Levonorgestrel butanoate formulations and related methods

Abstract

Disclosed herein are embodiments of formulations that include levonorgestrel butanoate ("LNGB") particles with particle sizes that facilitate administration of higher concentrations of LNGB in smaller volumes.The disclosed formulation embodiments exhibit long-lasting contraceptive effects and can be administered subcutaneously, which provides its utility in acting as a self-administerable contraceptive formulation that does not produce the side effects associated with other contraceptives.The present disclosure relates to embodiments of levonorgestrel butanoate formulations and methods of making and using them.

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of the earlier filing date of and priority to U.S. Provisional Patent Application No. 63 / 289,965, filed December 15, 2021, which is incorporated herein by reference in its entirety.

[0002] (Government support acknowledgement) This invention was made with Government support under Project No. ZHD008981-01 awarded by the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The U.S. Government has certain rights in this invention.

[0003] (Field) The present disclosure relates to embodiments of levonorgestrel butanoate formulations and methods of making and using same. [Background technology]

[0004] (background) Long-acting contraceptive methods, such as intrauterine devices (IUDs), have a typical failure rate of about 1%. Methods that require daily action, such as combination oral contraceptives (COCs) or progestin only pills (POPs), have a typical failure rate of 7% due to user error. Depomedroxyprogesterone acetate (DMPA), the only injectable product in the United States, has a typical failure rate of 4%. The DMPA regimen requires injections at 3-month intervals. A longer duration of action could improve the typical efficacy rate by requiring fewer injections per year. There is increasing concern about a possible increased risk of HIV acquisition with DMPA use, which may be due to the glucocorticoid activity of medroxyprogesterone acetate. DMPA has been associated with weight gain and can cause loss of bone density, prompting the FDA to require a black box warning regarding possible effects on fracture risk with long-term use or effects in women younger than 18. Injectable methods offer several advantages over other methods, and thus a need exists for additional injectable contraceptive options that are safe and effective.

[0005] Obesity is a major public health problem facing the US population and an independent risk for venous thromboembolism (VTE); therefore, there is a public health need to develop an effective contraceptive for obese women that does not increase VTE risk. Most conventional oral contraceptives contain the synthetic estrogen ethinyl estradiol (EE), which is associated with increased VTE risk. The combination of obesity and EE further increases VTE risk. Although women with health conditions such as moderate or morbid obesity, hypertension, and diabetes may be advised to avoid the use of EE-containing contraceptives, their risk of VTE due to pregnancy increases significantly beyond the risk associated with EE-containing products. Recently introduced combined oral contraceptives containing estradiol may have a slightly lower VTE risk compared to those containing EE, but their benefits have not been clearly established and they are underutilized due to poor tolerability and cycle control.

[0006] Levonorgestrel butanoate ("LNGB") is a steroidal progestin that has been under development since the early 1980s as an injectable, long-acting contraceptive by the World Health Organization (WHO) in collaboration with institutions around the world, including the National Institute of Child Health and Human Development. Initial clinical studies were conducted at two World Health Organization Collaborating Centers for Research in Human Reproduction in Mexico City and London. However, conventional LNGB formulations (e.g., the WHO formulation) have demonstrated undesirable stability issues, which reduce contraceptive activity and large-scale manufacturing capabilities.

[0007] The development of effective contraceptive products that are safe for women with high-risk conditions and provide sufficient long-lasting contraceptive efficacy is an important public health need. Summary of the Invention [Means for solving the problem]

[0008] (overview) Disclosed herein are embodiments of pharmaceutical formulations that include levonorgestrel butanoate particles; a wetting agent; and a dispersing agent, an emulsifying agent, or a combination thereof. The unique combination of particle size and concentration of the levonorgestrel butanoate is described.

[0009] Also disclosed are embodiments of methods of making a pharmaceutical formulation according to the present disclosure, the methods including subjecting levonorgestrel butanoate to sterile filtration to provide a filtrate containing sterile levonorgestrel butanoate; producing levonorgestrel butanoate particles from the filtrate; and combining the levonorgestrel butanoate particles with one or more of a wetting agent, a dispersing agent, an emulsifying agent, or combinations thereof; the methods do not include using irradiation for any sterilization.

[0010] Also disclosed is an embodiment of a method of making a pharmaceutical formulation according to the present disclosure, the method including the steps of micronizing levonorgestrel butanoate to provide levonorgestrel butanoate particles; and combining the levonorgestrel butanoate particles with one or more of a wetting agent, a dispersing agent, an emulsifying agent, or combinations thereof; the method does not include the step of using irradiation for any sterilization.

[0011] Also disclosed are embodiments of methods of providing contraception to a subject, the methods comprising administering a dosage of levonorgestrel butanoate in the range of 20 mg to 140 mg by administering to the subject by injection an embodiment of the formulation described herein.

[0012] Also disclosed are methods of treating or preventing a progestin-associated disease or condition in a subject, the methods comprising administering to the subject an embodiment of the formulation described herein.

[0013] The above and other objects and features of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings. [Brief description of the drawings]

[0014] [Figure 1] 1A and 1B are photographic images showing levonorgestrel butanoate ("LNGB") particles before (FIG. 1A) and after (FIG. 1B) exposure to an irradiation-based sterilization process, which show that irradiation causes the LNGB to have an undesirable yellow color.

[0015] [Diagram 2] FIG. 2 is a high performance liquid chromatography (HPLC) trace obtained from the analysis of LNGB particles prior to any irradiation-based sterilization process.

[0016] [Diagram 3] FIG. 3 is an HPLC trace obtained from the analysis of LNGB particles after a radiation-based sterilization process.

[0017] [Figure 4] FIG. 4 is an HPLC trace obtained from the analysis of LNGB particles after a radiation-based sterilization process, where the sample was purged with N2.

[0018] [Diagram 5] FIG. 5 shows HPLC traces obtained from the analysis of LNGB particles after a radiation-based sterilization process, where the sample was purged with Ar.

[0019] [Figure 6] FIG. 6 is a graph showing the “resumption of ovulation” obtained from injection of a representative LNGB formulation of the present disclosure via various routes of administration [(i) intramuscular ("IM") injection; and (ii) subcutaneous ("SC") injection] and various concentrations [(i) 70 mg / mL; and (ii) 20 mg / mL]. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] (Detailed Description) (Terminology Overview)

[0021] The following explanations of terms and / or symbols are provided to better describe the present disclosure and to guide those skilled in the art in the practice of the present disclosure. The singular forms "a", "an" and "the" refer to one or more, unless the context specifically indicates otherwise. The term "or" refers to one element of the listed alternative elements, or a combination of two or more elements, unless the context specifically indicates otherwise. As used herein, "comprise" means "include". Thus, "comprise A or B" means "include A, B, or A and B", without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference.

[0022] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, etc. used in the specification and claims should be understood to be modified by the term "about". Thus, unless otherwise expressly or implicitly indicated, the numerical parameters given are approximations that may depend on the desired properties sought and / or the limits of detection under standard test conditions / test methods. When directly and explicitly distinguishing an embodiment from the prior art being discussed, the number of that embodiment is not approximate unless the term "about" is specified.

[0023] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains.Methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, and suitable methods and materials are described below.These materials, methods, and examples are merely illustrative and are not intended to be limiting.Any functional group disclosed herein may be substituted or unsubstituted, unless otherwise specified herein.

[0024] Those skilled in the art will understand that compounds may exhibit the phenomenon of tautomerism, stereoisomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds, and as a result, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof (e.g., racemic mixtures). As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Since the various compound names, formulae, and compound figures in the present specification and claims may only show one of the possible tautomeric, stereoisomeric, optical, or geometric isomeric forms, those skilled in the art will understand that the disclosed compounds include all tautomeric, stereoisomeric, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of separate isomeric forms (including mixtures of enantiomers and / or stereoisomers) can be separated to provide each of the individual enantiomers and / or stereoisomers using techniques known to those of skill in the art, particularly with the aid of the present disclosure. In cases of restricted rotation, for example, around an amide bond or between two directly linked rings (e.g., pyridinyl rings, biphenyl groups, etc.), atropisomers are also possible and are also specifically included in the compounds disclosed herein.

[0025] In any embodiment, any or all hydrogens present in the compound or in a particular group or moiety within the compound may be replaced by deuterium or tritium. Thus, reference to alkyl includes deuterated alkyl, where one to up to a maximum number of hydrogens present may be replaced by deuterium. For example, methyl refers to CH 3 or CH in which one to three hydrogens are replaced by deuterium 3 (For example, CD x H 3-x )

[0026] In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided.

[0027] Administer (or administering or administering: Exposing a subject to an embodiment of a formulation of the present disclosure (including any components thereof). Modes of administration are discussed herein and may include, but are not limited to, injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular, or intrathecal), topical, ocular, oral, buccal, systemic, nasal, transdermal (e.g., by mixing with a penetrant (e.g., DMSO)), rectal, intravaginal, a form suitable for administration by inhalation or insufflation, a form suitable for implantation, or any combination thereof. Administering, as used herein, also contemplates self-administration, where the subject to be exposed performs the administration.

[0028] Pharmaceutically acceptable excipient: A substance other than an active ingredient (e.g., LNGB) that is included in a formulation of LNGB. As used herein, an excipient may be incorporated within a particle of LNGB, or the excipient may be physically mixed with a particle of LNGB. The excipient may also be in the form of a solution, suspension, emulsion, etc. An excipient may be used, for example, to dilute an active ingredient and / or to modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, wetting agents, dispersing agents, thickening agents, antiadherents, binders, coating agents, enteric coating agents, disintegrants, flavoring agents, sweeteners, coloring agents, lubricants, glidants, adsorbents, preservatives, buffers, emulsifiers, adjuvants, carriers, vehicles, isotonicity agents, bulking agents, pharma- ceutically acceptable solvents, stabilizers, flocculants, suspending agents, electrolytes, antioxidants, chelating agents, or any combination thereof. Exemplary excipients are described herein. Further additional representative excipients may include magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, xylitol, sorbitol, maltitol, polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, sesame oil, propyl gallate, sodium metabisulfite, lanolin, or any combination thereof. When water is included as a pharma- ceutically acceptable excipient, it is typically sterile water for injection ("WFI") (USP grade).

[0029] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts of LNGB and / or other compounds and / or components of formulations described herein derived from a variety of organic and inorganic counterions as known to those skilled in the art, by way of example only, sodium, potassium, calcium, magnesium, tetraalkylammonium, etc.; and, where the molecule contains a basic functional group, salts of organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with an acid partner while retaining the biological effectiveness of the free base. In particular, the components of the formulation form salts with various pharma- ceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases (e.g., sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like). Representative salts are ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharma- ceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). Representative organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference).

[0030] Prodrug: An embodiment of a compound disclosed herein (e.g., LNGB) that is most typically converted in vivo to yield a biologically active compound (particularly the parent compound (e.g., LNG)), for example, by enzymatic hydrolysis in the gastrointestinal (GI) tract (including the stomach and intestines). Common examples of prodrug moieties include, but are not limited to, pharma- ceutically acceptable ester, carbonate, amide, and / or carbamate forms of a compound having an active form bearing a carboxylic acid moiety and / or a hydroxyl group. Examples of pharma-ceutically acceptable esters of embodiments of the compounds disclosed herein include esters of phosphate groups and esters of carboxylic acids, for example, aliphatic esters, particularly alkyl esters (e.g., C 1~6 Other prodrug moieties include, but are not limited to, phosphate esters, e.g., -CH 2 -OP(O)(OR a ) 2or a salt thereof, and R a is hydrogen or aliphatic (e.g., C 1~6 The amides of the disclosed exemplary embodiments of the compounds are preferably aryl, ...

[0031] Subjects: Mammals and other animals, e.g., humans, companion animals (e.g., dogs, cats, rabbits, etc.), utility animals, and feed animals; thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0032] Symptom (or sign): Any subjective evidence of a disease or condition of a subject (e.g., evidence as perceived by the subject); any notable change in the condition of a subject that indicates some physical or mental state. A "sign" is any abnormality that is detectable in a test or evaluation of a subject and indicates a disease. A sign is generally an objective indicator of a disease. Signs include, but are not limited to, any measurable parameter, such as tests to detect neurodegenerative disorders or diseases.

[0033] Additional Therapeutic Agent: An optional component of certain formulation embodiments disclosed herein that is additionally included in some LNGB. In some embodiments, the additional therapeutic agent is a bioactive compound. Representative, but non-limiting, additional therapeutic agents may include gonadotropin releasing hormone ("GnRH") antagonists and / or agonists, E3 ubiquitin ligase recruiting ligands, anti-cancer drugs (e.g., chemotherapeutic drugs), kinase antagonists and / or agonists, GPCR antagonists and / or agonists, antimalarials, antifungals, antivirals, antibacterials, immunosuppressants, anti-inflammatory drugs, pulmonary agents, and the like.

[0034] Therapeutically effective amount: An amount of LNGB or a formulation thereof sufficient to provide or cause a contraceptive effect (e.g., inhibit ovulation) in a subject (in certain embodiments, a female subject); and / or to treat a particular disorder or disease, or to reduce or eradicate one or more of the symptoms thereof, and / or to prevent the onset of the disease or disorder.

[0035] Treating / Treatment: The treatment of a disease or condition of interest in a land mammal (including but not limited to humans, dogs, or cats) having the disease or condition, examples of which include, but are not limited to, the following: (i) prophylactic administration to prevent the disease or condition from developing in a subject or, where necessary, to alleviate symptoms associated with the condition, particularly where such subject is susceptible to but has not yet been diagnosed as having the condition; (ii) inhibiting the disease or condition, e.g., halting or slowing its progression; (iii) alleviating the disease or condition, e.g., causing regression of the disease or condition or its symptoms; or (iv) stabilizing the disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably, or the terms "disease" and "condition" may differ in that a particular disease or condition may not have a known causative factor (so that the etiology has not yet been determined and thus it has not yet been recognized as a disease but rather as an undesirable condition or syndrome, and more or less a specific set of symptoms has been identified by clinicians.

[0036] (introduction)

[0037] Levonorgestrel butanoate ("LNGB") (also referred to in the art as levonorgestrel 17β-butanoate) is a butyl prodrug of the widely used progestin levonorgestrel (LNG). LNGB is a long-acting, injectable means of contraception. As a progestin, LNG's mode of contraceptive effect is via inhibition of ovulation and possibly an additional defense mechanism since cervical mucus may have a role. LNGB is a long-acting, injectable compound that can be used without increased venous thromboembolism (VTE) risk. Furthermore, injection of LNGB improves compliance over progestin-only daily pills because it can be performed by subcutaneous self-administration. Such flexibility of administration is of great benefit to the user as they do not need to go to a clinic for a single injection, which takes less than a minute. Furthermore, levonorgestrel is not glucocorticoid receptor active, the receptor thought to affect weight gain.

[0038] A LNGB-containing contraceptive composition was developed by the World Health Organization (WHO); however, this composition exhibited aggregation of LNGB particles, resulting in loss of product stability and reproducibility of clinical batches. Other compositions have been developed that attempted to address this aggregation / stability issue; however, one such composition resulted in a shorter duration of activity than expected. This formulation was similar in content to the WHO formulation, but contained stabilizing excipients to prevent the aggregation observed in the WHO formulation. Other compositions in the art exhibited impurity issues that prevented their use in FDA clinical trials and therefore do not present a viable option for commercial formulations.

[0039] There is a need in the art for improved LNGB formulations. This is because LNG is a progestin that has been established to be one of the safest and most effective agents for use in contraception. Additionally, women with health conditions such as moderate or morbid obesity, hypertension, and diabetes may be advised to avoid the use of EE-containing contraceptives, but their risk of VTE due to pregnancy is significantly increased beyond the risk associated with EE-containing products. As noted above, LNGB would not increase VTE risk. There is also a need for formulations that can be administered in a manner that promotes confidentiality of the administration method. For example, injectable methods have the advantage of privacy, since the user is left with no evidence of use after injection. Injectable methods are relatively long-acting and have a lower typical failure rate than combined hormonal oral contraceptives, patches, or progestin-only pills ("POPs"). POPs require strict adherence to taking the POP at the same time each day (or with no more than 12 hours difference, as with desogestrel POPs), and efficacy may be reduced in obese women.

[0040] Described herein are embodiments of improved formulations comprising LNGB, which can be used to administer higher concentrations of LNGB that exhibit desirable activity and provide longer-lasting contraceptive effects that require smaller volumes for administration. Additionally, the disclosed formulations are suitable for subcutaneous administration, and thus are user-friendly as they can be self-administered. The disclosed formulation embodiments exhibit excellent stability of LNGB particles.

[0041] Formulation embodiments

[0042] Disclosed herein are embodiments of formulations that include levonorgestrel butanoate ("LNGB") and one or more pharma- ceutically acceptable excipients. In certain embodiments, the formulation is a water-based suspension of LNGB particles in combination with the one or more pharma-ceutically acceptable excipients. The LNGB particles are size-controlled and exhibit high stability without aggregation and / or degradation. In certain embodiments, the LNGB particles of the formulation embodiments exhibit a particle size that facilitates the ability to increase the LNGB concentration in the formulation.

[0043] In certain embodiments, the formulation comprises LNGB at a concentration of greater than 15 mg / mL, e.g., between 20 mg / mL and 100 mg / mL, or between greater than 20 mg / mL and less than 100 mg / mL, or between greater than 20 mg / mL and 90 mg / mL, or between 20 mg / mL and 90 mg / mL, or between 30 mg / mL and 90 mg / mL, or between 40 mg / mL and 90 mg / mL, between 50 mg / mL and 90 mg / mL, or between 60 mg / mL and 90 mg / mL, or between 70 mg / mL and 90 mg / mL, or between 80 mg / mL and 90 mg / mL. In certain embodiments, the LNGB concentration is in the range of 30 mg / mL to less than 90 mg / mL, or greater than 30 mg / mL to less than 80 mg / mL, or 40 mg / mL to 80 mg / mL, 50 mg / mL to 80 mg / mL, or 60 mg / mL to 80 mg / mL, or 70 mg / mL to 80 mg / mL. In certain embodiments, the LNGB is present at a concentration in the range of 30 mg / mL to 100 mg / mL, for example, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL.

[0044] In some embodiments, the amount of LNGB included in the formulation is in the range of greater than 2% (w / v), e.g., 3% (w / v) to 15% (w / v), or 4% (w / v) to 15% (w / v), or 5% (w / v) to 15% (w / v), or 6% (w / v) to 15% (w / v), or 7% (w / v) to The amount of LNGB in the formulation may be 15% (w / v), or 8% (w / v) to 15% (w / v), or 9% (w / v) to 15% (w / v), or 10% (w / v) to 15% (w / v), or 11% (w / v) to 15% (w / v), or 12% (w / v) to 15% (w / v), or 13% (w / v) to 15% (w / v), or 14% (w / v) to 15% (w / v). In certain embodiments, the amount of LNGB in the formulation is 2% (w / v), 5% (w / v), 7% (w / v), 8% (w / v), 10% (w / v), or 15% (w / v).

[0045] The formulation embodiments may be formulated to deliver LNGB in a dosage range of 20 mg to 160 mg, e.g., 30 mg to 140 mg, or 30 mg to 120 mg, or 30 mg to 100 mg, or 30 mg to 80 mg. In some embodiments, the dosage may range from 30 mg to 80 mg, or 40 mg to 80 mg, or 50 mg to 80 mg, or 60 mg to 80 mg, or 70 mg to 80 mg. In certain embodiments, the dosage is 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 150 mg. In representative embodiments, a 40 mg dose is administered at a LNGB concentration of 20 mg / mL, or a 40 mg dose at a LNGB concentration of 70 mg / mL, or a 50 mg dose at a LNGB concentration of 70 mg / mL, or a 60 mg dose at a LNGB concentration of 70 mg / mL, or a 70 mg dose at a LNGB concentration of 70 mg / mL.

[0046] The LNGB particles contained in the formulation have a median diameter (D) in the range of 5 μm to 20 μm, for example, 7 μm to 16 μm, or 9 μm to 16 μm, or 11 μm to 16 μm, or 12 μm to 16 μm, or 13 μm to 16 μm. 50In representative embodiments, the LNGB particles have a median diameter in the range of 11 μm to 15 μm, e.g., 12 μm to 15 μm, or 12.6 μm to 15 μm, or 12 μm to 14 μm, including 11.3 μm, 12.4 μm, 13.2 μm, 13.7 μm, or 14.2 μm. In separate embodiments, the median diameter is not or is other than 6.3 μm, 6.4 μm, 6.6 μm, 23.1 μm, 22.7 μm, 18.6 μm, 18.0 μm, 18.4 μm, 21.0 μm, or 15.8 μm. In representative embodiments, the LNGB particles have a median diameter of 11 μm to 13 μm (e.g., 11.3 μm or 12.4 μm); or a median diameter of 13 μm to 15 μm (e.g., 13 μm to 14 μm, or 13.2 μm, 13.7 μm, or 14.2 μm). In some such embodiments, the LNGB particles may be included in the formulation at a concentration ranging from 20 mg / mL to 100 mg / mL, e.g., 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL.

[0047] The formulation further comprises one or more pharma- ceutically acceptable excipients. Such pharma-ceutically acceptable excipients may include, but are not limited to, wetting agents, dispersing agents, emulsifying agents, thickening agents, buffering agents, and / or preserving agents. In certain embodiments, the pharma-ceutically acceptable excipients comprise at least one wetting agent, at least one dispersing agent, at least one thickening agent, at least one buffering component, and at least one preserving agent. In other embodiments, the pharma-ceutically acceptable excipients comprise at least one dispersing agent, at least one thickening agent, at least one buffering component, and at least one preserving agent. In representative embodiments, the pharma-ceutically acceptable excipients comprise a wetting agent, a dispersing agent, a thickening agent, a preserving agent, a buffering component comprising two buffering agents, and an optional emulsifying agent. In yet further representative embodiments, the pharma-ceutically acceptable excipients comprise a wetting agent, two dispersing agents, a thickening agent, a preserving agent, and a buffering component comprising two buffering agents. In yet further representative embodiments, the pharma- ceutically acceptable excipient comprises two dispersing agents, or a dispersing agent and an emulsifying agent; a thickening agent; a preservative; and a buffer component comprising two buffering agents. In some embodiments, the pharma-ceutically acceptable excipient may further comprise an isotonicity agent, a bulking agent, a solvent, a stabilizer, a lubricant, a flocculating agent, a suspending agent, an electrolyte, an antioxidant, a chelating agent, or any combination thereof.

[0048] Wetting and dispersing agents that may be used in embodiments of the disclosed formulations may include, but are not limited to, sorbitan surfactants, such as polysorbate surfactants (e.g., polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80); sorbitan fatty acid esters (e.g., sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan sesquioleate, sorbitan trioleate, or combinations thereof); polyalkylene oxide-containing compounds (e.g., polyoxyalkylated fats, polyoxyalkylated glycerides, polyoxyalkylated fatty acids, and the like); alkylphenol compounds; sulfate surfactants (e.g., sodium lauryl sulfate, and the like); glyceryl monooleate; lecithin; methyl laurate; linolizated glycerides (e.g., linolizated oleotriglyceride, and the like); and combinations thereof. In certain embodiments, the wetting agent is a sorbitan surfactant, such as a polysorbate surfactant (e.g., polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80). In certain embodiments, the dispersing agent is a sorbitan fatty acid ester, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan sesquioleate, sorbitan trioleate; a sulfate surfactant (e.g., sodium lauryl sulfate); or a combination thereof. In an exemplary embodiment, a combination of polysorbate 80 (TWEEN® 80) and sorbitan monopalmitate (Span® 40) is used. In another exemplary embodiment, a combination of polysorbate 80 (TWEEN® 80), sorbitan monopalmitate (Span® 40), and sorbitan monolaurate (Span® 20) is used.In yet additional embodiments, a combination of sorbitan monopalmitate (Span® 40) and sodium lauryl sulfate is used. In yet additional embodiments, sorbitan monolaurate (Span® 20) is used. The total amount of wetting agent and / or dispersing agent that may be used in the formulation may be in the range of 0.1% w / v to 11% w / v, for example, 0.2% w / v to 10.5% w / v, or 0.4% w / v to 10.5% w / v, or 0.9% w / v to 10.5% w / v, or 6% w / v to 10.5% w / v, or 7% w / v to 10.5% w / v, or 10% w / v to 10.5% w / v. In certain embodiments, the total amount of wetting agent and / or dispersing agent used is 0.2% w / v, 0.4% w / v, 0.9% w / v, 6.2% w / v, 7.2% w / v, or 10.2% w / v. In any or all of these embodiments, the total amount of wetting agent can be provided by using a single wetting agent, or a combination of wetting agent and dispersing agent, or a combination of two or more dispersing agents. In some embodiments where a wetting agent and dispersing agent (e.g., polysorbate 80 (TWEEN® 80) and sorbitan monopalmitate (Span® 40)) are used, the ratio of the wetting agent to the dispersing agent can be in the range of 2:0.1 to 6:0.1, e.g., 3:0.1 to 5:0.1 (polysorbate 80:sorbitan monopalmitate). In separate embodiments, when polysorbate 80 and sorbitan monopalmitate are used in the formulation, they are included in a ratio that is not 1:1 or is other than 1:1. In certain representative embodiments, polysorbate 80 is used in an amount ranging from 0.1% w / v to 10% w / v, such as 0.2% w / v to 10% w / v, or 6% w / v to 10% w / v, or 6% w / v, 7% w / v, 8% w / v, 9% w / v, or 10% w / v. In further representative embodiments, sorbitan monopalmitate is used in an amount ranging from 0.05% w / v to 0.2% w / v, such as 0.1% w / v to 0.2% w / v. In further representative embodiments, sorbitan monolaurate is used in an amount ranging from 0.0.5% w / v to 0.2% w / v, such as 0.1% w / v to 0.2% w / v.In a further exemplary embodiment, sodium lauryl sulfate is used in an amount ranging from greater than 0% w / v to 0.7% w / v, for example, 0.1% w / v to 0.7% w / v.

[0049] Viscosifying agents that may be used in embodiments of the disclosed formulations may include, but are not limited to, cellulose-based substances such as carboxymethylcellulose (or salt forms thereof, including sodium carboxymethylcellulose or calcium carboxymethylcellulose), methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and / or cross-linked forms thereof; polyvinyl alcohol; polyvinylpyrrolidone; acacia; gelatin; or combinations thereof. In certain embodiments, the viscosity increasing agent is a carboxymethylcellulose compound, such as sodium carboxymethylcellulose. The amount of viscosity increasing agent that may be used in embodiments of the disclosed formulations may range from 0.4% w / v to 2% w / v, e.g., 0.5% w / v to 2% w / v, or 1% w / v to 2% w / v, or 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.9% w / v, or 1% w / v.

[0050] The emulsifier that can be used in the disclosed formulation embodiments can include, but is not limited to, ionic surfactants or non-ionic surfactants.In some embodiments, the emulsifier is a polyalkylene oxide-based non-ionic surfactant, such as a polyalkoxylated castor oil compound (e.g., polyoxyl-35 castor oil [or "Kolliphor® EL"]) and / or a polyalkylene oxide hydroxylated fatty acid (e.g., polyethylene glycol (15)-hydroxystearate ["Kolliphor® HS"]); or a combination thereof. The amount of emulsifier that may be included in embodiments of the disclosed formulations may range from greater than 0% w / v to 8% w / v, for example, 2% w / v to 7.5% w / v, or 3% w / v to 7% w / v, or 4% w / v to 7% w / v, or 4.4% w / v to 7%, or 5% w / v to 7% w / v, or 3% w / v, 4%% w / v, 4.4%% w / v, 5%% w / v, 6%% w / v, or 7% w / v.

[0051] Preservatives that may be used in embodiments of the disclosed formulations include, but are not limited to, paraben compounds, such as methylparaben, propylparaben, butylparaben, and the like; phenylmercury compounds, such as phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, and the like; benzyl compounds, such as benzyl alcohol, benzalkonium chloride, and the like; aromatic compounds, such as thiomerosal, phenol, m-cresol, and the like; and alkyl halides, such as chlorobutanol. In a representative embodiment, the preservative is benzyl alcohol. The amount of preservative that may be used in embodiments of the disclosed formulations may range from greater than 0% w / v to 5% w / v, for example, 0.5% w / v to 2% w / v, or 1% w / v to 2% w / v, or 1.03% w / v.

[0052] The buffer components that can be used in the embodiments of the formulations disclosed herein can include, but are not limited to, phosphate buffer, such as disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, etc.; acetate buffer, such as sodium acetate, tris acetate, triethylammonium acetate, etc.; citrate buffer, such as sodium citrate, etc.; tartrate buffer, such as disodium tartrate dihydrate, diammonium tartrate, potassium sodium tartrate, potassium sodium tartrate tetrahydrate, etc.; and amine-based buffer, such as triethanolamine, etc.; or combinations thereof.In a representative embodiment, the buffer component comprises a combination of two buffers, such as disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate. The total amount of buffer components that may be used in embodiments of the disclosed formulations may range from greater than 0% w / v to 2% w / v, e.g., 0.2% w / v to 2% w / v, or 1% w / v to 2% w / v, or 1.5% w / v to 2% w / v, or 0.3% w / v, 1.49% w / v, or 1.79% w / v.

[0053] Embodiments of the formulation further include a balance of sterile water (eg, sterile water suitable for injection (eg, sterile WFI USP)) to reach, for example, 100% in the final volume of the formulation.

[0054] In certain embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB having a median diameter in the range of 10 μm to 16 μm (e.g., 13.2 μm, 13.7 μm, or 15.4 μm); a wetting agent (e.g., polysorbate 80); a dispersing agent (e.g., sorbitan monopalmitate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0055] In certain embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB; a wetting agent (e.g., polysorbate 80); a dispersing agent (e.g., sorbitan monolaurate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0056] In yet additional embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB having a median diameter in the range of 10 μm to 17 μm (e.g., 11.6 μm, 13.6 μm, 14.2 μm, or 16.3 μm); two dispersing agents (e.g., sodium lauryl sulfate and sorbitan monopalmitate); a viscosity increasing agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0057] In yet further embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB; a wetting agent (e.g., polysorbate 80); two dispersing agents (e.g., sorbitan monopalmitate and sorbitan monolaurate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0058] In yet further embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB having a median diameter in the range of 10 μm to 15 μm (e.g., 11.3 μm or 14.2 μm); a dispersing agent, e.g., sorbitan monopalmitate; an emulsifying agent (e.g., polyoxyl-35 castor oil or polyethylene glycol (15)-hydroxystearate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0059] In yet further embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB having a median diameter in the range of 11 μm to 17 μm (e.g., 12.4 μm, 13.6 μm, 14.2 μm, or 16.3 μm); a wetting agent (e.g., sorbitan monolaurate); an emulsifier (e.g., polyoxyl-35 castor oil or polyethylene glycol (15)-hydroxystearate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0060] In yet further embodiments, the formulation comprises, consists essentially of, or consists of a combination of LNGB having a median diameter in the range of 11 μm to 15 μm (e.g., 12.4 μm, 13.6 μm, or 14.2 μm); a wetting agent (e.g., sorbitan monolaurate); an emulsifier (e.g., polyoxyl-35 castor oil or polyethylene glycol (15)-hydroxystearate); a thickening agent (e.g., sodium carboxymethylcellulose); two buffer compounds (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (e.g., benzyl alcohol); and sterile WFI USP.

[0061] In any of the embodiments in which the formulation consists essentially of the components listed above, the formulation does not include components that are considered in the art to be toxic to subjects and / or that reduce the stability of the particles (e.g., by causing aggregation or degradation). Exemplary formulation embodiments are also described in the Examples section herein.

[0062] (Method embodiment)

[0063] Also disclosed herein are embodiments of methods for making the formulation embodiments described herein.The disclosed method embodiments are conventionally performed on a large scale, and they can be performed at a single manufacturing location, whereas other methods in the art require separate method steps to be performed at separate / discrete locations in separate geographic locations due to the need for specialized machinery and / or operating parameters.The disclosed method embodiments also provide the ability to control the particle size of the LNGB particles so that stable and / or more concentrated particle formulations can be made.

[0064] In certain embodiments, the method includes a step of preparing the LNGB particles before combining the LNGB particles with one or more pharmacologically acceptable excipients. In certain embodiments, the LNGB particles are prepared by performing sterile filtration followed by spray drying to prepare sterile particles with controlled median diameter. The sterile filtration produces a filtrate containing levonorgestrel butanoate, and the particles of levonorgestrel butanoate can be prepared from the filtrate by spray drying the filtrate. In an independent embodiment, spray drying can be replaced with micronization (e.g., dry or wet milling or grinding). An independent embodiment of such a method can further include an intermediate drying step or crystallization step before micronization. However, the embodiment of the method described herein does not include the use of a sterilization step (e.g., irradiation-based sterilization techniques (e.g., gamma irradiation or electron beam irradiation)). This is because such techniques result in the generation of impurities that make the formulation unsuitable for administration to a subject. The process embodiments described herein that involve spray drying also do not include a recrystallization step.

[0065] In certain embodiments, the method consists of, or consists essentially of, sterile filtration and spray drying. In certain embodiments, the method consists of, or consists essentially of, sterile filtration, drying and / or recrystallization, and micronization. When the method consists essentially of sterile filtration and spray drying, the method does not include using gamma radiation sterilization or e-beam radiation sterilization. This is because such sterilization techniques result in the generation of impurities that make the formulation unsuitable for administration to a subject. See, for example, Figures 1A and 1B. Figures 1A and 1B show that terminal radiation sterilization (e.g., gamma radiation or e-beam radiation) of LNGB particles results in impurities (Figure 1A) that cause the LNGB particles to have a yellow color (Figure 1B). These impurities are also identified using high performance liquid chromatography (HPLC). Representative such HPLC traces are shown in Figures 3-5, which show that the impurities cannot be removed or prevented even by purging with an inert gas. This color and the presence of impurities make the LNGB particles unsuitable for administration under FDA requirements and specifications.

[0066] Sterile filtration may include filtering the LNGB using a solvent (e.g., an ether-based solvent). In some embodiments, the solvent is tetrahydrofuran ("THF"), 2-methyl THF, or the like. The LNGB is filtered through an autoclaved membrane filter using the solvent and isolated as a filtrate. In some embodiments, the membrane filter is a 0.2 μm PTFE membrane filter. If tubing is used during the filtration process, the tubing is typically chemically resistant tubing that is chemically resistant to the solvent used during filtration.

[0067] In certain embodiments, spray drying involves utilizing a flow rate, inlet temperature, atomization pressure, and blower speed to produce LNGB particles from the filtrate obtained from the sterile filtration. In certain embodiments, the flow rate is in the range of 4 mL / min to 6 mL / min, e.g., 4 mL / min, 5 mL / min, 6 mL / min, or fractions thereof. The spray drying inlet temperature is in the range of 120°C to 145°C, e.g., 130°C to 140°C, or 130°C to 132°C. The atomization pressure is in the range of 0.05 mPa to 0.1 mPa, e.g., 0.05 mPa to 0.08 mPa, or 0.06 mPa, 0.07 mPa, or 0.08 mPa. The blower speed is in the range of 0.3 mPa to 0.5 mPa. 3 / min~0.6m 3 / min range, e.g., 0.4m 3 / min~0.55m 3 / min, or 0.45m 3 / min~0.5m 3 / min, or 0.49m 3 In a particular embodiment, the flow rate is 5 mL / min, the spray dryer inlet temperature is 132° C., the atomization pressure is 0.07 mPa, and the blower speed is 0.49 m 3 / min.

[0068] The method further comprises combining the LNGB particles with one or more pharma- ceutically acceptable excipients described herein. In some embodiments, the LNGB particles are combined with the pharma- ceutically acceptable excipients by making a first solution comprising one or more of the pharma-ceutically acceptable excipients and a second solution comprising the LNGB particles. In some embodiments, the first solution may comprise a thickening agent, a preservative, a buffer component, or any combination thereof; and sterile water. In some embodiments, the second solution may comprise the LNGB particles; sterile water; and any wetting agent, dispersant, and / or emulsifier. The first solution and the second solution are then combined in any order (e.g., by adding the first solution to the second solution, or adding the second solution to the first solution) to provide the formulation. In yet other embodiments, a single solution of the LNGB particles, sterile water, wetting agents, dispersing agents, thickening agents, buffer components, preservatives, and optional emulsifiers. In some embodiments, the formulation and / or the first solution and / or the second solution may be homogenized to provide a uniform dispersion.

[0069] Methods of using embodiments of the formulation are also disclosed herein. In certain embodiments, the methods include using the formulation as a contraceptive formulation to provide a long-lasting reversible contraceptive effect to a subject (e.g., a female subject). The disclosed formulation embodiments are stable, and the disclosed formulation embodiments exhibit adequate contraceptive effect (e.g., ovulation suppression) for at least two months, more typically longer than two months, e.g., at least three months, or four months, five months, or even six months. Furthermore, the disclosed formulation embodiments exhibit desirable activity without any significant negative effect on liver function during treatment and / or recovery. Side effects typically observed with conventional contraceptives (e.g., Depo-Provera®) can be avoided or at least significantly minimized with the disclosed formulation embodiments, especially because less hormone is required for contraceptive effect. Such side effects can include weight gain and mood swings. In additional embodiments, the methods may include using the formulations to treat or prevent progestin-associated diseases or disorders (e.g., abnormal uterine bleeding, endometrial hyperplasia, endometriosis, uterine fibroids, premenstrual syndrome, cancer, and other disorders or conditions of the reproductive system / tissues / organs).

[0070] The formulation embodiments are suitable for various types of administration techniques, including but not limited to injection techniques, such as subcutaneous (or "SC") or intramuscular (or "IM") injections. The formulation embodiments also have the advantage of being suitable for self-administration. In certain embodiments, the formulations exhibit superior contraceptive activity when administered by subcutaneous injection. For example, FIG. 6 presents a graph comparing the results obtained from intramuscular injection with those obtained from subcutaneous injection. As can be observed in FIG. 6, certain formulation embodiments evaluated in this example exhibited longer lasting contraceptive efficacy (or "resumption of ovulation" time) when administered subcutaneously compared to when administered intramuscularly. The formulation embodiment of FIG. 6 included LNGB having a median diameter in the range of 10 μm to 16 μm; a wetting and dispersing agent (i.e., polysorbate 80 and sorbitan monopalmitate); a viscosity increasing agent (i.e., sodium carboxymethylcellulose); two buffer compounds (i.e., disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate); a preservative (i.e., benzyl alcohol; and sterile WFI USP.

[0071] In certain embodiments, the method of use is a method of providing contraception to a subject, the method comprising administering a dosage of levonorgestrel butanoate by administering an embodiment of the formulation of the present disclosure to the subject by injection. In some embodiments, the injection comprises a subcutaneous injection. In other embodiments, the injection comprises an intramuscular injection. In yet other specific embodiments, the method of use is a method of treating or preventing a progestin-associated disease or condition in a subject, the method comprising administering an embodiment of the formulation of the present disclosure to the subject.

[0072] (Summary of Some Embodiments)

[0073] Disclosed herein are embodiments of a pharmaceutical formulation comprising: levonorgestrel butanoate particles having a median diameter in the range of 10 μm to 16 μm; a wetting agent; and a dispersing agent, emulsifying agent, or a combination thereof; wherein the levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL, with the proviso that, when the pharmaceutical formulation comprises a wetting agent and a dispersing agent, the wetting agent and the dispersing agent are present in a ratio of 2:0.1 to 6:0.1 (wetting agent:dispersing agent).

[0074] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter ranging from greater than 12.6 μm to a median diameter of 15 μm.

[0075] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter of 13 μm to 14 μm.

[0076] In any or all of the above embodiments, the formulation comprises a wetting agent and a dispersing agent, and the ratio of wetting agent to dispersing agent is from 3:0.1 to 5:0.1.

[0077] In any or all of the above embodiments, the formulation is formulated to administer a dose of levonorgestrel butanoate in the range of 30 mg to 90 mg.

[0078] In any or all of the above embodiments, the formulation provides contraceptive efficacy for at least 2 months to 6 months.

[0079] In any or all of the above embodiments, the formulation provides contraceptive efficacy for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0080] In any or all of the above embodiments, the wetting agent is a polysorbate surfactant selected from polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0081] In any or all of the above embodiments, the dispersing agent is a sorbitan surfactant selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan sesquioleate, sorbitan trioleate; a sulfate surfactant; or any combination thereof.

[0082] In any or all of the above embodiments, the formulation further comprises a viscosity increasing agent selected from carboxymethylcellulose and / or its salt forms; methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and / or cross-linked forms thereof; polyvinyl alcohol; polyvinylpyrrolidone; acacia; gelatin; or any combination thereof.

[0083] In any or all of the above embodiments, the formulation further comprises a buffer component selected from a phosphate buffer, an acetate buffer, a citrate buffer, a tartrate buffer, an amine-based buffer, or any combination thereof.

[0084] In any or all of the above embodiments, the formulation further comprises a preservative selected from a paraben compound, a phenylmercurial compound, a benzyl compound, an aromatic compound, an alkyl halide, or any combination thereof.

[0085] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter of 13 μm to 14.5 μm; the wetting agent is polysorbate 80; and the dispersing agent is present and is sorbitan monopalmitate.

[0086] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter of 13.5 μm to 14 μm; the wetting agent is polysorbate 80; and the dispersing agent is present and is sorbitan monopalmitate.

[0087] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter of 13.7 μm; the wetting agent is polysorbate 80; and the dispersing agent is present and is sorbitan monopalmitate.

[0088] In any or all of the above embodiments, the formulation further comprises sodium carboxymethylcellulose, disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and benzyl alcohol.

[0089] In any or all of the above embodiments, the emulsifier is present and is an ionic or non-ionic surfactant.

[0090] In any or all of the above embodiments, the pharmaceutical formulation comprises levonorgestrel butanoate particles having a median diameter in the range of 12 μm to 15 μm; a wetting agent; a dispersing agent, emulsifying agent, or a combination thereof; a thickening agent; a buffer component; and a preservative, wherein the levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL, with the proviso that, when the pharmaceutical formulation comprises a wetting agent and a dispersing agent, the wetting agent and the dispersing agent are present in a ratio of 3:0.1 to 5:0.1 (wetting agent:dispersing agent).

[0091] In any or all of the above embodiments, the pharmaceutical formulation comprises levonorgestrel butanoate particles having a median diameter of 13 μm to 14.5 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; the thickening agent is sodium carboxymethylcellulose; the buffer component is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate; and the preservative is benzyl alcohol.

[0092] In any or all of the above embodiments, the pharmaceutical formulation comprises levonorgestrel butanoate particles having a median diameter of 13.5 μm to 14 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; the thickening agent is sodium carboxymethylcellulose; the buffer component is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate; and the preservative is benzyl alcohol.

[0093] In any or all of the above embodiments, the formulation comprises levonorgestrel butanoate particles having a median diameter in the range of 11 μm to 15 μm; at least one dispersing agent; a viscosity enhancing agent; a buffer component; and a preservative, wherein the levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL.

[0094] In any or all of the above embodiments, the levonorgestrel butanoate particles have a median diameter ranging from greater than 11.3 μm to a median diameter of 14.2 μm.

[0095] In any or all of the above embodiments, the dispersing agent is sorbitan monopalmitate.

[0096] In any or all of the above embodiments, the formulation is formulated to administer a dose of levonorgestrel butanoate in the range of 30 mg to 90 mg.

[0097] Also disclosed are embodiments of methods of making a pharmaceutical formulation according to any or all of the above embodiments, the methods including subjecting levonorgestrel butanoate to sterile filtration to provide a filtrate containing sterile levonorgestrel butanoate; producing levonorgestrel butanoate particles from the filtrate; and combining the levonorgestrel butanoate particles with one or more of a wetting agent, a dispersing agent, an emulsifying agent, or combinations thereof; the methods do not include using irradiation for any sterilization.

[0098] In any or all of the above embodiments, the step of making levonorgestrel butanoate particles from the filtrate includes spray drying the filtrate.

[0099] In any or all of the above embodiments, spray drying the filtrate controls the median size of the levonorgestrel butanoate particles.

[0100] Also disclosed are embodiments of methods of making a pharmaceutical formulation according to any or all of the above embodiments, the method including micronizing levonorgestrel butanoate to provide levonorgestrel butanoate particles, and combining the levonorgestrel butanoate particles with one or more of a wetting agent, a dispersing agent, an emulsifying agent, or combinations thereof; the method does not include using irradiation for any sterilization.

[0101] In any or all of the above embodiments, the method does not include a step using gamma irradiation or electron beam irradiation.

[0102] Also disclosed are embodiments of methods of providing contraception to a subject, the methods comprising administering a dosage of levonorgestrel butanoate in the range of 20 mg to 140 mg by administering by injection to the subject any or all of the formulation embodiments described above.

[0103] In any or all of the above embodiments, the injection comprises a subcutaneous injection.

[0104] In any or all of the above embodiments, the injection comprises an intramuscular injection.

[0105] In any or all of the above embodiments, the concentration of levonorgestrel butanoate in the formulation is 70 mg / mL.

[0106] Also disclosed are methods of treating or preventing a progestin-associated disease or condition in a subject, the methods comprising administering to the subject any or all of the formulation embodiments described above. EXAMPLES

[0107] (Example)

[0108] Example 1

[0109] In this example, spray-dried micronized LNGB particles were prepared. The LNGB was prepared in an ISO5 clean room using a Yamato Organic Solvent Recovery Unit GAS410, a Watson Marlow peristaltic pump 520DiN, a Yamato Versatile Spray Dryer GB-210A equipped with a two-way nozzle system (0.4 μm inner diameter (ID)) and a specially designed flexible film isolator. Prior to spray drying, 5% LNGB in tetrahydrofuran (THF) was sterile filtered through an autoclaved 0.2 μm PTFE membrane filter. Gore® Sta-Pure® laminated PTFE tubing was used for chemical resistance to THF. The following controlled settings were used: flow rate approximately 5 mL / min, spray drying inlet temperature 132° C., atomization pressure 0.07 mPa, and blower speed 0.49 m. 3 / min. Release criteria are based on analysis for elemental impurities (using USP <232, 233>, the relevant portions of which are incorporated herein by reference), a validated GC method, residual solvents by X-ray powder diffractometry (XRPD) (USP <941> (relevant portions of which are incorporated herein by reference), particle size distribution (USP <429> (relevant portions of which are incorporated herein by reference), and sterility (USP <71> (relevant portions of which are incorporated herein by reference).

[0110] Two formulation embodiments were made using the spray-dried LNGB particles obtained from the above process, the contents and amounts of which are presented in Table 1 below. [Table 1-1] [Table 1-2]

[0111] Example 2

[0112] In this example, a representative Phase I study is described to evaluate the efficacy of the formulation embodiments disclosed herein.This example describes two specific formulation embodiments, but other formulation embodiments disclosed herein are equally applicable.

[0113] Normal weight (e.g., BMI < 30 kg / m 2 ) or obesity (e.g., BMI ≥ 30 kg / m 2 and <40kg / m 2Female subjects, age 65+, are divided into five groups using two formulation embodiments with different concentrations of LNGB. Three groups receive LNGB as a subcutaneous (SC) injection, and the other two groups receive LNGB as an intramuscular (IM) injection. The initial dose administered is 40 mg using 2 mL of the 20 mg / mL concentration. Repeats of this 40 mg SC dose (or second stage doses) are administered using either 2 mL of the 20 mg / mL concentration or 0.57 mL of the 70 mg / mL concentration. In yet other examples, another dose of 50 mg is administered using 0.71 mL of the 70 mg / mL concentration. In yet other examples, another dose of 60 mg is administered using 0.86 mL of the 70 mg / mL concentration. These SC injections are administered slowly under the skin of the abdomen following standard subcutaneous injection procedures to ensure that the drug is distributed to the tissue layers between the skin and the muscle. For IM injections, the formulation is injected slowly into the deltoid muscle following standard intramuscular injection procedures to avoid injection into a blood vessel; however, these SC injections may be in locations other than the abdomen and these IM injections may be in locations other than the deltoid muscle.

[0114] The first formulation used in this example is an LNGB injectable suspension at a concentration of 40 mg / 2 mL (20 mg / mL). This formulation includes a suspension of spray-dried LNGB particles with an approximate median diameter of 13 microns in an aqueous medium containing the following pharma- ceutically acceptable excipients: highly purified polysorbate 80 (Tween® 80), spray-dried sorbitan monopalmitate (Span® 40), sodium carboxymethylcellulose, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, benzyl alcohol, and WFI (USP). Each vial contains 2 mL at 20 mg / mL for a total of 40 mg.

[0115] The second formulation used in this example is a LNGB injectable suspension at a concentration of 140 mg / 2 mL (70 mg / mL). This higher concentration formulation includes a suspension of spray-dried LNGB particles with an approximate median diameter of 13.7 microns in an aqueous medium containing the following pharma- ceutically acceptable excipients: highly purified polysorbate 80 (Tween® 80), spray-dried sorbitan monopalmitate (Span® 40), sodium carboxymethylcellulose, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, benzyl alcohol, and WFI (USP). Each vial contains 2 mL at 70 mg / mL for a total of 140 mg. A 40 mg dose may be administered using 0.57 mL of the 2 mL total above. A 50 mg dose may be administered using 0.71 mL of the 2 mL total above. A 60 mg dose may be administered using 0.86 mL of the 2 mL total above.

[0116] Subjects are evaluated using the following pharmacokinetic / pharmacodynamic parameters: · Pharmacokinetic (PK) levels of LNG; · Serum progesterone (P4), luteinizing hormone (LH), estradiol (E2), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG); · Ovarian follicular activity assessed by transvaginal ultrasound; Endometrial thickness assessed by transvaginal ultrasound; and Bleeding profile (the bleeding pattern (number of bleeding days, light bleeding, absence of bleeding, length of the longest episode, and intensity of bleeding) will be analyzed over a 30-day and a 90-day reference period). After resumption of menstruation, the characteristics of the menstrual cycle will be recorded (length, intensity, duration of bleeding, symptoms).

[0117] The relationship between LNG levels following LNGB injection by separate delivery routes (IM and SC) will be evaluated along with the effect on ovulation as levels decline over several weeks. Other endpoints that may be evaluated include resumption of ovulation and normal menstrual cycles. Evaluation of these changes in ovarian function and hormone profile will then be followed up. The LNG plasma concentration levels achieved after administration of an injection of 100 mg / kg of LNG are correlated with the LNG plasma concentration levels achieved after administration of an injection of 100 mg / kg of LNG. The effect of BMI on the test results is also evaluated. In certain embodiments, blood samples to evaluate platelets, blood cell differentials (RBC, WBC, hemoglobin, hematocrit, basophil%, eosinophil%, lymphocyte%, monocyte%, neutrophil%, and platelets), and clinical chemistry, including basic metabolic panel and lipid profile (glucose, creatinine, calcium, potassium, sodium, chloride, BUN, total cholesterol, HDL, LDL, and triglycerides), are determined. In addition, liver function tests (SGPT, SGOT, albumin, total protein, total bilirubin, direct bilirubin, and GGT) are completed on the collected blood samples. Hormonal levels are also assessed, including progesterone, luteinizing hormone (LH), estradiol (E2), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), and LNG pharmacokinetic (PK) levels. Transvaginal ultrasound is also used to measure endometrial stripe thickness, endometrial appearance, measurement of all follicles >= 10 mm in each ovary, and an assessment of the dominant follicle.

[0118] The results from the assessment of the above metrics will be evaluated based on graded scales for systemic quantitative adverse events, subjective adverse events, and / or laboratory abnormalities using the following scales: Mild - the event requires minimal or no treatment and does not interfere with the subject's daily activities. Moderate - The event results in a low level of inconvenience or raises concerns regarding treatment options. Moderate events may cause some interference with functioning. Severe - The event prevents the subject from performing normal daily activities and the event may require systemic medication or other treatment. Severe events are usually incapacitating.

[0119] Representative grading rubrics are presented in Tables 2-4. [Table 2] [Table 3] [Table 4-1] [Table 4-2]

[0120] Example 3

[0121] This example provides additional representative formulation embodiments. The contents of the formulation embodiments of this example are described in Tables 5 and 6. The evaluation techniques described in Example 2 may be used for these additional formulations. In certain examples, when the LNGB particles are included in the formulation and the formulation remains homogenous for the desired period of time, a white homogenous suspension is obtained. [Table 5] [Table 6]

[0122] Example 4

[0123] In this example, the median days to ovulation was evaluated using formulation embodiments with different concentrations and / or particle sizes, and comparing different administration routes using these formulations. In particular, formulation number 1 and formulation number 2 from Example 1 were evaluated in subjects, and a comparison was made between the results obtained from the different formulations using two administration routes (subcutaneous and intramuscular). The results are shown in Figure 6. Figure 6 is a plot showing the days to ovulation as a function of administration route and concentration, which administration routes included intramuscular stage A (referred to as "IM-A"), subcutaneous stage B1 (referred to as "SC-B1"), and subcutaneous stage B2 (referred to as "SC-B2"). Findings from the results shown in Figure 6 are presented below.

[0124] As can be seen in Figure 6, the median days to ovulation was significantly different when using separate routes of administration for formulations with a concentration of 20 mg / mL and when using a 40 mg dose (compare data points for SC-B1 and IM-A). In particular, the median days to ovulation using SC-B1 reached 115 days compared to 86 days for IM-A. These results are significantly different, showing a difference of 29 days to ovulation for embodiments with identical injection volumes, doses, concentrations, and formulations; the only difference being the route of administration. The additional 29 days to reach median ovulation using SC injection was highly unexpected.

[0125] FIG. 6 further illustrates the striking difference in median days to ovulation using separate routes of administration for two formulations with the same dose of 40 mg but different concentrations (i.e., 70 mg / mL administered by the SC route and 20 mg / mL administered by the IM route). By comparing the data points for SC-B2 and IM-A, it can be observed that the median days to ovulation were significantly different using these separate routes of administration. In particular, the median days to ovulation using SC-B2 reached 141 days compared to 86 days for IM-A. These results are strikingly different, showing a difference of 60 days to ovulation for an embodiment with the same dose but different routes of administration (subcutaneous vs. intramuscular) and injection concentrations (70 mg / mL vs. 20 mg / mL). Given the results comparing SC-B1 with IM-A, we expected to also observe an additional 29 days longer to reach median ovulation in SC-B2 (compared to IM-A); however, the result of an additional 60 days longer to reach median ovulation using this SC injection route was highly unexpected.

[0126] As can also be seen from FIG. 6, when comparing the results for formulations with the same dose of 40 mg and using the same route of administration but with different concentrations (comparing data points for SC-B2 and SC-B1), a significant difference was observed in the median days to ovulation. The median days to ovulation using SC-B2 reached 141 days compared to 115 days for SC-B1. These results are significantly different and show a difference of 26 days to ovulation for the embodiment with the same dose but different concentrations. The reduction in injection volume using the 70 mg / mL formulation shows a significant delay in days to ovulation. This was very unexpected. These results also demonstrate that particle size can have an effect on the median days to ovulation, since this SC-B2 formulation contains LNGB particles with a larger average particle size compared to SC-B1.

[0127] Comparative Example 1

[0128] In this comparative example, a sample of LNGB particles was prepared using a gamma irradiation process to sterilize spray-dried particles. The LNGB particles were obtained by spray drying and then subjected to gamma irradiation to evaluate the effect of irradiation on the particles. The resulting particles exhibited a yellow color due to impurities present in the sample after gamma irradiation. Figure 1B shows the yellow sample compared to the starting white / translucent particles (Figure 1A) before gamma irradiation. Quantitative HPLC was performed to compare the peak profile of the LNGB particles before and after irradiation. Figures 2-5 show the HPLC traces of the samples before (Figure 2) and after (Figures 3-5). The irradiated sample produced three major peaks A, D, and E at >0.15% and a minor peak C at about 0.07%. Peaks F and G were observed in low amounts in the unpurged irradiated sample (Figure 3). N 2 In the irradiated samples purged with and purged with Ar (FIGS. 4 and 5, respectively), peaks F and G were not resolved from other peaks (either decomposed samples or gradient artifacts).

[0129] In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are merely preferred examples, and that the illustrated embodiments should not be viewed as limiting the scope of the present disclosure. Rather, that scope is defined by the appended claims. Accordingly, the inventors claim as their invention all that comes within the scope and spirit of these claims.

Claims

1. levonorgestrel butanoate particles having a median diameter in the range of 10 μm to 16 μm; A wetting agent; a dispersant, an emulsifier, or a combination thereof; A pharmaceutical formulation comprising: The pharmaceutical formulation wherein the levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL, with the proviso that, when the pharmaceutical formulation comprises a wetting agent and a dispersing agent, the wetting agent and the dispersing agent are present in a ratio of 2:0.1 to 6:0.1 (wetting agent:dispersing agent).

2. 2. The pharmaceutical formulation of claim 1, wherein the levonorgestrel butanoate particles have a median diameter ranging from greater than 12.6 μm to a median diameter of 15 μm.

3. 3. The pharmaceutical formulation of claim 1, wherein the levonorgestrel butanoate particles have a median diameter of 13 μm to 14 μm.

4. 4. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the formulation comprises the wetting agent and the dispersing agent, and the ratio of wetting agent to dispersing agent is from 3:0.1 to 5:0.

1.

5. 5. The pharmaceutical preparation of any one of claims 1 to 4, formulated for administration of a dose of levonorgestrel butanoate in the range of 30 mg to 90 mg.

6. The pharmaceutical formulation of any one of claims 1 to 5, which provides a contraceptive effect for at least 2 months to 6 months.

7. 6. The pharmaceutical formulation of any one of claims 1 to 5, which provides contraceptive efficacy for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

8. 8. The pharmaceutical formulation of any one of claims 1 to 7, wherein the wetting agent is a polysorbate surfactant selected from polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

9. 9. The pharmaceutical formulation of any one of claims 1 to 8, wherein the dispersing agent is a sorbitan surfactant selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan sesquioleate, sorbitan trioleate; a sulfate surfactant; or any combination thereof.

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, further comprising a viscosity enhancing agent selected from carboxymethylcellulose and / or its salt forms; methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and / or their cross-linked forms; polyvinyl alcohol; polyvinylpyrrolidone; gum arabic; gelatin; or any combination thereof.

11. 11. The pharmaceutical formulation of any one of claims 1 to 10, further comprising a buffer component selected from a phosphate buffer, an acetate buffer, a citrate buffer, a tartrate buffer, an amine-based buffer, or any combination thereof.

12. 12. The pharmaceutical formulation of any one of claims 1 to 11, further comprising a preservative selected from a paraben compound, a phenylmercury compound, a benzyl compound, an aromatic compound, an alkyl halide, or any combination thereof.

13. the levonorgestrel butanoate particles have a median diameter of 13 μm to 14.5 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; 2. The pharmaceutical formulation of claim 1.

14. the levonorgestrel butanoate particles have a median diameter of 13.5 μm to 14 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; 2. The pharmaceutical formulation of claim 1.

15. the levonorgestrel butanoate particles have a median diameter of 13.7 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; 2. The pharmaceutical formulation of claim 1.

16. 16. The pharmaceutical formulation of any one of claims 13 to 15, further comprising sodium carboxymethylcellulose, disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and benzyl alcohol.

17. A pharmaceutical formulation according to any one of claims 1 to 16, wherein the emulsifying agent, if present, is an ionic or non-ionic surfactant.

18. levonorgestrel butanoate particles having a median diameter in the range of 12 μm to 15 μm; A wetting agent; a dispersant, an emulsifier, or a combination thereof; A thickening agent; A buffer component; A preservative; A pharmaceutical formulation comprising: The pharmaceutical formulation wherein the levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL, with the proviso that, when the pharmaceutical formulation comprises a wetting agent and a dispersing agent, the wetting agent and the dispersing agent are present in a ratio of 3:0.1 to 5:0.1 (wetting agent:dispersing agent).

19. the levonorgestrel butanoate particles have a median diameter of 13 μm to 14.5 μm; the wetting agent is polysorbate 80; the dispersing agent is present and is sorbitan monopalmitate; the thickening agent is sodium carboxymethylcellulose; the buffer component being a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate; The preservative is benzyl alcohol.

19. The pharmaceutical formulation of claim 18.

20. The pharmaceutical formulation of claim 18 or 19, wherein the levonorgestrel butanoate particles have a median diameter of 13.5 μm to 14 μm.

21. levonorgestrel butanoate particles having a median diameter in the range of 11 μm to 15 μm; At least one dispersant; A thickening agent; A buffer component; A preservative; A pharmaceutical formulation comprising: The levonorgestrel butanoate is present in a concentration ranging from greater than 20 mg / mL to a concentration of 100 mg / mL. Pharmaceutical preparations.

22. 22. The pharmaceutical formulation of claim 21, wherein the levonorgestrel butanoate particles have a median diameter ranging from greater than 11.3 μm to a median diameter of 14.2 μm.

23. 23. The pharmaceutical formulation of claim 21 or 22, wherein the dispersing agent is sorbitan monopalmitate.

24. 24. The pharmaceutical preparation of any one of claims 21 to 23, formulated for administration of a dose of levonorgestrel butanoate in the range of 30 mg to 90 mg.

25. A method for making a pharmaceutical formulation according to any one of claims 1 to 24, comprising the steps of: subjecting the levonorgestrel butanoate to sterile filtration to provide a filtrate comprising sterile levonorgestrel butanoate; preparing levonorgestrel butanoate particles from the filtrate; and combining the levonorgestrel butanoate particles with one or more of the wetting agent, the dispersing agent, the emulsifying agent, or combinations thereof; wherein the method does not include the step of using irradiation for any sterilization.

26. 26. The method of claim 25, wherein the step of producing levonorgestrel butanoate particles from the filtrate comprises spray drying the filtrate.

27. 27. The method of claim 26, wherein spray drying the filtrate controls the median size of the levonorgestrel butanoate particles.

28. A method for making a pharmaceutical formulation according to any one of claims 1 to 24, comprising the steps of: micronizing levonorgestrel butanoate to provide said levonorgestrel butanoate particles; and combining the levonorgestrel butanoate particles with one or more of the wetting agent, the dispersing agent, the emulsifying agent, or combinations thereof; wherein the method does not include the step of using irradiation for any sterilization.

29. The method of any one of claims 25 to 28, which does not include a step using gamma irradiation or electron beam irradiation.

30. 1. A method of providing contraception to a subject, comprising: administering a dosage of levonorgestrel butanoate in the range of 20 mg to 140 mg by administering to said subject by injection a formulation according to any one of claims 1 to 24. A method comprising:

31. 31. The method of claim 30, wherein the injection comprises a subcutaneous injection.

32. 31. The method of claim 30, wherein the injection comprises an intramuscular injection.

33. The method of any one of claims 30 to 32, wherein the concentration of levonorgestrel butanoate in the formulation is 70 mg / mL.

34. 1. A method of treating or preventing a progestin-associated disease or condition in a subject, comprising: Administering to said subject a formulation according to any one of claims 1 to 24. A method comprising:

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