this disclosure are not entitled to antedate the present disclosure by virtue of prior invention.

[0055] Pharmaceutical preparations The embodiments described herein are directed to pharmaceutical formulations for oral administration that include a daily dose of minoxidil or a pharmaceutically acceptable salt thereof, and that are modified release formulations.

[0056] In some embodiments, the pharmaceutical formulations described herein comprise minoxidil or a pharmaceutically acceptable salt thereof, a release-modifying agent, a filler, a glidant, a lubricant, and combinations thereof.

[0057] In some embodiments, the pharmaceutical formulations described herein contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.075% to about 33% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations described herein contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.083% to about 33% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations described herein contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 20% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations contain minoxidil or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, in an amount of about 1% to about 10% (w / w) of the total formulation. In some examples, the pharmaceutical formulations contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 5% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulation comprises minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 1.5% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulation comprises minoxidil or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, in an amount (w / w) of about 0.075%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 15%, about 16%, about 18%, about 20%, about 25%, about 30%, about 33%, or an amount within these ranges.

[0058] In some embodiments, the pharmaceutical formulations described herein comprise a release modifier in an amount of about 20% to about 95% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a release modifier in an amount of about 50% to about 80% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a release modifier in an amount of about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or an amount (w / w) within these ranges.

[0059] In some embodiments, the pharmaceutical formulations described herein comprise a lubricant in an amount of about 0.01% to about 2% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a lubricant in an amount of about 0.1% to about 0.3% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a lubricant in an amount (w / w) of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.35%, or any range of these values.

[0060] In some embodiments, the pharmaceutical formulations described herein comprise a lubricant in an amount of about 0.1% to about 1% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a lubricant in an amount of about 0.4% to about 0.6% (w / w) of the total formulation. In some embodiments, the pharmaceutical formulations comprise a lubricant in an amount (w / w) of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, or any range of these values.

[0061] In some embodiments, the release modifier is hydroxypropyl methylcellulose (HPMC) or lactose monohydrate. In some embodiments, the hydroxypropyl methylcellulose is HPMC K4M or HPMC K200M. In some embodiments, the HPMC K4M is present in an amount of 0 mg to about 45 mg in a 150 mg formulation. In some embodiments, the HPMC K4M is 0% to about 30% (w / w) of the total formulation. In some embodiments, the HPMC K200M is in an amount of 0 mg to about 120 mg in a 150 mg formulation. In some embodiments, the HPMC K200M is about 0% to about 80% of the total formulation. In some embodiments, the lactose monohydrate is in an amount of about 0 mg to about 55 mg in a 150 mg formulation. In some embodiments, the lactose monohydrate is about 0% to about 40% of the total formulation.

[0062] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is present in an amount of about 25 mg to about 55 mg per 150 mg formulation. In some embodiments, the microcrystalline cellulose is present in an amount of about 15% to about 40% (w / w) of the total formulation.

[0063] In some embodiments, the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, or a combination thereof. In some embodiments, the lubricant is silica. In some embodiments, the silica is colloidal anhydrous. In some embodiments, the lubricant is in an amount of about 0.3 mg to about 5 mg per 150 mg formulation. In some embodiments, the lubricant is about 0.001% to about 0.04% (w / w) of the total formulation.

[0064] In some embodiments, the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof. In some embodiments, the lubricant is present in an amount of about 0.75 mg to about 1.5 mg per 150 mg formulation. In some embodiments, the lubricant is present in an amount of about 0.005% to about 0.01% (w / w) of the total formulation.

[0065] In some embodiments, the pharmaceutical formulations described herein further comprise one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the pharmaceutical formulations further comprise medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0066] In any embodiment of the pharmaceutical preparations described herein, the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof. In any embodiment, the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof. In any embodiment, the 19-norprogesterone derivative is nomegestrol acetate. In any embodiment, the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof. In any embodiment, the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof. In any embodiment, the 5-alpha reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, izonsteride, epigallocatechin, fluridil, and combinations thereof. In any embodiment, the estrogen is selected from estradiol, estradiol ester, ethinylestradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof. In any embodiment, the GnRH analog is a GnRH agonist, and the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof. In any embodiment, the GnRH analog is a GnRH antagonist, and the GnRH antagonist is cetrorelix. In any embodiment, the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof. In any embodiment, the prostamide is bimatoprost. In any embodiment, the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.In any of the embodiments, the prostaglandin D2 receptor antagonist is laropirant, AM211, and combinations thereof. In any of the embodiments, the prostaglandin E2 analog is sulprostone. In any of the embodiments, the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof. In any one of the embodiments, the JAK inhibitor is durxolitinib, duclavacitinib, gusacitinib, oclacitinib, upadacitinib, abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, duclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, ritrecitinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof. In any one of the embodiments, the drug for treating alopecia areata is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof. In either embodiment, the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0067] In some embodiments of the pharmaceutical preparations described herein, the modified release preparation is selected from sustained release preparation, sustained release preparation, controlled release preparation or delayed release preparation.In some embodiments, the modified release preparation can release minoxidil or its pharmaceutically acceptable salt at a sustained or controlled rate for a long period of time, or can release after a delayed time after administration.For example, the composition may be released 4 hours after administration, 8 hours after administration, 12 hours after administration, 16 hours after administration or 24 hours after administration.Modified release preparations include sustained release, sustained, controlled release preparation and delayed release composition. In some examples, the modified release composition may release about 10% in about 2 hours, about 20% in about 2 hours, about 40% in about 2 hours, about 50% in about 2 hours, about 10% in about 3 hours, about 20% in about 3 hours, about 40% in about 3 hours, about 50% in about 3 hours, about 10% in about 4 hours, about 20% in about 4 hours, about 40% in about 4 hours, about 50% in about 4 hours, about 10% in about 6 hours, about 20% in about 6 hours, about 40% in about 6 hours, or about 50% in about 6 hours.

[0068] In some embodiments of the pharmaceutical formulations described herein, the sustained-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration. In some embodiments of the pharmaceutical formulations described herein, the sustained-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 18 hours after oral administration. In some embodiments described herein, the sustained-release formulation releases about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or an amount within these ranges of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours to about 18 hours after oral administration.

[0069] In some embodiments of the pharmaceutical formulations described herein, the controlled-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration. In some embodiments, the controlled-release formulation releases about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or an amount within these values, of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0070] In some embodiments of the pharmaceutical formulations described herein, the delayed-release formulation releases a daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 6 hours after oral administration. In some embodiments, the delayed-release formulation releases a daily dose of minoxidil or a pharmaceutically acceptable salt thereof in multiple, discrete releases within about 18 hours after oral administration.

[0071] In some embodiments, the pharmaceutical formulations described herein exhibit a dissolution profile in which about 25% of the formulation dissolves in a neutral pH solution in less than about 2 hours or less than about 4 hours. In some embodiments, about 25% of the formulation dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

[0072] In some embodiments, the pharmaceutical formulations described herein exhibit a dissolution profile in which about 50% of the formulation dissolves in less than about 2 hours, less than about 6 hours, or less than about 12 hours in a neutral pH solution, hi some embodiments, about 50% of the formulation dissolves in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours in a neutral pH solution.

[0073] In some embodiments, the pharmaceutical formulations described herein exhibit a dissolution profile in which about 75% of the formulation dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours. In some embodiments, about 75% of the formulation dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

[0074] In some embodiments, the pharmaceutical formulations described herein exhibit a dissolution profile in which about 100% of the formulation dissolves in less than about 12 hours, less than about 24 hours, or less than about 48 hours at neutral pH, hi some embodiments, about 100% of the formulation dissolves in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours at neutral pH.

[0075] In some embodiments, the pharmaceutical formulations described herein exhibit zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments of the pharmaceutical formulations described herein, minoxidil or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. In some embodiments, one or more active ingredients are present in a therapeutically effective amount. In some embodiments, the pharmaceutical formulation comprises a subtherapeutic amount of minoxidil or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical formulation comprises a subtherapeutic amount of one or more active ingredients. In some embodiments, the pharmaceutical formulation comprises minoxidil or a pharmaceutically acceptable salt thereof and one or more active ingredients, wherein the minoxidil or a pharmaceutically acceptable salt thereof and the one or more active ingredients are each present in a subtherapeutic amount.

[0077] In some embodiments of the pharmaceutical formulations described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.25 mg to about 50 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.5 mg to about 2.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.625 mg to about 7.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.5 mg to about 10 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.25 mg to about 20 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.125 mg to about 100 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 2.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 0.125 mg, about 0.25 mg, about 5 mg, about 0.625 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, An amount of about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, or any range of amounts therebetween.

[0078] In some embodiments of the pharmaceutical formulations described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.000625 mg / kg / day to about 1.25 mg / kg / day. In some embodiments of the pharmaceutical formulations described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.00625 mg / kg / day to about 0.5 mg / kg / day. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 0.00625 mg / kg / day to about 0.375 mg / kg / day. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 0.000625 mg / kg / day, about 0.00125 mg / kg / day, about 0.0025 mg / kg / day, about 0.00375 mg / kg / day, about 0.005 mg / kg / day, about 0.00625 mg / kg / day, about 0.0125 mg / kg / day, about 0.025 mg / kg / day, about 0.037 5 mg / kg / day, about 0.05 mg / kg / day, about 0.0625 mg / kg / day, about 0.075 mg / kg / day, about 0.0875 mg / kg / day, about 0.1 mg / kg / day, about 0.125 mg / kg / day, about 0.25 mg / kg / day, about 0.5 mg / kg / day, about 0.75 mg / kg / day, about 1 mg / kg / day, about 1.25 mg / kg / day, or an amount within these ranges.

[0079] In some embodiments described herein, the pharmaceutical formulation is administered only once a day. In some embodiments, the pharmaceutical formulation is administered at least once a day. In some embodiments, the pharmaceutical formulation is administered four times a day. In some embodiments, the pharmaceutical formulation is administered three times a day. In some embodiments, the pharmaceutical formulation is administered twice a day.

[0080] In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a steady-state blood concentration of minoxidil or a pharmaceutically acceptable salt thereof from about 1 ng / ml to about 20 ng / ml. In some embodiments, the steady-state blood concentration of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is maintained for at least about 12 hours. In some examples, the steady-state blood concentration of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is maintained for at least about 6 hours, at least about 8 hours, at least about 10 hours, or within any range of these values.

[0081] In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Cmax of about 0.25 ng / ml to about 20 ng / ml. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Cmax that is indicative of no cardiac effects.

[0082] In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Tmax of about 30 minutes to about 360 minutes. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides delayed release with a Tmax of both between 30 minutes and 360 minutes and between 390 minutes and 1080 minutes.

[0083] In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a greater AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a lesser AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the pharmaceutical formulations described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in an AUC equal to an equivalent dose of an immediate-release formulation.

[0084] Embodiments described herein are directed to pharmaceutical formulations comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof that releases about 50% to about 98% of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0085] In some embodiments, the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof. In some embodiments, the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0086] Embodiments described herein are directed to pharmaceutical formulations comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, having a Tmax of about 30 minutes to about 360 minutes.

[0087] In some embodiments, the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof. In some embodiments, the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0088] Embodiments described herein are directed to pharmaceutical formulations comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, having a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0089] In some embodiments, the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof. In some embodiments, the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0090] In some embodiments of the pharmaceutical formulations described herein, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour to about 24 hours. In some embodiments, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, or any range of these values.

[0091] In some embodiments of the pharmaceutical formulations described herein, the subject has a plasma concentration versus time curve of minoxidil or a pharmaceutically acceptable salt thereof with a Tmax of about 30 minutes to about 360 minutes.

[0092] In some embodiments, the pharmaceutical formulation is an inert solid medium, or matrix, in which the drug is uniformly suspended, including in the form of a tablet or small beads. In some embodiments, the matrix is ​​a gelling agent including gelatin, methylcellulose, tragacanth gum, Veegum, and alginic acid. In some embodiments, the matrix is ​​a polymer including polylactic acid copolymer, polyacrylate, methacrylate, polyester, ethylene-vinyl acetate copolymer (EVA), polyglycolide, polylactide, and silicone. In some embodiments, the modified release formulation is a sustained-release pellet, bead, or granule. In some embodiments, the modified release formulation is a sustained-release tablet in which the solubility of the drug is modified for sustained release. In some embodiments, the sustained-release tablet is formed using the non-ionized base or acid form of the drug. In some embodiments, extended-release tablets are formed by granulating the drug with excipients (including stearates, castor oil, high molecular weight polyethylene glycol (Carbowax), glyceryl monostearate, white wax, whale oil, magnesium stearate, and hydrogenated vegetable oil (Sterotex)) to reduce the water solubility of the drug. In some embodiments, the modified-release formulation is an ion-exchange formulation in which an anionic or cationic drug is complexed with an ionic resin of the opposite charge to form an insoluble, non-absorbable resin-drug complex.

[0093] In some embodiments described herein, the pharmaceutical formulation is a tablet. In some embodiments, the tablet is a sustained-release or controlled-release tablet. The sustained-release or controlled-release tablet may be an osmotic pump-type controlled-release tablet, a matrix-type controlled-release tablet, or a sustained-release and controlled-release tablet based on sustained-release pellets. Among them, osmotic pump-type controlled-release tablets include osmotic pump controlled-release tablets and osmotic pump immediate and sustained dual-release formulations, while matrix-type controlled-release tablets include matrix-type sustained-release tablets, matrix-type immediate and sustained dual-release bilayer tablets, and matrix-type immediate and sustained dual-release coated tablets. The sustained-release and controlled-release tablets based on sustained-release pellets include sustained-release tablets based on sustained-release pellets and immediate-release and sustained dual-release tablets based on sustained-release pellets and immediate-release pellets. The sustained-release and controlled-release tablets described above can specifically achieve the drug release behavior of the present invention in the manner of an osmotic pump-type controlled-release tablet, a matrix-type controlled-release tablet, or a sustained-release pellet-based sustained-release tablet.

[0094] The osmotic pump controlled release tablets of the present invention can be single-layer osmotic pump tablets, single-layer osmotic pump immediate and sustained dual release tablets, bilayer osmotic pump controlled release tablets, or bilayer osmotic pump immediate and sustained dual release tablets. The bilayer osmotic pump controlled-release tablet of the present invention mainly comprises: 1) a controlled-release drug layer formed from a controlled-release drug layer composition, disposed within the hard film shell, and adjacent to the drug-release pores; 2) a push layer (also called a boost layer), formed from a push layer composition and disposed within the hard film shell, away from the drug-release pores; 3) an optional seal-coating layer, prepared by drying from a seal-coating composition, disposed between the inner surface of the hard film shell and the core composed of the drug layer and the push layer; 4) a moisture-permeable hard film shell obtained by drying a controlled-release coating solution and having one or more drug-release pores at one end of the film shell; 5) an optional, non-limiting outer layer for aesthetic purposes; and 6) an optional, non-limiting immediate-release drug layer formed from an immediate-release drug composition and disposed outside the hard film shell and / or the optional, non-limiting outer layer coating. Further description of controlled-release formulations is provided in U.S. Patent Publication No. 20200108008, the entire contents of which are incorporated herein by reference.

[0095] The matrix-type controlled-release tablets of the present invention can have dual release profiles of immediate release and sustained release. The controlled-release matrix-type tablets of the present invention are primarily composed of a sustained-release phase and an optional immediate-release phase. A bilayer tablet consisting of a sustained-release phase and an immediate-release phase is a dual-release matrix-type tablet of immediate release and sustained release, while a monolayer tablet consisting only of a sustained-release phase is a conventional sustained-release matrix-type tablet. The sustained-release phase contains 100 to 900 parts by weight, preferably 150 to 700 parts by weight, more preferably 200 to 600 parts by weight, of minoxidil or a pharmaceutically acceptable salt thereof in an improved dissolution form; 10 to 300 parts by weight, preferably 30 to 150 parts by weight, of a release rate-controlling matrix polymer; 0 to 50 parts by weight of a diluent; and 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight, of other common tablet additives. The sustained-release phase is prepared by thoroughly mixing the ingredients and pressing them together using a conventional method well known to those skilled in the art. The release rate controlling matrix polymer may be one or a combination of two or more selected from the group consisting of polyoxyethylene, hydroxypropyl cellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably one or a combination of two or more selected from the group consisting of hydroxypropyl cellulose, sodium alginate, hypromellose, and carbomer.

[0096] The sustained release tablets based on the sustained release pellets of the present invention can be sustained release tablets based on sustained release pellets or dual immediate and sustained release tablets based on immediate release matrix / sustained release pellets.

[0097] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation is a capsule. In some embodiments, the capsule is a controlled-release capsule formulation selected from the group consisting of pellet-based sustained- and controlled-release capsules and tablet-based sustained- and controlled-release capsules. In some embodiments, the capsule is a mini-tablet-based controlled-release capsule. The pellet-based sustained- and controlled-release capsules of the present invention may be controlled-release capsules composed of sustained-release pellets or immediate-release and sustained-release dual-release capsules composed of sustained-release pellets and immediate-release pellets, and may include capsules containing matrix-type sustained-release pellets, capsules containing coated sustained-release pellets, capsules containing sustained-release pellets with an immediate-release coating, immediate-release and sustained-release dual-release capsules containing immediate-release pellets and matrix-type sustained-release pellets, and immediate-release and sustained-release dual-release capsules containing immediate-release pellets and coated sustained-release pellets.

[0098] The sustained and controlled release capsules based on the microtablets of the present invention may be controlled release capsules composed of sustained release microtablets, or immediate release and sustained dual release capsules composed of sustained release microtablets and immediate release microtablets, and may include capsules containing matrix type sustained release microtablets, capsules containing matrix type sustained release microtablets with an immediate release coating, and capsules containing immediate release microtablets and matrix type sustained release microtablets. Generally, for filling hard capsules, the diameter of the produced microtablets is usually less than 5 mm.

[0099] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises an enteric coating. The one or more coatings can include an enteric coating, which is a tablet coating that delays tablet digestion until the tablet passes from the stomach into the intestine. Enteric-coated formulations bypass the acidic environment of the stomach to eliminate the effect of acidic pH on minoxidil solubility. Enteric coatings typically contain pH-sensitive polymers. The polymers are carboxylates and generally have little interaction with water at low pH. However, at high pH, ​​the polymers ionize, thereby dissolving. Thus, coatings can be designed to remain intact in the acidic environment of the stomach and dissolve in the more alkaline environment of the intestine. Examples include cellulose acetate phthalate, hydroxypropylmethylethylcellulose succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and methacrylic acid-methyl methacrylate copolymer. In one aspect, the first surface coating comprises polyvinyl alcohol. In yet another aspect, the first surface coating comprises a methacrylic acid-ethyl acrylate copolymer. In yet another aspect, the first surface coating comprises polyvinyl alcohol and a methacrylic acid-ethyl acrylate copolymer. In a further aspect, the first surface coating is an enteric coating comprising one or more of polyvinyl alcohol or a methacrylic acid-ethyl acrylate copolymer. In yet another aspect, the first surface coating is an enteric coating comprising one or more of CAP, PVAP, an acrylic polymer, an acrylic copolymer, HPMCAS, HPMCP, or shellac. Details of enteric coatings are described in U.S. Patent Publication No. 20170020920, the entire contents of which are incorporated herein by reference.

[0100] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients that may be present in the composition include, but are not limited to, fillers / solvents, solvents / co-solvents, preservatives, antioxidants, suspending agents, surfactants, antifoaming agents, buffers, chelating agents, sweeteners, flavoring agents, binders, fillers, disintegrants, diluents, lubricants, fillers, wetting agents, glidants, and combinations thereof.

[0101] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulations may further comprise one or more exemplary fillers. Examples of exemplary fillers include cellulose and cellulose derivatives such as microcrystalline cellulose and powdered cellulose, starches such as dextrates, starch derivatives such as dry starch, hydrolyzed starch, and corn starch, cyclodextrin, sugars such as powdered sugar, and sugar alcohols such as lactose, mannitol, sucrose, and sorbitol, inorganic fillers such as aluminum hydroxide gel, calcium carbonate (granular or powder), precipitated calcium carbonate, carbonate, magnesium aluminometasilicate, dicalcium phosphate, and sodium chloride, silicon dioxide, silicic acid, titanium dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, alumina, kaolin, talc, or combinations thereof. The filler may be present in the composition in an amount of from about 20% to about 65% by weight, from about 20% to about 50% by weight, from about 20% to about 40% by weight, from about 45% to about 65% by weight, from about 50% to about 65% by weight, or from about 55% to about 65% by weight, or any value within these ranges, based on the total weight of the composition.

[0102] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises one or more disintegrants. Examples of disintegrants include starch, alginic acid, cross-linked polymers such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, potassium starch glycolate, sodium starch glycolate, clay, cellulose, starch, gum, or combinations thereof. The disintegrant may be present in an amount of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, or about 1% to about 5% by weight, based on the total weight of the composition, or any amount within these ranges.

[0103] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises one or more binders, including, but not limited to, celluloses such as hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; starches such as cornstarch, pregelatinized starch, and hydroxypropyl starch; waxes and natural and synthetic gums such as acacia, tragacanth, and sodium alginate; synthetic polymers such as polymethacrylates and polyvinylpyrrolidone; and povidone, dextrin, pullulan, agar, gelatin, tragacanth, macrogol, or combinations thereof. The binder may be present in an amount of about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, or about 0.5% to about 1% by weight, based on the total weight of the composition, or any amount within these ranges.

[0104] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises one or more wetting agents, including, but not limited to, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, poloxamer, poloxamer 188, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate, etc.), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and combinations thereof. The humectant may be present in an amount of about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, or about 0.1% to about 5% by weight, based on the total weight of the composition, or any amount within these ranges.

[0105] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises one or more lubricants, including, but not limited to, stearate, magnesium stearate, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal salts and alkaline earth metal salts, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (PEG), methoxypolyethylene glycol, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof. The lubricant may be present in the composition in an amount ranging from about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1% by weight, based on the total weight of the composition, or in any range therein.

[0106] In some embodiments, the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, and combinations thereof. The lubricant may be present in the composition from about 0.05% to about 1%, from about 0.05% to about 0.9%, from about 0.05% to about 0.8%, from about 0.05% to about 0.5%, or from about 0.05% to about 0.1% by weight, based on the total weight of the composition, or any value within these ranges.

[0107] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation is a tablet and further comprises a topcoat, such as a hydroxypropyl methylcellulose coating or a polyvinyl alcohol coating, available under the trade name Opadry, such as Opadry White or Opadry II (Opadry is a registered trademark of BPSI Holdings LLC, Wilmington, Delaware, USA). The topcoat may be present in an amount of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, or about 1% to about 5% by weight, based on the total weight of the composition, or any value within these ranges.

[0108] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulations may further comprise one or more preservatives. Examples of preservatives include sodium benzoate, parahydroxybenzoates, methylparaben, ethylparaben, butylparaben, and propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride (BKC), benzethonium chloride, phenol, phenylmercuric nitrate, thimerosal, or a combination thereof. Preservatives may be included in liquid dosage forms. Preservatives may be included in an amount sufficient to extend the shelf life or storage stability, or both, of the liquid dosage form. The preservative may be present in the composition from about 0.05% to about 1%, from about 0.05% to about 0.9%, from about 0.05% to about 0.8%, from about 0.05% to about 0.5%, or from about 0.05% to about 0.1% by weight of the total weight of the composition, or any value within these ranges.

[0109] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulations can further comprise one or more flavoring agents. Examples of flavoring agents include synthetic flavor oils and aromatic flavors and / or natural oils, extracts from plant leaves, flowers, fruits, etc., and the like, or any combination thereof. Other examples include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, cassia oil, and the like, or any combination thereof. Also useful as flavoring agents are citrus oils, including vanilla, lemon, orange, grape, lime, and grapefruit, and fruit essential oils, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, strawberry flavor, tutti-fruity flavor, mint flavor, or any combination thereof. Flavoring Agents Flavoring agents may be present from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, or from about 0.1% to about 1% by weight of the total weight of the composition, or any value within these ranges.

[0110] Pharmaceutical formulations can generally be in any physical form suitable for use in treating a subject. These forms can be referred to as unit dosage forms, such as individual pills or tablets. In some examples, pharmaceutical compositions can be formulated as tablets, capsules, granules, powders, liquids, suspensions, gels, syrups, slurries, suppositories, patches, nasal sprays, aerosols, injectables, implantable sustained-release formulations, or mucoadhesive films. In some examples, pharmaceutical formulations may be formed as tablets, bilayer tablets, capsules, multiparticulates, drug-coated spheres, matrix tablets, or multicore tablets. The physical form can be selected according to the desired method of treatment.

[0111] Pharmaceutical preparations can be manufactured by various conventional methods, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical preparations can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the active ingredient into a pharmaceutically usable preparation. An appropriate formulation can be selected depending on the selected oral administration route.

[0112] In some embodiments, the pharmaceutical formulation is a core tablet, or tablet-within-a-tablet, in which the inner core is used for the sustained-release component and the outer shell contains the immediate-release dose of the drug. In some embodiments, the pharmaceutical formulation is achieved by microencapsulation, in which fine drug particles are encapsulated with a special coating material such as ethylcellulose. In some embodiments, the pharmaceutical formulation is an osmotic drug delivery system in the form of a tablet having an outer semipermeable membrane and an inner core filled with a mixture of the drug and an osmotic agent (salt solution). In some embodiments, the pharmaceutical formulation is a gastroretentive system that can remain in the stomach area for several hours, extending the gastric residence time of the drug. In some embodiments, the pharmaceutical formulation is a combination of any of the embodiments described above.

[0113] For oral administration, pharmaceutical preparations can be prepared by combining minoxidil or its pharmaceutically acceptable salts with other agents and one or more pharmaceutically acceptable carriers well known in the art. Such carriers facilitate the formulation of the preparation into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the patient receiving treatment. For example, for oral solid preparations such as powders, capsules, and tablets, suitable excipients include sugars such as lactose, sucrose, mannitol, and sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, cellulose preparations such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP), granulating agents, and binders. If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate may be added. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

[0114] For example, for oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents, etc. For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.

[0115] In some examples, the modified release formulation can comprise a matrix selected from microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkyl celluloses such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, polyethylene oxide, alkyl celluloses such as methyl cellulose and ethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylates, polyvinyl acetate, and mixtures thereof.

[0116] Hair loss treatment methods Embodiments described herein are directed to methods for treating hair loss, comprising administering to a subject in need thereof a daily dosage of a composition comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments of the methods described herein, the composition comprises minoxidil or a pharmaceutically acceptable salt thereof, a release-modifying agent, a filler, a glidant, a lubricant, and combinations thereof.

[0118] In some embodiments, the methods described herein comprise minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.075% to about 33% (w / w) of the total formulation. In some embodiments, the methods described herein comprise minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.083% to about 33% (w / w) of the total formulation. In some embodiments of the methods described herein, the composition comprises about 0.1% to about 20% (w / w) of minoxidil or a pharmaceutically acceptable salt thereof relative to the total composition. In some embodiments, the composition comprises about 1% to about 10% (w / w) of minoxidil or a pharmaceutically acceptable salt thereof relative to the total composition. In some embodiments, the methods comprise about 1% to about 5% (w / w) of minoxidil or a pharmaceutically acceptable salt thereof relative to the total formulation. In some embodiments, the methods comprise about 1% to about 1.5% (w / w) of minoxidil or a pharmaceutically acceptable salt thereof relative to the total formulation. In some embodiments, the composition comprises minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.075%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 15%, about 16%, about 18%, about 20%, about 25%, about 30%, about 33% (w / w), or any range of these values.

[0119] In some embodiments of the methods described herein, the composition comprises a release modifier in an amount of about 20% to about 95% (w / w) of the total composition. In some embodiments, the composition comprises a release modifier in an amount of about 50% to about 80% (w / w) of the total composition. In some embodiments, the composition comprises about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or any amount (w / w) within these ranges of values.

[0120] In some embodiments of the methods described herein, the composition comprises a lubricant in an amount of about 0.01% to about 2% (w / w) of the total composition. In some embodiments, the composition comprises a lubricant in an amount of about 0.1% to about 0.3% (w / w) of the total composition. In some embodiments, the composition comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.35%, or any range of these values.

[0121] In some embodiments of the methods described herein, the composition comprises a lubricant in an amount of about 0.1% to about 1% (w / w) of the total composition. In some embodiments, the composition comprises a lubricant in an amount of about 0.4% to about 0.6% (w / w) of the total composition. In some embodiments, the composition comprises a lubricant in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1% (w / w), or any range of amounts therebetween.

[0122] In some embodiments of the methods described herein, the release-modifying agent is hydroxypropyl methylcellulose (HPMC) or lactose monohydrate. In some embodiments, the hydroxypropyl methylcellulose is HPMC K4M or HPMC K200M. In some embodiments, the HPMC K4M is present in an amount of 0 mg to about 45 mg per 150 mg of the composition. In some embodiments, the HPMC K4M is present in an amount of 0% to about 30% (w / w) of the total composition. In some embodiments, the HPMC K200M is present in an amount of 0 mg to about 120 mg per 150 mg of the composition. In some embodiments, the HPMC K200M is present in an amount of about 0% to about 80% (w / w) of the total composition. In some embodiments, the lactose monohydrate is present in an amount of about 0 mg to about 55 mg per 150 mg of the composition. In some embodiments, the lactose monohydrate is present in an amount of about 0% to about 40% (w / w) of the total composition.

[0123] In some embodiments of the methods described herein, the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the filler is present in an amount of about 25 mg to about 55 mg per 150 mg of the composition. In some embodiments, the microcrystalline cellulose is about 15% to about 40% (w / w) of the total composition.

[0124] In some embodiments, the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, or a combination thereof. In some embodiments of the methods described herein, the lubricant is silica. In some embodiments, the silica is colloidal anhydrous. In some embodiments, the lubricant is present in an amount of about 0.3 mg to about 5 mg per 150 mg of the composition. In some embodiments, the lubricant is about 0.001% to about 0.04% (w / w) of the total composition.

[0125] In some embodiments of the methods described herein, the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof. In some embodiments, the lubricant is present in an amount of about 0.75 mg to about 1.5 mg per 150 mg of the composition. In some embodiments, the lubricant is about 0.005% to about 0.01% (w / w) of the total composition.

[0126] In some embodiments of the methods described herein, the composition further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the composition further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0127] In any embodiment of the methods described herein, the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof. In any embodiment, the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof. In any embodiment, the 19-norprogesterone derivative is nomegestrol acetate. In any embodiment, the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof. In any embodiment, the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof. In any embodiment, the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, isonosteride, epigallocatechin, fluridil, and combinations thereof.In any embodiment, the estrogen is selected from estradiol, estradiol ester, ethinylestradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.In any embodiment, the GnRH analog is a GnRH agonist, and the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.In any embodiment, the GnRH analog is a GnRH antagonist, and the GnRH antagonist is cetrorelix. In any embodiment, the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof. In any embodiment, the prostamide is bimatoprost. In any embodiment, the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.In any embodiment, the prostaglandin D2 receptor antagonist is laropirant, AM211, or a combination thereof. In any embodiment, the prostaglandin E2 analog is sulprostone. In any embodiment, the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, or a combination thereof. In any embodiment, the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, ritretinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.In any embodiment, the alopecia areata treatment drug is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.In any embodiment, the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0128] In some embodiments of the methods described herein, the composition is administered orally. In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof is present in an orally dissolving tablet.

[0129] In some embodiments of the methods described herein, the modified release formulation is a sustained release formulation, a controlled release formulation, or a delayed release formulation.

[0130] In some embodiments of the methods described herein, the sustained-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration. In some embodiments of the pharmaceutical formulations described herein, the sustained-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 18 hours after oral administration. In some embodiments described herein, the sustained-release formulation releases about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or any amount within these ranges of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours to about 18 hours after oral administration.

[0131] In some embodiments of the methods described herein, the controlled-release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration. In some embodiments, the controlled-release formulation releases about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof, or any amount within these ranges, within about 12 hours after oral administration.

[0132] In some embodiments of the methods described herein, the delayed-release formulation releases a daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 6 hours after oral administration. In some embodiments, the delayed-release formulation releases a daily dose of minoxidil or a pharmaceutically acceptable salt thereof in multiple, distinct releases within about 18 hours after oral administration.

[0133] In some embodiments of the methods described herein, the compositions described herein exhibit a dissolution profile in which about 25% of the composition dissolves in a neutral pH solution in less than about 2 hours or less than about 4 hours. In some embodiments, about 25% of the composition dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

[0134] In some embodiments of the methods described herein, the compositions described herein exhibit a dissolution profile in which about 50% of the composition dissolves in a neutral pH solution in less than about 2 hours, less than about 6 hours, or less than about 12 hours. In some examples, about 50% of the composition dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

[0135] In some embodiments of the methods described herein, the compositions described herein exhibit a dissolution profile in which about 75% of the composition dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours. In some embodiments, about 75% of the composition dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

[0136] In some embodiments of the methods described herein, the compositions described herein exhibit a dissolution profile in which about 100% of the composition dissolves in less than about 12 hours, less than about 24 hours, or less than about 48 hours at neutral pH, hi some embodiments, about 100% of the composition dissolves in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours at neutral pH.

[0137] In some embodiments of the methods described herein, the compositions described herein exhibit zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments of the methods described herein, the subject in need of diagnosis of alopecia is diagnosed with alopecia. In some embodiments, the alopecia is selected from male pattern baldness, female pattern baldness, hereditary alopecia, telogen effluvium, alopecia areata, central centrifugal cicatricial alopecia, lichen planus pilaris, or traction alopecia.

[0139] In some embodiments of the methods described herein, administration results in hair regrowth. In some embodiments, administration results in hair regrowth within about 1 month to about 12 months. In some embodiments, administration results in hair regrowth within about 6 months. In some embodiments, administration results in hair regrowth within about 4 months. In some embodiments, administration results in hair regrowth within about 3 months. In some examples, administration results in hair regrowth within about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or any time period within these ranges. In some examples, administration results in further improvement in hair growth compared to administration of an immediate-release dosage form of minoxidil or a pharmaceutically acceptable salt thereof.

[0140] Use of the described methods and pharmaceutical preparations can result in a reduction or elimination of a disease, symptom, or other undesirable characteristic in a subject compared to a control population (e.g., a population not treated with the described methods and materials). The reduction can generally be by any amount. For example, the reduction can be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and in ideal situations, about a 100% reduction (complete elimination of the disease, symptom, viral concentration, or other undesirable characteristic).

[0141] In some embodiments of the methods described herein, the subject is diagnosed with at least one cardiac disease selected from heart disease, chronic congestive heart failure, cardiomyopathy, tachyarrhythmia, renal disease, pre-existing pulmonary hypertension, and chronic congestive heart failure not secondary to hypertension.

[0142] In some embodiments of the methods described herein, the subject is taking at least one of an antihypertensive agent, an ACE inhibitor, an angiotensin receptor blocker, a direct renin inhibitor, a loop diuretic, a thiazide diuretic, a calcium channel blocker, a beta-blocker, an antiarrhythmic agent, and a diuretic for the treatment of at least one cardiac condition.

[0143] In some embodiments of the methods described herein, the pharmaceutical formulation is administered only once a day. In some embodiments, the pharmaceutical formulation is administered at least once a day. In some embodiments, the pharmaceutical formulation is administered four times a day. In some embodiments, the pharmaceutical formulation is administered three times a day. In some embodiments, the pharmaceutical formulation is administered twice a day.

[0144] In some embodiments of the methods described herein, the composition is administered daily for at least about three months with substantially no side effects and substantially no cardiac effects. In some embodiments, the composition is administered daily for at least four months with substantially no side effects and substantially no cardiac effects. In some embodiments, the composition is administered daily for at least six months with substantially no side effects and substantially no cardiac effects. In some embodiments, the composition is administered daily for at least one year with substantially no side effects and substantially no cardiac effects. In some embodiments, the composition is administered daily indefinitely with substantially no side effects and substantially no cardiac effects.

[0145] In some embodiments of the methods described herein, administration results in substantially no cardiac effects, hi some embodiments, the cardiac effects are selected from tachycardia, hypotension, premature ventricular contractions, and other tachyarrhythmias.

[0146] In some embodiments of the methods described herein, administration results in hair regrowth without causing substantially clinically significant hemodynamic changes in blood pressure. In some embodiments, administration results in hair regrowth without causing substantially cardiac effects. In some embodiments, a daily dose of minoxidil or a pharmaceutically acceptable salt thereof has substantially no cardiac or hemodynamic effects compared to administration of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, a daily dose of minoxidil or a pharmaceutically acceptable salt thereof has substantially no cardiac effects compared to administration of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0147] In some embodiments of the methods described herein, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof produces fewer cardiac or hemodynamic effects than a dosage of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, the cardiac effects are selected from tachycardia, hypotension, premature beats, and other tachyarrhythmias.

[0148] In some embodiments of the methods described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 25% to about 500% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 10% to about 90% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 425%, about 450%, about 475%, about 500%, or a range of any of these values, of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0149] In some embodiments of the methods described herein, minoxidil or a pharmaceutically acceptable salt thereof is included in a therapeutically effective amount. In some embodiments, one or more active ingredients are included in a therapeutically effective amount. In some embodiments, the pharmaceutical formulation includes a subtherapeutic amount of minoxidil or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical formulation includes one or more subtherapeutic amounts of the active ingredients. In some embodiments, the pharmaceutical formulation includes minoxidil or a pharmaceutically acceptable salt thereof and one or more active ingredients, wherein the minoxidil or a pharmaceutically acceptable salt thereof and the one or more active ingredients are each subtherapeutic.

[0150] In some embodiments of the methods described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.25 mg to about 50 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.5 mg to about 2.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.625 mg to about 7.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.5 mg to about 10 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.25 mg to about 20 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.125 mg to about 100 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 2.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 0.125 mg, about 0.25 mg, about 5 mg, about 0.625 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 ... The compound is present in an amount of about 0.5 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, or any range of amounts therein.

[0151] In some embodiments of the methods described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.000625 mg / kg / day to about 1.25 mg / kg / day. In some embodiments of the methods described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.00625 mg / kg / day to about 0.5 mg / kg / day. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 0.00625 mg / kg / day to about 0.375 mg / kg / day. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 0.000625 mg / kg / day, about 0.00125 mg / kg / day, about 0.0025 mg / kg / day, about 0.00375 mg / kg / day, about 0.005 mg / kg / day, about 0.00625 mg / kg / day, about 0.0125 mg / kg / day, about 0.025 mg / kg / day, about 0.0375 mg / kg / day, about 0.0 5 mg / kg / day, about 0.0625 mg / kg / day, about 0.075 mg / kg / day, about 0.0875 mg / kg / day, about 0.1 mg / kg / day, about 0.125 mg / kg / day, about 0.25 mg / kg / day, about 0.325 mg / kg / day, about 0.5 mg / kg / day, about 0.625 mg / kg / day, about 0.75 mg / kg / day, about 1 mg / kg / day, about 1.25 mg / kg / day, or within these ranges of values.

[0152] In some embodiments of the methods described herein, minoxidil or a pharmaceutically acceptable salt thereof is present in an amount of about 0.625 mg four times daily.

[0153] In some embodiments of the methods described herein, the modified release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0154] In some embodiments of the methods described herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a Cmax of about 0.25 ng / ml to about 20 ng / ml. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a Cmax that is cardiac-neutral.

[0155] In some embodiments of the methods described herein, the subject has a plasma concentration versus time curve of minoxidil or a pharmaceutically acceptable salt thereof with a Tmax of about 30 minutes to about 360 minutes. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides delayed release with a Tmax of between 30 minutes and 360 minutes and between 390 minutes and 1080 minutes.

[0156] In some embodiments of the methods described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a greater AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the methods described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a lesser AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the methods described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in an AUC equal to an equivalent dose of an immediate-release formulation.

[0157] In some embodiments of the methods described herein, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour to about 24 hours. In some embodiments, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, or any range of these values.

[0158] Embodiments described herein are directed to methods for treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0159] In some embodiments of the methods described herein, the composition further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the composition further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0160] Embodiments described herein are directed to methods of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Tmax of about 30 to 360 minutes.

[0161] In some embodiments of the methods described herein, the composition further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the composition further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0162] Embodiments described herein are directed to methods of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0163] In some embodiments of the methods described herein, the composition further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the composition further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0164] In some embodiments of the methods described herein, the modified-release formulation is an inert solid medium, or matrix, in which the drug is uniformly suspended, including in the form of a tablet or small beads. In some embodiments, the matrix is ​​a gelling material including gelatin, methylcellulose, tragacanth gum, Veegum, and alginic acid. In some embodiments, the matrix is ​​a polymer including polylactic acid copolymer, polyacrylate, methacrylate, polyester, ethylene-vinyl acetate copolymer (EVA), polyglycolic acid, polylactic acid, and silicone. In some embodiments, the modified-release formulation is a sustained-release pellet, bead, or granule. In some embodiments, the modified-release formulation is a sustained-release tablet in which the solubility of the drug is modified for sustained release. In some embodiments, the sustained-release tablet is formed using the non-ionized base or acid form of the drug. In some embodiments, extended-release tablets are formed by granulating the drug with excipients (including stearates, castor oil, high molecular weight polyethylene glycol (Carbowax), glyceryl monostearate, white wax, whale oil, magnesium stearate, and hydrogenated vegetable oil (Sterotex)) to reduce the water solubility of the drug. In some embodiments, the modified-release formulation is an ion-exchange formulation in which an anionic or cationic drug is complexed with an ionic resin of the opposite charge to form an insoluble, non-absorbable resin-drug complex.

[0165] In some embodiments of the methods described herein, the modified-release formulation further comprises one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients that may be present in the composition include, but are not limited to, fillers / solvents, solvents / co-solvents, preservatives, antioxidants, suspending agents, surfactants, antifoaming agents, buffers, chelating agents, sweeteners, flavoring agents, binders, fillers, disintegrants, diluents, lubricants, fillers, wetting agents, glidants, and combinations thereof.

[0166] In some embodiments of the methods described herein, the modified-release formulation can further comprise one or more exemplary fillers. Examples of exemplary fillers include cellulose and cellulose derivatives such as microcrystalline cellulose and powdered cellulose, starches such as dextrates, dry starch, hydrolyzed starch, and starch derivatives such as corn starch, cyclodextrin, sugars such as powdered sugar, and sugar alcohols such as lactose, mannitol, sucrose, and sorbitol, inorganic fillers such as aluminum hydroxide gel, calcium carbonate (granular or powder), precipitated calcium carbonate, carbonate, magnesium aluminometasilicate, calcium dihydrogen phosphate, and sodium chloride, silicon dioxide, silicic acid, titanium dioxide, titanium oxide, calcium dihydrogen phosphate dihydrate, calcium sulfate, alumina, kaolin, talc, or combinations thereof. The filler may be present from about 20% to about 65%, from about 20% to about 50%, from about 20% to about 40%, from about 45% to about 65%, from about 50% to about 65%, or from about 55% to about 65% by weight of the total weight of the composition, or any value within these ranges.

[0167] In some embodiments of the methods described herein, the modified-release formulation further comprises one or more disintegrants. Examples of disintegrants include starch, alginic acid, cross-linked polymers such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, potassium starch glycolate, sodium starch glycolate, clay, cellulose, starch, gum, or combinations thereof. The disintegrant may be present in an amount of from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, or from about 1% to about 5% by weight, based on the total weight of the composition, or any value within these ranges.

[0168] In some embodiments of the methods described herein, the modified-release formulation further comprises one or more binders, including, but not limited to, celluloses such as hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose, starches such as corn starch, pregelatinized starch, and hydroxypropyl starch, waxes, natural and synthetic gums such as acacia, tragacanth, and sodium alginate, synthetic polymers such as polymethacrylates and polyvinylpyrrolidone, and povidone, dextrin, pullulan, agar, gelatin, tragacanth, macrogol, or combinations thereof. The binder may be present in an amount of from about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, or about 0.5% to about 1% by weight, or any percentage within these ranges, based on the total weight of the composition.

[0169] In some embodiments of the methods described herein, the modified release formulation further comprises one or more wetting agents, including, but not limited to, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, poloxamer, poloxamer 188, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and combinations thereof. The humectant may be present in an amount from about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, or about 0.1% to about 5%, based on the total weight of the composition, or any value within these ranges.

[0170] In some embodiments of the methods described herein, the modified-release formulation further comprises one or more lubricants, including, but not limited to, stearate, magnesium stearate, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal salts and alkaline earth metal salts, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (PEG), methoxypolyethylene glycol, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof. The lubricant may be present in an amount of from about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1%, or any value within these ranges, based on the total weight of the composition.

[0171] In some embodiments of the methods described herein, the modified-release formulation further comprises one or more lubricants, including, but not limited to, silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, or combinations thereof. The lubricant may be present from about 0.05% to about 1% by weight, about 0.05% to about 0.9% by weight, about 0.05% to about 0.8% by weight, about 0.05% to about 0.5% by weight, or about 0.05% to about 0.1% by weight, based on the total weight of the composition, or any value therebetween.

[0172] In some embodiments of the methods described herein, the modified-release formulation is a tablet and further comprises a topcoat, such as a hydroxypropyl methylcellulose coating or a polyvinyl alcohol coating, available under the trade name Opadry, such as Opadry White, Opadry II, etc. (Opadry is a registered trademark of BPSI Holdings LLC, Wilmington, Delaware, USA.) The topcoat may be present from about 1% to about 10% by weight, about 1% to about 9% by weight, about 1% to about 8% by weight, about 1% to about 7% by weight, about 1% to about 6% by weight, or about 1% to about 5% by weight, or any value within these ranges, based on the total weight of the composition.

[0173] In some embodiments of the methods described herein, the modified-release formulation can further comprise one or more preservatives. Examples of preservatives include sodium benzoate, parahydroxybenzoates, methyl, ethyl, butyl, and propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride (BKC), benzethonium chloride, phenol, phenylmercuric nitrate, thimerosal, or combinations thereof. The preservative can be included in the liquid dosage form. The preservative can be present in an amount sufficient to extend the shelf life or storage stability, or both, of the liquid dosage form. The preservative may be present in an amount from about 0.05% to about 1% by weight, about 0.05% to about 0.9% by weight, about 0.05% to about 0.8% by weight, about 0.05% to about 0.5% by weight, or about 0.05% to about 0.1% by weight of the total composition, or any value within these ranges.

[0174] In some embodiments of the methods described herein, the modified-release formulation can further comprise one or more flavoring agents. Examples of flavoring agents include synthetic flavor oils and aromatic flavoring agents and / or natural oils, extracts from plant leaves, flowers, fruits, etc., and the like, or any combination thereof. Additional examples include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil, and the like, or any combination thereof. Citrus oils, including vanilla, lemon, orange, grape, lime, and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, strawberry flavor, tutti-fruity flavor, mint flavor, or combinations thereof, are also useful as flavoring agents. Flavoring Agents Flavoring agents may be present from about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1% by weight, based on the total weight of the composition, or any value within these ranges.

[0175] In some embodiments of the methods described herein, the modified-release formulations can generally be in any physical form suitable for use in treating a subject. These forms can be referred to as unit dosage forms, such as individual pills or tablets. In some examples, the pharmaceutical compositions can be formulated as tablets, capsules, granules, powders, liquids, suspensions, gels, syrups, slurries, suppositories, patches, nasal sprays, aerosols, injectables, implantable sustained-release formulations, or mucoadhesive films. In some examples, the pharmaceutical formulations can be formed as tablets, bilayer tablets, capsules, multiparticulates, drug-coated spheres, matrix tablets, or multicore tablets. The physical form can be selected according to the desired method of treatment.

[0176] In some embodiments of the methods described herein, the modified-release formulations can be prepared by a variety of conventional methods, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, embedding, or lyophilizing methods. The modified-release formulations can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate processing of the active ingredient into a pharmaceutically usable formulation. The appropriate formulation can be selected depending on the selected oral administration route.

[0177] In some embodiments, the modified-release formulation is a core tablet, or tablet within a tablet, whereby the inner core is used for the sustained-release drug component and the outer shell contains the immediate-release drug dose. In some embodiments, the modified-release formulation is achieved by microencapsulation, whereby minute drug particles are encapsulated with a special coating material, such as ethylcellulose. In some embodiments, the modified-release formulation is an osmotic drug delivery system in the form of a tablet containing an outer semipermeable membrane and an inner core filled with a mixture of drug and osmotic agent (salt solution). In some embodiments, the modified-release formulation is a gastroretentive system that can remain in the stomach area for several hours, extending the gastric residence time of the drug. In some embodiments, the modified-release formulation is a combination of any of the above embodiments.

[0178] In some embodiments of the methods described herein, for oral administration, modified-release formulations can combine minoxidil or a pharmaceutically acceptable salt thereof with another agent with one or more pharmaceutically acceptable carriers well known in the art. Such carriers facilitate the formulation of pills, tablets, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by patients receiving treatment. For example, for oral solid formulations such as powders, capsules, and tablets, suitable excipients include fillers such as sugars such as lactose, sucrose, mannitol, and sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, cellulose preparations such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP), granulating agents, and binders. If necessary, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt of alginic acid (such as sodium alginate) can be added. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

[0179] For example, for oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents and the like can be added. For buccal administration, the compositions can take the form of tablets, lozenges, etc. formulated in conventional manner.

[0180] In some embodiments of the methods described herein, the modified release formulation can comprise a matrix selected from microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkyl celluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide, alkyl celluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyacetic acid phthalate, polyalkyl methacrylate, polyacetic acid, and mixtures thereof.

[0181] kit Embodiments described herein are directed to kits that include a sustained release modified release vehicle containing an oral formulation comprising minoxidil or a pharmaceutically acceptable salt thereof, and an information sheet.

[0182] In some embodiments of the kits described herein, the oral pharmaceutical formulation comprises minoxidil or a pharmaceutically acceptable salt thereof, a release-modifying agent, a filler, a glidant, a lubricant, and combinations thereof.

[0183] In some embodiments, the kits described herein contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.075% to about 33% (w / w) of the total formulation. In some embodiments, the kits described herein contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.083% to about 33% (w / w) of the total formulation. In some embodiments of the kits described herein, the oral pharmaceutical formulation contains minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 20% (w / w) of the total formulation. In some embodiments, the kits include an oral pharmaceutical formulation containing minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 10% (w / w) of the total formulation. In some embodiments, the kits contain minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 5% (w / w) of the total formulation. In some embodiments, the kit comprises minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 1.5% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising minoxidil or a pharmaceutically acceptable salt thereof in an amount of about 0.075%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 15%, about 16%, about 18%, about 20%, about 25%, about 30%, about 33%, or any range of these values.

[0184] In some embodiments of the kits described herein, the oral pharmaceutical formulation comprises a release modifier in an amount of about 20% to about 95% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a release modifier in an amount of about 50% to about 80% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a release modifier in an amount of about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% (w / w), or any range between these values.

[0185] In some embodiments of the kits described herein, the oral pharmaceutical formulation comprises a lubricant in an amount of about 0.01% to about 2% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a lubricant in an amount of about 0.1% to about 0.3% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a lubricant in an amount of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.35%, or any range of these values.

[0186] In some embodiments of the kits described herein, the oral pharmaceutical formulation comprises a lubricant in an amount of about 0.1% to about 1% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a lubricant in an amount of about 0.4% to about 0.6% (w / w) of the total formulation. In some embodiments, the kit comprises an oral pharmaceutical formulation comprising a lubricant in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1% (w / w), or any range of amounts therebetween.

[0187] In some embodiments of the kits described herein, the release-modifying agent is hydroxypropyl methylcellulose (HPMC) or lactose monohydrate. In some embodiments, the hydroxypropyl methylcellulose is HPMC K4M or HPMC K200M. In some embodiments, the HPMC K4M is present in an amount of 0 mg to about 45 mg in a 150 mg formulation. In some embodiments, the HPMC K4M is 0% to about 30% (w / w) of the total formulation. In some embodiments, the HPMC K200M is present in an amount of 0 mg to about 120 mg in a 150 mg formulation. In some embodiments, the HPMC K200M is about 0% to about 80% (w / w) of the total formulation. In some embodiments, the lactose monohydrate is present in an amount of about 0 mg to about 55 mg in a 150 mg formulation. In some examples, the lactose monohydrate is about 0% to about 40% (w / w) of the total formulation.

[0188] In some embodiments of the kits described herein, the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the filler is present in an amount of about 25 mg to about 55 mg per 150 mg formulation. In some embodiments, the microcrystalline cellulose is about 15% to about 40% (w / w) of the total formulation.

[0189] In some embodiments, the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, or a combination thereof. In some embodiments of the kits described herein, the lubricant is silica. In some embodiments, the silica is colloidal anhydrous. In some embodiments, the lubricant is present in an amount of about 0.3 mg to about 5 mg per 150 mg formulation. In some examples, the lubricant is about 0.001% to about 0.04% (w / w) of the total formulation.

[0190] In some embodiments of the kits described herein, the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof. In some embodiments, the lubricant is present in an amount of about 0.75 mg to about 1.5 mg per 150 mg formulation. In some embodiments, the lubricant is about 0.005% to about 0.01% (w / w) of the total formulation.

[0191] In some embodiments of the kits described herein, the sustained-release controlled release vehicle further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, alopecia areata medications, supplements, and combinations thereof. In some embodiments, the sustained-release controlled release vehicle further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0192] In any embodiment of the kit described herein, the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof. In any embodiment, the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof. In any embodiment, the 19-norprogesterone derivative is nomegestrol acetate. In any embodiment, the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof. In any embodiment, the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof. In any embodiment, the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, isonosteride, epigallocatechin, fluridil, and combinations thereof.In any embodiment, the estrogen is selected from estradiol, estradiol ester, ethinylestradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.In any embodiment, the GnRH analog is a GnRH agonist selected from goserelin, buserelin, leuprorelin, and combinations thereof.In any embodiment, the GnRH analog is a GnRH antagonist, and the GnRH antagonist is cetrorelix. In any embodiment, the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof. In any embodiment, the prostamide is bimatoprost. In any embodiment, the prostanoid receptor agonist is fluprostenol, ticaprost, and combinations thereof.In any embodiment, the prostaglandin D2 receptor antagonist is laropirant, AM211, or a combination thereof. In any embodiment, the prostaglandin E2 analog is sulprostone. In any embodiment, the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, or a combination thereof. In any embodiment, the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itatinib, oclacitinib, pacritinib, pefitinib, ritretinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.In any embodiment, the alopecia areata treatment drug is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.In any embodiment, the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0193] In some embodiments of the kits described herein, the kits include an information sheet. In some embodiments, the information sheet includes instructions for selecting an oral dosage form based on the patient's weight. In some embodiments, the information sheet includes instructions for selecting a daily dose of minoxidil or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments of the kits described herein, the information sheet includes a warning about side effects, which in some embodiments are selected from peripheral edema and hirsutism.

[0195] In some embodiments of the kits described herein, minoxidil or a pharmaceutically acceptable salt thereof is administered only once a day. In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof is administered at least once a day. In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof is administered four times a day. In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof is administered three times a day. In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof is administered twice a day.

[0196] In some embodiments of the kits described herein, the sustained release modified release vehicle releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration. In some embodiments of the pharmaceutical formulations described herein, the sustained release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 18 hours after oral administration. In some examples described herein, the sustained release modified release vehicle releases about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or within a range of these values, of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 18 hours after oral administration.

[0197] In some embodiments of the kits described herein, the oral pharmaceutical formulation exhibits a dissolution profile in which about 25% of the formulation dissolves in a neutral pH solution in less than about 2 hours or less than about 4 hours. In some embodiments, about 25% of the formulation dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

[0198] In some embodiments of the kits described herein, the oral pharmaceutical formulation exhibits a dissolution profile in which about 50% of the pharmaceutical formulation dissolves in a neutral pH solution in less than about 2 hours, less than about 6 hours, or less than about 12 hours. In some embodiments, about 50% of the formulation dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

[0199] In some embodiments of the kits described herein, the oral pharmaceutical formulation exhibits a dissolution profile in which about 75% of the pharmaceutical formulation dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours. In some embodiments, about 75% of the pharmaceutical formulation dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

[0200] In some embodiments of the kits described herein, the oral pharmaceutical formulation exhibits a dissolution profile in which about 100% of the pharmaceutical formulation dissolves in less than about 12 hours, less than about 24 hours, or less than about 48 hours at neutral pH, hi some embodiments, about 100% of the formulation dissolves in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours at neutral pH.

[0201] In some embodiments of the kits described herein, the oral pharmaceutical formulation exhibits zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments of the kits described herein, minoxidil or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. In some embodiments, one or more active ingredients are present in a therapeutically effective amount. In some embodiments, the pharmaceutical formulation comprises a subtherapeutic amount of minoxidil or a pharmaceutically acceptable salt thereof. In some examples, the pharmaceutical formulation comprises a subtherapeutic amount of one or more active ingredients. In some examples, the pharmaceutical formulation comprises minoxidil or a pharmaceutically acceptable salt thereof and one or more active ingredients, wherein the minoxidil or a pharmaceutically acceptable salt thereof and the one or more active ingredients are each present in a subtherapeutic amount.

[0203] In some embodiments of the kits described herein, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 25% to about 500% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 10% to about 90% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 425%, about 450%, about 475%, about 500%, or any range of these values, of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0204] In some embodiments of the kits described herein, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 50 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 2.5 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.625 mg to about 7.5 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 10 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 20 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.125 mg to about 100 mg. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 2.5 mg. In some embodiments, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 0.125 mg, about 0.25 mg, about 5 mg, about 0.625 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, or any range of these values.

[0205] In some embodiments of the kits described herein, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.000625 mg / kg / day to about 1.25 mg / kg / day. In some embodiments of the kits described herein, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.00625 mg / kg / day to about 0.5 mg / kg / day. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 0.00625 mg / kg / day to about 0.375 mg / kg / day. In some embodiments, the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 0.000625 mg / kg / day, about 0.00125 mg / kg / day, about 0.0025 mg / kg / day, about 0.00375 mg / kg / day, about 0.005 mg / kg / day, about 0.00625 mg / kg / day, about 0.0125 mg / kg / day, about 0.025 mg / kg / day, about 0.0375 mg / kg / day, kg / day, about 0.05 mg / kg / day, about 0.0625 mg / kg / day, about 0.075 mg / kg / day, about 0.0875 mg / kg / day, about 0.1 mg / kg / day, about 0.125 mg / kg / day, about 0.25 mg / kg / day, about 0.5 mg / kg / day, about 0.625 mg / kg / day, about 0.75 mg / kg / day, about 1 mg / kg / day, or any range within these values.

[0206] In some embodiments of the methods described herein, the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is in an amount of about 0.625 mg, four times a day.

[0207] In some embodiments of the kits described herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Cmax of about 0.25 ng / ml to about 20 ng / ml. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Cmax that is cardiac-friendly.

[0208] In some embodiments of the kits described herein, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour to about 24 hours. In some embodiments, oral administration results in a half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, or any range of these values.

[0209] In some embodiments of the kits herein, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Tmax of about 30 minutes to about 360 minutes. In some embodiments, oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides delayed-release with a Tmax of both between 30 minutes and 360 minutes and between 390 minutes and 1080 minutes.

[0210] In some embodiments of the kits described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a greater AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the kits described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in a lesser AUC than an equivalent dose of an immediate-release formulation. In some embodiments of the kits described herein, oral administration of a daily dose of modified-release minoxidil or a pharmaceutically acceptable salt thereof results in an AUC equal to an equivalent dose of an immediate-release formulation.

[0211] In some embodiments of the kits described herein, the sustained-release modified vehicle is an inert solid medium, or matrix, in which the drug is uniformly suspended, including in the form of a tablet or small beads. In some embodiments, the matrix is ​​a gelling material including gelatin, methylcellulose, tragacanth gum, Veegum, and alginic acid. In some embodiments, the matrix is ​​a polymer including polylactic acid copolymer, polyacrylate, methacrylate, polyester, ethylene-vinyl acetate copolymer (EVA), polyglycolic acid, polylactic acid, and silicone. In some embodiments, the sustained-release modified vehicle is sustained-release pellets, beads, or granules. In some embodiments, the modified-release formulation is a sustained-release tablet in which the solubility of the drug is modified for sustained release. In some embodiments, the sustained-release tablet is formed using a non-ionized base or acid form of the drug. In some embodiments, sustained-release tablets are formed by granulating the drug with excipients (including stearates, castor oil, high molecular weight polyethylene glycol (Carbowax), glyceryl monostearate, white wax, whale oil, magnesium stearate, and hydrogenated vegetable oil (Sterotex)) to reduce the drug's water solubility. In some embodiments, the sustained-release modifying vehicle is an ion-exchange formulation in which an anionic or cationic drug is complexed with an ionic resin of the opposite charge to form an insoluble, non-absorbable resin-drug complex.

[0212] In some embodiments of the kits described herein, the sustained release modified release vehicle further comprises one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients that may be present in the composition include, but are not limited to, fillers / solvents, solvents / co-solvents, preservatives, antioxidants, suspending agents, surfactants, antifoaming agents, buffers, chelating agents, sweeteners, flavoring agents, binders, fillers, disintegrants, diluents, lubricants, fillers, wetting agents, glidants, and combinations thereof.

[0213] In some embodiments of the kits described herein, the sustained release modified vehicle can further comprise one or more exemplary fillers. Examples of preferred fillers include cellulose and cellulose derivatives such as microcrystalline cellulose and powdered cellulose, starches such as dextrates, dry starch, hydrolyzed starch, and starch derivatives such as cornstarch, cyclodextrin, sugars such as powdered sugar, and sugar alcohols such as lactose, mannitol, sucrose, and sorbitol, inorganic fillers such as aluminum hydroxide gel, calcium carbonate (granular or powder), precipitated calcium carbonate, carbonate, magnesium aluminometasilicate, dicalcium phosphate, and sodium chloride, silicon dioxide, silicic acid, titanium dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, alumina, kaolin, talc, or combinations thereof. The filler may be present in the composition from about 20% to about 65%, about 20% to about 50%, about 20% to about 40%, about 45% to about 65%, about 50% to about 65%, or about 55% to about 65% by weight of the total weight of the composition, or any value within these ranges.

[0214] In some embodiments of the kits described herein, the sustained release modified vehicle further comprises one or more disintegrants. Examples of disintegrants include starch, alginic acid, cross-linked polymers such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, potassium starch glycolate, sodium starch glycolate, clay, cellulose, starch, gum, or combinations thereof. The disintegrant may be present in an amount of from about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, or about 1% to about 5% by weight, based on the total weight of the composition, or any value within these ranges.

[0215] In some embodiments of the kits described herein, the sustained release modified vehicle further comprises one or more binders, including, but not limited to, celluloses such as hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose, starches such as corn starch, pregelatinized starch, and hydroxypropyl starch, waxes, natural and synthetic gums such as acacia, tragacanth, and sodium alginate, synthetic polymers such as polymethacrylates and polyvinylpyrrolidone, and povidone, dextrin, pullulan, agar, gelatin, tragacanth, macrogol, or combinations thereof. The binder may be present in the composition from about 0.5% to about 5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 0.5% to about 2% by weight, or about 0.5% to about 1% by weight, or any value within these ranges, based on the total weight of the composition.

[0216] In some embodiments of the kits described herein, the sustained release modified vehicle further comprises one or more humectants, including, but not limited to, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, poloxamer, poloxamer 188, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate salts, etc.), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and combinations thereof. The humectant may be present in the composition from about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, or about 0.1% to about 5% by weight, or any value within these ranges, based on the total weight of the composition.

[0217] In some embodiments of the kits described herein, the sustained release modifying vehicle further comprises one or more lubricants, including, but not limited to, stearate, magnesium stearate, calcium hydroxide, talc, cornstarch, sodium stearyl fumarate, alkali metal salts and alkaline earth metal salts, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (PEG), methoxypolyethylene glycol, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof. The lubricant may be present in an amount of from about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1% by weight, or any value within these ranges, based on the total weight of the composition.

[0218] In some embodiments of the kits described herein, the sustained release modified vehicle further comprises one or more lubricants, including, but not limited to, colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, and combinations thereof. The lubricant may be present in the composition in an amount of from about 0.05% to about 1%, about 0.05% to about 0.9%, about 0.05% to about 0.8%, about 0.05% to about 0.5%, or about 0.05% to about 0.1% by weight, based on the total weight of the composition, or any value within these ranges.

[0219] In some embodiments of the kits described herein, the sustained release modified vehicle is a tablet and further comprises a topcoat, such as a hydroxypropyl methylcellulose coating or a polyvinyl alcohol coating, available under the trade name Opadry, such as Opadry White, Opadry II, etc. (Opadry is a registered trademark of BPSI Holdings LLC, Wilmington, Delaware, USA.) The topcoat may be present in the composition in an amount from about 1% to about 10% by weight, about 1% to about 9% by weight, about 1% to about 8% by weight, about 1% to about 7% by weight, about 1% to about 6% by weight, or about 1% to about 5% by weight, or any value within these ranges, based on the total weight of the composition.

[0220] In some embodiments of the kits described herein, the sustained release modified vehicle can further comprise one or more preservatives. Examples of preservatives include sodium benzoate, parahydroxybenzoates, methyl, ethyl, butyl, and propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride (BKC), benzethonium chloride, phenol, phenylmercuric nitrate, thimerosal, or a combination thereof. The preservative can be included in a liquid dosage form. The preservative can be present in an amount sufficient to extend the shelf life or storage stability, or both, of the liquid dosage form. The preservative may be present in the composition from about 0.05% to about 1% by weight, about 0.05% to about 0.9% by weight, about 0.05% to about 0.8% by weight, about 0.05% to about 0.5% by weight, or about 0.05% to about 0.1% by weight, or any value within these ranges, based on the total weight of the composition.

[0221] In some embodiments of the kits described herein, the sustained-release modified release vehicle can further comprise one or more flavoring agents. Examples of flavoring agents include synthetic flavor oils and flavoring agents, and / or natural oils, extracts from plant leaves, flowers, fruits, etc., and the like, or combinations thereof. Additional examples include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil, and the like, or any combination thereof. Also useful as flavoring agents are citrus oils, including vanilla, lemon, orange, grape, lime, and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, strawberry flavor, tutti-fruity flavor, mint flavor, or combinations thereof. Flavoring Agents Flavoring agents may be present in the composition from about 0.1% to about 5% by weight, about 0.1% to about 4% by weight, about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, or about 0.1% to about 1% by weight, or any value within these ranges, based on the total weight of the composition.

[0222] In some embodiments of the kits described herein, the sustained release modified release vehicle can generally be present in any physical form suitable for use in treating a subject. These forms can be referred to as unit dosage forms, such as individual pills or tablets. In some examples, the pharmaceutical composition can be formulated as a tablet, capsule, granules, powder, liquid, suspension, gel, syrup, slurry, suppository, patch, nasal spray, aerosol, injectable, implantable sustained-release formulation, or mucoadhesive film. In some examples, the pharmaceutical formulation can be formed as a tablet, bilayer tablet, capsule, multiparticulate, drug-coated sphere, matrix tablet, or multicore tablet. The physical form can be selected according to the desired method of treatment.

[0223] In some embodiments of the kits described herein, the sustained-release modified release vehicle can be prepared by a variety of conventional methods, such as conventional mixing, dissolving, granulating, dragee-making, purifying, emulsifying, encapsulating, embedding, or lyophilizing. The sustained-release modified release vehicle can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate processing of the active ingredient into a pharmaceutically usable preparation. The appropriate formulation can be selected depending on the selected oral administration route.

[0224] In some embodiments, the sustained-release modified release vehicle is a core tablet, or tablet within a tablet, whereby the inner core is used for the sustained-release drug component and the outer shell contains the immediate-release drug dose. In some embodiments, the sustained-release modified release vehicle is achieved by microencapsulation, whereby minute drug particles are encapsulated with a special coating material such as ethyl cellulose. In some embodiments, the sustained-release modified release vehicle is an osmotic drug delivery system in the form of a tablet comprising an outer semipermeable membrane and an inner core filled with a mixture of drug and osmotic agent (salt solution). In some embodiments, the sustained-release modified release vehicle is a gastroretentive system that can remain in the stomach region for several hours, extending the gastric residence time of the drug. In some embodiments, the sustained-release modified release vehicle is a combination of any of the above embodiments.

[0225] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation is a tablet. In some embodiments, the tablet is a sustained-release or controlled-release tablet. The sustained-release or controlled-release tablet may be an osmotic pump-type controlled-release tablet, a matrix-type controlled-release tablet, or a sustained-release and controlled-release tablet based on sustained-release pellets. Among these, osmotic pump-type controlled-release tablets include osmotic pump-type controlled-release tablets and osmotic pump immediate and sustained dual-release tablets, and matrix-type controlled-release tablets include matrix-type sustained-release tablets, matrix-type immediate and sustained dual-release bilayer tablets, matrix-type immediate and sustained dual-release coated tablets, etc. The sustained-release and controlled-release tablets based on sustained-release pellets include sustained-release tablets based on sustained-release pellets and immediate-release and sustained dual-release tablets based on sustained-release pellets and immediate-release pellets. The sustained-release and controlled-release tablets described above can specifically achieve the drug release behavior of the present invention in the manner of an osmotic pump-type controlled-release tablet, a matrix-type controlled-release tablet, or a sustained-release tablet based on sustained-release pellets.

[0226] The osmotic pump controlled release tablets of the present invention can be monolayer osmotic pump tablets, monolayer osmotic pump immediate and sustained dual release tablets, bilayer osmotic pump controlled release tablets, or bilayer osmotic pump immediate and sustained dual release tablets. The bilayer osmotic pump controlled-release tablet of the present invention mainly includes: 1) a controlled-release drug layer formed from a controlled-release drug layer composition, disposed within the hard film shell, and adjacent to the drug-release pores; 2) a push layer (also called a boost layer) formed from a push layer composition, disposed within the hard film shell, away from the sides of the drug-release pores; 3) an optional seal-coating layer disposed between the core composed of the drug layer and the push layer and the inner surface of the hard film shell, prepared by drying a seal-coating composition; 4) a moisture-permeable hard film shell obtained by drying a controlled-release coating solution, having one or more drug-release pores at one end of the film shell; 5) an optional outer layer, which is not limited to cosmetic purposes; and 6) an optional immediate-release drug layer formed from an immediate-release drug composition and disposed on the outside of the hard film shell and any cosmetic coating. Further details regarding controlled-release formulations are described in U.S. Patent Publication No. 20200108008, the entire contents of which are incorporated herein by reference.

[0227] The matrix-type controlled-release tablets of the present invention can have dual release profiles, immediate and sustained. The controlled-release matrix-type tablets of the present invention are primarily composed of a sustained-release phase and an optional immediate-release phase. A bilayer tablet consisting of a sustained-release phase and an immediate-release phase is a dual-release matrix-type tablet, while a monolayer tablet consisting only of a sustained-release phase is a conventional sustained-release matrix-type tablet. The sustained-release phase contains 100 to 900 parts by weight, preferably 150 to 700 parts by weight, more preferably 200 to 600 parts by weight, of minoxidil or a pharmaceutically acceptable salt thereof in an improved dissolution form; 10 to 300 parts by weight, preferably 30 to 150 parts by weight, of a release rate-controlling matrix polymer; 0 to 50 parts by weight of a diluent; and 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight, of other common tablet additives. The sustained-release phase is prepared by thoroughly mixing the ingredients and pressing them together using a conventional method well known to those skilled in the art. The release rate controlling matrix polymer may be one or a combination of two or more selected from polyoxyethylene, hydroxypropyl cellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resins, carbomer, or preferably one or a combination of two or more selected from the group consisting of hydroxypropyl cellulose, sodium alginate, hypromellose, and carbomer.

[0228] The sustained release tablets based on the sustained release pellets of the present invention can be sustained release tablets based on sustained release pellets or dual immediate and sustained release tablets based on immediate release matrix / sustained release pellets.

[0229] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation is a capsule. In some embodiments, the capsule is a controlled-release capsule formulation selected from the group consisting of pellet-based sustained- and controlled-release capsules and tablet-based sustained- and controlled-release capsules. In some embodiments, the capsule is a microtablet-based controlled-release capsule. The pellet-based sustained- and controlled-release capsules of the present invention may be sustained-release pellets or immediate-release and sustained-dual-release capsules consisting of sustained-release pellets and immediate-release pellets, and may include capsules containing matrix-type sustained-release pellets, capsules containing coated sustained-release pellets, capsules containing sustained-release pellets with an immediate-release coating, immediate-release and sustained-dual-release capsules containing immediate-release pellets and matrix-type sustained-release pellets, and immediate-release and sustained-dual-release capsules containing immediate-release pellets and coated sustained-release pellets.

[0230] The sustained- and controlled-release capsules based on microtablets of the present invention may be controlled-release capsules composed of sustained-release microtablets, or immediate-release and sustained-dual-release capsules composed of sustained-release microtablets and immediate-release microtablets, and may include capsules containing matrix-type sustained-release microtablets, capsules containing matrix-type sustained-release microtablets with an immediate-release coating, and capsules containing immediate-release microtablets and matrix-type sustained-release microtablets. Generally, for filling hard capsules, the produced microtablets typically have a small diameter, usually less than 5 mm in diameter.

[0231] In some embodiments of the pharmaceutical formulations described herein, the pharmaceutical formulation further comprises an enteric coating. The one or more coatings can include an enteric coating, which is a tablet coating that delays tablet digestion until the tablet passes from the stomach to the intestine. Enteric-coated formulations bypass the acidic environment of the stomach to eliminate the effect of acidic pH on minoxidil solubility. Enteric coatings typically contain pH-sensitive polymers. The polymers are carboxylates, which generally have little interaction with water at low pH. However, at high pH, ​​the polymers ionize, thereby dissolving. Thus, coatings can be designed to remain intact in the acidic environment of the stomach and dissolve in the more alkaline environment of the intestine. Examples include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, polyacetic acid phthalate, and methacrylic acid-methyl methacrylate copolymer. In one aspect, the first surface coating comprises polyvinyl alcohol. In a further aspect, the first surface coating comprises a methacrylic acid-ethyl acrylate copolymer. In a further aspect, the first surface coating comprises polyvinyl alcohol and a methacrylic acid-ethyl acrylate copolymer. In a further aspect, the first surface coating is an enteric coating comprising one or more of polyvinyl alcohol or a methacrylic acid-ethyl acrylate copolymer. In a further aspect, the first surface coating is an enteric coating comprising one or more of CAP, PVAP, an acrylic polymer, an acrylic copolymer, HPMCAS, HPMCP, or shellac. Further description of enteric coatings is provided in U.S. Patent Publication No. 20170020920, the entire contents of which are incorporated herein by reference.

[0232] In some embodiments of the kits described herein, for oral administration, the sustained-release controlled-release vehicle can combine minoxidil or a pharmaceutically acceptable salt thereof with other agents using one or more pharmaceutically acceptable carriers known in the art. Such carriers facilitate formulation into pills, tablets, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by the patient receiving treatment. For example, for oral solid formulations such as powders, capsules, and tablets, suitable excipients include sugars such as lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP); granulating agents; and binders. If necessary, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate) may be added. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

[0233] For example, for oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents and the like can be added. For buccal administration, the compositions can take the form of tablets, lozenges, etc. formulated in conventional manner.

[0234] In some embodiments of the kits described herein, the sustained release modified vehicle may comprise a matrix selected from microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkyl celluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide, alkyl celluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylate, polyvinyl acetate, and mixtures thereof.

[0235] Further embodiments Provided herein is a pharmaceutical formulation, embodiment A, for oral administration, comprising (preferably a daily dosage) minoxidil or a pharmaceutically acceptable salt thereof, which is a modified release formulation.

[0236] In embodiment B, there is provided the pharmaceutical formulation of embodiment A, further comprising a release modifier, a filler, a glidant, a lubricant, and combinations thereof.

[0237] In embodiment C, there is provided a pharmaceutical formulation of embodiment A or B comprising about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release-modifying agent, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0238] In embodiment D, there is provided a pharmaceutical formulation according to any of the above embodiments, comprising about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release-modifying agent, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0239] In embodiment E, there is provided a pharmaceutical formulation according to any of the above embodiments, comprising about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release-modifying agent, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0240] In embodiment F, there is provided a pharmaceutical formulation according to any of the above embodiments, comprising about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release-modifying agent, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0241] In embodiment G, there is provided the pharmaceutical formulation of embodiment B, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

[0242] In embodiment H, there is provided the pharmaceutical formulation of embodiment B, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or a combination thereof.

[0243] In embodiment I, there is provided the pharmaceutical formulation of embodiment B, wherein the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, silica aerogel, or a combination thereof.

[0244] In embodiment J, there is provided the pharmaceutical formulation of embodiment B, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene, monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

[0245] In embodiment K, there is provided the pharmaceutical formulation of embodiment A, further comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

[0246] In embodiment L, there is provided the pharmaceutical formulation of embodiment A, comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0247] In embodiment M, there is provided the pharmaceutical formulation of embodiment K, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

[0248] In embodiment N, there is provided the pharmaceutical formulation of embodiment K, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

[0249] In embodiment O, there is provided the pharmaceutical formulation of embodiment K, wherein the 19-norprogesterone derivative is nomegestrol acetate.

[0250] In embodiment P, there is provided the pharmaceutical formulation of embodiment K, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

[0251] In embodiment Q, there is provided the pharmaceutical formulation of embodiment K, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

[0252] In embodiment R, there is provided the pharmaceutical formulation of embodiment K, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, beclosteride, isonosteride, epigallocatechin, fluridil, and combinations thereof.

[0253] In embodiment S, there is provided the pharmaceutical formulation of embodiment K, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

[0254] In embodiment T, there is provided the pharmaceutical formulation of embodiment K, wherein the GnRH analog is a GnRH agonist.

[0255] In embodiment U, there is provided the pharmaceutical formulation of embodiment T, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

[0256] In embodiment V, there is provided the pharmaceutical formulation of embodiment K, wherein the GnRH analogue is a GnRH antagonist.

[0257] In embodiment W, there is provided the pharmaceutical formulation of embodiment V, wherein the GnRH antagonist is cetrorelix.

[0258] In embodiment X, there is provided the pharmaceutical formulation of embodiment K, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

[0259] In embodiment Y, there is provided the pharmaceutical formulation of embodiment K, wherein the prostamide is bimatoprost.

[0260] In embodiment Z, there is provided the pharmaceutical formulation of embodiment K, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.

[0261] In embodiment AA, there is provided the pharmaceutical formulation of embodiment K, wherein the prostaglandin D2 receptor antagonist is laropirant, AM211, and combinations thereof.

[0262] In embodiment BB, there is provided the pharmaceutical formulation of embodiment K, wherein the prostaglandin E2 analog is sulprostone.

[0263] In embodiment CC, there is provided the pharmaceutical formulation of embodiment K, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

[0264] In embodiment DD, the pharmaceutical formulation of embodiment K is provided, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, ritrecitinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.

[0265] In embodiment EE, there is provided the pharmaceutical formulation of embodiment K, wherein the alopecia areata therapeutic agent is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

[0266] In embodiment FF, there is provided the pharmaceutical formulation of embodiment K, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0267] In embodiment GG, there is provided the pharmaceutical formulation of embodiment A, wherein the modified release formulation is selected from a sustained release formulation, a sustained release formulation, a controlled release formulation, or a delayed release formulation.

[0268] In embodiment HH, there is provided the pharmaceutical formulation of embodiment A, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is present in an amount of about 0.25 mg to about 50 mg.

[0269] In embodiment II, there is provided a pharmaceutical formulation of embodiment A, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a steady-state blood concentration of minoxidil or a pharmaceutically acceptable salt thereof of from about 1 ng / ml to about 20 ng / ml.

[0270] In Embodiment JJ, there is provided a pharmaceutical formulation of Embodiment II, wherein steady-state blood concentrations of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof are maintained for at least about 12 hours.

[0271] In embodiment KK, there is provided the pharmaceutical formulation of embodiment A, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof provides a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0272] In embodiment LL, there is provided the pharmaceutical formulation of embodiment A, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a Tmax of about 30 minutes to about 360 minutes.

[0273] In embodiment MM, there is provided the pharmaceutical formulation of embodiment A, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.000625 mg / kg / day to about 1.25 mg / kg / day.

[0274] In embodiment NN, there is provided the pharmaceutical formulation of embodiment A, wherein upon oral administration, the half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 1 hour to about 24 hours.

[0275] In embodiment 00, there is provided the pharmaceutical formulation of embodiment GG, wherein the sustained release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0276] In embodiment PP, there is provided the pharmaceutical formulation of embodiment A, wherein about 25% of the formulation dissolves in less than 2 hours or less than 4 hours in a neutral pH solution.

[0277] In embodiment QQ, there is provided the pharmaceutical formulation of embodiment A, wherein about 25% of the formulation dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

[0278] In embodiment RR, there is provided the pharmaceutical formulation of embodiment A, wherein about 50% of the formulation dissolves in a neutral pH solution in less than 2 hours, less than 6 hours, or less than 12 hours.

[0279] In embodiment SS, there is provided the pharmaceutical formulation of embodiment A, wherein about 50% of the formulation dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

[0280] In embodiment TT, there is provided the pharmaceutical formulation of embodiment A, wherein about 75% of the formulation dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours.

[0281] In embodiment UU, there is provided the pharmaceutical formulation of embodiment A, wherein about 75% of the formulation dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

[0282] In embodiment VV, there is provided the pharmaceutical formulation of embodiment A, wherein about 100% of the formulation dissolves at neutral pH in less than about 12 hours, less than about 24 hours, or less than about 48 hours.

[0283] In embodiment WW, there is provided the pharmaceutical formulation of embodiment A, wherein about 100% of the formulation dissolves at neutral pH in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours.

[0284] In Embodiment XX, there is provided a pharmaceutical formulation of Embodiment A that exhibits zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

[0285] In embodiment YY, the pharmaceutical formulation of embodiment A is provided, which includes an enteric coating.

[0286] In embodiment ZZ, there is provided a pharmaceutical formulation of embodiment A that is administered only once daily.

[0287] In embodiment AAA, there is provided the pharmaceutical formulation of embodiment A, which is administered at least once daily.

[0288] In embodiment BBB, there is provided the pharmaceutical formulation of embodiment A, which is administered four times daily.

[0289] In embodiment CCC, there is provided the pharmaceutical formulation of embodiment A, which is administered three times daily.

[0290] In embodiment DDD, there is provided the pharmaceutical formulation of embodiment A, which is administered twice daily.

[0291] Provided herein is Embodiment EEE, which comprises a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified-release formulation is a pharmaceutical formulation that releases from about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0292] In embodiment FFF, there is provided the pharmaceutical formulation of embodiment EEE, further comprising one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5-α reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an agent for treating alopecia areata, a supplement, and combinations thereof.

[0293] In Embodiment GGG, there is provided the pharmaceutical formulation of Embodiment EEE, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0294] Provided herein is Embodiment HHH, which is a pharmaceutical formulation comprising a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified-release formulation has a Tmax of about 30 minutes to about 360 minutes.

[0295] In embodiment III, there is provided the pharmaceutical formulation of embodiment HHH, comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

[0296] In Embodiment JJJ, there is provided the pharmaceutical formulation of Embodiment HHH, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0297] Provided herein is embodiment KKK, a pharmaceutical formulation comprising a modified-release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified-release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0298] In embodiment LLL, there is provided embodiment KKK, a pharmaceutical formulation further comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

[0299] In embodiment MMM, there is provided the pharmaceutical formulation of embodiment KKK, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0300] Provided herein is embodiment NNN, a method of treating or preventing hair loss, comprising daily administering to a subject in need thereof a composition comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof.

[0301] In Embodiment OOO, there is provided the method of Embodiment NNN, wherein the composition further comprises a release modifier, a filler, a glidant, a lubricant, and combinations thereof.

[0302] In embodiment PPP, the method of embodiment NNN or OOO is provided, wherein the composition comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0303] In embodiment QQQ, the method of embodiment NNN or OOO is provided, wherein the composition comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

[0304] In embodiment RRR, the method of embodiment NNN or OOO is provided, wherein the composition comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release-modifying agent, about 0.1% to about 0.3% lubricant, and / or about 0.4% to about 0.6% lubricant.

[0305] In embodiment SSS, the method of embodiment NNN or OOO is provided, wherein the composition comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release modifier, about 0.1% to about 0.3% lubricant, and / or about 0.4% to about 0.6% lubricant.

[0306] In embodiment TTT, there is provided the method of embodiment OOO, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

[0307] In embodiment UUU, the method of embodiment OOO is provided, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0308] In embodiment VVV, the method of embodiment OOO is provided, wherein the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, and silica aerogel.

[0309] In embodiment WWW, there is provided the method of embodiment OOO, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene, monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

[0310] In embodiment XXX, the method of embodiment NNN is provided, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 17α-spirolactone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5α-reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an alopecia areata medication, a supplement, and combinations thereof.

[0311] In Embodiment YYY, there is provided the method of Embodiment NNN, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0312] In Embodiment ZZZ, there is provided the method of Embodiment XXX, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

[0313] In embodiment AAAA, the method of embodiment XXX is provided, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

[0314] In embodiment BBBB, there is provided the method of embodiment XXX, wherein the 19-norprogesterone derivative is nomegestrol acetate.

[0315] In embodiment CCCC, there is provided the method of embodiment XXX, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

[0316] In embodiment DDDD, the method of embodiment XXX is provided, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

[0317] In embodiment EEEE, there is provided the method of embodiment XXX, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, izonsteride, epigallocatechin, fluridil, and combinations thereof.

[0318] In embodiment FFFF, the method of embodiment XXX is provided, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

[0319] In embodiment GGGG, there is provided the method of embodiment XXX, wherein the GnRH analog is a GnRH agonist.

[0320] In Embodiment HHHH, there is provided the method of Embodiment GGGG, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

[0321] In embodiment III, there is provided the method of embodiment XXX, wherein the GnRH analog is a GnRH antagonist.

[0322] In Embodiment JJJJ, there is provided the method of Embodiment IIII, wherein the GnRH antagonist is cetrorelix.

[0323] In Embodiment KKKK, there is provided the method of Embodiment XXX, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

[0324] In embodiment LLLL, the method of embodiment XXX is provided, wherein the prostamide is bimatoprost.

[0325] In embodiment MMMM, there is provided the method of embodiment XXX, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.

[0326] In Embodiment NNNN, there is provided the method of Embodiment XXX, wherein the prostaglandin D2 receptor antagonist is laropiprant, AM211, and combinations thereof.

[0327] In embodiment OOOO, the method of embodiment XXX is provided, wherein the prostaglandin E2 analog is sulprostone.

[0328] In Embodiment PPPP, there is provided the method of Embodiment XXX, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

[0329] In embodiment QQQQ, there is provided the method of embodiment XXX, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, litorcitinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jacucinib, and combinations thereof.

[0330] In Embodiment RRRR, there is provided the method of Embodiment XXX, wherein the alopecia areata drug is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

[0331] In embodiment SSSS, the method of embodiment XXX is provided, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0332] In embodiment TTTT, there is provided the method of embodiment NNN, wherein the composition is administered orally.

[0333] In Embodiment UUUU, there is provided the method of Embodiment TTTT, wherein the modified release formulation is a sustained, extended, controlled, or delayed release formulation.

[0334] In embodiment VVVV, there is provided the method of embodiment TTTT, wherein the subject in need thereof is diagnosed with hair loss.

[0335] In embodiment WWWW, a method of embodiment VVVV is provided, wherein the subject is diagnosed with at least one cardiac disease selected from cardiac disease, chronic congestive heart failure, cardiomyopathy, tachyarrhythmia, renal disease, pre-existing pulmonary hypertension, and chronic congestive heart failure not secondary to hypertension.

[0336] In embodiment XXXX, the method of embodiment VVVV is provided, wherein the hair loss is selected from male pattern hair loss, female pattern hair loss, hereditary hair loss, telangiectasia, alopecia areata, central centrifugal cicada alopecia, lichen planus pilaris, or traction alopecia.

[0337] In embodiment YYYY, the method of embodiment WWWW is provided, wherein the subject is taking at least one of an antihypertensive agent, an ACE inhibitor, an angiotensin receptor blocker, a direct renin inhibitor, a loop diuretic, a thiazide diuretic, a calcium channel blocker, a beta-blocker, an antiarrhythmic agent, and a diuretic for the treatment of at least one cardiac condition.

[0338] In Embodiment ZZZZ, there is provided the method of Embodiment TTTT, wherein the administration results in hair regrowth.

[0339] In Embodiment AAAAA, there is provided the method of Embodiment TTTT, wherein the administration results in hair regrowth within about 6 months.

[0340] In embodiment BBBBB, there is provided the method of embodiment TTTT, wherein administration results in increased improvement in hair growth as compared to administration of an immediate release dosage form of minoxidil or a pharmaceutically acceptable salt thereof.

[0341] In Embodiment CCCCC, there is provided the method of Embodiment NNN, wherein about 25% of the composition dissolves in a neutral pH solution in less than about 2 hours or less than about 4 hours.

[0342] In Embodiment DDDDD, there is provided the method of Embodiment NNN, wherein about 25% of the composition dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

[0343] In Embodiment EEEEE, there is provided the method of Embodiment NNN, wherein about 50% of the composition dissolves in the neutral pH solution in less than about 2 hours, less than about 6 hours, or less than about 12 hours.

[0344] In embodiment FFFFF, there is provided the method of embodiment NNN, wherein about 50% of the composition dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

[0345] In Embodiment GGGGG, there is provided the method of Embodiment NNN, wherein about 75% of the composition dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours.

[0346] In embodiment HHHHH, there is provided the method of embodiment NNN, wherein about 75% of the composition dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

[0347] In embodiment IIIII, there is provided the method of embodiment NNN, wherein about 100% of the composition dissolves at neutral pH in less than about 12 hours, less than about 24 hours, or less than about 48 hours.

[0348] In embodiment JJJJJ, there is provided the method of embodiment NNN, wherein about 100% of the composition dissolves at neutral pH in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours.

[0349] In Embodiment KKKKK, there is provided the method of Embodiment NNN, wherein the composition exhibits zero order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero order release of minoxidil or a pharmaceutically acceptable salt thereof, first order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first order release of minoxidil or a pharmaceutically acceptable salt thereof, or second order release of minoxidil or a pharmaceutically acceptable salt thereof.

[0350] In Embodiment LLLLL, there is provided the pharmaceutical formulation of Embodiment NNN, which comprises an enteric coating.

[0351] In embodiment MMMMM, there is provided the method of embodiment TTTT, wherein the composition is administered only once a day.

[0352] In Embodiment NNNNN, there is provided the method of Embodiment TTTT, wherein the composition is administered at least once daily.

[0353] In Embodiment OOOOO, there is provided the method of Embodiment TTTT, wherein the composition is administered four times daily.

[0354] In embodiment PPPP, there is provided the method of embodiment TTTT, wherein the composition is administered three times daily.

[0355] In embodiment QQQQQ, there is provided the method of embodiment TTT, wherein the composition is administered twice daily.

[0356] In Embodiment RRRRR, there is provided the method of Embodiment TTTT, wherein the composition is administered daily for at least about 3 months with substantially no side effects and substantially no cardiac effects.

[0357] In Embodiment SSSSS, there is provided the method of Embodiment TTTT, wherein the composition is administered daily for at least about 4 months with substantially no side effects and substantially no cardiac effects.

[0358] In Embodiment TTTTT, there is provided a method of Embodiment TTTT, wherein the composition is administered daily for at least about six months with substantially no side effects and substantially no cardiac effects.

[0359] In Embodiment UUUUU, there is provided the method of Embodiment TTTT, wherein the composition is administered daily for at least about one year with substantially no side effects and substantially no cardiac effects.

[0360] In embodiment VVVVV, there is provided the method of embodiment TTTT, wherein the composition is administered daily indefinitely with substantially no side effects and substantially no cardiac effects.

[0361] In embodiment WWWWW, there is provided a method of embodiment 98, wherein the administration results in hair regrowth substantially without clinically significant hemodynamic changes in blood pressure.

[0362] In embodiment XXXXX, there is provided the method of embodiment TTTT, wherein the administration results in substantially no cardiac effects.

[0363] In Embodiment YYYYY, there is provided the method of Embodiment XXXXX, wherein the cardiac effect is selected from tachycardia, hypotension, premature ventricular contractions, and other tachyarrhythmias.

[0364] In Embodiment ZZZZZ, there is provided the method of Embodiment TTTT, wherein said administering results in hair regrowth in the absence of substantial cardiac effects.

[0365] In Embodiment AAAAAA, there is provided the method of Embodiment TTTT, wherein the daily dosage of minoxidil, or a pharmaceutically acceptable salt thereof, has reduced cardiac or hemodynamic effects as compared to administration of the same daily dosage of immediate-release oral minoxidil, or a pharmaceutically acceptable salt thereof, used to treat hypertension.

[0366] In Embodiment BBBBBB, there is provided the method of Embodiment AAAAAA, wherein the cardiac effect is selected from tachycardia, hypotension, premature ventricular contractions, and other tachyarrhythmias.

[0367] In Embodiment CCCCCC, there is provided the method of Embodiment AAAAAA, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof produces substantially no cardiac or hemodynamic effects compared to administration of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0368] In Embodiment DDDDDD, there is provided the method of Embodiment AAAAAA, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 25% to about 500% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0369] In Embodiment EEEEEE, there is provided the method of Embodiment AAAAAA, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 10% to about 90% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

[0370] In Embodiment FFFFFF, there is provided the method of Embodiment TTT, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 50 mg.

[0371] In Embodiment GGGGGG, there is provided the method of Embodiment TTT, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is selected from an amount of about 0.625 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0372] In Embodiment HHHHHH, there is provided the method of Embodiment TTT, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 20 mg per day.

[0373] In Embodiment IIIIII, there is provided the method of Embodiment TTT, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is about 2.5 mg per day.

[0374] In Embodiment JJJJ, there is provided the method of Embodiment TTT, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.00625 mg / kg / day to about 0.5 mg / kg / day.

[0375] In Embodiment KKKKKK, there is provided the method of Embodiment TTT, wherein the modified release formulation releases from about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

[0376] In Embodiment LLLLLL, there is provided the method of Embodiment TTTT, wherein the subject has a plasma concentration versus time curve of minoxidil, or a pharmaceutically acceptable salt thereof, with a Tmax of about 30 to about 360 minutes.

[0377] In Embodiment MMMMMM, there is provided the method of Embodiment TTT, wherein the subject has a plasma concentration versus time curve of minoxidil or a pharmaceutically acceptable salt thereof with a Cmax of about 2.5 ng / ml to about 20 ng / ml.

[0378] In Embodiment NNNNNN, there is provided the method of Embodiment TTT, wherein the half-life or effective half-life of minoxidil or a pharmaceutically acceptable salt thereof in said subject is from about 1 hour to about 24 hours.

[0379] In Embodiment OOOOOO, there is provided the method of Embodiment TTT, wherein minoxidil or a pharmaceutically acceptable salt thereof is present in an amount of about 0.625 mg four times a day.

[0380] In Embodiment PPPPP, there is provided the method of Embodiment TTT, wherein the minoxidil or a pharmaceutically acceptable salt thereof is present in an orally dissolving tablet.

[0381] Provided herein is embodiment QQQQQQ, a method of treating or preventing hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation releases from about 50% to about 98% of the daily dose of minoxidil within about 12 hours after oral administration.

[0382] In Embodiment RRRRRR, there is provided the method of Embodiment QQQQQQ, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5α-reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an alopecia areata medication, a supplement, and combinations thereof.

[0383] In Embodiment SSSSSS, there is provided the method of Embodiment QQQQQQ, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0384] Provided herein is embodiment TTTTTT, a method of treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Tmax of about 30 to about 360 minutes.

[0385] In embodiment UUUUUU, there is provided the method of embodiment TTTTTT, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5α-reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

[0386] In embodiment VVVVVV, there is provided the method of embodiment TTTTTT, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0387] Provided herein is embodiment WWWWWW, a method of treating hair loss comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

[0388] In Embodiment XXXXXX, there is provided the method of Embodiment WWWWWW, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5α-reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

[0389] In Embodiment YYYYYY, there is provided the method of Embodiment WWWWWW, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

[0390] Provided herein is embodiment ZZZZZZ, a kit including a sustained release modified release vehicle containing oral minoxidil or a pharmaceutically acceptable salt thereof.

[0391] In Embodiment AAAAAAA, the kit of Embodiment ZZZZZZ is provided, wherein the sustained release modified vehicle further comprises a release modifying agent, a filler, a glidant, a lubricant, and combinations thereof.

[0392] In Embodiment BBBBBBB, there is provided the kit of Embodiment AAAAAAA, wherein the sustained release modified vehicle n comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

[0393] In embodiment CCCCCCC, there is provided the kit of embodiment AAAAAAA, wherein the sustained release modified release vehicle comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

[0394] In Embodiment DDDDDDD, there is provided the kit of Embodiment AAAAAAA, wherein the sustained release modified release vehicle comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

[0395] In Embodiment EEEEEEE, there is provided the kit of Embodiment AAAAAAA, wherein the sustained release modified release vehicle comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

[0396] In Embodiment FFFFFFF, the kit of Embodiment AAAAAAA is provided, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M; hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

[0397] In Embodiment GGGGGGG, there is provided the kit of Embodiment AAAAAAA, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0398] In Embodiment HHHHHHH, there is provided the kit of Embodiment AAAAAAA, wherein the lubricant is silica (colloidal anhydrous) starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, and silica aerogel.

[0399] In Embodiment IIIIII, there is provided the kit of Embodiment AAAAAAA, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

[0400] In Embodiment JJJJJJJ, there is provided the kit of Embodiment ZZZZZZZ, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5α-reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an alopecia areata treatment, a supplement, and combinations thereof.

[0401] In Embodiment KKKKKKK, there is provided the kit of Embodiment ZZZZZZZ, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, cetiprant, valproic acid, and combinations thereof.

[0402] In Embodiment LLLLLLL, there is provided the kit of Embodiment JJJJJJJ, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

[0403] In Embodiment MMMMMMM, there is provided the kit of Embodiment JJJJJJJ, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

[0404] In Embodiment NNNNNNN, there is provided the kit of Embodiment JJJJJJJ, wherein the 19-norprogesterone derivative is nomegestrol acetate.

[0405] In Embodiment OOOOOOO, there is provided the kit of Embodiment JJJJJJJ, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

[0406] In Embodiment PPPPPPP, there is provided the kit of Embodiment JJJJJJJ, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

[0407] In embodiment QQQQQQQ, there is provided the kit of embodiment JJJJJJJ, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, izonsteride, epigallocatechin, fluridil, and combinations thereof.

[0408] In Embodiment RRRRRRR, there is provided the kit of Embodiment JJJJJJJ, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

[0409] In Embodiment SSSSSSS, there is provided the kit of Embodiment JJJJJJJ, wherein the GnRH analog is a GnRH agonist.

[0410] In Embodiment TTTTTTT, there is provided the kit of Embodiment SSSSSSS, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

[0411] In Embodiment UUUUUUU, there is provided the kit of Embodiment JJJJJJJ, wherein the GnRH analog is a GnRH antagonist.

[0412] In Embodiment VVVVVVV, there is provided the kit of Embodiment UUUUUUU, wherein the GnRH antagonist is cetrorelix.

[0413] In embodiment WWWWWW, there is provided a kit of embodiment JJJJJJJ, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

[0414] In Embodiment XXXXXXX, the kit of Embodiment JJJJJJJ is provided, wherein the prostamide is bimatoprost.

[0415] In Embodiment YYYYYYY, there is provided the kit of Embodiment JJJJJJJ, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.

[0416] In Embodiment ZZZZZZZ, there is provided the kit of Embodiment JJJJJJJ, wherein the prostaglandin D2 receptor antagonist is laropirant, AM211, and combinations thereof.

[0417] In Embodiment AAAAAAAA, the kit of Embodiment JJJJJJJ is provided, wherein the prostaglandin E2 analog is sulprostone.

[0418] In Embodiment BBBBBBBB, provided is the kit of Embodiment JJJJJJJ, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

[0419] In Embodiment CCCCCCCC, there is provided a kit of Embodiment JJJJJJJJ, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itatinib, oclacitinib, pacritinib, peficitinib, ritretinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.

[0420] In Embodiment DDDDDDDD, the kit of Embodiment JJJJJJJ is provided, wherein the alopecia areata treatment agent is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

[0421] In embodiment EEEEEEEE, the kit of embodiment JJJJJJJ is provided, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

[0422] In embodiment FFFFFFFF, there is provided a kit of embodiment ZZZZZZZ that includes an information sheet.

[0423] In embodiment GGGGGGGG, the kit of embodiment FFFFFFFF is provided, wherein the information sheet includes instructions for selecting an oral dosage form based on the patient's weight.

[0424] In embodiment HHHHHHHH, there is provided a kit of embodiment FFFFFFFF, wherein the information sheet includes warnings about adverse effects.

[0425] In Embodiment IIIIIIII, there is provided the kit of Embodiment HHHHHHHH, wherein the adverse effect is selected from peripheral edema and hirsutism.

[0426] Example The following are provided for illustrative purposes only and are not intended to limit the scope of the embodiments broadly described above.

[0427] Example 1 Case Study - Male, 28 years old, Male Pattern Baldness A 28-year-old man with androgenetic alopecia received 1.25 mg of minoxidil four times daily. At baseline, the patient's blood pressure was 118 / 82. His resting heart rate was 64. After one week of minoxidil or its pharmaceutically acceptable salts, the patient's blood pressure and heart rate were measured again 30 minutes after each dose. No changes of 10% or more from baseline were observed in heart rate, systolic blood pressure, or diastolic blood pressure. The patient reported subjective improvement in hair thickness and density on the forehead and vertex, and improvement in his androgenetic alopecia. No unwanted hair growth or other adverse events, including cardiac effects, were observed.

[0428] Example 2: Case Study - Male, 51 years old, with male pattern baldness and hypertension A 51-year-old man with androgenetic alopecia (androgenetic alopecia) received oral minoxidil 2.5 mg tablets twice daily and observed a decrease in blood pressure after administration. The patient administered minoxidil orally between 6:00 AM and 9:00 PM each morning and between 6:00 PM and 9:00 PM each evening. His blood pressure was remeasured 30 minutes after each minoxidil dose for one week. The patient observed a decrease in systolic blood pressure of approximately 10 mmHg, which continued to decrease. Even after reducing the daily dose to 2.5 mg, the patient continued to observe a decrease in blood pressure of approximately 10 mmHg within 30 minutes after administration. The patient was instructed to take 0.625 mg of minoxidil or its pharmaceutically acceptable salt four times daily, but surprisingly, no significant decrease in blood pressure was observed. The patient also reported subjective improvement in hair thickness and density on the frontal and vertex areas, as well as improvement in his androgenetic alopecia. No unwanted hair growth or other adverse events were observed. The patient reported that minoxidil 0.625 mg four times daily did not significantly reduce blood pressure and improved hair growth, despite the same total daily dose as 2.5 mg.

[0429] Example 3: Case Study - Male, 81 years old, with male pattern baldness and atrial fibrillation An 81-year-old man with androgenetic alopecia presented for treatment of hair loss. He specifically requested a prescription for immediate-release minoxidil. The patient disclosed a history of chronic atrial fibrillation requiring amiodarone therapy. After consultation with the patient's other physicians, it was decided not to administer minoxidil therapy due to the risk of worsening the atrial fibrillation.

[0430] Example 4: Case Study - 70 year old male with male pattern baldness and premature ventricular contractions A 70-year-old man with androgenetic alopecia presented for treatment of his hair loss. He specifically requested a prescription for an immediate-release formulation of minoxidil. The patient disclosed a history of chronic premature ventricular contractions requiring flecainide therapy. After consultation with the patient's other physicians, it was decided not to administer minoxidil therapy due to the risk of worsening the premature ventricular contractions.

[0431] Example 5: Study to evaluate the pharmacokinetics of modified-release minoxidil tablets A Phase 1, single-part, non-randomized, open-label, six-period sequential crossover study designed to evaluate the pharmacokinetic (PK) profile of a single-dose modified-release formulation of minoxidil or its pharmaceutically acceptable salts compared with an immediate-release formulation of minoxidil or its pharmaceutically acceptable salts as a reference in healthy subjects.

[0432] Primary Objective: To evaluate the PK profile and determine the relative bioavailability of modified-release formulations of minoxidil or its pharmaceutically acceptable salts following single oral administration of a modified-release (MR) prototype tablet and a reference immediate-release (IR) formulation to healthy fasting subjects. Primary Endpoint: Measurement of PK parameters (including but not limited to Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), and T1 / 2) for minoxidil or its pharmaceutically acceptable salts, and, where possible and appropriate, measurement of Frels (MR vs. IR) based on the PK parameters Cmax, AUC(0-last), and AUC(0-inf).

[0433] Secondary objective: To provide additional information regarding the safety and tolerability of single oral doses of the MR prototype tablet formulation and the reference IR formulation of minoxidil or its pharmaceutically acceptable salts in healthy subjects. Secondary endpoints: Incidence, severity and causality of adverse events (AEs), changes from baseline in vital signs, electrocardiogram (ECG), physical examination and laboratory safety.

[0434] Exploratory Objective: To determine the PK profile and relative bioavailability of minoxidil or its pharmaceutically acceptable salts after single oral administration of selected MR prototype tablets in the fed and fasted state. Exploratory Endpoints: Measurement of PK parameters (including but not limited to Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), and T1 / 2) for minoxidil or its pharmaceutically acceptable salts, and, where possible and appropriate, measurement of Frels (fed vs. fasted) based on the PK parameters Cmax, AUC(0-last), and AUC(0-inf).

[0435] Methods: This is a single-center, open-label, non-randomized, six-period sequential crossover study in healthy men and women aged 18 to 55 years to evaluate the PK and safety of the MR prototype tablet formulation of minoxidil or its pharmaceutically acceptable salt, and the reference IR tablet formulation, at a dose range to be determined throughout the study. Optionally, the effect of food on the PK of the selected MR prototype tablet formulation of minoxidil or its pharmaceutically acceptable salt, in Regimen F, may be evaluated by administering it after a high-fat breakfast, as described in the Regimen Tablets.

[0436] Sixteen subjects will be enrolled and will receive a single oral dose of the investigational drug (IMP). Each subject will receive the following dosing schedule:

[0437] [Table 1] Modified-release tablet prototypes 1 through 5 of minoxidil or its pharmaceutically acceptable salts are selected from a two-dimensional design space that accounts for dose strength and release rate (dose strength 2 mg to 10 mg, release rate 6 hours to 18 hours). The test drugs are free base equivalents. The dosing sequence may be altered for logistical reasons. a. In all dosing regimens, multiple tablets may be administered to achieve the required dose. b. The dose and formulation for Regimen F will be determined at an interim decision meeting using all available data. The selected dose is expected to not exceed a geometric mean Cmax of 20 ng / mL or 30 mg, based on impurity limits. If the selected formulation does not provide the required data, a previously tested formulation may be used in subsequent study periods; however, if that dose meets the dose determination criteria or study discontinuation criteria, it should not be repeated. c. If the fed option is selected, the dose will be the same as the fasted dose listed for that prototype.

[0438] Study Design: Each period will follow the same study design. Subjects will undergo preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). For all dosing regimens, subjects will be admitted to the clinical unit on the evening of Day -1 and will remain on-site until 48 hours post-dose (Day 3). In each period, subjects will receive study drug on the morning of Day 1 after a 10-hour fast or 30 ± 5 minutes after the start of a high-fat breakfast (and after an 8-hour fast, optional for Regimen F). Blood samples will be collected at regular intervals from Day 1 until discharge from the clinical unit 48 hours post-dose for PK and safety analyses. A follow-up telephone call will be conducted 3 to 7 days after the last dose to confirm the subject's health. If a subject reports a concerning adverse event, a visit to the clinical unit for a follow-up evaluation will be required. This will be an unscheduled visit.

[0439] After administration of Regimen B, C, D, and E, an interim analysis will be conducted to review PK and safety data from prior periods to determine the dose and prototype composition, and, if applicable, the food condition, to be used in the next regimen. There will be a minimum of a 7-day washout period between each dose of study drug, but sufficient time will be allowed between periods to allow for the decision process and product manufacturing.

[0440] Expected Subject Size: This study is an exploratory study, and no formal sample size calculation was performed. Based on experience with previous studies of similar design, we have determined that a sample size of 16 subjects to obtain 12 evaluable subjects will be sufficient to achieve the objectives of this study. For the primary endpoint of relative bioavailability of MR and IR, evaluable subjects will be defined as subjects who receive at least one dose of the prototype MR tablet and the IR reference tablet under fasted conditions and have PK data available through 48 hours post-dose for both doses. For the primary PK endpoint, evaluable subjects will be defined as subjects who receive at least one dose of the study drug and have PK data available through 48 hours post-dose. For the secondary safety endpoint, evaluable subjects will be defined as subjects who receive at least one dose of the study drug and have safety data available through 48 hours post-dose. For the optional exploratory endpoint of relative bioavailability with regard to food effect, subjects will be defined as subjects who receive the same dose of the same MR tablet drug substance under both fed and fasted conditions and have PK data available through 48 hours post-dose for both doses.

[0441] Subjects who drop out due to adverse events related to the investigational drug will not be replaced. Subjects who drop out for other reasons may be replaced, as necessary, by agreement between the investigator and the applicant, to ensure a sufficient number of evaluable subjects.

[0442] Study duration: Subjects will receive six single doses. The estimated duration from screening to final follow-up call is approximately 14 weeks.

[0443] Study Drug, Dosage, and Administration: The following study drugs will be used in this clinical trial (Table 2). Oral doses will be administered with a total of 240 mL of water. If necessary, additional 50 mL portions of water may be administered with the study drug.

[0444] [Table 2] Modified-release tablet prototypes 1 through 5 of minoxidil or a pharmaceutically acceptable salt thereof were selected from a two-dimensional design space that accounted for dosage strength and release rate (dosage strength 2 mg to 10 mg, release rate 6 hours to 18 hours). IMP is the free base equivalent. a Multiple tablet units may be administered to achieve the total required dose.

[0445] Study Evaluations: The following blood and urine samples will be collected at specified time points and evaluated: 1) Minoxidil or its pharmaceutically acceptable salts in plasma for PK analysis purposes; 2) Safety assessments, including adverse event monitoring, laboratory tests (clinical chemistry, hematology, urinalysis), physical examination, weight measurement, single 12-lead electrocardiogram, and vital signs.

[0446] Statistical Analysis: PK parameters of minoxidil or its pharmaceutically acceptable salts will be calculated using standard noncompartmental analysis, including at least Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), and T1 / 2, where possible and appropriate. A narrative summary of all safety and PK data by dosing regimen (including change from baseline, if appropriate) will be provided. Additionally, formal statistical analysis of the PK parameters Cmax, AUC(0-last), and AUC(0-inf) will be performed to assess the relative bioavailability of the test and reference formulations, and, where appropriate, the effect of food on selected prototypes. PK parameters will be natural log-transformed and analyzed using a mixed-effects model with dosing regimen as a fixed effect and subject as a random effect. Formal statistical analysis of the log-transformed PK parameters Cmax, AUC(0-last), and AUC(0-inf) may also be performed to assess dose proportionality. This will be assessed using a mixed-effects model with log-dose as a fixed effect and subject as a random effect.

[0447] 5.2 Investigational Medications: The investigational medications used in this clinical trial are listed in Table 2. Only subjects enrolled in the study will receive study treatment, and study medications may only be provided or administered by authorized site staff. All study medications will be stored in a secure, environmentally controlled, and monitored (manual or automated) location with access only to the investigator and authorized site staff, in accordance with the storage conditions stated on the label.

[0448] 5.3 Previous Research Findings: Because the safety and efficacy profile of minoxidil or its pharmaceutically acceptable salts is well established, no nonclinical or clinical trials have been conducted in humans to date for MR oral formulations of minoxidil or its pharmaceutically acceptable salts. However, other marketed products containing minoxidil or its pharmaceutically acceptable salts have been studied, and such relevant information is provided below. Nevertheless, factors such as the drug's formulation, route of administration, in vivo release profile, dosage, and concentration can substantially alter the drug's safety and efficacy profile, whether favorable or unfavorable. Therefore, the information provided herein about other products containing minoxidil or its pharmaceutically acceptable salts is provided only as supporting background information. The relevance of these findings to MR oral formulations of minoxidil or its pharmaceutically acceptable salts remains to be determined.

[0449] 5.3.1 Nonclinical Study Results: The applicant has not conducted nonclinical studies on the MR oral formulation of minoxidil or its pharmaceutically acceptable salts. Nonclinical information on the active ingredient is available in the Summary of Product Characteristics for the previously approved oral formulation, Loniten®, containing minoxidil or its pharmaceutically acceptable salts.

[0450] Non-clinical toxicity: The oral lethal dose (LD50) in rats is 1321 mg / kg to 3492 mg / kg, and in mice is 2456 mg / kg to 2648 mg / kg. Side effects include rapid weight gain, accelerated heart rate, fainting, dizziness, and other cardiovascular effects associated with hypotension.

[0451] In dogs, a variety of cardiac lesions have been observed after short-term administration of minoxidil or its pharmaceutically acceptable salts (0.5 mg to 10 mg / kg / day), including macroscopic hemorrhagic lesions in the right atrium, necrosis of the papillary muscles and subendocardial regions of the left ventricle, hemorrhagic lesions in the epicardium, endocardium, and left atrium, in the walls of small coronary arteries and arterioles, and in the left atrium. Furthermore, long-term animal studies have demonstrated cardiac hypertrophy, dilatation, and serous pericardial effusion.

[0452] Nonclinical Carcinogenicity: Minoxidil or its pharmaceutically acceptable salts have been studied in mice and rats for two years in dermal and oral carcinogenicity studies. No positive findings were observed in rats administered orally. Oral administration of minoxidil or its pharmaceutically acceptable salts to mice for two years resulted in an increased incidence of malignant lymphomas in females at all doses (10, 25, and 63 mg / kg / day) and an increased incidence of liver nodules in males (at 63 mg / kg / day). Dietary minoxidil or its pharmaceutically acceptable salts did not affect the incidence of malignant liver tumors. The neoplastic changes observed to increase in incidence in oral carcinogenicity studies were typical of those expected in rodents treated with other antihypertensive agents (adrenal pheochromocytoma in rats) or represented normal variation within the historical range of rodent neoplastic incidence (malignant lymphoma, liver nodule / adenoma in mice).

[0453] Minoxidil or its pharmaceutically acceptable salts were not found to be mutagenic in the Salmonella (Ames) test, the deoxyribonucleic acid (DNA) damage alkaline elution test, the in vitro rat hepatocyte unscheduled DNA synthesis test, the rat bone marrow micronucleus test, or the mouse bone marrow micronucleus test. An in vitro cytogenetic test using Chinese hamster cells gave equivocal results after prolonged exposure, but a similar test using human lymphocytes was negative.

[0454] Minoxidil or its pharmaceutically acceptable salts were administered to rats at 15 times the normal human dose for 22 months with no evidence of carcinogenicity.

[0455] Reproductive Toxicity: Orally administered minoxidil or its pharmaceutically acceptable salts was associated with increased fetal resorptions when administered to rabbits at five times the maximum recommended oral antihypertensive dose. This effect was not observed in rats. No evidence of teratogenic effects was observed in rats or rabbits.

[0456] 5.3.2 Clinical Findings: No human PK studies have been conducted to date for MR oral formulations of minoxidil or its pharmaceutically acceptable salts. However, studies have been conducted for other products containing minoxidil or its pharmaceutically acceptable salts. The relevance of these study results to MR oral formulations of minoxidil or its pharmaceutically acceptable salts is unclear, but they represent the only supporting information currently available. The PK of other oral formulations of minoxidil or its pharmaceutically acceptable salts has been evaluated in humans. The clinical trials database, clinicaltrials.gov, currently lists 71 clinical trials involving minoxidil or its pharmaceutically acceptable salts (as of February 2023). Of these, 39 are completed, with results from 10 trials detailed in the IB. Seven of these studies investigated topical administration of minoxidil or its pharmaceutically acceptable salts for alopecia. The majority of these trials (5 / 7) used minoxidil or its pharmaceutically acceptable salts as the active comparator. One study compared a 5% topical foam of minoxidil or its pharmaceutically acceptable salts to a 2% topical solution of minoxidil or its pharmaceutically acceptable salts for female pattern hair loss. A total of 322 subjects were enrolled in this study. Ten serious adverse events (SAEs) were reported, none of which were reported more than once (NCT01145625). Another study compared a 5% topical foam of minoxidil or its pharmaceutically acceptable salts to a topical vehicle foam. A total of 404 subjects were enrolled in this study. Six serious adverse events were reported in subjects receiving minoxidil or its pharmaceutically acceptable salts, including cardiovascular disease, gastritis, dehydration, osteoarthritis, ovarian neoplasms, uterine fibroids, renal failure, and hypertensive crisis (NCT01226459). Nine studies were listed as "recruiting."

[0457] Clinical Pharmacokinetics and Product Metabolism: Minoxidil or its pharmaceutically acceptable salts are almost completely absorbed (>90%) from the gastrointestinal tract. Peak plasma concentrations are reached within 1 hour. Minoxidil or its pharmaceutically acceptable salts are widely distributed to tissues with an apparent volume of distribution of 2.8 L / kg to 3.3 L / kg. The half-life of minoxidil or its pharmaceutically acceptable salts is 2.77 to 4.2 hours. Approximately 90% of orally administered minoxidil or its pharmaceutically acceptable salts is metabolized, primarily by conjugation with glucuronic acid. The drug and its metabolites are largely excreted in the urine. Renal clearance is 73.3 mL / min. The absorption and excretion of orally administered minoxidil or its pharmaceutically acceptable salts have been studied in 29 healthy volunteers and 7 hypertensive patients.

[0458] In a study of healthy volunteers, subjects were administered 2.5 mg, 5 mg, or 10 mg of minoxidil or its pharmaceutically acceptable salts orally. PK and urinary excretion data supported dose-independent PK across the dose range studied. Repeated-measures analysis of variance (ANOVA) revealed significant treatment and time effects for both systolic and diastolic blood pressure (p = 0.0779 and p = 0.0203, respectively). ANOVA analysis of systolic and diastolic blood pressure results at each sampling time point revealed no significant treatment effects. Significant time effects within treatment were observed, but the differences were generally less than 10%. These observations indicate that minoxidil or its pharmaceutically acceptable salts have little effect on blood pressure in normotensive subjects. This study generated the PK data shown in Table 3.

[0459] [Table 3]

[0460] In hypertensive patients, the total clearance of minoxidil or its pharmaceutically acceptable salts significantly exceeded renal clearance, suggesting that metabolism plays a dominant role in its excretion. The glucuronide conjugate of minoxidil or its pharmaceutically acceptable salts was the predominant metabolite in urine during the first 12 hours. More than 80% of radiolabeled minoxidil or its pharmaceutically acceptable salts and its metabolites were recovered in urine within 24 hours after oral administration. The remainder accumulated in urine over the next 4 hours. In total, 97% of the radioactivity was recovered in urine, with only 3% detected in feces.

[0461] Clinical Safety: A study evaluated the clinical, laboratory, and cardiovascular effects of oral administration of 5 mg of minoxidil or its pharmaceutically acceptable salts before bedtime in adult males with androgenetic alopecia (AGA). Thirty-four subjects without cardiovascular disease were evaluated before and 24 weeks after treatment using biochemical profiles, 24-hour Holter electrocardiograms, and 24-hour ambulatory blood pressure monitoring. At 24 weeks of follow-up, 20.6% of subjects reported headache, 2.9% reported dizziness, and 2.9% reported edema. No cardiovascular adverse events were observed. 19 subjects (55.9%) reported hirsutism. No significant differences were observed in laboratory values ​​before and after treatment. One subject developed tachycardia during follow-up, but there was no overall change in mean heart rate. Mean heart rate values ​​after 24 weeks were highly correlated with pretreatment values. The incidence of premature beats did not differ between before and after treatment. There was no significant change in ventricular repolarization. Overall, oral administration of low-dose minoxidil or its pharmaceutically acceptable salts for 24 weeks was safe in men with androgenetic alopecia, with no relevant changes observed in biochemical profiles, 24-hour Holter electrocardiograms, or ambulatory blood pressure monitoring.

[0462] 6. Rationale: The applicant aims to develop a once-daily modified-release oral solid dosage form of minoxidil or its pharmaceutically acceptable salts at a dose that stimulates hair growth and limits the potential for undesirable hemodynamic and cardiac effects. The study will employ a crossover design to compare formulations administered to the same subjects. Because this is a six-period crossover study in which subjects will receive the study drug in a sequential order, the study will be open-label and will not require randomization.

[0463] The clinical trial application for this study describes a flexible protocol design using the concept of formulation design space, which allows for flexible dose ranges and release rates to be considered and decisions to be made depending on the results of interim PK observations. The principles of the flexible protocol were discussed and agreed upon at a scientific advisory meeting between the Medicines and Healthcare products Regulatory Agency (MHRA) and the study site.

[0464] Based on the concept of formulation design space, a specific investigational product is not detailed in the investigational new drug dossier (IMPD), but rather a defined range of formulation inputs and corresponding performance outputs are described and justified based on in vitro studies. For the first prototype to be administered, the formulation selected from the approved design space is described in the decision document and approved by the applicant and the investigator prior to administration.

[0465] Prototypes 1 through 5 of modified-release tablets of minoxidil or a pharmaceutically acceptable salt thereof will be selected from a two-dimensional design space that accounts for dosage strength and release rate.

[0466] 6.2 Dosage Rationale: The dose selected for the immediate-release formulation is 2.5 mg, which has been shown to be well tolerated in healthy adults. This is the lowest commercially available single dose and is less than the recommended starting dose of 5 mg daily for the treatment of severe hypertension.

[0467] The proposed starting dose for the modified-release formulation is set at 2.5 mg to ensure adequate safety even if the new modified-release dosage is rapidly released and behaves similarly to an immediate-release formulation. The maximum dose administered in this study is limited by the upper exposure limit for maximum plasma concentration (Cmax), which is considered the most relevant pharmacokinetic parameter contributing to potential cardiovascular adverse events. The selected Cmax exposure limit of 20 ng / mL is based on a series of previous studies investigating the PK and safety of minoxidil or its pharmaceutically acceptable salts. In a study investigating the hemodynamic effects of steady-state intravenous infusion of minoxidil or its pharmaceutically acceptable salts in hypertensive patients, the effects on systolic blood pressure, diastolic blood pressure, and heart rate were evaluated for steady-state concentrations of 4.5 ng / mL to 83.0 ng / mL. In patients, no significant effect on systolic blood pressure was observed, but effects on diastolic blood pressure and heart rate were observed. Steady-state plasma concentrations greater than 20 ng / mL were associated with significant changes in heart rate (≥5 beats per minute). In another study, healthy subjects were administered 2.5 mg, 5 mg, and 10 mg tablets of minoxidil or its pharmaceutically acceptable salts and the oral pharmacokinetic profile was investigated. The estimated Cmax values ​​for each dose were 16.8 ng / mL, 37.2 ng / mL, and 74.7 ng / mL, respectively. This suggests that only the highest two doses exerted significant hemodynamic effects (defined as an increase in heart rate of more than 5 bpm). Furthermore, the observed half-life for these immediate-release doses was approximately 1 hour, indicating that plasma concentrations remained above the 20 ng / mL threshold for a short period of time. At the 5 mg dose, plasma concentrations remained above 20 ng / mL for approximately 1 hour, and at the 10 mg dose, plasma concentrations remained above 20 ng / mL for approximately 2 hours. Therefore, the starting doses are expected to be well tolerated.

[0468] The target pharmacokinetic profile for modified-release formulations is to maintain plasma concentrations throughout the planned dosing interval while maintaining Cmax below the upper exposure limit. Therefore, although AUC will be monitored throughout the study, it is not necessary to limit AUC because the long-term safety of minoxidil or its pharmaceutically acceptable salts is well established and Cmax appears to be important when considering acute cardiovascular adverse events.

[0469] A modified-release formulation greater than 2.5 mg is expected to be required to achieve the target PK profile. After Period 2, an interim analysis of the data will be conducted, and subsequent doses will be selected based on the PK and safety of the first modified-release (MR) formulation tested. The release rate of the formulation may be adjusted if the drug is released too quickly or too slowly in the gastrointestinal tract. Additionally, if the release rate is acceptable but the overall Cmax, AUC, and C24 are too high or too low, the dose may be adjusted. The maximum dose that can be administered in this study will be 30 mg, based on impurity limits in the modified-release prototype formulation.

[0470] For comparison, the recommended starting dose of Loniten® for patients with severe hypertension is 5 mg per day. If necessary, this dose can be increased to 20 mg and then 40 mg per day (administered as a single dose or in two divided doses) to achieve the required reduction in blood pressure. It is recommended that dose increases be made in increments of 5 mg to 10 mg of minoxidil or a pharmaceutically acceptable salt thereof per day, spaced 3 days or more apart. Once the dose of minoxidil or a pharmaceutically acceptable salt thereof reaches 50 mg, the dose can be increased by 25 mg per day, up to a maximum of 100 mg per day. This exceeds the maximum dose of 30 mg per day permitted in this study.

[0471] 6.3 Rationale for Target Population: Because this is a Phase I study evaluating the PK, relative bioavailability, and safety of an MR oral formulation of minoxidil or its pharmaceutically acceptable salts, the most relevant target population is healthy volunteers, in accordance with recommendations from the US FDA and the European Medicines Agency (EMA). To avoid interactions with drug metabolism and non-compliance, proposed subjects are non-smokers with no history of alcohol or drug abuse and not taking regular concomitant medications (except hormonal contraceptives and hormone replacement therapy (HRT)).

[0472] There are limited data regarding the use of minoxidil or its pharmaceutically acceptable salts in pregnant women. Due to reproductive toxicity in animal studies, minoxidil or its pharmaceutically acceptable salts are not recommended for use during pregnancy or in women of childbearing potential who are not using contraception. Therefore, women of childbearing potential may participate in this study only if they adhere to the contraceptive requirements detailed in the study protocol.

[0473] Based on the above considerations and the target population, healthy non-pregnant, non-lactating female subjects and healthy male subjects between the ages of 18 and 55 are considered suitable for this study.

[0474] 6.4 Risks and Benefits Associated with the Administration of Minoxidil or Its Pharmaceutically Acceptable Salts: Minoxidil or its pharmaceutically acceptable salts was selected for development as an oral formulation for the treatment of AGA due to its widespread use as a topical agent for AGA. Minoxidil or its pharmaceutically acceptable salts has a long history (over 35 years) of safe and effective use as a treatment for various types of hair loss, including AGA. To date, no clinical safety and efficacy studies have been conducted on MR oral formulations of minoxidil or its pharmaceutically acceptable salts. However, numerous clinical trials evaluating safety and efficacy have been conducted as part of the development program for another oral formulation of minoxidil or its pharmaceutically acceptable salts, Loniten®, which is approved for use.

[0475] When used as monotherapy for chronic treatment of severe hypertension, minoxidil or its pharmaceutically acceptable salts can cause significant salt and fluid retention, leading to physical symptoms such as edema and clinical deterioration in some patients with heart failure. Therefore, all patients taking minoxidil or its pharmaceutically acceptable salts require diuretic monotherapy or diuretic combined with salt restriction. Hemodilution may occur, resulting in transient decreases in hematocrit, hemoglobin, and red blood cell count (initially by approximately 7%, but subsequently returning to pretreatment levels). Electrolyte balance should be monitored for signs of fluid retention. In this study, a single dose of minoxidil or its pharmaceutically acceptable salts, followed by an appropriate washout period, is not expected to result in significant salt or fluid retention. Furthermore, this study will recruit only healthy volunteers with normal cardiac and renal function, and laboratory tests (clinical chemistry and hematology) will be performed throughout the study to monitor for fluid or electrolyte disturbances.

[0476] Minoxidil or its pharmaceutically acceptable salts are vasodilators that can induce reflex tachycardia and angina in at-risk patients. However, this study will recruit healthy young adults with normal electrocardiograms (ECGs) and no history or risk factors for cardiac disease. The selected dose, upper dose limit, and upper exposure limit will limit the likelihood and severity of cardiovascular effects, making safety issues related to this risk unlikely. Subjects experiencing cardiovascular adverse events will be closely monitored and supportive care (e.g., intravenous fluid administration, supine or head-down positioning) initiated.

[0477] Minoxidil or its pharmaceutically acceptable salts may have additive effects with concomitant antihypertensives and other medications that lower blood pressure. Interactions between minoxidil or its pharmaceutically acceptable salts and sympatholytics, such as guanethidine or betanidine, may result in excessive hypotension and / or orthostatic hypotension. Subjects who are taking or have taken any prescription, over-the-counter, or herbal medication (excluding paracetamol up to 4g daily and HRT / hormonal contraceptives) within 14 days prior to study drug administration will be excluded from this study.

[0478] Because of the risk of hypotension, orthostatic hypotension, orthostatic instability, presyncope, and syncope associated with peak plasma concentrations, subjects should be encouraged to remain on bed rest for 4 hours after administration, followed by a gradual ascent to an upright position before standing. For example, they should remain seated for several minutes before standing, and then stand by the bed for several minutes before moving out of bed. This will reduce the chance of sudden loss of consciousness and injury.

[0479] Shortly after initiating minoxidil or its pharmaceutically acceptable salts treatment, approximately 60% of patients experience electrocardiographic changes in T-wave direction and magnitude. Major changes may extend to the ST segment without signs of ischemia. These asymptomatic changes usually resolve with continued minoxidil or its pharmaceutically acceptable salts treatment. Discontinuing minoxidil or its pharmaceutically acceptable salts results in a return to pretreatment electrocardiograms. In this study, electrocardiograms will be performed once during each treatment period to monitor cardiovascular effects.

[0480] Hemodynamic effects are usually observed at plasma concentrations of 20 ng / mL or higher and are uncommon in normotensive patients. Therefore, appropriate use of MR oral formulations of minoxidil or its pharmaceutically acceptable salts is not expected to have cardiovascular effects. However, vital signs such as systolic blood pressure, diastolic blood pressure, and heart rate should be continuously monitored throughout the study period.

[0481] Hirsutism occurs in most patients treated with minoxidil or its pharmaceutically acceptable salts, and although its occurrence is considered unlikely in this single-dose pharmacokinetic study, all patients should be warned of this possibility before initiating treatment. Most patients experience increased hair length, thickening, and pigmentation. These signs usually appear 3 to 6 weeks after initiating treatment. They first appear on the face and may subside slightly with continued treatment. However, in less than 10% of patients, hirsutism was tolerated with little or no effect. Spontaneous return to pretreatment status can be expected 1 to 6 months after cessation of treatment.

[0482] Therefore, potential reactions to the products in this study may include, but are not limited to, transient edema, pericarditis, pericardial effusion and cardiac tamponade, hirsutism, bullous rash, toxic epidermal necrolysis, rash including Stevens-Johnson syndrome, thrombocytopenia and leukopenia, nausea and / or vomiting, breast pain, electrocardiogram changes, hemodilution, increased alkaline phosphatase, and increased serum creatinine.

[0483] Phototoxicity is not included in the warnings for use of the approved product, Loniten®, so there are no safety concerns regarding sun exposure in this study.

[0484] 6.4.2 General Risks and Overall Risk-Benefit Assessment: Taking a blood sample from a vein may cause pain, swelling, bruising, dizziness, fainting, and, very rarely, blood clot formation, nerve damage and / or infection at the needle site.

[0485] During cannulation, one or more attempts may be required to cannulate the subject's vein, which may result in bruising and / or irritation at the cannulation site.

[0486] The electrocardiogram stickers applied to the subject's chest and extremities may cause local irritation and may cause discomfort when removed, but the subject should be closely monitored to ensure that the local irritation does not persist.

[0487] There are no benefits to subjects from participating in this study. The development of products that improve the treatment of alopecia or AGA may benefit patients with alopecia and / or AGA.

[0488] Therefore, the overall risk / benefit balance is judged to be acceptable.

[0489] 7. Objectives and Evaluation Items:

[0490] Primary Objective: To assess the PK profile and determine the relative bioavailability of a single oral dose of an MR oral formulation of minoxidil or its pharmaceutically acceptable salt compared to a reference immediate-release (IR) formulation in healthy fasting subjects. Primary Endpoints: To measure PK parameters of minoxidil or its pharmaceutically acceptable salt, including, but not limited to, Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), and T1 / 2, where possible and appropriate, and Frels (MR vs. IR) based on the PK parameters Cmax, AUC(0-last) and AUC(0-inf).

[0491] Secondary Objective: To provide additional information regarding the safety and tolerability of single oral doses of the MR oral formulation and the reference IR formulation of minoxidil or its pharmaceutically acceptable salts in healthy subjects. Secondary Endpoints: Incidence, severity and causality of adverse events (AEs), changes from baseline in vital signs, electrocardiogram (ECG), physical examination and laboratory safety tests.

[0492] Exploratory Objective: To evaluate the PK profile and relative bioavailability of selected MR oral formulations of minoxidil or its pharmaceutically acceptable salts administered orally in a single fed and fasted state compared to the fasted state. Exploratory Endpoints: Measurement of PK parameters of minoxidil or its pharmaceutically acceptable salts, including, but not limited to, Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), and T1 / 2, and Frels (fed and fasted) based on the PK parameters Cmax, AUC(0-last) and AUC(0-inf), where possible and appropriate.

[0493] 8. Study design details

[0494] 8.1 On-Study Decision Criteria: On-study decisions will be made by the Safety Advisory Committee (SAC), which will be composed of the Investigator, the applicant's lead medical monitor or the applicant's medically qualified designee (familiar with the study protocol and IB), and a PK expert, as appropriate.

[0495] 8.1.1 Decision Points: Interim reviews will be conducted after regimens B, C, D, and E. The following in-study decisions will be made using data from all periods to date: 1) MR formulation and dose (selected from a two-dimensional design space accounting for dose strength and release rate) for the next regimen; 2) Meal state (regimen F only).

[0496] If the selected formulation does not provide the necessary data, a previously tested formulation may be used in the next study period, provided that the dose should not be repeated if it meets any of the dose-determining or study-discontinuation criteria.

[0497] 8.1.2 Criteria for Selection of Formulation, Dose, and Food Condition: The selection of formulation release rate, formulation dose, and food condition (if applicable) will be made only after a complete review of all data collected from the previous dosing group. Formulation, dose, and food condition selection requires data from approximately 12 subjects who have completed the planned PK and safety assessments through 48 hours post-dose. If data on 12 subjects are not available, the investigator, lead scientist, and sponsor will determine whether the available data are sufficient to support the formulation selection decision. If data from fewer subjects are used in the decision-making process and the formulation prototype is determined to be suboptimal in terms of exposure, additional subjects will not be dosed to increase the number of subjects in the completed dosing regimen. However, additional subjects may be enrolled to achieve the target number of subjects in subsequent dosing regimens.

[0498] The following data are required: adverse events, vital signs, electrocardiograms, safety laboratory tests, plasma concentrations of minoxidil or its pharmaceutically acceptable salts, and PK parameter estimates (Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), C24, Frel, and T1 / 2) (if available and appropriate).

[0499] Decisions regarding the selection of formulation, dose, and dietary status (if applicable) will be made by the SAC. Decisions will be documented and signed by the Investigator according to current Standard Operating Procedures (SOPs). Evidence of decisions will be kept on file in the ISF.

[0500] The rules for determining the dosage in this study are as follows: 1) The dosage should not increase by more than two-fold between each period. 2) The selected dosage should not exceed 30 mg. 3) The selected dosage should not be one that is expected to result in a geometric mean Cmax of more than 20 ng / mL. 4) If the study is discontinued due to protocol-based criteria, no further dosage determinations will be made.

[0501] 8.2 Subject Withdrawal: If a subject wishes to withdraw from the study, they will be permitted to do so at any time. Every reasonable effort will be made to complete the final evaluation / discharge procedures.

[0502] Early withdrawal is defined as the date of the subject's decision to withdraw from the study. Subject completion is defined as the date of the last treatment or contact (e.g., phone call or unscheduled visit) performed with the subject.

[0503] If a subject wishes to be discharged from the clinical unit earlier than the scheduled discharge time, for example due to unforeseen personal circumstances, but wishes to return to the clinical unit to complete the study, this will be recorded as a subject self-discharge and protocol deviation. Subjects must complete scheduled assessments / discharge procedures before being discharged from the clinical unit and may, if agreed by the applicant and investigator, return to the clinical unit for the next study period / assessment as scheduled.

[0504] Subjects will be excluded from study drug administration for the following reasons: 1) Occurrence of a serious or severe adverse event (AE), including but not limited to: a) Fridericia corrected QT interval (QTcF) ≥ 500 ms or an increase in QTcF interval ≥ 60 ms from baseline (confirmed by repeat electrocardiogram); b) Alanine aminotransferase (ALT) concentration ≥ 3 times the upper limit of the reference range (confirmed by repeat ALT blood testing); 2) Pregnancy; 3) End of study; 4) Subject request (withdrawal of consent); 5) Significant protocol deviation; 6) Intercurrent illness or need for prohibited medication that may adversely affect subject safety or data integrity; 7) Investigator discretion.

[0505] For purposes of discontinuation criteria, baseline will be considered the last available assessment before the first dose. Subjects who discontinue due to an adverse event related to the investigational drug will be followed until the adverse event has resolved, if possible, and every effort will be made to have the subject complete follow-up. Subjects who prematurely withdraw consent to participate in further activities will be distinguished from discontinuation for any of the other reasons listed above.

[0506] 8.3 Subject Replacement: In order to achieve the objectives of the study, a dropped subject may be replaced, at the discretion of the Investigator and Sponsor. The replaced subject will receive the treatment assigned to the replaced subject. The Sponsor and Investigator will determine the duration of treatment that each replacement subject must complete in order to achieve the objectives of the study.

[0507] The enrolled replacement subject will receive the next dose of the regimen scheduled for the dropped subject, but will not receive the dose already received by the dropped subject, unless an increase in the number of subjects is necessary to ensure the number of evaluable subjects required for interim decisions or to obtain data necessary for valid comparisons (e.g., test drug vs. reference drug, or fed vs. fasted).

[0508] Subjects who drop out due to adverse events related to the study drug will not be replaced.

[0509] Subjects who drop out for other reasons may be replaced by alternate subjects, as necessary, by agreement between the investigator and the applicant, to ensure a sufficient number of evaluable subjects.

[0510] 8.4 Discontinuation Criteria: If any of the following criteria are met, the study will be discontinued and the risk to other subjects will be assessed: 1) A serious adverse reaction (i.e., a serious adverse event judged at least possibly related to administration of the study drug) occurs in one subject. 2) Two subjects in the same cohort experience a non-serious serious adverse reaction (i.e., a non-serious adverse event judged at least possibly related to administration of the study drug), regardless of whether they are in the same organ system.

[0511] The investigator will determine whether the change is related to the investigational product. If the trial is discontinued, the provisional discontinuation will be reported to the MHRA and the Ethics Committee (EC) as a major change. The trial may be restarted or terminated, but will not resume until a further major change to restart the trial has been submitted to and approved by the MHRA and the Ethics Committee.

[0512] 8.5 Study Termination: After protocol activity has commenced but before dosing begins, the applicant and investigator may terminate a study without consulting the MHRA and the ethics committee. The MHRA and the ethics committee must be notified immediately and, at the latest, within 15 days of study termination, specifying the reasons for the termination. Any follow-up actions taken for safety reasons must also be reported.

[0513] If a trial is stopped before protocol activity has commenced, the investigator or sponsor must notify the ethics committee and the MHRA in writing, stating the reasons for stopping the trial.

[0514] Once dosing has begun, the study will be completed as planned unless one of the following criteria is met, which would require temporary discontinuation or early termination of the study: 1) A serious or severe adverse event, as defined in Section 8.5, is determined to be related to the investigational drug, as defined in Section 14.2. 2) New information regarding the safety of the investigational drug changes the risk / benefit profile of the compound such that the risk / benefit is no longer acceptable for study participants. 3) There is a serious violation of Good Clinical Practice (GCP) that makes it impossible to achieve the primary objective of the study or compromises subject safety. 4) An interim decision conference prior to the next cohort determines that the study objectives have been achieved.

[0515] If any of the above occurs, the overall risk / benefit analysis described in Section 6.4 will be carefully considered and, if the assumptions change and the overall balance proves to be no longer acceptable, the trial will be stopped. In such circumstances, the trial may only be stopped with the consent of the investigator and sponsor. Cancellation of the trial will be reported to the MHRA and the ethics committee.

[0516] If it becomes necessary to consider discontinuing the study after administration has begun, the investigator and sponsor will consult and may temporarily suspend administration. For safety reasons, administration will be immediately discontinued.

[0517] A trial may be stopped or suspended at the request of the MHRA or an ethics committee.

[0518] 8.6 Lost to Follow-up: Subjects who do not show up for a scheduled visit and cannot be contacted by the clinical department are considered lost to follow-up.

[0519] If a subject fails to return to the clinical unit for a required study visit: 1) The clinical unit must attempt to contact the subject and reschedule the visit as soon as possible. 2) Before considering the subject lost to follow-up, the investigator or their designee must make every effort to reestablish contact with the subject (e.g., by calling on three different occasions and, if necessary, sending an email or letter to the subject's last known email or mailing address). These contact attempts must be documented with the subject's source. 3) If the subject cannot be contacted, the subject will be considered lost to follow-up.

[0520] 8.7 Treatment Assignment: Because this is a non-randomized trial, no randomization schedule will be prepared. Prior to administration, investigational drug administration and dosage instructions will be prepared and the treatment sequence for each subject will be specified. Administration and dosage instructions will be kept on file in the ISF.

[0521] 8.7.1 Subject Number: Subject numbers will be assigned the morning of dosing, starting with the lowest available number, according to the code from 001 to 016. Replacement subjects will be assigned subject numbers from 901 to 916 with the same last two digits as the original subject (e.g., if subject 005 drops out, the replacement subject will be assigned subject number 905 and will receive the dosing regimen that subject 005 did not receive, in addition to the dosing regimen required to make the necessary comparisons).

[0522] 8.7.2 Blinding: As this is an open-label study, blinding is not required.

[0523] 9. Subject Selection: Subjects will be recruited from an existing subject panel or through direct recruitment to the general public. Before admitting subjects to the clinical unit, over-volunteer protection will be checked to ensure that each subject has not received any other study dose within 90 days of the first scheduled dose in this study.

[0524] 9.1 Informed Consent: Subjects will be provided with a written explanation of the study at least one day before the screening visit. Additionally, subjects may be provided with an informational video introducing the study prior to the screening visit. During the video and / or screening visit, a doctor or nurse will explain to each subject the nature, purpose, and expected duration of the study, as well as the benefits and risks associated with participation. Subjects will be informed that, for safety reasons, brief details regarding their participation in the study may be disclosed to other institutions and companies conducting clinical research in Japan. Subjects will then be given the opportunity to ask questions and informed of their right to withdraw from the study without repercussion. Following this explanation, subjects will voluntarily sign an informed consent form (ICF) before participating in the study. No study-specific procedures or investigations will be performed until written consent is obtained from the subject. If the Participant Information Sheet (PIS) is changed, participants will re-consent to the latest ICF, as necessary.

[0525] 9.2 Selection Criteria

[0526] Informed consent and compliance: 1) Providing written informed consent. 2) Being willing and able to communicate and participate in the entire study.

[0527] Demographics and Contraception: 3) Be between the ages of 18 and 55 at the time you sign the informed consent. 4) Agree to comply with the contraception requirements defined in Section 9.4.

[0528] Baseline characteristics: 5) Men or women who are not pregnant or lactating. 6) Participants who are determined to be healthy by the investigator or their designee at screening based on a medical evaluation including medical history, physical examination, vital signs, a single 12-lead electrocardiogram, and laboratory tests (blood tests, clinical chemistry tests, and urinalysis). 7) Body mass index (BMI) at screening between 18.0 and 32.0 kg / m 28) Weight 50 kg or more at the time of screening.

[0529] Other: 9) It is okay to have a high-fat breakfast that includes pork.

[0530] Selection criteria 2 and 4 above will be reassessed at admission / before administration in Period 1.

[0531] 9.3 Exclusion criteria:

[0532] Medical / Surgical History and Mental Health: 1) Serious adverse reactions or severe hypersensitivity to any medication or formulation excipient. 2) History or presence of clinically significant allergies requiring treatment as determined by the investigator. Hay fever is permitted as long as it is not active. 3) History of cardiovascular, renal, hepatic, skin, chronic respiratory, gastrointestinal, neurological, or psychiatric disease as determined by the investigator. 4) Subjects with a history of cholecystectomy or gallstones.

[0533] Physical Examination: 5) Subjects who, at screening, the investigator or their designee determines do not have veins suitable for multiple venipuncture / cannulation.

[0534] Diagnostic Assessment: 6) Clinical chemistry, hematology, or urinalysis abnormalities determined by the investigator to be clinically significant (test parameters are listed in Table 5). Subjects with Gilbert syndrome are eligible. 7) Positive test results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) 1 and 2 antibodies. 8) Creatinine clearance (CLcr) estimated using the Cockcroft-Gaulle equation of less than 80 mL / min at screening and evidence of renal dysfunction. 9) Signs of orthostatic hypotension, i.e., a decrease in systolic blood pressure of more than 20 mmHg upon standing, a decrease in diastolic blood pressure of more than 10 mmHg upon standing, or a heart rate increase of more than 30 bpm upon standing. Or, dizziness, presyncope, or syncope during the evaluation for orthostatic hypotension. 10) Clinically significant abnormal electrocardiogram findings at screening or before the first dose. 11) Resting supine heart rate >90 bpm. 12) Resting supine systolic blood pressure <90 mmHg. 13) Resting supine diastolic blood pressure <50 mmHg. 14) Pregnant or lactating women (all female subjects must have a negative high-sensitivity urine pregnancy test).

[0535] Previous Study Participation: 15) Subjects who received an investigational drug in a clinical trial within 90 days of Day 1 of Period 1 or within 5 or more half-lives by Day 1 of Period 1, whichever is longer. 16) Subjects who have donated blood or plasma or lost 400 mL or more of blood within the past 3 months.

[0536] Pre- and Current Medications: 17) Subjects who are taking or have taken any prescription, over-the-counter, or herbal medication (excluding paracetamol up to 4g daily and HRT / hormonal contraceptives) in the 14 days prior to the first dose of study drug (see section 11.4). COVID-19 vaccines are permitted as concomitant medications. Exceptions may be made at the investigator's discretion if all of the following criteria are met: medications with short half-lives and no PD activity is expected prior to study drug administration, and the use of the medication does not compromise the safety of the study subject and does not interfere with the objectives of the study. 18) Subjects who have received a COVID-19 vaccine 3 days prior to the first dose.

[0537] Lifestyle characteristics: 19) History of drug or alcohol abuse in the past 2 years. 20) Regular alcohol intake (men: 21 units or more per week, women: 14 units or more per week) (1 unit = 1 / 2 pint of beer or 25 mL of 40% spirits, 1.5 to 2 units = 125 mL of wine, depending on type). 21) Positive alcohol breath test result at screening or initial admission. 22) Current smokers and those who have smoked within the past 12 months. 23) Positive urinary cotinine test result at screening or initial admission. 24) Current users of e-cigarettes and nicotine replacement products and those who have used these products within the past 12 months. 25) Positive drug abuse test result at screening or initial admission (drug abuse tests are listed in Table 5).

[0538] Other: 26) Male subjects with a pregnant or lactating partner. 27) Subjects who are employees of the study site or sponsor, or their close relatives. 28) Subjects who are deemed unsuitable for participation by the investigator for any other reason.

[0539] Exclusion criteria 2, 9, 10, 11, 12, 13, 14, 15, 17, 18, 21, 23, 25, 26, and 28 listed above will be reassessed between admission and administration in Period 1.

[0540] Healthy subjects who do not meet the inclusion / exclusion criteria for this study will not be enrolled.

[0541] 9.4 Contraception and Restrictions:

[0542] Male subjects with partners of childbearing potential. Male subjects who are sexually active with partners of childbearing potential must use condoms and approved highly effective contraception with their partners from the time of informed consent until 91 days after the last dose of study drug. This is calculated based on 90 days (one spermatogenic cycle) and five half-lives of the study drug. Five half-lives is calculated as approximately one day.

[0543] The following methods are acceptable:

[0544] Partner use of combined (estrogen and progesterone-containing) hormonal contraceptives with ovulation suppression: 1) oral (used for at least one cycle (e.g., 4 or 8 weeks) before initial admission), 2) vaginal (used for at least 1 week before initial admission), 3) transdermal (used for at least 1 week before initial admission).

[0545] Partner use of progesterone-only hormonal contraceptives associated with ovulation suppression: 1) oral forms (used for at least one cycle (e.g., 4 or 8 weeks) before initial hospitalization), 2) injectable / implantable forms (used for at least 1 week before initial hospitalization), 3) intrauterine hormone-releasing systems (used for at least 1 week before initial hospitalization).

[0546] Use of an intrauterine device by the partner (must have started use for at least 1 week before the initial hospitalization).

[0547] Having had a vasectomy (must have been performed at least 6 months prior to initial admission).

[0548] Bilateral tubal occlusion in the partner (must have been performed at least 6 months before the initial admission).

[0549] These contraception requirements are considered more conservative than guidance issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group.

[0550] Men with partners of non-reproductive potential: There is a significantly increased risk of harmful drug exposure to sexual partners via ejaculate (this also applies to men who have had a vasectomy). Therefore, even men who are sexually active with partners of non-reproductive potential are urged to use condoms from the first dose of study drug through follow-up phone calls.

[0551] Female Subjects of Childbearing Potential: Sexually active female subjects of childbearing potential must use an approved, highly effective method of contraception with their partner from the time of informed consent until 31 days after the last dose of study drug. This is calculated based on 30 days (one female menstrual cycle) plus five half-lives of the study drug. Five half-lives is calculated as approximately one day.

[0552] The following highly effective methods are acceptable:

[0553] Combined (estrogen and progesterone) hormonal contraceptives with ovulation suppression: 1) Oral (must have been used for at least one cycle (e.g., 4 or 8 weeks) before initial admission), 2) Vaginal (must have been used for at least 1 week before initial admission), 3) Transdermal (must have been used for at least 1 week before initial admission).

[0554] Progesterone-only hormonal contraceptives with ovulation suppression: 1) oral (used for at least one cycle (e.g., 4 or 8 weeks) before initial admission), 2) injectable / implantable (used for at least 1 week before initial admission), 3) intrauterine hormone-releasing system (used for at least 1 week before initial admission).

[0555] Intrauterine device (used for at least 1 week before first hospitalization).

[0556] Partner who has had a vasectomy (must have been performed at least 6 months prior to the initial admission).

[0557] Bilateral tubal occlusion (must have been performed at least 6 months prior to the initial admission).

[0558] Female subjects are not required to use any of the above contraceptive methods if their sexual partners are female.

[0559] These contraception requirements are considered more conservative than the guidance issued by the European Summit on Medicines Regulation: Clinical Trial Facilitation Coordination Group.

[0560] All male subjects and female subjects of childbearing potential: Alternatively, sexual abstinence will be considered highly effective only if defined as abstinence from heterosexual intercourse for the entire period of risk associated with study treatment. The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the subject's preferred usual lifestyle.

[0561] Women of Non-Child-Rearing Potential: Female subjects of non-child-rearing potential are not required to use any method of contraception. Women are considered to be of child-rearing potential unless they are postmenopausal or permanently infertile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause, confirmed by a follicle-stimulating hormone (FSH) result of 40 IU / L or greater.

[0562] 9.4.1 Sperm Donation: Male subjects must not donate sperm during the study and for 91 days after the last dose of study drug.

[0563] 9.4.2 Egg Donation: Female subjects must not participate in egg donation during the study and for 31 days after the last dose of study drug.

[0564] 9.5 Pregnancy: Subjects are instructed to inform the investigator if they or their partner become pregnant during the study. Pregnancies that occur during the study but are confirmed after the study has concluded must also be reported to the investigator. If it becomes known that the subject or their partner is pregnant after the subject has participated in the study, consent will be sought from the subject or their partner, and if consent is given, the pregnancy will be monitored and the status of the mother and / or child(ren) will be reported to the applicant after delivery. Subjects who report a pregnancy during the study will discontinue study treatment and all reasonable efforts will be made to monitor the pregnancy until delivery.

[0565] Pregnancy notification forms and follow-ups are completed.

[0566] 9.6 Additional Study Restrictions: During the Study Period, the following additional restrictions apply:

[0567] 1. Subjects must not consume alcohol for 24 hours prior to screening and from 24 hours prior to each admission until 48 hours after administration.

[0568] 2. Subjects must not consume any liquids or foods containing cranberry, caffeine, or other xanthines from 24 hours prior to each admission until 48 hours after each dose.

[0569] 3. Subjects must avoid consuming any food containing poppy seeds for 48 hours prior to screening and from 48 hours prior to each admission until 48 hours after each administration.

[0570] 4. Subjects must not engage in any unaccustomed strenuous exercise for 72 hours prior to the screening visit and for 72 hours prior to each admission until they are released from the study.

[0571] 5. Do not donate blood or plasma (outside of this study) from screening through the study period and for at least 90 days after the last dose of study drug.

[0572] 6. Subjects will be advised to remain lying in bed for 4 hours after administration, after which they will be encouraged to gradually progress to an upright position by standing from a sitting position for a few minutes, remaining in a standing position at the bedside for a few minutes, and then leaving the bed to begin ambulating.

[0573] The above additional restrictions are not exclusion criteria and, if violated, will be recorded as a protocol deviation.

[0574] 10 Study Procedures: Study procedures will be conducted as detailed in the Evaluation Schedule in Table 6 and in accordance with the SOPs unless otherwise stated in this protocol.

[0575] 10.1 Screening: All subjects will be required to attend a screening visit within 28 days prior to the first dose. Screening visits will be performed according to the Schedule of Assessments.

[0576] If the start of the study is delayed for any reason and the interval between screening and the first dose exceeds 28 days, the investigator may, at his discretion, repeat all or part of the screening procedures.

[0577] If there are concerns about a subject's safety or eligibility to participate in the study, screening safety procedures such as safety blood tests, electrocardiogram, vital signs, urine cotinine testing, breath alcohol testing, and urine testing may be repeated if deemed clinically necessary, at the discretion of the investigator or co-investigator.

[0578] 10.1.1 Subject Rescreening: This study will permit rescreening of subjects who discontinued the study due to pre-treatment failure (i.e., the subject is not receiving treatment). The reason for failure must be temporary and have a prospect of resolution. If rescreening occurs, consent must be obtained again from the subject.

[0579] 10.2 Admission and Pre-Administration Procedures: Subject identity will be verified at each admission and administration.

[0580] Additionally, a subject's continuing eligibility will be reassessed at the time of first admission / prior to administration, as described in Sections 9.2 and 9.3.

[0581] If there are concerns about a subject's safety or eligibility to participate in the clinical trial, at the discretion of the investigator or co-investigator, admission / pre-administration safety procedures (e.g., safety blood draws, ECG, vital sign measurements, urinalysis, drug abuse screening) may be repeated if deemed clinically necessary.

[0582] In either group, preliminary subjects receiving the first dose will not need to undergo the hospitalization procedure again if the dose is administered within two days.

[0583] If dosing is delayed, subjects who have completed the admission process will not need to complete the admission process again if dosing is within 2 days and the subject remains in the clinical unit.

[0584] Subjects are admitted to the clinical unit the evening before dosing (day -1).

[0585] Additionally, subjects may be required to visit the clinical unit prior to admission to the clinical unit on day -1 of each treatment period to undergo a SARS-CoV-2 antigen test (if required, see sections 6.4.2.2 and 14.5.8).

[0586] Admission and pre-administration procedures are presented in the assessment schedule.

[0587] 10.3 Test Day Operations

[0588] 10.3.1 Blood Volume: The number and timing of sample collections may be modified after estimation of interim PK parameters, provided that the total blood volume collected from each subject must not exceed 550 mL over a 4-week period.

[0589] The first 0.5 mL of blood drawn from the cannula is discarded.

[0590] 10.3.2 Timing of Operations: A protocol may require two or more operations to be completed at the same point in time.

[0591] As a guideline, the order of evaluation priority is ECG → vital signs → nominal time PK blood sampling → other evaluations (e.g., physical examination). If scheduled at the same time, ECG will be performed before vital signs, and ECG and vital signs will be performed before PK sample collection. Every effort will be made to collect PK samples at the time specified in the protocol. Other evaluations will be performed within the required time frame. All safety evaluations will be performed relative to and in line with the time of initiation of dosing.

[0592] 10.3.3 Discharge from Clinical Unit: Subjects may be discharged from the site 48 hours after dosing, following completion of study-specific procedures, without further consultation by the Investigator or Co-Investigator, if the following conditions are met: 1) No adverse events are reported during the study visit. 2) The subject responds affirmatively when asked about their condition.

[0593] If any of these symptoms are observed, the subject will not be allowed to leave the clinical unit without permission from the investigator or co-investigator.

[0594] This study involves only healthy volunteers, and subjects will not receive any ongoing study interventions or treatments.

[0595] 10.3.4 Medical Oversight: A physician will be responsible for the clinical aspects of the trial and will be available throughout the trial. In accordance with current Association of the British Pharmaceutical Industry guidelines, each subject will be given a card containing the investigator's telephone number and the contact details of the doctor on call, who will be available 24 hours a day, 365 days a year.

[0596] 10.3.5 Follow-up: A follow-up telephone call will be made 3 to 7 days after the final dose to continue to monitor the subject's health. If the subject reports any adverse events of concern, they will be required to undergo further follow-up evaluation (unscheduled visit) in the clinical unit. The study will be terminated once the final follow-up telephone call or unscheduled follow-up visit has been completed.

[0597] 11. Subject Dosing: Dosing will occur at the times detailed in the Evaluation Study Schedule in Table 6.

[0598] 11.1 Food and Fluid Intake: Subjects will be allowed fluids up to 1 hour before their scheduled dosing time on Day 1, and will be provided with 240 mL of fluid 1 hour after dosing (to ensure adequate hydration). Fluids will be available ad libitum 1 hour after dosing. Non-caffeinated fluids will be available ad libitum beginning at lunchtime on the day of dosing.

[0599] If, for technical reasons, dosing is delayed by more than 2 hours from the scheduled dosing time, subjects will consume a 200 mL electrolyte drink (e.g., Lucozade Sport) at the originally scheduled dosing time or earlier if possible.

[0600] Fed Administration (Optional for Regimen F): If fed administration is selected, the calorie / fat content of breakfast on Day 1 of Regimen F will be controlled according to the breakfast details detailed in Table 7. For other meals, subjects will be provided with a standardized menu.

[0601] For fed doses, a high-fat breakfast is given 30 minutes before dosing.

[0602] Subjects were provided with a light dinner and asked to abstain from eating or drinking anything (except water) for at least 8 hours before being served a high-fat breakfast the following morning.

[0603] Breakfast is to be eaten within 25 minutes, and dosing is to occur 30 minutes (± 5 minutes) after the start of breakfast. Subjects are instructed to eat meals evenly over a 25-minute period. Some subjects may eat less time, but dosing is to occur 30 minutes (± 5 minutes) after the start of breakfast. Subjects must consume at least 90% of their breakfast before dosing in order to receive dosing. Breakfast start and end times, as well as breakfast consumption percentage, must be recorded in the source.

[0604] Lunch will be served approximately 4 hours after dosing, dinner approximately 10 hours after dosing, and a midnight snack approximately 14 hours after dosing. Meals will be served at appropriate times on subsequent days.

[0605] Fasting administration: There is no need to control the calorie / fat content of the meal. Subjects will be provided with a standardized menu.

[0606] On Day -1 of Periods 1 through 5, and of Period 6 if fasting dosing is selected, subjects will be offered a light meal and will then be asked to refrain from eating or drinking anything other than water for at least 10 hours before dosing and approximately 4 hours after dosing. An evening meal will be offered approximately 10 hours after dosing, and a light dinner will be offered approximately 14 hours after dosing. Meals will be served at appropriate times on subsequent days.

[0607] 11.2 Administration of Study Drug: Details of the study drug and dosage administered are provided in Sections 5.2 and 8.1, respectively. Subjects will be administered the morning of Day 1 of each study period.

[0608] The exact time of administration will be determined based on logistics and recorded in the source. The order of administration may be altered for logistical reasons.

[0609] The minimum withdrawal period between dosing regimens may be changed if data collected during the study support a change, except that the minimum withdrawal period will not be reduced to less than five half-lives of the investigational drug.

[0610] Subjects will receive five divided doses of the MR oral formulation of minoxidil or a pharmaceutically acceptable salt thereof for a total of five doses, and one dose of minoxidil or a pharmaceutically acceptable salt thereof as a tablet (reference).

[0611] Oral doses will be administered with a total of 240 mL of water. If necessary, additional water may be administered with the study drug in 50 mL increments. If this occurs, the dose will be recorded at the source of administration but will not be classified as a protocol deviation.

[0612] 11.3 Compliance with Dosing: During all clinical phases of the study, subjects will be observed by study staff to ensure compliance with all study procedures, including dosing.

[0613] After administration, mouth and hands are checked to ensure the tablet has been swallowed.

[0614] The date and time each subject was dosed will be recorded in the subject's source data. Non-compliance will require an evaluation by the investigator and sponsor to determine whether the subject can continue in the study.

[0615] 11.4 Prior and Concomitant Medications: All prescription and over-the-counter medications and herbal remedies are prohibited.

[0616] From 14 days before the first study drug dose until the follow-up telephone call, with the exception of paracetamol up to 4g daily, HRT / hormonal contraceptives, and those deemed necessary by the investigator to treat adverse events (exceptions may apply; see also section 9.3). All medications used will be recorded in the source.

[0617] COVID-19 vaccines are permitted as combination medications. However, subjects should not receive a COVID-19 vaccine within 3 days before the first dose of the investigational drug (see also Section 9.3). This will allow any vaccine side effects (e.g., fever, fatigue, pain / stiffness at the injection site) to subside by the time of administration. Thereafter, if possible, subjects should not receive a vaccine within 72 hours before receiving the investigational drug, but subjects cannot be excluded from the study for this reason.

[0618] Emergency equipment and medications will be available within the clinical unit in accordance with current standard operating procedures, and their use will be documented should they be required.

[0619] Medications taken within 14 days of screening will be recorded in the source. Concomitant medications taken within 14 days of administration will be included in the electronic case report form (eCRF).

[0620] 12 Efficacy Assessment: Not applicable in this Phase I study.

[0621] 13 Pharmacokinetic and Pharmacodynamic Evaluations: PK evaluations will be performed as detailed in the evaluation schedule in Table 6.

[0622] 13.1 Pharmacokinetic Assessment: A trained member of the clinical team will collect venous blood samples from subjects. Subjects will obtain consent for the use of these samples for the pu...

Claims

1. A pharmaceutical formulation for oral administration comprising a daily dose of minoxidil or a pharmaceutically acceptable salt thereof, said formulation being a modified release formulation.

2. 10. The pharmaceutical formulation of claim 1, further comprising a release modifier, a filler, a glidant, a lubricant, and combinations thereof.

3. 3. The pharmaceutical formulation of claim 1, comprising about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

4. 4. The pharmaceutical formulation of claim 1, comprising about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

5. 5. The pharmaceutical formulation of claim 1, comprising about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

6. 6. The pharmaceutical formulation of claim 1, comprising about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

7. 3. The pharmaceutical formulation of claim 2, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

8. 3. The pharmaceutical formulation of claim 2, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or a combination thereof.

9. 3. The pharmaceutical formulation of claim 2, wherein the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, silica aerogel, or a combination thereof.

10. 3. The pharmaceutical formulation of claim 2, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

11. 10. The pharmaceutical formulation of claim 1, further comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

12. 10. The pharmaceutical formulation of claim 1, comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

13. 12. The pharmaceutical formulation of claim 11, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

14. 12. The pharmaceutical formulation of claim 11, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

15. 12. The pharmaceutical formulation of claim 11, wherein the 19-norprogesterone derivative is nomegestrol acetate.

16. 12. The pharmaceutical formulation of claim 11, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

17. 12. The pharmaceutical formulation of claim 11, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

18. 12. The pharmaceutical formulation of claim 11, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, beclosteride, isonosteride, epigallocatechin, fluridil, and combinations thereof.

19. 12. The pharmaceutical formulation of claim 11, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

20. 12. The pharmaceutical formulation of claim 11, wherein the GnRH analogue is a GnRH agonist.

21. 21. The pharmaceutical formulation of claim 20, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

22. 12. The pharmaceutical formulation of claim 11, wherein the GnRH analogue is a GnRH antagonist.

23. 23. The pharmaceutical formulation of claim 22, wherein the GnRH antagonist is cetrorelix.

24. 12. The pharmaceutical formulation of claim 11, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

25. 12. The pharmaceutical formulation of claim 11, wherein the prostamide is bimatoprost.

26. 12. The pharmaceutical formulation of claim 11, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, or a combination thereof.

27. 12. The pharmaceutical formulation of claim 11, wherein the prostaglandin D2 receptor antagonist is laropirant, AM211, and combinations thereof.

28. 12. The pharmaceutical formulation of claim 11, wherein the prostaglandin E2 analog is sulprostone.

29. 12. The pharmaceutical formulation of claim 11, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

30. 12. The pharmaceutical formulation of claim 11, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, ritrecitinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.

31. 12. The pharmaceutical formulation of claim 11, wherein the alopecia areata therapeutic agent is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

32. 12. The pharmaceutical formulation of claim 11, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

33. 10. The pharmaceutical formulation of claim 1, wherein the modified release formulation is selected from a sustained release formulation, a sustained release formulation, a controlled release formulation, or a delayed release formulation.

34. 10. The pharmaceutical formulation of claim 1, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is present in an amount of from about 0.25 mg to about 50 mg.

35. 10. The pharmaceutical formulation of claim 1, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a steady state blood concentration of minoxidil or a pharmaceutically acceptable salt thereof of about 1 ng / ml to about 20 ng / ml.

36. 36. The pharmaceutical formulation of claim 35, wherein steady-state blood concentrations of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof are maintained for at least about 12 hours.

37. 10. The pharmaceutical formulation of claim 1, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a Cmax of about 0.25 ng / ml to about 20 ng / ml.

38. 10. The pharmaceutical formulation of claim 1, wherein oral administration of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof results in a Tmax of about 30 minutes to about 360 minutes.

39. 10. The pharmaceutical formulation of claim 1, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.000625 mg / kg / day to about 1.25 mg / kg / day.

40. 2. The pharmaceutical formulation of claim 1, wherein upon oral administration, the half-life or effective half-life of a daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 1 hour to about 24 hours.

41. 34. The pharmaceutical formulation of claim 33, wherein the sustained release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

42. 10. The pharmaceutical formulation of claim 1, wherein about 25% of the formulation dissolves in less than 2 hours or less than 4 hours in a neutral pH solution.

43. 10. The pharmaceutical formulation of claim 1, wherein about 25% of the formulation dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

44. 10. The pharmaceutical formulation of claim 1, wherein about 50% of the formulation dissolves in less than 2 hours, less than 6 hours, or less than 12 hours in a neutral pH solution.

45. 10. The pharmaceutical formulation of claim 1, wherein about 50% of the formulation dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

46. 10. The pharmaceutical formulation of claim 1, wherein about 75% of the formulation dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours.

47. 10. The pharmaceutical formulation of claim 1, wherein about 75% of the formulation dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

48. 10. The pharmaceutical formulation of claim 1, wherein about 100% of the formulation dissolves in less than about 12 hours, less than about 24 hours, or less than about 48 hours at neutral pH.

49. 10. The pharmaceutical formulation of claim 1, wherein about 100% of the formulation dissolves at neutral pH in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours.

50. 10. The pharmaceutical formulation of claim 1, which exhibits zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

51. 10. The pharmaceutical formulation of claim 1, comprising an enteric coating.

52. 10. The pharmaceutical formulation of claim 1, which is administered only once a day.

53. 10. The pharmaceutical formulation of claim 1, which is administered at least once daily.

54. 10. The pharmaceutical formulation of claim 1, which is administered four times daily.

55. 10. The pharmaceutical formulation of claim 1, which is administered three times daily.

56. 10. The pharmaceutical formulation of claim 1, which is administered twice daily.

57. A pharmaceutical formulation comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

58. 58. The pharmaceutical formulation of claim 57, further comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

59. 58. The pharmaceutical formulation of claim 57, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

60. 1. A pharmaceutical formulation comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Tmax of about 30 minutes to about 360 minutes.

61. 61. The pharmaceutical formulation of claim 60, comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

62. 61. The pharmaceutical formulation of claim 60, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

63. 1. A pharmaceutical formulation comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

64. 64. The pharmaceutical formulation of claim 63, further comprising one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5-α reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

65. 64. The pharmaceutical formulation of claim 63, further comprising medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

66. 1. A method for treating or preventing hair loss, comprising daily administering to a subject in need thereof a composition comprising a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof.

67. 67. The method of claim 66, wherein the composition further comprises a release modifier, a filler, a glidant, a lubricant, and combinations thereof.

68. 68. The method of claim 66 or 67, wherein the composition comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

69. 68. The method of claim 66 or 67, wherein the composition comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release modifier, about 0.1% to about 0.3% glidant, and / or about 0.4% to about 0.6% lubricant.

70. 68. The method of claim 66 or 67, wherein the composition comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release modifier, about 0.1% to about 0.3% lubricant, and / or about 0.4% to about 0.6% lubricant.

71. 68. The method of claim 66 or 67, wherein the composition comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release modifier, about 0.1% to about 0.3% lubricant, and / or about 0.4% to about 0.6% lubricant.

72. 68. The method of claim 67, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

73. 68. The method of claim 67, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

74. 68. The method of claim 67, wherein the lubricant is silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, and silica aerogel.

75. 68. The method of claim 67, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

76. 67. The method of claim 66, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 17α-spirolactone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5α-reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an agent for treating alopecia areata, a supplement, and combinations thereof.

77. 67. The method of claim 66, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

78. 77. The method of claim 76, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

79. 77. The method of claim 76, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

80. 77. The method of claim 76, wherein the 19-norprogesterone derivative is nomegestrol acetate.

81. 77. The method of claim 76, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

82. 77. The method of claim 76, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

83. 77. The method of claim 76, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, izonsteride, epigallocatechin, fluridil, and combinations thereof.

84. 77. The method of claim 76, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

85. 77. The method of claim 76, wherein the GnRH analogue is a GnRH agonist.

86. 86. The method of claim 85, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

87. 77. The method of claim 76, wherein the GnRH analogue is a GnRH antagonist.

88. 88. The method of claim 87, wherein the GnRH antagonist is cetrorelix.

89. 77. The method of claim 76, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

90. 77. The method of claim 76, wherein the prostamide is bimatoprost.

91. 77. The method of claim 76, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.

92. 77. The method of claim 76, wherein the prostaglandin D2 receptor antagonist is laropiprant, AM211, and combinations thereof.

93. 77. The method of claim 76, wherein the prostaglandin E2 analog is sulprostone.

94. 77. The method of claim 76, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

95. 77. The method of claim 76, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itacitinib, oclacitinib, pacritinib, peficitinib, litorcitinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jacktinib, and combinations thereof.

96. 78. The method of claim 77, wherein the alopecia areata medication is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

97. 77. The method of claim 76, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

98. 67. The method of claim 66, wherein the composition is administered orally.

99. 99. The method of claim 98, wherein the modified release formulation is a sustained release formulation, a sustained release formulation, a controlled release formulation, or a delayed release formulation.

100. 99. The method of claim 98, wherein the subject in need of diagnosis of hair loss is diagnosed with hair loss.

101. 101. The method of claim 100, wherein the subject is diagnosed with at least one cardiac disease selected from heart disease, chronic congestive heart failure, cardiomyopathy, tachyarrhythmia, renal disease, pre-existing pulmonary hypertension, and chronic congestive heart failure not secondary to hypertension.

102. 101. The method of claim 100, wherein the hair loss is selected from male pattern hair loss, female pattern hair loss, hereditary hair loss, telangiectasia, alopecia areata, central centrifugal cicada alopecia, lichen planus pilaris, or traction alopecia.

103. 102. The method of claim 101, wherein the subject is taking at least one of an antihypertensive drug, an ACE inhibitor, an angiotensin receptor antagonist, a direct renin inhibitor, a loop diuretic, a thiazide diuretic, a calcium channel blocker, a beta-blocker, an antiarrhythmic drug, and a diuretic for the treatment of at least one cardiac condition.

104. 99. The method of claim 98, wherein administration results in hair regrowth.

105. 99. The method of claim 98, wherein administration results in hair regrowth within about 6 months.

106. 99. The method of claim 98, wherein administration results in increased improvement in hair growth compared to administration of an immediate release dosage form of minoxidil or a pharmaceutically acceptable salt thereof.

107. 67. The method of claim 66, wherein about 25% of the composition dissolves in a neutral pH solution in less than about 2 hours or less than about 4 hours.

108. 67. The method of claim 66, wherein about 25% of the composition dissolves in a neutral pH solution in about 0.5 hours, about 0.75 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or about 4 hours.

109. 67. The method of claim 66, wherein about 50% of the composition dissolves in a neutral pH solution in less than about 2 hours, less than about 6 hours, or less than about 12 hours.

110. 67. The method of claim 66, wherein about 50% of the composition dissolves in a neutral pH solution in about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, or about 10 hours.

111. 67. The method of claim 66, wherein about 75% of the composition dissolves in a neutral pH solution in less than about 4 hours, less than about 8 hours, less than about 12 hours, or less than about 18 hours.

112. 67. The method of claim 66, wherein about 75% of the composition dissolves in a neutral pH solution in about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours.

113. 67. The method of claim 66, wherein about 100% of the composition dissolves in less than about 12 hours, less than about 24 hours, or less than about 48 hours at neutral pH.

114. 67. The method of claim 66, wherein about 100% of the composition dissolves at neutral pH in about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours.

115. 67. The method of claim 66, wherein the composition exhibits zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-zero-order release of minoxidil or a pharmaceutically acceptable salt thereof, first-order release of minoxidil or a pharmaceutically acceptable salt thereof, pseudo-first-order release of minoxidil or a pharmaceutically acceptable salt thereof, or second-order release of minoxidil or a pharmaceutically acceptable salt thereof.

116. 67. The pharmaceutical formulation of claim 66, comprising an enteric coating.

117. 99. The method of claim 98, wherein the composition is administered only once a day.

118. 99. The method of claim 98, wherein the composition is administered at least once daily.

119. 99. The method of claim 98, wherein the composition is administered four times daily.

120. 99. The method of claim 98, wherein the composition is administered three times daily.

121. 99. The method of claim 98, wherein the composition is administered twice daily.

122. 99. The method of claim 98, wherein the composition is administered daily for at least about three months with substantially no side effects and substantially no cardiac effects.

123. 99. The method of claim 98, wherein the composition is administered daily for at least about four months with substantially no side effects and substantially no cardiac effects.

124. 99. The method of claim 98, wherein the composition is administered daily for at least about six months with substantially no side effects and substantially no cardiac effects.

125. 99. The method of claim 98, wherein the composition is administered daily for at least about one year with substantially no side effects and substantially no cardiac effects.

126. 99. The method of claim 98, wherein the composition is administered daily indefinitely with substantially no side effects and substantially no cardiac effects.

127. 99. The method of embodiment 98, wherein the administration results in hair regrowth substantially without clinically significant hemodynamic changes in blood pressure.

128. 99. The method of claim 98, wherein administration results in substantially no cardiac effects.

129. 129. The method of claim 128, wherein the cardiac effect is selected from tachycardia, hypotension, premature ventricular contractions, and other tachyarrhythmias.

130. 99. The method of claim 98, wherein said administration results in hair regrowth with substantially no cardiac effects.

131. 99. The method of claim 98, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof has less cardiac or hemodynamic effects compared to administration of the same daily dosage of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

132. 132. The method of claim 131, wherein the cardiac effect is selected from tachycardia, hypotension, premature ventricular contractions, and other tachyarrhythmias.

133. 132. The method of claim 131, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof produces substantially no cardiac or hemodynamic effects compared to administration of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used in the treatment of hypertension.

134. 132. The method of claim 131, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 25% to about 500% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

135. The method of claim 131, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 10% to about 90% of the amount of immediate-release oral minoxidil or a pharmaceutically acceptable salt thereof used to treat hypertension.

136. 99. The method of claim 98, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 50 mg.

137. 99. The method of claim 98, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is selected from an amount of about 0.625 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

138. 99. The method of claim 98, wherein the daily dose of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.25 mg to about 20 mg per day.

139. 99. The method of claim 98, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is about 2.5 mg per day.

140. 99. The method of claim 98, wherein the daily dosage of minoxidil or a pharmaceutically acceptable salt thereof is from about 0.00625 mg / kg / day to about 0.5 mg / kg / day.

141. 99. The method of claim 98, wherein the modified release formulation releases about 50% to about 98% of the daily dose of minoxidil or a pharmaceutically acceptable salt thereof within about 12 hours after oral administration.

142. 99. The method of claim 98, wherein the subject has a plasma concentration versus time curve of minoxidil or a pharmaceutically acceptable salt thereof with a Tmax of about 30 to about 360 minutes.

143. 99. The method of claim 98, wherein the subject has a plasma concentration versus time curve of minoxidil or a pharmaceutically acceptable salt thereof with a Cmax of about 2.5 ng / ml to about 20 ng / ml.

144. In embodiment NNNNNN, the method of claim 98, wherein the half-life or effective half-life of minoxidil or a pharmaceutically acceptable salt thereof in the subject is from about 1 hour to about 24 hours.

145. 99. The method of claim 98, wherein minoxidil or a pharmaceutically acceptable salt thereof is present in an amount of about 0.625 mg four times a day.

146. 99. The method of claim 98, wherein minoxidil or a pharmaceutically acceptable salt thereof is present in an orally dissolving tablet.

147. 1. A method for treating or preventing hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation releases from about 50% to about 98% of the daily dose of minoxidil within about 12 hours after oral administration.

148. 148. The method of claim 147, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5α-reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

149. 148. The method of claim 147, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

150. 1. A method for treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Tmax of about 30 to about 360 minutes.

151. 151. The method of claim 150, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5α-reductase inhibitors, estrogens, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

152. 151. The method of claim 150, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

153. A method for treating hair loss, comprising administering to a subject in need thereof a modified release formulation of minoxidil or a pharmaceutically acceptable salt thereof, wherein the modified release formulation has a Cmax of about 0.25 ng / ml to about 20 ng / ml.

154. 154. The method of claim 153, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from nonsteroidal antiandrogens, 17α-hydroxyprogesterone derivatives, 19-norprogesterone derivatives, 19-nortestosterone derivatives, 17α-spirolactone derivatives, 5α-reductase inhibitors, estrogen, GnRH analogs, prostaglandin F2α analogs, prostamides, prostanoid receptor agonists, prostaglandin D2 receptor antagonists, prostaglandin E2 analogs, EP2 receptor agonists, JAK inhibitors, drugs for treating alopecia areata, supplements, and combinations thereof.

155. 154. The method of claim 153, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

156. A kit comprising a sustained release modified release vehicle containing oral minoxidil or a pharmaceutically acceptable salt thereof.

157. 157. The kit of claim 156, wherein the sustained release modified vehicle further comprises a release modifying agent, a filler, a glidant, a lubricant, and combinations thereof.

158. The kit of claim 157, wherein the sustained release modifying vehicle n comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 75% to about 85% release modifying agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

159. The kit of claim 157, wherein the sustained release modified vehicle comprises about 1% to about 1.5% minoxidil or a pharmaceutically acceptable salt thereof, about 60% to about 70% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

160. The kit of claim 157, wherein the sustained release modified vehicle comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 50% to about 60% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

161. The kit of claim 157, wherein the sustained release modified vehicle comprises about 6% to about 7% minoxidil or a pharmaceutically acceptable salt thereof, about 65% to about 75% release modified agent, about 0.1% to about 0.3% lubricant, and about 0.4% to about 0.6% lubricant.

162. The kit of claim 157, wherein the release-modifying agent is hydroxypropyl methylcellulose K4M; hydroxypropyl methylcellulose K200M, lactose monohydrate, and combinations thereof.

163. 158. The kit of claim 157, wherein the filler is microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

164. 158. The kit of claim 157, wherein the lubricant is silica (colloidal anhydrous) starch, talc, magnesium stearate, calcium stearate, zinc stearate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, and silica aerogel.

165. 158. The kit of claim 157, wherein the lubricant is magnesium stearate, calcium stearate, zinc stearate, stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene, monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, or a combination thereof.

166. 157. The kit of claim 156, wherein the pharmaceutical formulation further comprises one or more active ingredients selected from a nonsteroidal antiandrogen, a 17α-hydroxyprogesterone derivative, a 19-norprogesterone derivative, a 19-nortestosterone derivative, a 17α-spirolactone derivative, a 5α-reductase inhibitor, an estrogen, a GnRH analog, a prostaglandin F2α analog, a prostamide, a prostanoid receptor agonist, a prostaglandin D2 receptor antagonist, a prostaglandin E2 analog, an EP2 receptor agonist, a JAK inhibitor, an agent for treating alopecia areata, a supplement, and combinations thereof.

167. 157. The kit of claim 156, wherein the pharmaceutical formulation further comprises medrogestone, cetirizine, setiprant, valproic acid, and combinations thereof.

168. 167. The kit of claim 166, wherein the nonsteroidal antiandrogen is selected from flutamide, clascoterone, bicalutamide, pirilutamide, enzualutamide, nilutamide, apalutamide, proxilutamide, cimetidine, topalutamide, and combinations thereof.

169. 167. The kit of claim 166, wherein the 17α-hydroxyprogesterone derivative is selected from chlormadinone acetate, cyproterone acetate, megestrol acetate, osaterone acetate, and combinations thereof.

170. The kit of claim 166, wherein the 19-norprogesterone derivative is nomegestrol acetate.

171. 167. The kit of claim 166, wherein the 19-nortestosterone derivative is selected from dienogest, oxendolone, and combinations thereof.

172. The kit of claim 166, wherein the 17α-spirolactone derivative is selected from drospirenone, spironolactone, and combinations thereof.

173. 167. The kit of claim 166, wherein the 5α-reductase inhibitor is selected from alphatradiol, dutasteride, epristeride, finasteride, saw palmetto extract, bexlosteride, izonsteride, epigallocatechin, fluridil, and combinations thereof.

174. 167. The kit of claim 166, wherein the estrogen is selected from estradiol, estradiol esters, ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and combinations thereof.

175. 167. The kit of claim 166, wherein the GnRH analog is a GnRH agonist.

176. 176. The kit of claim 175, wherein the GnRH agonist is selected from goserelin, buserelin, leuprorelin, and combinations thereof.

177. 167. The kit of claim 166, wherein the GnRH analog is a GnRH antagonist.

178. 178. The kit of claim 177, wherein the GnRH antagonist is cetrorelix.

179. The kit of claim 166, wherein the prostaglandin F2α analog is latanoprost, travoprost, tafluprost, unoprostone, dinoprost, AS604872, BOL303259X, PF3187207, carboprost, and combinations thereof.

180. 167. The kit of claim 166, wherein the prostamide is bimatoprost.

181. The kit of claim 166, wherein the prostanoid receptor agonist is fluprostenol, cicaprost, and combinations thereof.

182. The kit of claim 166, wherein the prostaglandin D2 receptor antagonist is laropirant, AM211, and combinations thereof.

183. The kit of claim 166, wherein the prostaglandin E2 analog is sulprostone.

184. The kit of claim 166, wherein the EP2 receptor agonist is butaprost, diazoxide, kopexil, pinacidil, ET-02, and combinations thereof.

185. 167. The kit of claim 166, wherein the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, durxolitinib, deuclavacitinib, fedratinib, filgotinib, gusacitinib, itatinib, oclacitinib, pacritinib, peficitinib, ritretinib, ruxolitinib, tofacitinib, upadacitinib, SHR0302, ATI-2138, jactinib, and combinations thereof.

186. 167. The kit of claim 166, wherein the alopecia areata therapeutic agent is selected from etrasimod, fingolimod, ozanimod, siponimod, ponesimod, and combinations thereof.

187. 167. The kit of claim 166, wherein the supplement is selected from biotin, zinc, selenium, caffeine, sodium chloride, marine collagen, and combinations thereof.

188. 157. The kit of claim 156, comprising an information sheet.

189. 189. The kit of claim 188, wherein the information sheet includes instructions for selecting an oral dosage form based on the patient's weight.

190. 189. The kit of claim 188, wherein the information sheet includes warnings about adverse effects.

191. 191. The kit of claim 190, wherein the adverse effect is selected from peripheral edema and hirsutism.

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