Compositions for modified release of active ingredients - Patents.com

Abstract

The present disclosure relates to the field of sustained release compositions of active ingredients capable of modulating endocrine or hormonal signaling and their uses. Formulations according to the present disclosure respond to the chronotherapeutic events of natural level fluctuations in signaling over a 24 hour period.

Description

[Technical field]

[0001] The present disclosure relates to the field of sustained release compositions of active ingredients that can mimic or modulate endocrine or hormonal signaling and their uses. Formulations according to the present disclosure respond to chronotherapeutic events that alter the level of natural signaling over a 24-hour period. [Background technology]

[0002] Many hormones or endocrine signaling systems fluctuate over the course of a day, evolved due to the compelling need of organisms to adapt to the fluctuations of daily stimuli and maintain biological processes within physiological boundaries. Not only do circulating levels of endocrine factors cycle over a 24-hour period, but the responsiveness of target receptors and tissues to the factors also cycle.

[0003] Hormonal factors and systems such as cortisol, growth hormone, testosterone, prolactin, thyroid-stimulating hormone, triiodothyronine, renin-angiotensin-aldosterone system, fibroblast growth factor 21, ghrelin, adiponectin, leptin, vasopressin, insulin, or melatonin are known to cycle with a 24-hour periodicity in humans. The cyclical variation of these systems depends on the time of day. 12 .

[0004] This presents a unique challenge from a therapeutic point of view for active ingredients that can regulate these systems.It is not trivial to achieve a therapeutically effective dose in subjects that respond to this cyclical variation.This is especially true for systems whose signaling increases or decreases during the night or early in the morning.Because it is impossible or very inconvenient for patients to administer active ingredients before these times.

[0005] It is highly desirable to provide pharmaceutical preparations that can release active ingredients in a manner that corresponds to these fluctuating levels, and may benefit patients suffering from multiple conditions.This is especially true for patients undergoing chronic or long-term treatment.Therefore, there is currently a need in the art to develop such preparations.

[0006] For example, thyroid disorders, namely hypothyroidism (HOT) and hyperthyroidism (HT), affect more than 10% of the world's population, are highly prevalent in the age group over 65 years, and are 10 times more prevalent in women. 1 Thyroid hormone levels cycle in the body according to a circadian rhythm, fluctuating naturally according to the day-night cycle. In healthy individuals, triiodothyronine (T3) levels naturally increase gradually during the night and return to baseline in the morning. 4 .

[0007] Current treatment involves the use of triiodothyroxine (T4) and T3. T4 is an inactive hormone that is converted in the body to T3 by two enzymes, deiodinase. T3 is the active hormone that controls cellular metabolism, heart rate, body temperature, peristalsis, muscle contraction, and apoptosis. 80% of patients currently being treated for hypothyroidism report being dissatisfied with their current treatment, and of these, 60% report reduced quality of life (QoL), fatigue, weight gain, and are commonly overtreated, resulting in long-term side effects. 2 Of these, 10–20% of patients do not respond to LT4 monotherapy due to known / unknown underlying genetic factors (e.g., mutations in enzymes that convert T4 to T3, e.g., DiO2 T92A, or thyroid hormone transporters, e.g., MCT10), but the overwhelming majority 3 choose to coadminister T3 4 .

[0008] Currently, T3 is administered as an immediate release form (LT3), which does not mimic the natural circadian rhythm. Treatment with T3 has historically failed due to its short half-life (e.g., in thyroidectomized patients (i.e., without endogenous T4 or T3)).15 and patients who received exogenous LT4 or LT3 (T1 1 / 2 Half-life 3.62 hours, Tmax 2.9 hours, i.e. 11 days after discontinuation of last LT3 dose 15 As seen in a study in the US, the elimination half-life of T3 is 23-25 ​​hours in adults, the biological half-life is 2.5 days, and the estimated baseline-corrected half-life is 4 hours. 11 and side effects. The short half-life leads to multiple dosing per day and poor patient compliance. This often leads to long-term overdosing and serious side effects such as cardiovascular disease, hypertension, and mineral metabolism complications.

[0009] Currently, there are no delayed-release T3 drugs commercially available as a standard alternative to T4 monotherapy. Attempts to design extended-release formulations of T3 that can mimic circadian rhythm profiles have been unsatisfactory, as past attempts at extended release have not returned to natural baseline levels, increasing the probability of overdosing and inducing side effects.

[0010] Thus, the art could provide an alternative to currently inefficient treatments for hypothyroidism that respect the natural cyclical fluctuations in hormone levels and ideally avoid physiological pitfalls. 8 There is currently a need for sustained release T3 formulations that can avoid Summary of the Invention

[0011] The present disclosure addresses the above-mentioned problems by providing improved sustained release compositions and formulations of active ingredients capable of mimicking or modulating hormone or endocrine signaling, taking into account the natural cycle of hormone levels fluctuating due to circadian rhythms.

[0012] Thus, in one aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: a. an active ingredient, or a pharma- ceutically acceptable salt thereof; b. 0.1% by weight to 20% by weight of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC); c. polyethylene oxide (PEO) in an amount of from 80 to 99.9% by weight.

[0013] The inventors have surprisingly discovered that formulations according to the present disclosure exhibit dissolution profiles and release of active ingredients that match physiological levels of natural hormonal signaling that follow day and night cycles with a safe return to baseline levels.

[0014] One aspect of the present disclosure is a. preparing a molten homogenous dispersion comprising i) PEO, ii) hydroxypropyl methylcellulose and / or HPMC-AS, and iii) an active ingredient or a pharma-ceutically acceptable salt thereof; b. cooling the melt to obtain a solid composition.

[0015] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: i. mixing powders of an active ingredient or a pharma- ceutically acceptable salt thereof, HPMC and / or HPMC-AS, and PEO; ii. compressing said mixture to obtain a uniform distribution of the components in the matrix.

[0016] In another aspect, the disclosure provides a composition or pharmaceutical formulation as described herein for use as a medicament.

[0017] In another aspect, the disclosure provides a composition or pharmaceutical formulation as described herein for use in modulating hormone or endocrine signaling.

[0018] In another aspect, the present disclosure relates to the use of a composition or pharmaceutical formulation described herein for the treatment of hypothyroidism and / or for use in preventing or reducing the occurrence of side effects associated with the treatment of hypothyroidism. [Brief description of the drawings]

[0019] [Figure 1] Dissolution profiles of ibuprofen as a T3 model compound shown in formulations A, B, C, E, and F. [Diagram 2] Predicted T3 plasma profiles at different doses of T3 obtained by in vitro-in vivo correlation (IVIVC) based on the dissolution rate of T3 model compound in formulation C. [Diagram 3] Dissolution profile of 50 μg T3 in Formulation D in two tablets analyzed by ELISA. [Figure 4A] Superimposed mean T3 plasma profile (120ng / dL estimated baseline) of 40μg T3 formulation D (n=3, quantified by ELISA) compared to 50μg generic liothyronine (T3 immediate release, experimental in vivo profile13). Superimposition method adopted from Qureshi et al. [Figure 4B] Dissolution profiles analyzed by ELISA of T3 tablets of formulations G, H, and I prepared by dry granulation using roller compaction. [Figure 4C] Superimposed IVIVC T3 plasma profiles of Formulations G, H and I tablets (estimated baseline of 120ng / dL). [Figure 4D] The superimposed mean T3 plasma profiles (estimated baseline of 120 ng / dL) show delayed release of T3 estimated at 20 μg, 30 μg, 40 μg and 50 μg in the 200 mg tablet (Formulation I). [Figure 4E] The superimposed mean T3 plasma profiles (estimated baseline of 120 ng / dL) show delayed release of T3 estimated at 20 μg, 30 μg, 40 μg and 50 μg in the 150 mg tablet (Formulation H). [Figure 4F]The superimposed mean T3 plasma profiles (estimated baseline of 120 ng / dL) show delayed release of T3 estimated at 20 μg, 30 μg, 40 μg and 50 μg in the 100 mg tablet (Formulation G). [Diagram 5] Dissolution rate of two different ibuprofen tablets with different dimensions and amount of matrix. Tablet photos included. Cylindrical tablet dimensions (height mm x diameter mm): round disc 3mm x 20mm, small cylinder 3mm x 8mm. [Figure 6] Cyclic variation of T3 levels over a 24-hour period. The time axis of the graph represents time from 9 am (time = 0). Results adapted from J Clin Endocrinol Metab 93:2300-2306,20084. [Figure 7A] Mean melatonin release for formulations J and K. [Figure 7B] Superimposed IVIVC melatonin plasma profiles of Formulations J and K tablets. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition "Cmax" is a term used in pharmacokinetics to refer to the maximum (or peak) serum concentration that a drug achieves in a particular compartment or test area of ​​the body after the drug is administered and before a second dose is administered.

[0021] "Tmax" is a term used in pharmacokinetics to describe the time at which Cmax is observed.

[0022] "Half-life (t 1 / 2 ) is a term that refers to the time it takes for half of a drug to be eliminated from the blood.

[0023] "Apparent volume of distribution (Vd)" or "apparent volume of drug distribution" is a parameter calculated from the amount of drug administered and its concentration (mass / volume) observed for an individual of a given body weight.

[0024] "Oral bioavailability" refers to the fraction of an orally administered drug that is available in the blood, calculated relative to the drug concentration following intravenous injection.

[0025] "Sustained release" is a term used to refer to a mechanism used in a composition or formulation to release a drug or active pharmaceutical ingredient from the composition or formulation over an extended period of time, as opposed to all at once, or as opposed to an immediate or burst release. In some embodiments, as used herein, the terms "sustained release," "extended release," "controlled release," and "modified release" are used interchangeably to refer to this mechanism.

[0026] In some embodiments, as used herein, the terms "composition" and "formulation" are used interchangeably.

[0027] As used herein, "active ingredient" refers to any ingredient that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or that affects the structure or any function of the human or animal body.

[0028] "Hormones" or "endocrine factors" refer to substances produced by organs of the body that travel through the blood to cause activity elsewhere, or synthetic compounds that have the same activity as natural hormones.

[0029] "Hormonal signaling" or "endocrine signaling" refers to the inhibition of hormone receptors of activation. Hormonal signaling is regulated by natural hormones or other compounds that have the same activity as natural hormones.

[0030] The term "about" as used herein to refer to an amount or percentage is to be interpreted as a variation of ±10%, such as ±5% relative to the value of the amount or percentage to which it refers.

[0031] As used herein, "matrix" refers to an intimately mixed complex of one or more active ingredients with one or more excipients, especially polymers.

[0032] Detailed Description of the Invention The present invention relates to sustained release pharmaceutical compositions and formulations of active ingredients capable of modulating hormonal or endocrine signaling taking into account natural periodic variations over a 24 hour period according to circadian rhythms.

[0033] Thus, one aspect of the present disclosure is a. an active ingredient, or a pharma- ceutically acceptable salt thereof; b. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC); c. polyethylene oxide (PEO), and pharmaceutical compositions and formulations comprising the same.

[0034] Another aspect of the present disclosure relates to compositions and formulations described herein for use as a medicament.

[0035] In one aspect, the disclosure relates to compositions and formulations described herein for use in the treatment of hypothyroidism and / or for use to prevent or reduce side effects associated with the treatment of hypothyroidism.

[0036] The inventors have surprisingly shown that the compositions disclosed herein provide dissolution rates and release profiles of active ingredients suitable for regulating hormone and endocrine signaling levels according to the natural cyclical fluctuations of hormone or endocrine signaling of different systems over a 24 hour period with a safe return to baseline.

[0037] This is advantageous for hormone or endocrine signaling where signaling increases or decreases throughout the night or early morning, because administration of the active ingredient during those times is inconvenient for the patient. Furthermore, sustained release provides a concentration that is more compatible with natural levels throughout these periods. Thus, the composition according to the present disclosure has a high possibility of providing the active ingredient according to the needs of the patient, resulting in better therapeutic outcomes, reduced side effects, and / or improved quality of life, especially in patients who require chronic treatment.

[0038] The advantages of the formulations and compositions disclosed herein are many and include: ·  ... The possibility of combining the preparation according to the invention with standard nursing care procedures. · Improving the quality of life for patients who are experiencing difficulties with the current standard of nursing care.

[0039] Pharmaceutical Compositions Sustained or controlled release technology is a collection of mechanisms, such as erosion and diffusion, used in a composition or formulation to slowly dissolve and release or slowly release and dissolve a drug over time. Extended release formulations can be taken less frequently than immediate release formulations, and they usually maintain steadier drug levels in the bloodstream.

[0040] Sustained release compositions can be prepared by embedding the active ingredient in a matrix of material(s) that allows the dissolving drug to flow out through the pores of the matrix. In some formulations, the drug dissolves into the matrix and the matrix physically swells to form a gel, which allows the drug to exit through the outer surface of the gel. In other cases, the matrix of material slowly breaks apart and erodes, releasing the drug in a sustained release profile.

[0041] The inventors have shown that a composition comprising an active ingredient and a matrix comprising hydroxypropyl methylcellulose (HPMC) and / or hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and polyethylene oxide (PEO) provides sustained release of the active ingredient with a desired profile of the active ingredient that can regulate physiological levels of endocrine or hormones that cycle periodically over a 24-hour period according to the day and night cycle with a safe return to baseline.

[0042] Thus, in one embodiment, the present disclosure provides a method for producing a method for treating a cancer cell comprising: a. an active ingredient, or a pharma- ceutically acceptable salt thereof; b. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC); c. polyethylene oxide (PEO).

[0043] The inventors have shown that pharmaceutical compositions comprising specific amounts of PEO, HPMC and / or HPMC-AS provide sustained release of active ingredients in a desired profile that follows physiological levels of endocrine or hormonal signaling that cycle within a 24 hour period according to the day and night cycle.

[0044] Polyethylene oxide (PEO) is obtained by polymerization of ethylene oxide. It has a structure similar to polyethylene glycol (PEG), which is obtained by condensation of ethylene glycol molecules. In this specification, the terms "PEG" and "PEO" are used interchangeably.

[0045] HPMC and HPMC-AS are cellulose derivatives in which some of the free hydroxyl groups in the cellulose are replaced with hydroxypropyl and methyl groups. In the case of HPMC-AS, additional hydroxyl groups are replaced with acetate and succinate groups. These materials are generally used as coatings to delay the release of medicinal compounds into the digestive tract.

[0046] In one embodiment, the HPMC-AS comprises 4-28% by weight succinyl groups and 2-16% by weight acetyl groups, such as 8-20% by weight succinyl groups and 4-12% by weight acetyl groups, such as 14-18% by weight succinyl groups and 4-9% by weight acetyl groups. In one embodiment, the acetyl content in the HPMC-AS is less than 12% by weight, such as less than 10%, and the succinyl content is greater than 6% by weight, such as greater than 8% by weight.

[0047] Thus, in one embodiment, the present disclosure provides a method for producing a method for treating a cancer cell comprising: a. an active ingredient, or a pharma- ceutically acceptable salt thereof; b. 0.1% by weight to 20% by weight of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC); c. polyethylene oxide (PEO) in an amount of 80 to 99.9% by weight.

[0048] In another embodiment, the composition comprises HPMC and / or HPMC-AS in a total amount of about 1%-20%, such as about 2%-20%, for example, about 5%-15%, such as about 6%-14%, for example, about 7%-13%, such as about 8%-12%, for example, about 9%-11%, for example, about 10%.

[0049] Additionally, the inventors have surprisingly demonstrated that compositions comprising HPMC-AS mixed into a matrix, rather than coated or encapsulated, provide sustained release profiles with favorable pharmacokinetic properties for treatment with active ingredients that modulate hormonal or endocrine signaling in systems that cycle within 24 hours. Additionally, due to the functional groups present in HPMC-AS, this ingredient also provides improved protection for the active ingredient through the multiple and varied conditions of the gastrointestinal tract, particularly pH.

[0050] In one embodiment, the composition is free of HPMC, e.g., the composition is substantially free of HPMC.

[0051] Thus, in one embodiment, the composition comprises HPMC-AS in an amount of about 1% to 20% by weight, such as about 2% to 20%, for example, about 5% to 15%, such as about 6% to 14%, for example, about 7% to 13%, such as about 8% to 12%, for example, about 9% to 11%, such as about 10%.

[0052] In one embodiment, the composition comprises HPMC-AS in an amount of about 3% to 14% by weight, such as 3% to 4%, for example, 4% to 5%, for example, 5% to 6%, for example, 6% to 7%, for example, 7% to 8%, for example, 8% to 9%, for example, 9% to 10%, for example, 10% to 11%, for example, 11% to 12%, for example, 12% to 13%, for example, 13% to 14%. In one embodiment, the composition comprises HPMC-AS in an amount of about 5% to about 14% by weight. In one embodiment, the composition comprises HPMC-AS in an amount of about 8% to about 14% by weight.

[0053] In one embodiment, the composition does not include HPMC-AS.

[0054] In one embodiment, the composition comprises HPMC in an amount of about 1% to 20% by weight, such as about 2% to 20%, for example, about 5% to 15%, such as about 6% to 14%, for example, about 7% to 13%, such as about 8% to 12%, for example, about 9% to 11%, for example, about 10%.

[0055] In one embodiment, the composition comprises HPMC in an amount of about 5% to 15% by weight, such as 5% to 6%, for example, 6% to 7%, such as 7% to 8%, for example, 8% to 9%, such as 9% to 10%, for example, 10% to 11%, such as 11% to 12%, for example, 12% to 13%, such as 13% to 14%, for example, 14% to 15%, such as 15% to 16%, for example, 16% to 17%, such as 17% to 18%, for example, 18% to 19%, for example, 19% to 20%.

[0056] In one embodiment, the PEO has an average molecular weight between 10 kDa and 2000 kDa, e.g., 50 kDa to 1000 kDa, e.g., 100 kDa to 500 kDa, e.g., 150 kDa to 300 kDa. In one embodiment, the PEO has an average molecular weight between 100 kDa and 500 kDa. In one embodiment, the PEO has an average molecular weight between 100 kDa and 400 kDa. In one embodiment, the PEO has an average molecular weight between 100 kDa and 300 kDa. In one embodiment, the PEO has an average molecular weight of about 200 kDa.

[0057] In one embodiment, PEO is present in the pharmaceutical composition in an amount of about 80%-99%, such as about 85%-95%, such as about 88%-92%, such as about 90%. In one embodiment, PEO is present in the composition in an amount of about 80%-99% by weight. In one embodiment, PEO is present in the composition in an amount of about 83%-97% by weight. In one embodiment, PEO is present in the composition in an amount of about 85%-95% by weight. In one embodiment, PEO is present in the composition in an amount of about 87%-93% by weight. In one embodiment, PEO is present in the composition in an amount of about 90% by weight.

[0058] In one embodiment, PEO is present in the pharmaceutical composition in an amount of about 85% to 95% by weight, such as 85% to 86%, for example, 86% to 87%, for example, 87% to 88%, for example, 88% to 89%, for example, 89% to 90%, such as 90% to 91%, for example, 91% to 92%, for example, 92% to 93%, for example, 93% to 94%, for example, 94% to 95% by weight.

[0059] In one embodiment according to the present disclosure, the active ingredient, PEO, and HPMC and / or HPMC-AS are in a single matrix. In one embodiment, the composition is a homogeneous dispersion comprising the active ingredient, HPMC and / or HPMC-AS, and PEO. By "homogeneous dispersion" is meant that the ingredients are distributed evenly or homogeneously throughout the dispersion.

[0060] PEO, HPMC, and HPMC-AS are considered to be hydrophilic and gel forming. In water, matrices composed of any of them or mixtures thereof undergo a series of processes leading to dissolution: water penetration, hydration, relaxation, gel formation, and migration to the loose chain medium. If the matrix is ​​produced in such a way as to prevent the first step of rapid water penetration, only a thin release layer will form on the surface, resulting in gradual erosion of the dosage unit.

[0061] Such matrices can be obtained by thermoplastic processes such as injection molding, hot melt extrusion, calendaring, etc., or by compression under sufficient pressure, due in particular to the high deformability / plasticity and low melting point of PEO. The aim is to prevent the penetration of water by reducing the occurrence of cracks or interparticle channels.

[0062] The composition according to the present disclosure mainly releases active ingredient by erosion.Therefore, the release of active ingredient closely follows the erosion rate.This mechanism is less prone to variation between different types of active ingredient, as opposed to release controlled mainly by diffusion.The examples demonstrate that different active ingredients show comparable dissolution profiles.

[0063] One aspect of the present disclosure is i. an active ingredient as described herein, or a pharma- ceutically acceptable salt thereof; ii. HPMC and / or HPMC-AS; iii. A composition comprising a matrix comprising polyethylene oxide (PEO), wherein the weight ratio of PEO (component i.) to HPMC and / or HPMC-AS (component ii.) is between 8:2 and 9:0.1.

[0064] In one embodiment, the PEO, HPMC, and HPMC-AS are as described herein.

[0065] In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is between about 8:1 and about 9.5:1, e.g., 8.1:1, 8.2:1, 8.3:1, 8.4:1, 8.5:1, 8.6:1, 8.7:1, 8.8:1, 8.9:1, 9.0:1, 9.1:1, 9.2:1, 9.3:1, 9.4:1, or 9.5:1.

[0066] In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 9:1. In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 8:2. In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 9.5:1. In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 9:0.5. In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 8.5:1. In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is 8.6:1.

[0067] In one embodiment, the composition does not include HPMC.

[0068] Further Polymers The composition according to the present disclosure may comprise one or more additional polymers. The one or more additional polymers may be independently selected from the group consisting of ionic, non-ionic, water-insoluble polymers, and water-soluble polymers. In one embodiment, the one or more polymers are one or more water-soluble polymers.

[0069] In one embodiment, the one or more additional polymers are selected from the group consisting of polysaccharides, acrylates, and polysiloxanes, and derivatives thereof.

[0070] In another embodiment, the one or more additional polymers are independently selected from the group consisting of polyethylene oxide glucomannan, galactan, glucan, polygalacturonic acid, polyhydroxyalkanoates, polyxylans, polygalactomannans, lanogalacturonans, polyxyloglycans, arabinogalactans, starches, alginates, xanthan gum, carrageenans, agar, dextran, pectin, cellulose, polyvinyl alcohol, polyvinyl butyral, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose stearate, carboxymethylcellulose, carbomer, polyacrylic acid, poly(methylacrylic) acid, poly(methyl methacrylate), polyhydroxybutyrate, polyhydroxyvalerates, polyhydroxyphenyl valerates, polylactic acid, polyglycolic acid, polyacrylamide, and derivatives or copolymers thereof.

[0071] The inventors have surprisingly shown that the composition according to the present disclosure does not require the presence of a lubricant. A lubricant is generally required to improve the properties of the powder during the processing of the formulation, and functions by reducing friction. Due to the properties of PEO and the amount of PEO used, a lubricant is not required during the processing to prepare the composition according to the present disclosure. Thus, in one embodiment, the composition according to the present disclosure does not include a lubricant. In one embodiment, the composition does not include an additional lubricant. For example, the composition does not include a lubricant selected from a divalent salt of fatty acid, for example, a metal salt of fatty acid, such as a magnesium, calcium, or zinc salt of fatty acid, a fatty acid, a fatty acid ester, or talc.

[0072] Active Pharmaceutical Ingredients The compositions according to the present invention provide sustained release of the active ingredient or a pharma- ceutically acceptable salt thereof.

[0073] The inventors have shown that formulations according to the present disclosure provide an advantageous sustained release profile for active ingredients capable of regulating hormone or endocrine factor levels, particularly hormones and endocrine factors whose levels cycle in the human body over a 24-hour period. Thus, in one embodiment, the active ingredient is selected from the group consisting of thyroid hormones or thyroid hormone regulators such as triiodothyronine or triiodothyroxine, dopamine reuptake inhibitors, serotonin reuptake inhibitors, renin inhibitors, angiotensin inhibitors, angiotensin receptor agonists, angiotensin converting enzyme inhibitors, renin-angiotensin-aldosterone pathway inhibitors, prolactin releasing agents, melatonin receptor agonists such as melatonin, corticosteroids such as hydrocortisone, prednisolone, prednisone, follicle stimulating hormone receptor agonists, androgens such as testosterone or testosterone derivatives, growth hormone secretagogues, ghrelin receptor agonists, fibroblast growth factor 21 analogues, fibroblast growth factor 21 receptor agonists, adiponectin receptor agonists, leptin analogues, leptin receptor agonists, and vasopressin receptor agonists.

[0074] The release profile of the active ingredient provided by the composition according to the present disclosure is advantageous for active ingredients that modulate hormone or endocrine signaling of hormones or endocrine factors whose natural healthy levels increase or decrease throughout the night or early morning and then return to baseline. In contrast to immediate release formulations, the compositions disclosed herein allow for administration of the active ingredient at a time convenient for the patient, and the release profile is favorable according to the natural cyclical fluctuations of the hormone or endocrine signaling being affected.

[0075] The active ingredient can regulate hormone or endocrine signal transduction through different mechanisms, as understood by those skilled in the art.For example, the active ingredient or its salt can be an endocrine factor or hormone itself, such as triiodothyronine or melatonin.The active ingredient can be a prodrug that is converted into an active ingredient that can affect hormone or endocrine signal transduction.The active ingredient can act on the same receptor in the same manner as an endogenous hormone or endocrine factor.It is also possible that the active ingredient acts on the receptor upstream or downstream of the signal transduction pathway of a particular hormone or endocrine factor, with the same effect as the hormone or endocrine factor, such as the release of a second messenger.

[0076] Thus, in one embodiment, the active ingredient may modulate hormonal or endocrine signaling of a hormone or endocrine factor whose natural healthy levels increase or decrease overnight, hi one embodiment, the active ingredient modulates hormonal or endocrine signaling of a hormone or endocrine factor whose natural levels increase or decrease between the hours of 12:00 AM and 6:00 AM.

[0077] In one embodiment, the natural signaling level of the hormone or endocrine signaling, or the natural level of the hormone or endocrine factor, is increased or decreased 1 to 6 hours after the onset of a major sleep episode, e.g., 1 to 5 hours, 1 to 4 hours, or 1 to 3 hours after the onset of a major sleep episode.

[0078] In one embodiment, the active ingredient may modulate hormonal or endocrine signaling of hormonal or endocrine factors whose natural healthy levels increase or decrease throughout the early morning hours.

[0079] For example, signaling of hormones and endocrine factors such as thyroid hormones, melatonin, prolactin, ghrelin, leptin, or vasopressin increases during the nighttime hours. 12Thus, in one embodiment, the active ingredient is selected from the group consisting of thyroid hormones, melatonin receptor agonists, prolactin releasing agents, ghrelin receptor agonists, leptin receptor agonists, and vasopressin receptor agonists.

[0080] Signaling of hormones and endocrine factors, such as cortisol, testosterone, fibroblast growth factor or adiponectin, increases throughout the early morning hours. Thus, in one embodiment, the active ingredient is selected from the group consisting of corticosteroids, androgens, fibroblast growth factor 21 analogs, and adiponectin receptor agonists.

[0081] The renin-angiotensin-aldosterone system is a key regulator of blood pressure, mainly through the production of angiotensin II. The secretion of renin is activated early in the morning before awakening as a result of sympathetic activation. Both renin and aldosterone show a pronounced circadian pattern in both normotensive and hypertensive individuals, with peak values ​​detected early in the morning and declining to a nadir late in the night. Thus, renin-angiotensin inhibitors can be administered to reduce signaling in hypertensive patients, thereby reducing blood pressure. In one embodiment, the active ingredient is selected from the group consisting of renin inhibitors, angiotensin inhibitors, angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, and renin-angiotensin-aldosterone pathway inhibitors.

[0082] As shown by the examples, the formulations according to the present disclosure provide sustained release of active ingredients that are suitable to match the natural cyclical fluctuations of different hormone or endocrine factor levels during a 24-hour period in healthy individuals with a safe return to baseline. Thus, the compositions according to the present disclosure have a high potential to provide active ingredients according to the needs of patients, resulting in better therapeutic outcomes, reduced side effects, and / or improved quality of life, especially in patients requiring chronic treatment.

[0083] In one embodiment, the present disclosure provides: a. an active ingredient, as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0084] In one embodiment, the present disclosure provides: a. an active ingredient, as described herein, or a pharma- ceutically acceptable salt thereof; b. hydroxypropyl methylcellulose acetate succinate (HPMC-AS), as described herein, in an amount of 0.1% to 20% by weight; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0085] In one embodiment, the present disclosure provides: a. an active ingredient, as described herein, or a pharma- ceutically acceptable salt thereof; b. hydroxypropyl methylcellulose (HPMC), as described herein, in an amount of 0.1% to 20% by weight; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0086] In one embodiment, the active ingredient is a thyroid hormone, such as triiodothyronine or triiodothyroxine.

[0087] In one embodiment, the active ingredient is triiodothyroxine (also referred to herein as T4 or thyroxine) or a pharma- ceutically acceptable salt thereof.

[0088] In one embodiment, the active ingredient is triiodothyronine (also referred to herein as T3, LT3 or liothyronine) or a pharma- ceutically acceptable salt thereof.

[0089] Triiodothyronine is not stable under the pH and enzymatic conditions of the stomach. Thus, one advantage of the sustained release composition according to the present disclosure is that it at least partially protects T3 from degradation in the stomach, allowing for higher bioavailability compared to immediate release formulations.

[0090] In one embodiment, the composition according to the invention comprises triiodothyronine or a pharma- ceutically acceptable salt thereof in an amount of between 1 and 100 μg, such as between about 2 and 70 μg, for example between about 5 and 50 μg.

[0091] In one embodiment, the composition according to the invention comprises triiodothyronine or a pharma- ceutically acceptable salt thereof in an amount of between 5 and 50 μg, such as 5-7 μg, for example, 7-9 μg, for example, 9-11 μg, such as 11-13 μg, for example, 13-15 μg, for example, 15-17 μg, for example, 19-21 μg, for example, 21-23 μg, such as, for example, 23-25 ​​μg, for example, 25-27 μg, for example, 27-29 μg, for example, 29-31 μg, such as, for example, 31-33 μg, for example, 33-35 μg, for example, 35-37 μg, for example, 37-39 μg, for example, 39-41 μg, such as, for example, 41-43 μg, for example, 43-45 μg, for example, 45-47 μg, for example, 47-50 μg.

[0092] In one embodiment, the present disclosure provides: a. triiodothyronine, or a pharma- ceutically acceptable salt thereof, as described herein; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0093] In one embodiment, the active ingredient is a corticosteroid, such as hydrocortisone, prednisolone, prednisone, or a pharma- ceutically acceptable salt thereof.

[0094] In one embodiment, the present disclosure provides: a. a corticosteroid as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0095] In one embodiment, the active ingredient is a dopamine reuptake inhibitor, such as bupropion, Wellbutrin, Forfibo, or Aprezin, or a pharma- ceutically acceptable salt thereof.

[0096] In one embodiment, the present disclosure provides: a. a dopamine reuptake inhibitor as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0097] In one embodiment, the active ingredient is a serotonin reuptake inhibitor, such as sertraline, fluoxetine, citalopram, escitalopram, paroxetine, or fluvoxamine, or a pharma- ceutically acceptable salt thereof.

[0098] In one embodiment, the present disclosure provides: a. a serotonin reuptake inhibitor as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0099] In one embodiment, the active ingredient is a melatonin receptor agonist, such as melatonin or a pharma- ceutically acceptable salt thereof.

[0100] In one embodiment, the present disclosure provides a composition comprising: a. a melatonin receptor agonist as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; and c. Polyethylene oxide (PEO) in an amount of 80 to 99.9% by weight.

[0101] In one embodiment, the active ingredient is melatonin or a pharma- ceutically acceptable salt thereof.

[0102] In one embodiment, the active ingredient is a renin inhibitor, such as aliskiren, that can reduce blood pressure, or a pharma- ceutically acceptable salt thereof. In one embodiment, the active ingredient is an angiotensin inhibitor, an angiotensin receptor blocker, or an angiotensin-converting enzyme inhibitor, that can reduce blood pressure, or a pharma-ceutically acceptable salt thereof. In one embodiment, the active ingredient is a renin-angiotensin-aldosterone pathway inhibitor, or a pharma-ceutically acceptable salt thereof.

[0103] In one embodiment, the present disclosure provides: a. a renin inhibitor or angiotensin inhibitor as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0104] In one embodiment, the active ingredient is a prolactin releasing agent or a pharma- ceutically acceptable salt thereof, capable of inducing the secretion of prolactin.

[0105] In one embodiment, the present disclosure provides: a. a prolactin releasing agent as described herein, or a pharma- ceutically acceptable salt thereof; b. 0.1% to 20% by weight total of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), as described herein; c. polyethylene oxide (PEO) in an amount of from 80 to 99.9 weight %.

[0106] Preparation method One aspect of the present disclosure is a. preparing a molten homogenous dispersion comprising i) PEO, ii) hydroxypropyl methylcellulose and / or HPMC-AS, and iii) an active ingredient or a pharma-ceutically acceptable salt thereof; b. cooling the melt to obtain a solid composition.

[0107] The melt may be prepared by heating the mixture of powders to a temperature that at least partially melts the powders, or one of the powders. In one embodiment, step a) comprises heating the mixture to a temperature that at least partially melts the powders, or one of the powders. In one embodiment, step a) further comprises compressing the mixture.

[0108] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: i. mixing powders of an active ingredient or a pharma- ceutically acceptable salt thereof, HPMC and / or HPMC-AS, and PEO; ii. compressing said mixture to obtain a uniform distribution of the components in the matrix.

[0109] Processes and methodologies for achieving uniform dispersion, either by melt dispersing or by mixing and compressing solids, are known to those skilled in the art. 14 For example, methodologies for carrying out the methods described herein include, but are not limited to, dry granulation, such as achieved by roller compaction, calendaring, slugging or pneumatic dry granulation, compression molding, such as vacuum compression molding (VCM), direct compression (DCT), hot melt extrusion (HME), ultrasonically assisted compression, or wet granulation.

[0110] In one embodiment, step i) of compressing the mixture to obtain a uniform distribution of the ingredients in the matrix is ​​carried out by dry granulation, in one embodiment, the dry granulation is carried out by roller compaction.

[0111] In one embodiment, the method further comprises compressing the composition into a solid composition, hi one embodiment, the composition is pressed into a tablet.

[0112] Therefore, in one embodiment, the composition according to the present disclosure is compressed into a tablet. Compressing with sufficient force will result in a tablet with small intergranular cracks, which will reduce the rate of water penetration and ensure adequate tablet erosion. Those skilled in the art will know how to achieve adequate compression to ensure a slow rate of water penetration, and how to optimize compression force depending on the material or equipment used.

[0113] In one embodiment, the PEO, HPMC and / or HPMC-AS and active ingredient are as described herein.

[0114] Excipients Compositions according to the present disclosure may include one or more additional excipients. An excipient is a pharmacologically inactive substance that is formulated with an active pharmaceutical ingredient.

[0115] In one embodiment, a pharmaceutical composition according to the invention comprises one or more excipients which may function as solid carriers, diluents, flavoring agents, solubilizers, lubricants, flow agents, suspending agents, binders, fillers, preservatives, anti-adherents, wetting agents, tablet disintegrants, adsorbents, and / or encapsulating / coating materials.

[0116] In one embodiment, the one or more additional excipients are selected from one or more of the group consisting of binders, fillers, lubricants, release controlling excipients, stabilizers, plasticizers, antioxidants, and preservatives.

[0117] In one embodiment, the composition comprises a filler such as a filler selected from the group consisting of calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugars, dextrates, dextrin, dextrose, ethyl cellulose, fructose, isomalt, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose (MCC), polydextrose, sodium alginate, sorbitol, talc, and xylitol.

[0118] In one embodiment, the composition comprises a binder such as a binder selected from the group consisting of acacia, alginic acid, carbomer, sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, chitosan, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, guar gum, hydroethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, hypromellose, methylcellulose, poloxamer, polydextrose, polyethylene oxide, povidone, sodium alginate, sucrose, starch, pregelatinized starch, and maltodextrin.

[0119] In one embodiment, the composition comprises a lubricant, such as a lubricant selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, palmitic acid, polyethylene glycol, sodium lauryl sulfate, stearic acid, talc, silica, and zinc stearate.

[0120] The preservative can be an antibacterial agent or an antioxidant. The preservative can also be a light filter or light blocking agent, such as TiO2. In one embodiment of the present disclosure, the composition comprises one or more preservatives. In one embodiment, the one or more preservatives are independently selected from the group consisting of an antibacterial agent, an antioxidant, a light filter, or a light blocking agent.

[0121] In one embodiment, the composition comprises a controlled release excipient, such as a controlled release excipient selected from the group consisting of functionalized cellulose, glyceryl monostearate, glyceryl monooleate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oil, guar gum, polyvinyl alcohol, alginate, xanthan gum, carnauba wax, yellow wax, white wax, zein, carrageenan, carbomer, and agar.

[0122] Any other excipient suitable for the purposes of the present invention and known to those skilled in the art is considered to be encompassed by the present invention.

[0123] Sustained-release formulations tablet In one embodiment, the present disclosure relates to a pharmaceutical formulation or composition comprising a composition described herein.

[0124] Thus, in one embodiment, the compositions described herein are pharmaceutical compositions. In one embodiment, the compositions described herein are pharmaceutical formulations.

[0125] The terms pharmaceutical formulation, pharma- ceutically safe formulation, and pharma- ceutically acceptable formulation are used interchangeably.

[0126] In one embodiment, the pharmaceutical formulation or composition described herein provides a sustained release of triiodothyronine or a pharma- ceutically acceptable salt thereof.

[0127] A tablet is a pharmaceutical dosage form that contains a mixture of active ingredient(s) and excipients and is pressed or compressed into a solid dose. Tablets are simple and convenient to use. Tablets provide a precisely measured dose of active ingredient(s) in a convenient, portable package. Manufacturing processes and techniques can provide special properties of tablets, such as extended release or fast dissolving formulations. Tablets are easy to measure and have high physical integrity.

[0128] Tablets can be manufactured by methods known in the art, including, but not limited to, vacuum compression molding (VCM), wet granulation, dry granulation, direct compression (DCT), hot melt extrusion and calendaring, roller compaction, or combinations thereof. In one embodiment, the tablets are prepared as described herein.

[0129] In one embodiment, the pharmaceutical formulation is selected from the group consisting of tablets, minitablets, microtablets, coated tablets, coated minitablets, coated microtablets, spheres, and coated spheres.

[0130] In one embodiment, the pharmaceutical formulation is a monolithic dosage form, such as, for example, a cylindrical monolithic tablet.

[0131] In one embodiment, the pharmaceutical formulation is a tablet having a total weight of 50 to 800 mg.

[0132] In one embodiment, the pharmaceutical formulation is a tablet having a total weight of 50-250 mg, for example, 100-200 mg, for example, 150 mg.

[0133] In another embodiment, the tablet has a volume / weight ratio of between 100 and 200, such as 130-170, such as 140-160, such as 150.

[0134] In one embodiment the pharmaceutical formulation is a cylindrical tablet, wherein the tablet has one dimension of 2-4 mm, for example 3 mm, and another dimension of 6-20 mm, for example 8 mm.

[0135] According to the present disclosure, the pharmaceutical formulation may include a coating. The coating may be formed of a material that provides protection and stabilization of the formulation. The coating may include additional excipients as described herein.

[0136] Thus, in one embodiment, the pharmaceutical formulation further comprises a coating. In a further embodiment, the coating comprises one or more polymers. In another embodiment, the coating comprises one or more of the group consisting of polyacrylates, polyacrylate derivatives, and copolymers thereof. In another embodiment, the coating comprises one or more cellulose derivatives. In another embodiment, the coating comprises shellac.

[0137] In one embodiment, the pharmaceutical formulation is orally available.

[0138] In another aspect, the pharmaceutical composition is a solid dosage form. In one embodiment, the formulation is an orally available solid dosage form.

[0139] In one embodiment, the pharmaceutical composition is a single unit oral dosage form. In another embodiment, the pharmaceutical composition is a multiple unit oral dosage form.

[0140] In one embodiment, the dosage unit is selected from the group consisting of coated or uncoated tablets, coated or uncoated minitablets, coated or uncoated microtablets, and coated or uncoated spheres, or thermoformed solid oral dosage forms.

[0141] In one embodiment, the pharmaceutical formulation is contained within a capsule, such as a hard shell capsule, such as a hard shell capsule further comprising an outer coating.

[0142] In sustained release compositions, multiple factors can affect the release rate of the active ingredient. The release rate can be determined by evaluating the dissolution profile of the manufactured batch. In vitro drug dissolution data generated from dissolution testing experiments can be related to in vivo pharmacokinetic data by in vitro-in vivo correlation (IVIVC).

[0143] Medical Use In one aspect, the disclosure relates to a composition or pharmaceutical formulation described herein for use as a medicament.

[0144] In one aspect, the disclosure relates to a composition or pharmaceutical formulation described herein for use in modulating hormonal or endocrine signaling.

[0145] In one embodiment, the natural level of hormone or endocrine signaling cycles over a 24 hour period, hi one embodiment, the natural level of hormone or endocrine signaling increases or decreases between the hours of 12:00 AM and 7:00 AM.

[0146] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation as described herein for use in the treatment of hypothyroidism and / or for use in preventing or reducing the occurrence of side effects associated with the treatment of hypothyroidism.

[0147] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation as described herein for use in the treatment of bone damage, cartilage damage, myxedema, goiter, and / or in the treatment of stroke.

[0148] Hypothyroidism can result from multiple causes, such as autoimmune disease, radiation treatment, surgical removal of part or all of the thyroid gland, treatment with other drugs, congenital disease, or pregnancy. It can also occur in patients with cancer or be caused by treatment with other drugs, known as drug-induced hypothyroidism.

[0149] Thus, in one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for use in the treatment of hypothyroidism, where the hypothyroidism results from one or more selected from the group consisting of an autoimmune disease, radiation treatment, surgical removal of part or all of the thyroid gland (thyroidectomy), treatment with other drugs, congenital disease, and pregnancy.

[0150] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for use in the treatment of hypothyroidism, wherein the hypothyroidism is drug-induced hypothyroidism.

[0151] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for use in treating hypothyroidism in generalized cancer patients exhibiting low levels of thyroid hormone. In another embodiment, the cancer patient is treated with a checkpoint inhibitor. In a further embodiment, the checkpoint inhibitor is selected from the group consisting of CTLA-4 and / or a-PDL1.

[0152] One advantage of the invention disclosed herein is that it results in physiological hormone levels that follow circadian rhythms and natural periodic fluctuations with a safe return to baseline levels.

[0153] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation for use in reducing and / or preventing side effects of the treatment of hypothyroidism. In another embodiment, the side effects are one or more selected from the group consisting of cardiovascular disease, high blood pressure, mineral metabolism complications, depression, dyspnea, headache, tremors, nervousness or irritability, muscle weakness, increased appetite, diarrhea, menstrual irregularities, weight loss, feeling hot, rash, and sleep disorders.

[0154] In one embodiment, a pharmaceutical composition or formulation described herein is administered to a patient suffering from the side effects of treatment for hypothyroidism.

[0155] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation described herein for use in the treatment or prevention of a neurodegenerative disease, such as Alzheimer's disease or Huntington's disease.

[0156] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation as described herein for use in stimulating and maturing chondrocytes and in the progression of endochondral ossification during fracture or injury to cartilage.

[0157] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation as described herein for use in the treatment of post-ischemic brain injury or stroke in accidents.

[0158] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in an underweight patient, the composition or pharmaceutical formulation comprising between 10 and 75 μg of triiodothyronine or a pharma- ceutically acceptable salt thereof.

[0159] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation for use as described herein in children under 18 years of age, underweight patients, or patients requiring multiple doses, the composition or formulation comprising between 2.5 and 25 μg of triiodothyronine or a pharma- ceutical acceptable salt thereof.

[0160] Administration time and parameters In one embodiment, the composition or pharmaceutical formulation described herein is administered between 18h and 00h, such as between 20h and 22h, such as at 21h.

[0161] In one embodiment, a composition or pharmaceutical formulation described herein is administered during or after dinner, such as within 3 hours after dinner, such as within 2 hours after dinner, such as within 1 hour after dinner, such as within 30 minutes after dinner.

[0162] In one embodiment, a composition or pharmaceutical formulation described herein is administered prior to a major sleep episode, such as within 3 hours prior to a major sleep episode, such as within 2 hours prior to a major sleep episode, such as within 1 hour prior to a major sleep episode, such as within 30 minutes prior to a major sleep episode.

[0163] In one embodiment, the compositions or pharmaceutical formulations described herein are administered once daily.

[0164] In one embodiment, the compositions or pharmaceutical formulations described herein are administered multiple times daily.

[0165] In one embodiment, the compositions or pharmaceutical formulations described herein are administered on an empty stomach.

[0166] In one embodiment, the compositions or pharmaceutical formulations described herein provide a reduced T of triiodothyronine compared to an equivalent amount of triiodothyronine administered as an immediate release formulation. max This results in an increase in

[0167] In one embodiment, the T max The increase is at least about 1 hour, such as at least about 2 hours, such as at least about 3 hours, such as at least about 4 hours, such as at least about 6 hours, compared to an equivalent amount of triiodothyronine administered as an immediate release formulation.

[0168] In one embodiment, the compositions or pharmaceutical preparations described herein provide a cI of between 150 and 400 ng / dL, e.g., between 200 and 350 ng / dL of triiodothyronine. max results. EXAMPLES

[0169] Example 1: Preparation of formulation the purpose The preparation of sustained release formulations will now be described.

[0170] Materials and Methods Formulations using ibuprofen as a T3 substitute: Formulations A, B, C, E, and F were prepared as detailed below: Methocel™ (hydroxypropyl methylcellulose, HPMC, Methocel K100M) or Aqoat® (hydroxypropyl methylcellulose acetate succinate, HPMC_AS, Aqoat-AS-LF) were mixed with polyethylene oxide, (PEO Polyox™ NF80 with a molecular weight of 200 kDa).

[0171] 5 mg of ibuprofen (Sigma-Aldrich) was homogeneously mixed with PEO (molecular weight 200 kDa) alone or with 5-10% Methocel™ or 5-10% Aqoat® and formed into tablets using a vacuum melt extruder (MeltPrep® VCM). The cylindrical tablet size was 8 mm in diameter, 3 mm in height, (volume / weight=11), with a total tablet weight of 150 mg.

[0172] Formulations containing T3: Formulations D, G, H, and I were prepared as detailed below: Aqoat® (hydroxypropyl methylcellulose acetate succinate, HPMC-AS) was mixed with PEO of molecular weight 200 kDa.

[0173] T3 as API was purchased from T3 TOCRIS (catalog number 6666). For Formulation D, 50 μg of T3 was mixed homogeneously using aliquot dilution to ensure homogeneity with 200 kDa molecular weight PEO with 10% Aqoat using a vacuum melt extruder (MeltPrep® VCM). The cylindrical tablet size was (diameter 8 mm), (height 3 mm), (volume / weight=1), total tablet weight 150 mg.

[0174] Formulations G, H, and I were prepared by dry granulation using roller compaction. Three different amounts of T3 were used (40 μg, 30 μg, and 20 μg) with varying total weight of matrix and amount of HPMC-AS as listed in Table 1.

[0175] [Table 1] a VCM: Vacuum Compression Molding using MeltPrep®. b DGRC - Dry granulation using roller compaction. c Size and weight: Cylindrical size height mm x diameter mm, weight (mg). d Ibuprofen

[0176] Example 2: Dissolution experiments with T3 substitutes the purpose API analogues are used to study the dissolution profile of sustained release formulations.

[0177] Materials and Methods Dissolving method: Experiments were conducted to measure the cumulative % drug release as a function of time when ibuprofen was used as a T3 surrogate.

[0178] Dissolution experiments were performed in a USP Apparatus 2 (Erweka DT70, Heusenstamm, Germany) equipped with a special insert and a 250 mL vessel. Tablets are studied in duplicate (n=2). 2 liters of 0.1 M phosphate buffer (pH 6.8) are prepared. The USP bath is preheated. 250 ml of 0.1 M phosphate buffer (pH 6.8) is added to each of the six dissolution vessels. The vessels are then brought to 37°C (15 min). FaSSGF medium is added to the beaker to simulate artificial intestinal fluid and brought to pH 6.8 with phosphate buffer to simulate artificial intestinal fluid. Dissolution experiments were performed at 37±0.1°C with a paddle stirring speed of 50 rpm for up to 24 h at pH 6.8 (two of each formulation). Samples (1 mL) are removed after 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 hours, and 0.5 mL samples are taken from each container and placed directly into HPLC vials. Samples are also taken after 24 hours and analyzed, completing the experiment. After the experiment is completed, the samples are subjected to HPLC without any treatment. A standard curve is also prepared in triplicate from 250 to 1 ug / mL.

[0179] A high performance liquid chromatographic (HPLC) method was used to quantify ibuprofen using an Ultimate 3000 HPLC system from Dionex (Sunnyvale, USA). A reversed-phase Kinetex 100A XB-C18 column (4.6 x 100 mm, 5 μm) from Phenomenex (Vaerlose, Denmark) was used for the separation, and the mobile phase contained A) 0.1% acetic acid and B) 0.1% acetic acid in acetonitrile. A gradient of solvent B was mixed consecutively with solvent A in the following order: 0 min 50% B, 2 min 80% B, 3 min 100% B, 7 min 55% B, 10 min 50% B. A volume of 10 μl was eluted at a flow rate of 1.0 ml / min, and the eluent was detected at a wavelength of 230 nm after approximately 2.9 min. The concentration of ibuprofen was then calculated using the average peak areas obtained from the standard curve. The standard curve was linear over the range of 1 to 250 μg / ml.

[0180] result These results indicate that formulations A, B, C, E, and F delay the drug release of ibuprofen as a T3 substitute (Figure 1). The dissolution profiles of formulations A, B, C, E, and F were compared with those reported by Bowerbank et al. 9 and delayed compared to published values ​​from immediate release liothyronine products such as those described in US 9,526,701. Formulation A exhibited a delayed dissolution profile of 1-2 hours and Formulations B, C, E and F exhibited delayed dissolution profiles of 3-4 hours compared to immediate release liothyronine products.

[0181] conclusion The formulations according to the present disclosure provide delayed drug release compared to existing immediate release liothyronine formulations.

[0182] Example 3: IVIVC correlation of T3 substitutes the purpose The ability of the formulation to provide sustained release that matches the natural fluctuations in hormone levels is demonstrated.

[0183] method The in vitro in vivo correlation (IVIVC) method uses in vitro dissolution data to derive blood drug levels using the pharmacokinetic parameters of the test product. The convolution approach starts with a dissolution result or profile and develops into an in vivo or drug concentration-time estimated profile. Thus, the dissolution rate data obtained for formulations A-C with ibuprofen, a T3 surrogate, was used to derive the expected profiles of T3 at different doses, as reported by Qureshi et al. 2010. 10 The profiles are modeled using a well-validated method described in. Briefly, these profiles are converted into individual dose segments. The bioavailability of T3 is estimated to be 95%, the half-life (t1 / 2) is 4 hours corrected to a baseline (120 ng / dL), and the volume of distribution (Vd) is 0.2 L / kg body weight (BW) for a 75 kg euthyroid individual. The different pharmacokinetic parameters were then calculated.

[0184] result The superimposed predicted total T3 serum plasma profile (IVIC) of formulation C at different T3 doses is shown in Figure 2. The different predicted pharmacokinetic parameters of formulations A-C assuming a dose of 50 μg T3 are shown in Table 2.

[0185] Expected values ​​from the IVIVC correlation show a delayed release and return to baseline after 24 h. This is consistent with Bowerbank et al. 2019 9 and US 9,526, 701. Furthermore, the predicted values ​​are in accordance with the desired physiological values ​​of T3 and the variations in the day / night cycle.

[0186] [Table 2] a Expected dose of T3.

[0187] conclusion Formulations according to the present disclosure exhibit delayed release of IVIVC and return to baseline at 24 hours.

[0188] Example 4: IVIVC correlation with dissolution rate and T3 the purpose This demonstrates the ability of the formulation to provide a sustained release of triiodothyronine that matches the natural fluctuations in hormone levels for T.

[0189] Materials and Methods The dissolution rate of formulations D, G, H, and I was carried out under the same conditions as described in Example 2. The amount of T3 was quantified using an ELISA kit according to the manufacturer's instructions (EliKine™ Triiodothyronine (T3) ELISA Kit, Tebu-bio).

[0190] The mathematical model was updated based on the additional drug release obtained during the dissolution rate study and an IVIVC correlation was performed as described in Example 3.

[0191] result The results show that formulation D retards the drug release of T3 (Figure 3). The dissolution rate is comparable to that observed with formulation C, which used a T3 substitute.

[0192] The predicted values ​​obtained from the IVIVC correlation showed a delayed release profile, returning to baseline after 24 hours in accordance with the desired physiological values ​​of T3 and day / night cycle variations (Figure 4A). When the dose of T3 was changed, the different tablets adjusting the amount of matrix (formulations G, H, and I) showed the appropriate dissolution profile as shown in Figure 4B. The IVIVC correlations shown in Figures 4C-4F confirmed the delayed release profile, returning to baseline after 24 hours (shown in Figure 6), in accordance with the desired physiological values ​​of T3 and day / night cycle variations.

[0193] [Table 3] a Actual T3 dose.

[0194] conclusion The formulations according to the invention provide a delayed release of triiodothyronine with a safe return to baseline corresponding to the natural circadian rhythm profile.

[0195] Different dosages depending on the patient's needs can be accommodated using the formulations of the present disclosure.

[0196] Example 5: Effect of matrix size and amount the purpose How the size and amount of matrix affects the release of the active ingredient is studied.

[0197] Materials and Methods Formulations using the ibuprofen surrogate molecule: A 5 mg formulation of ibuprofen with formulation A (PEO only in the matrix) was prepared according to Example 1 using the VCM method and the dissolution rate was studied as in Example 2. Two formulations were prepared. - Round disc: total weight 942mg, height 3mm x diameter 20mm. Small cylindrical: total weight 301mg, size 3mm height x 8mm diameter.

[0198] result The dissolution profiles (shown in FIG. 5) indicate that the formulations according to the present disclosure with different shapes and amounts of matrix can delay drug release within an appropriate range.

[0199] conclusion Different shapes and amounts of matrix provide suitable sustained release of the T3 replacement.

[0200] Example 6: Study of preparation parameters the purpose The release of ibuprofen (IBU) from different tablets prepared using direct compression and vacuum compression moulding at five different compression forces is studied.

[0201] Materials and Methods Six different 8mm tablet compression formulations were manufactured and tested in triplicate using a standard dissolution USP2 apparatus. Tablet dissolution was performed in a USP2 vessel at 50 rpm using 250mL of 0.1M phosphate buffer, pH 6.8. Samples were taken at 30, 60, 90, 120, 150, 180, 210, 240, and 300 minutes and analyzed for ibuprofen content using HPLC. Tablets are analyzed for water penetration and imaged by UV imaging.

[0202] result The compression pressure range tested was 1 to 7.5 N, i.e., 20 to 150 ton / m 2 The results indicate that variations in tablet hardness or tablet quality at melting temperatures between 85 and 145°C did not affect overall tablet performance within the stated compression force and temperature limits.

[0203] Example 7: Melatonin release studies the purpose The release of melatonin using the formulation according to the present disclosure is studied.

[0204] Materials and Methods Two melatonin tablets were prepared using geometric blending and direct compression according to the following parameters: Formulation J: 200 mg tablet, 3 x 8 mm, melatonin 5 mg, HPMC-AS 19.5 mg, PEO 175 mg (n=3) Formulation K: 500 mg, 3 x 10 mm, melatonin 5 mg, HPMC-AS 49.5 mg, PEO 445.5 mg

[0205] As described in Example 2, the release of each formulation was performed in triplicate tablets (n=3) and melatonin was detected using HPLC for the intestinal environment. The release rate was measured according to the method of Qureshi et al. 2010. 10 Using the method described in, the in vivo serum profile was overlaid using IVIVC with the following assumed parameters: oral bioavailability (BA) of 15%, half-life (T1 / 2 ) = 45 min, distribution volume (Vd) is 16 As published in, we assume 1602L for a body weight (BW) of 75kg.

[0206] result The release rates and overlaid plasma profiles are shown in Figures 7A and 7B, respectively. The calculated pharmacokinetic parameters are shown in the table below.

[0207] [Table 4]

[0208] conclusion The formulations according to the invention provide a delayed release of melatonin with a safe return to baseline corresponding to the natural circadian rhythm profile.

[0209] Different formulations depending on the patient's needs can be accommodated using the formulations of the present disclosure.

[0210] References 1. Munoz-Ortiz,J.,Sierra-Cote,M.C.,Zapata-Bravo,E.et al.Prevalence of hyperthyroidism,hypothyroidism,and euthyroidism in thyroid eye disease:a systematic review of the literature. Syst Rev 9,201(2020). 2. Hegedus L,Bianco AC,Jonklaas J,Pearce SH,Weetman AP,Perrus P.PrimaryCOVIDs and quality of Life. Nat Rev Endocrinol. 2022 Apr;18(4):230-242。 3. Carle A,Faber J,Steffensen R,Laurberg P,Nygaard B.Hypothyloid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment - Data Use ablind,randomized,linical study. Eur Thyroid J. 2017 Jul;6(3):143-151. 4. W.Russell,R.F.Harrison,N.Smith,K.Darzy,S.Shalet,A.P.Weetman,R.J.Ross,Free Triiodothyronine Has a Distinct Circadian Rhythm That Is Delayed but Parallels Thyrotropin Levels,The Journal of Clinical Endocrinology & Metabolism,Volume 93,Issue 6,1 June 2008,Pages 2300-2306. 5. Taylor PN,Albrecht D,Scholz A,Gutierrez-Buey G,Lazarus JH,Dayan CM,Okosieme OE. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018 May;14(5):301-316. 6. Camilla Virili,Aletsandro Antonelli,Maria Giulia Santaguida,Salvatore Benvenga,Marco Centanni,Gastrointestinal Malabsorption of Thryroxine,Endocrine Reviews,Volume 40, Issue 1,February 2019,Pages 118-136 7. Alexandra M.Dumitrescu,Erin C.Hanlon,Marilyn Arosemena,Olga Duchon,Matthew Ettleson,Mihai Giurcanu,and Antonio C.Bianco.Thyroid.Feb2022.196-205. 8. Virili C,Brusca N,Capriello S and Centanni M(2021)Levothyroxine Therapy in Gastric Maabsorptive Disorders. Front. Endocrinol.11:621616. 9. Bowerbank SL,Carlin MG,Dean JR. Dissolution Testing of Single- and Dual-Component Thyroid Hormone Supplements. Separations.2019;6(1):18. 10. Qureshi SA.In Vitro-In Vivo Correlation (IVIVC) and Determining Drug Concentrations in Blood from Dissolution Testing - A Simple and Practical Approach.The Open Drug Delivery Journal,2010,Volume4 11. Jonklaas J,Burman KD,Wang H,Latham KR. Single-dose T3 administration:kinetics and effects on biochemical and physiological parameters.Ther Drug Monit.2015;37(1):110-118. 12. Gamble KL,Berry R,Flank SJ, Young ME. Circadian clock control of endocrine factors. Nat Rev Endocrinol.2014 Aug;10(8):466-75. 13. Dumitrescu AM,Hanlon EC,Arosemena M,Duchon O,Ettleson M,Giurcanu M,Bianco AC. Extended Absorption of Liothyronine from Poly-Zinc-Liothyronine: Results from a Phase 1, Double-Blind, Randomized, and Controlled Study in Humans.Thyroid.2022 Feb;32(2):196-205. 14. Handbook of granulation technology,2nd ed.International Standard Book Number-10:0-8247-2647-2.Taylor and Francis,2005. 15. van Tassell et al.,“Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal,”Thyroid,vol. 29,no.10,pp.1371-1379,Oct.2019,doi:10.1089 / thy.2019.0101. 16. Harpsoe et al.“Clinical pharmacokinetics of melatonin: a systematic review”.European Journal of Clinical Pharmacology 71,901-909(2015)。

Claims

1. a. Triiodothyronine, or a pharmaceutically acceptable salt thereof, b. A total of 0.1% to 20% by weight of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), c. A composition comprising polyethylene oxide (PEO) in an amount ranging from 80 to 99.9% by weight.

2. The composition according to claim 1, wherein triiodothyronine or a pharmaceutically acceptable salt thereof is present in an amount between 1 and 100 μg, or between 5 and 50 μg.

3. The composition according to claim 1, wherein the HPMC-AS and / or hydroxypropyl methylcellulose is present in an amount of about 1% to 20%, about 2% to 20%, or about 5% to 15%.

4. The composition according to claim 3, wherein the composition does not contain HPMC.

5. The composition according to any one of claims 1 to 4, wherein the PEO has an average molecular weight between 10 kDa and 2000 kDa, for example, 50 kDa to 1000 kDa, for example, 100 kDa to 500 kDa, for example, 150 kDa to 300 kDa.

6. The composition according to any one of claims 1 to 4, wherein the PEO is present in an amount of about 80% to 99% or about 85% to 95%.

7. The composition according to any one of claims 1 to 4, wherein the components a), b), and c) are in a single matrix.

8. The composition according to any one of claims 1 to 4, wherein the weight ratio of PEO to the total amount of HPMC and / or HPMC-AS is between about 8:2 and about 9:0.

1.

9. i. Further polymers independently selected from the group consisting of polyethylene oxide glucomannan, galactan, glucan, polygalacturonic acid, polyhydroxyalkanoate, polyxylan, polygalactomannan, lanogalacturonan, polyxyloglycan, arabinogalactan, starch, alginate, xanthan gum, carrageenan, agar, dextran, pectin, cellulose, polyvinyl alcohol, polyvinyl butyral, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose stearate, carboxymethylcellulose, carbomer, polyacrylic acid, poly(methylacrylic) acid, poly(methyl methacrylate), polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxyphenylvalerate, polylactic acid, polyglycolic acid, polyacrylamide, and derivatives or copolymers thereof, and / or ii. Additional excipients selected from the group consisting of binders, fillers, lubricants, release-controlled excipients, stabilizers, antioxidants, and preservatives. A composition according to any one of claims 1 to 4, further comprising one or more of the above.

10. The composition is i. It is in solid dosage form. ii. It is a single-unit oral dosage form. iii. It is an oral dosage form with multiple units. iv. Coated or uncoated tablets, coated or uncoated minitablets, coated or uncoated microtablets, and coated or uncoated spheres v. It is a monolithic tablet. vi. It is a monolithic cylindrical tablet. vii. Tablets with a total weight of 50-800 mg. viiii. A tablet having a volume / weight ratio between 100 and 200, or ix. A cylindrical tablet having one dimension of 2-4 mm and the other dimension of 6-10 mm. The composition according to any one of claims 1 to 4.

11. The composition according to any one of claims 1 to 4, further comprising a coating.

12. A pharmaceutical composition according to any one of claims 1 to 4, for use in the treatment of hypothyroidism, for use in reducing and / or preventing side effects of treatment for hypothyroidism, or for use in the treatment of bone injury, cartilage injury and / or stroke.

13. The composition according to claim 12, wherein the hypothyroidism is drug-induced hypothyroidism, or the hypothyroidism is caused by one or more selected from the group consisting of autoimmune disease, radiation therapy, treatment with other drugs, surgical removal of part or all of the thyroid gland, congenital disease, and pregnancy.

14. The composition is i. To be administered to patients suffering from one or more side effects of treatment for hypothyroidism, ii. To be administered to patients suffering from one or more side effects resulting from treatment for hypothyroidism, iii. Administered between 18h and 00h. iv. To be administered during or after dinner. v. Administered before the main sleep episode, vi. Administered once daily, or vii. The composition according to claim 12, which is administered on an empty stomach.

Images