Compositions for improved release of active ingredients

Abstract

The present disclosure relates to the field of sustained release compositions of active ingredients capable of modulating endocrine or hormone signaling and uses thereof. Formulations according to the present disclosure accommodate temporal treatment events of fluctuating levels of natural signal transduction over a 24-hour period.

Description

Technical Field

[0001] The present disclosure relates to the field of sustained release compositions of active ingredients capable of mimicking or modulating endocrine or hormonal signaling and their uses. The formulations according to the present disclosure accommodate chronotherapeutic events of fluctuating levels of natural signaling within a 24-hour cycle. Background Art

[0002] A large number of hormones or endocrine signaling systems undergo fluctuations over the course of a day. This is due to the organism's critical need to maintain biological processes within physiological limits to accommodate fluctuations in daily stimuli. Not only do the circulating levels of endocrine factors oscillate over a 24-hour cycle, but so do the responsiveness of target receptors and tissues to the factors.

[0003] It is known that hormonal factors and systems, such as cortisol, growth hormone, testosterone, prolactin, thyroid-stimulating hormone, triiodothyronine, the renin-angiotensin-aldosterone system, fibroblast growth factor 21, ghrelin, adiponectin, leptin, vasopressin, insulin or melatonin, oscillate in the human body with a 24-hour cycle. The oscillation of these systems depends on the time of day. 12 .

[0004] From a therapeutic perspective, this presents unique challenges for active ingredients that can modulate these systems. Achieving therapeutically effective doses in subjects who are attuned to such oscillations is nontrivial. This is particularly true for systems where signaling increases or decreases in the middle of the night or early morning, as administering the active ingredient at those earlier times would be impossible or highly inconvenient for the patient.

[0005] Providing pharmaceutical formulations that can release active ingredients in a manner that accommodates these fluctuating levels is highly desirable and can benefit patients with a variety of conditions. This is especially true for patients receiving chronic or long-term treatments. Therefore, there is currently a need in the art to develop such formulations.

[0006] For example, thyroid diseases (hypothyroidism (HOT) and hyperthyroidism (HT)) affect more than 10% of the population worldwide, are highly prevalent in the age group over 65 years old, and are 10 times more prominent in women. 1 Thyroid hormone levels oscillate in the body according to a circadian rhythm, which naturally oscillates according to the day-night cycle. In healthy individuals, concentrations of triiodothyronine (T3) naturally increase gradually during the night and return to baseline levels in the morning4.

[0007] Current treatments include the use of triiodothyroxine (T4) and T3. T4 is an inactive hormone that is converted to T3 in the body by the dual enzyme deiodinase. T3 is the active hormone that controls cellular metabolism, heart rate, body temperature, motility, muscle contraction, and apoptosis. 80% of patients receiving current hypothyroidism therapy report dissatisfaction with current treatment, with 60% reporting poor quality of life (QoL), fatigue, weight gain, and are often overtreated, leading to long-term side effects2. 10-20% of these patients do not respond to LT4 monotherapy due to known / unknown underlying genetic factors (e.g., mutations in the enzyme that converts T4 to T3 (e.g., DiO2 T92A), or mutations in the thyroid hormone transporter (e.g., MCT10)), but the vast majority of patients 3 Prefer co-administration of T3 4 .

[0008] Today, T3 is administered as a rapid-release drug (LT3), which does not mimic the natural circadian rhythm. T3 therapy has historically been limited by its short half-life (T3 has an elimination half-life of 23-25 ​​hours in adults, a biological half-life of 2.5 days, and an estimated baseline-corrected half-life of 4 hours). 11 ) and adverse reactions. For example, in patients after thyroidectomy (i.e., no endogenous T4 or T3) 15 Studies with exogenous LT4 or LT3 have shown that T 1 / 2 The half-life is 3.62 hours and the Tmax is 2.9 hours, which is 11 days after the last LT3 is discontinued. 15 The short half-life leads to multiple dosing per day, which results in poor patient compliance. This often leads to long-term overdose and severe side effects such as cardiovascular disease, hypertension, mineral metabolism complications, etc.

[0009] Currently, there are no commercially available extended-release T3 drugs on the market as standard alternatives to T4 monotherapy. Attempts to design extended-release T3 formulations that mimic the circadian rhythm spectrum have been unsatisfactory because past attempts at extended release have not returned to natural baseline levels and have increased the potential for overdose and induction of side effects.

[0010] Therefore, there is a need in the art for a sustained-release T3 formulation that can follow the natural oscillations of hormone levels and provide an alternative to current ineffective hypothyroidism treatments, ideally avoiding physiological pitfalls. 8 . Summary of the invention

[0011] The present disclosure solves the above problems by providing improved sustained release compositions and formulations of active ingredients that can mimic or modulate hormone or endocrine signaling by following the natural fluctuations in hormone levels according to the circadian rhythm.

[0012] Thus, in one aspect, the present disclosure relates to compositions and pharmaceutical formulations comprising:

[0013] a. an active ingredient or a pharmaceutically acceptable salt thereof,

[0014] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), and

[0015] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0016] The inventors surprisingly found that the formulations according to the present disclosure showed a dissolution profile and release of the active ingredient that matched the physiological levels of natural hormone signaling according to the circadian cycle and returned safely to baseline levels.

[0017] One aspect of the present disclosure provides a method for manufacturing a composition, comprising the following steps:

[0018] a. preparing a melt-homogeneous dispersion comprising i) PEO, ii) hydroxypropyl methylcellulose and / or HPMC-AS and iii) an active ingredient or a pharmaceutically acceptable salt thereof, and

[0019] b. Cooling the melt to obtain a solid composition.

[0020] In one aspect, the present disclosure provides a method of making a composition, comprising the steps of:

[0021] i. mixing powders of the active ingredient or a pharmaceutically acceptable salt thereof, HPMC and / or HPMC-AS and PEO, and

[0022] ii. Compacting the mixture to obtain a uniform dispersion of the components in the matrix.

[0023] In another aspect, the present disclosure provides a composition or pharmaceutical formulation as described herein for use as a medicament.

[0024] In another aspect, the present disclosure provides a composition or pharmaceutical formulation as described herein for use in the modulation of hormone or endocrine signaling.

[0025] In another aspect, the disclosure relates to the use of a composition or pharmaceutical formulation as described herein for treating hypothyroidism and / or for preventing or reducing the incidence of side effects associated with hypothyroidism treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Formulations A, B, C, E and F present the dissolution profiles of ibuprofen as a T3 model compound.

[0027] Figure 2 . Predicted T3 plasma profiles of different doses of T3 obtained by in vitro-in vivo correlation (IVIVC) based on the dissolution rate of T3 model compound in formulation C.

[0028] Figure 3 The dissolution profile of 50 μg T3 in formulation D in two tablets was analyzed by ELISA.

[0029] Figure 4 .A and 50 μg of generic liothyronine (T3 immediate release, experimental in vivo spectrum 13 ) compared with the mean T3 plasma profile (estimated baseline 120 ng / dL) of 40 μg of T3 preparation D (n=3, quantified by ELISA). The convolution method was adopted from Qureshi et al., 2010 10 Methods in. B Dissolution profiles of T3 tablets of formulations G, H and I produced using roller compaction dry granulation analyzed by ELISA. C Convoluted IVIVC T3 plasma profiles of tablets of formulations G, H and I (estimated baseline of 120 ng / dL). D Convoluted mean T3 plasma profiles (estimated baseline of 120 ng / dL) describe the delayed release of hypothetical 20 μg, 30 μg, 40 μg and 50 μg of T3 for 200 mg tablets (formulation I). E Convoluted mean T3 plasma profiles (estimated baseline of 120 ng / dL) describe the delayed release of hypothetical 20 μg, 30 μg, 40 μg and 50 μg of T3 for 150 mg tablets (formulation H). F Convoluted mean T3 plasma profiles (estimated baseline of 120 ng / dL) describe the delayed release of hypothetical 20 μg, 30 μg, 40 μg and 50 μg of T3 for 100 mg tablets (formulation G).

[0030] Figure 5 Dissolution rates of two different ibuprofen tablets with different sizes and amounts of matrix, including pictures of the tablets. Dimensions of cylindrical tablets (height mm x diameter mm): discs 3mm x 20mm, small cylinders 3mm x 8mm.

[0031] Figure 6 .T3 level oscillations over a 24-hour period, with the time axis in the chart starting at 9:00 AM (time = 0). The results are adapted from J Clin Endocrinol Metab 93:2300–2306,2008 4 .

[0032] Figure 7.A Mean melatonin release of formulations J and K; B Curled IVIVC melatonin plasma profiles of tablets of formulations J and K.

[0033] definition

[0034] "Cmax" is a term used in pharmacokinetics to refer to the maximum (or peak) serum concentration of a drug achieved in a specific compartment or tested area of ​​the body after the drug has been administered and before a second dose is administered.

[0035] "Tmax" is a term used in pharmacokinetics to describe the time at which Cmax is observed.

[0036] "Half-life (t1 / 2)" is a term that refers to the time required for half of a drug to be eliminated from the blood.

[0037] "Apparent volume of distribution (Vd)" or "apparent drug distribution volume" is a parameter calculated based on the amount of drug administered and its observed concentration (mass / volume) for an individual of a given body weight.

[0038] "Oral bioavailability" refers to the fraction of an orally administered drug that is available in the blood calculated relative to the drug concentration after intravenous injection.

[0039] "Sustained release" is a term used to refer to a mechanism in a composition or formulation for releasing a drug or active pharmaceutical ingredient from a composition or formulation over an extended period of time, rather than all at once, or in an immediate or sudden release. In some embodiments, as used herein, the terms "sustained release," "extended release," "controlled release," and "modified release" can be used interchangeably to refer to this mechanism.

[0040] In some embodiments, as used herein, the terms "composition" and "formulation" are used interchangeably.

[0041] As used herein, "active ingredient" refers to any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or affects the structure or any function of the human or animal body.

[0042] "Hormone" or "endocrine factor" refers to substances produced by organs of the body that travel through the bloodstream to trigger activities elsewhere, or synthetic compounds that have the same activity as natural hormones.

[0043] "Hormonal signaling" or "endocrine signaling" refers to the inhibition and activation of hormone receptors. Hormone signaling is regulated by natural hormones or other compounds that have the same activity as natural hormones.

[0044] As used herein, the term "about" means that an amount or percentage should be interpreted as a variation of ±10%, such as ±5%, relative to the numerical value of the amount or percentage to which it refers.

[0045] As used herein, "matrix" refers to a composite material of one or more active ingredients intimately mixed with one or more excipients, particularly polymers. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention relates to sustained-release pharmaceutical compositions and formulations of active ingredients capable of regulating hormone or endocrine signaling following natural oscillations within the 24-hour cycle of the circadian rhythm.

[0048] Thus, one aspect of the present disclosure relates to pharmaceutical compositions and pharmaceutical formulations comprising:

[0049] a. an active ingredient or a pharmaceutically acceptable salt thereof,

[0050] b. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), and

[0051] c. Polyethylene oxide (PEO).

[0052] Another aspect of the present disclosure relates to compositions and formulations as described herein for use as medicaments.

[0053] In one aspect, the present disclosure relates to compositions and formulations as described herein for use in treating hypothyroidism and / or for preventing or reducing side effects associated with hypothyroidism treatment.

[0054] The inventors have surprisingly demonstrated that the compositions disclosed herein provide a dissolution rate and release profile of the active ingredient sufficient to regulate hormone and endocrine signaling levels according to the natural oscillations of hormone or endocrine signaling of different systems over a 24-hour cycle and safely return to baseline.

[0055] This is advantageous for hormone or endocrine signaling, which increases or decreases during the night or throughout the early morning hours, as it is inconvenient for the patient to take the active ingredient at these times. In addition, sustained release provides a concentration that better matches the natural levels during these time periods. Therefore, the compositions according to the present disclosure have great potential to provide active ingredients according to patient needs, thereby leading to better treatment outcomes, reduced side effects and / or improved quality of life, particularly for patients requiring chronic treatment.

[0056] The advantages of the formulations and compositions disclosed herein are numerous and include:

[0057] Compared with standard of care, fewer doses are required and dosing regimens are simplified, thereby improving patient compliance.

[0058] • Possibility to combine the preparation according to the invention with standard of care treatment.

[0059] Improve the quality of life of patients who have difficulty with current standard of care treatments.

[0060] Pharmaceutical composition

[0061] Sustained-release or controlled-release technology is a collection of mechanisms (such as erosion and diffusion) in a composition or formulation that slowly dissolves and releases or slowly releases and dissolves a drug over time. Extended-release formulations can be taken less frequently than immediate-release formulations, and they generally keep drug levels in the bloodstream more constant.

[0062] Sustained-release compositions can be prepared so that the active ingredient is embedded in a matrix of material, so that the dissolved drug must find its way out through the pores in the matrix. In some formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to be expelled through the outer surface of the gel. In other cases, the material matrix slowly decomposes and erodes, releasing the drug in a sustained-release profile.

[0063] The inventors have demonstrated 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 a sustained release of the active ingredient with a desired active ingredient profile, wherein the active ingredient is capable of regulating endocrine or hormone physiological levels that oscillate periodically within 24 hours according to the diurnal cycle and safely return to baseline.

[0064] Thus, in one embodiment, the present disclosure relates to a pharmaceutical composition comprising:

[0065] a. an active ingredient or a pharmaceutically acceptable salt thereof,

[0066] b. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), and

[0067] c. Polyethylene oxide (PEO).

[0068] The inventors have demonstrated that pharmaceutical compositions comprising specific amounts of PEO, HPMC and / or HPMC-AS provide sustained release of the active ingredient in a desired profile according to physiological levels of endocrine or hormone signaling, which oscillate within a 24-hour cycle according to the circadian cycle.

[0069] Polyethylene oxide (PEO) is obtained by polymerization of ethylene oxide. Its structure is similar to polyethylene glycol (PEG), which is obtained by condensation of ethylene glycol molecules. In this text, the terms "PEG" and "PEO" are used interchangeably.

[0070] HPMC and HPMC-AS are cellulose derivatives in which some of the free hydroxyl groups in the cellulose have been replaced by hydroxypropyl and methyl groups. In the case of HPMC-AS, the other hydroxyl groups are replaced by acetate and succinate groups. Typically, these materials are used as coatings to delay the release of drug compounds into the digestive tract.

[0071] In one embodiment, HPMC-AS comprises 4 wt% to 28 wt% succinyl and 2 wt% to 16 wt% acetyl, such as 8 wt% to 20 wt% succinyl and 4 wt% to 12 wt% acetyl, such as 14 wt% to 18 wt% succinyl and 4 wt% to 9 wt% acetyl. In one embodiment, the acetyl content in HPMC-AS is less than 12 wt%, such as less than 10 wt%, and the succinyl content is greater than 6 wt%, such as greater than 8 wt%.

[0072] Thus, in one embodiment, the present disclosure relates to a pharmaceutical composition comprising:

[0073] a. an active ingredient or a pharmaceutically acceptable salt thereof,

[0074] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), and

[0075] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0076] In another embodiment, the composition comprises HPMC and / or HPMC-AS in a total amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, such as about 10%.

[0077] Furthermore, the inventors surprisingly demonstrated that compositions comprising HPMC-AS mixed in a matrix (rather than as a coating or encapsulant) provide a sustained release profile of the active ingredient and provide pharmacokinetic properties that are favorable for therapies employing active ingredients that modulate hormonal or endocrine signaling of systems that oscillate within a 24-hour cycle. Furthermore, due to the functional groups present in HPMC-AS, the component further provides improved protection for the active ingredient as it passes through the various conditions (particularly pH) in the gastrointestinal tract.

[0078] In one embodiment, the composition does not contain HPMC. For example, the composition is substantially free of HPMC.

[0079] Thus, in one embodiment, the composition comprises HPMC-AS in an amount of about 1 wt % to 20 wt %, such as about 2 wt % to 20 wt %, such as about 5 wt % to 15 wt %, such as about 6 wt % to 14 wt %, such as about 7 wt % to 13 wt %, such as about 8 wt % to 12 wt %, such as about 9 wt % to 11 wt %, such as about 10 wt %.

[0080] In one embodiment, the composition comprises about 3wt% to 14wt%, such as 3wt% to 4wt%, such as 4wt% to 5wt%, such as 5wt% to 6wt%, such as 6wt% to 7wt%, such as 7wt% to 8wt%, such as 8wt% to 9wt%, such as 9wt% to 10wt%, such as 10wt% to 11wt%, such as 11wt% to 12wt%, such as 12wt% to 13wt%, such as 13wt% to 14wt% of HPMC-AS. In one embodiment, the composition comprises about 5wt% to about 14wt% of HPMC-AS. In one embodiment, the composition comprises about 8wt% to about 14wt% of HPMC-AS.

[0081] In one embodiment, the composition does not comprise HPMC-AS.

[0082] In one embodiment, the composition comprises HPMC in an amount of about 1 wt % to 20 wt %, such as about 2 wt % to 20 wt %, such as about 5 wt % to 15 wt %, such as about 6 wt % to 14 wt %, such as about 7 wt % to 13 wt %, such as about 8 wt % to 12 wt %, such as about 9 wt % to 11 wt %, such as about 10 wt %.

[0083] In one embodiment, the composition comprises HPMC in an amount of about 5wt% to 15wt%, such as 5wt% to 6wt%, such as 6wt% to 7wt%, such as 7wt% to 8wt%, such as 8wt% to 9wt%, such as 9wt% to 10wt%, such as 10wt% to 11wt%, such as 11wt% to 12wt%, such as 12wt% to 13wt%, such as 13wt% to 14wt%, such as 14wt% to 15wt%, such as 15wt% to 16wt%, such as 16wt% to 17wt%, such as 17wt% to 18wt%, such as 18wt% to 19wt%, such as 19wt% to 20wt%.

[0084] In one embodiment, PEO has a mean molecular weight of 10kDa to 2000kDa, for example 50kDa to 1000kDa, for example 100kDa to 500kDa, for example 150kDa to 300kDa. In one embodiment, PEO has a mean molecular weight of 100kDa to 500kDa. In one embodiment, PEO has a mean molecular weight of 100kDa to 400kDa. In one embodiment, PEO has a mean molecular weight of 100kDa to 300kDa. In one embodiment, PEO has a mean molecular weight of about 200kDa.

[0085] In one embodiment, PEO is present in the pharmaceutical composition in an amount of about 80% to 99%, for example, about 85% to 95%, for example, about 88% to 92%, for example, about 90%. In one embodiment, PEO is present in the composition in an amount of about 80wt% to 99wt%. In one embodiment, PEO is present in the composition in an amount of about 83wt% to 97wt%. In one embodiment, PEO is present in the composition in an amount of about 85wt% to 95wt%. In one embodiment, PEO is present in the composition in an amount of about 87wt% to 93wt%. In one embodiment, PEO is present in the composition in an amount of about 90wt%.

[0086] In one embodiment, PEO is present in the pharmaceutical composition in an amount of about 85wt% to 95wt%, for example 85wt% to 86%, for example 86wt% to 87wt%, for example 87wt% to 88wt%, for example 88wt% to 89wt%, for example 89wt% to 90wt%, for example 90wt% to 91wt%, for example 91wt% to 92wt%, for example 92wt% to 93wt%, for example 93wt% to 94wt%, for example 94wt% to 95wt%.

[0087] 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 uniform dispersion comprising the active ingredient, HPMC and / or HPMC-AS and PEO. "Uniform dispersion" means a dispersion in which the components are uniformly or homogeneously distributed in the dispersion.

[0088] PEO, HPMC and HPMC-AS are considered to be hydrophilic and gel-forming. In water, a matrix composed of any of them or their mixture undergoes a series of processes leading to dissolution: water penetration, hydration, disentanglement, gel formation and migration of loose chains into the medium.

[0089] In the case where the matrix is ​​produced in such a way that it prevents rapid water penetration, the result of the first step is that the dosage unit is gradually eroded, with only a thin release layer forming on the surface. Due to the high deformability / plasticity and low melting point of PEO in particular, this matrix can be achieved by thermoplastic processes (such as injection molding, hot melt extrusion, calendering) or by compression under sufficient pressure. The purpose is to prevent water penetration by reducing the appearance of cracks or interparticle channels.

[0090] Compositions according to the present disclosure release active ingredients primarily by erosion. Therefore, the release of active ingredients is closely related to the erosion rate. In contrast to release primarily by diffusion control, this mechanism is less prone to change between different types of active ingredients. The examples show that different active ingredients show comparable dissolution profiles.

[0091] One aspect of the present disclosure provides a composition comprising a matrix, the composition comprising:

[0092] i. an active ingredient as described herein or a pharmaceutically acceptable salt thereof,

[0093] ii. HPMC and / or HPMC-AS; and

[0094] iii. Polyethylene oxide (PEO), wherein the weight ratio of PEO (component i.) to HPMC and / or HPMC-AS (component ii.) is 8:2 to 9:0.1.

[0095] In one embodiment, PEO, HPMC and HPMC-AS are as described herein.

[0096] In one embodiment, the weight ratio of PEO to HPMC and / or HPMC-AS is from about 8: 1 to 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.

[0097] 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.

[0098] In one embodiment, the composition does not comprise HPMC.

[0099] Other polymers

[0100] The composition according to the present disclosure may include one or more other polymers. The one or more other polymers may be independently selected from ionic, nonionic, water-insoluble polymers and water-soluble polymers. In one embodiment, the one or more polymers are one or more water-soluble polymers.

[0101] In one embodiment, the one or more other polymers are selected from polysaccharides, acrylates and polysiloxanes and derivatives thereof.

[0102] In another embodiment, the one or more additional polymers are independently selected from polyoxyethylene glucomannan, galactan, dextran, polygalacturonic acid, polyhydroxyalkanoate, polyxylan, polygalactomannan, rhanogalacturonan, polyxyloglucan, arabinogalactan, starch, alginate, xanthan gum, carrageenan, agar, dextran, pectin, cellulose, polyvinyl alcohol, polyvinyl butyral, polyvinyl pyrrolidone, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose stearate, carboxymethylcellulose, carbomer, polyacrylic acid, poly(methacrylic) acid, poly(methyl methacrylate), polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxyphenylvalerate, polylactic acid, polyglycolic acid, polyacrylamide, and derivatives or copolymers thereof.

[0103] The inventors surprisingly demonstrated that the composition according to the present disclosure does not require the presence of a lubricant. During the formulation process, a lubricant is usually required to improve the performance of the powder and to play a role by reducing friction. Due to the properties of PEO and the amount of PEO used, a lubricant is not required to prepare the composition according to the present disclosure during processing. Therefore, 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 the following: a metal salt of a fatty acid, such as a divalent salt of a fatty acid, such as a magnesium, calcium or zinc salt of a fatty acid; a fatty acid, a fatty acid ester or talc.

[0104] Active pharmaceutical ingredients

[0105] The composition according to the present invention provides sustained release of the active ingredient or a pharmaceutically acceptable salt thereof.

[0106] The inventors have demonstrated that formulations according to the present disclosure provide a sustained release profile that is advantageous for active ingredients capable of regulating the levels of hormones or endocrine factors, particularly hormones and endocrine factors whose levels oscillate in a 24-hour cycle in the human body. Thus, in one embodiment, the active ingredient is selected from the group consisting of: thyroid hormones or thyroid hormone modulators, such as triiodothyronine or triiodothyronine; dopamine reuptake inhibitors; serotonin reuptake inhibitors; renin inhibitors; angiotensin inhibitors; angiotensin receptor antagonists; 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 analogs; fibroblast growth factor 21 receptor agonists; adiponectin receptor agonists; leptin analogs; leptin receptor agonists and vasopressin receptor agonists.

[0107] 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 a hormone or endocrine factor whose natural healthy levels increase or decrease at night or throughout the early morning and then return to baseline. Compared to immediate release formulations, the compositions disclosed herein allow the administration of the active ingredient at a time convenient for the patient, based on which the release profile will be advantageous based on the natural oscillation of the affected hormone or endocrine signaling.

[0108] Those skilled in the art will appreciate that active ingredients may be able to regulate hormone or endocrine signaling through different mechanisms. For example, the active ingredient or its salt may be an endocrine factor or hormone itself, such as triiodothyronine or melatonin. The active ingredient may be a prodrug that is converted into an active ingredient that can affect hormone or endocrine signaling. The active ingredient may act on the same receptor in the same manner as an endogenous hormone or endocrine factor. The active ingredient may also act on receptors upstream or downstream of a specific hormone or endocrine factor signaling pathway that has the same effect as the hormone or endocrine factor, such as releasing a second messenger.

[0109] Thus, in one embodiment, the active ingredient is capable of modulating hormone or endocrine signaling of a hormone or endocrine factor whose natural healthy levels increase or decrease during the night. In one embodiment, the active ingredient modulates hormone or endocrine signaling whose natural levels increase or decrease between 12 am and 6 am.

[0110] In one embodiment, the natural signaling level of the hormone or endocrine signaling; or the natural level of the hormone or endocrine factor increases or decreases 1 to 6 hours after the onset of the main sleep cycle, for example, 1 to 5 hours, 1 to 4 hours, or 1 to 3 hours after the onset of the main sleep cycle.

[0111] In one embodiment, the active ingredient is capable of modulating hormone or endocrine signaling of a hormone or endocrine factor whose natural healthy levels increase or decrease throughout the morning.

[0112] For example, signaling of hormones and endocrine factors such as thyroid hormone, melatonin, prolactin, ghrelin, leptin, or vasopressin increases at night. 12 Thus, in one embodiment, the active ingredient is selected from the group consisting of: thyroid hormone, melatonin receptor agonist, prolactin releaser, ghrelin receptor agonist, leptin receptor agonist and vasopressin receptor agonist.

[0113] The signaling of hormones and endocrine factors (such as Cortisol, testosterone, fibroblast growth factor or adiponectin) increases in the early morning. Therefore, in one embodiment, the active ingredient is selected from: corticosteroids, androgens, fibroblast growth factor 21 analogs and adiponectin receptor agonists.

[0114] The renin-angiotensin-aldosterone system is a key regulator of blood pressure, mainly through the production of angiotensin II. Due to sympathetic neuron activation, renin secretion is activated before waking up in the morning. Both renin and aldosterone show a significant circadian rhythm pattern in normotensive and hypertensive individuals, with a peak detected in the early morning, and then falling to the lowest point in the middle of the night. Therefore, renin-angiotensin inhibitors can be used to reduce the signal conduction of hypertensive patients, thereby reducing blood pressure. In one embodiment, the active ingredient is selected from: renin inhibitors, angiotensin inhibitors, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors and renin-angiotensin-aldosterone pathway inhibitors.

[0115] As demonstrated in the examples, the formulations according to the present disclosure provide a sustained release of the active ingredient that is sufficient to match the natural oscillations of the levels of different hormones or endocrine factors in a healthy individual over a 24-hour period and safely return to baseline. Therefore, the formulations according to the present disclosure have great potential to provide active ingredients according to patient needs, thereby bringing better treatment results, reducing side effects and / or improving quality of life, especially for patients who require chronic treatment.

[0116] In one embodiment, the present disclosure provides a composition comprising:

[0117] a. an active ingredient as described herein or a pharmaceutically acceptable salt thereof,

[0118] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0119] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0120] In one embodiment, the present disclosure provides a composition comprising:

[0121] a. an active ingredient as described herein or a pharmaceutically acceptable salt thereof,

[0122] b. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in an amount of 0.1 wt % to 20 wt % as described herein, and

[0123] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0124] In one embodiment, the present disclosure provides a composition comprising:

[0125] a. an active ingredient as described herein or a pharmaceutically acceptable salt thereof,

[0126] b. 0.1 wt % to 20 wt % hydroxypropyl methylcellulose (HPMC) as described herein, and

[0127] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0128] In one embodiment, the active ingredient is a thyroid hormone, such as triiodothyronine or triiodothyronine.

[0129] In one embodiment, the active ingredient is triiodothyronine (also referred to herein as: T4 or thyroxine) or a pharmaceutically acceptable salt thereof.

[0130] In one embodiment, the active ingredient is triiodothyronine (also referred to herein as: T3, LT3 or liothyronine) or a pharmaceutically acceptable salt thereof.

[0131] Triiodothyronine is unstable under the pH and enzymatic conditions of the stomach. Therefore, one advantage of the sustained-release composition according to the present disclosure is that T3 is at least partially protected from degradation in the stomach, thereby having a higher bioavailability compared to an immediate-release formulation.

[0132] In one embodiment, the composition according to the invention comprises triiodothyronine or a pharmaceutically acceptable salt thereof in an amount of 1 μg to 100 μg, such as about 2 μg to 70 μg, such as about 5 μg to 50 μg.

[0133] In one embodiment, the composition according to the invention comprises 5 μg to 50 μg, for example 5 μg to 7 μg, for example 7 μg to 9 μg, for example 9 μg to 11 μg, for example 11 μg to 13 μg, for example 13 μg to 15 μg, for example 15 μg to 17 μg, for example 19 μg to 21 μg, for example 21 μg to 23 μg, for example 23 μg to 25 μg, for example 25 μg to 27 μg, for example 27 triiodothyronine or a pharmaceutically acceptable salt thereof in an amount of 1 μg to 29 μg, for example 29 μg to 31 μg, for example 31 μg to 33 μg, for example 33 μg to 35 μg, for example 35 μg to 37 μg, for example 37 μg to 39 μg, for example 39 μg to 41 μg, for example 41 μg to 43 μg, for example 43 μg to 45 μg, for example 45 μg to 47 μg, for example 47 μg to 50 μg.

[0134] In one embodiment, the present disclosure provides a composition comprising:

[0135] a. triiodothyronine as described herein or a pharmaceutically acceptable salt thereof,

[0136] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0137] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0138] In one embodiment, the active ingredient is a corticosteroid or a pharmaceutically acceptable salt thereof, such as hydrocortisone, prednisolone, prednisone.

[0139] In one embodiment, the present disclosure provides a composition comprising:

[0140] a. a corticosteroid as described herein or a pharmaceutically acceptable salt thereof,

[0141] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0142] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0143] In one embodiment, the active ingredient is a dopamine reuptake inhibitor or a pharmaceutically acceptable salt thereof, such as bupropion, wellbutrin, forfivo, or aplezin.

[0144] In one embodiment, the present disclosure provides a composition comprising:

[0145] a. a dopamine reuptake inhibitor as described herein or a pharmaceutically acceptable salt thereof,

[0146] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0147] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0148] In one embodiment, the active ingredient is a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, such as sertraline, fluoxetine, citalopram, escitalopram, paroxetine, or fluvoxamine.

[0149] In one embodiment, the present disclosure provides a composition comprising:

[0150] a. a serotonin reuptake inhibitor as described herein or a pharmaceutically acceptable salt thereof,

[0151] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0152] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0153] In one embodiment, the active ingredient is a melatonin receptor agonist or a pharmaceutically acceptable salt thereof, such as melatonin.

[0154] In one embodiment, the present disclosure provides a composition comprising:

[0155] a. a melatonin receptor agonist as described herein or a pharmaceutically acceptable salt thereof,

[0156] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0157] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0158] In one embodiment, the active ingredient is melatonin or a pharmaceutically acceptable salt thereof.

[0159] In one embodiment, the active ingredient is a renin inhibitor capable of lowering blood pressure or a pharmaceutically acceptable salt thereof, such as aliskiren. In one embodiment, the active ingredient is an angiotensin inhibitor, angiotensin receptor blocker or angiotensin converting enzyme inhibitor capable of lowering blood pressure or a pharmaceutically acceptable salt thereof. In one embodiment, the active ingredient is a renin-angiotensin-aldosterone pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0160] In one embodiment, the present disclosure provides a composition comprising:

[0161] a. a renin inhibitor or angiotensin inhibitor as described herein, or a pharmaceutically acceptable salt thereof,

[0162] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0163] c. Polyethylene oxide (PEO) in an amount of 80 wt % to 99.9 wt %.

[0164] In one embodiment, the active ingredient is a prolactin-releasing agent capable of inducing prolactin secretion, or a pharmaceutically acceptable salt thereof.

[0165] In one embodiment, the present disclosure provides a composition comprising:

[0166] a. a prolactin releasing agent as described herein or a pharmaceutically acceptable salt thereof,

[0167] b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC) as described herein, and

[0168] c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

[0169] Preparation method

[0170] One aspect of the present disclosure provides a method for manufacturing a composition, comprising the following steps:

[0171] a. preparing a melt-homogeneous dispersion comprising i) PEO, ii) hydroxypropyl methylcellulose and / or HPMC-AS and iii) an active ingredient or a pharmaceutically acceptable salt thereof, and

[0172] b. Cooling the melt to obtain a solid composition.

[0173] The melt may be prepared by heating the powder mixture to a temperature that at least partially melts the powder or one of the powders. In one embodiment, step a) comprises heating the mixture to a temperature that at least partially melts the powder or one of the powders. In one embodiment, step a) further comprises compressing the mixture.

[0174] In one aspect, the present disclosure provides a method of making a composition, comprising the steps of:

[0175] i. mixing powders of the active ingredient or a pharmaceutically acceptable salt thereof, HPMC and / or HPMC-AS and PEO,

[0176] ii. Compacting the mixture to obtain a uniform dispersion of the components in the matrix.

[0177] Processes and methods for achieving uniform dispersion by melt dispersion or by mixing and compacting solids are well known to those skilled in the art. 14 For example, methods of implementing the methods described herein include, but are not limited to: dry granulation, such as by roller compaction, calendering, slugging, or pneumatic dry granulation; compression molding, such as vacuum compression molding (VCM); direct compression (DCT); hot melt extrusion (HME); ultrasound-assisted compaction; or wet granulation.

[0178] In one embodiment, the step i) of compacting the mixture to obtain a uniform dispersion of the components in the matrix is ​​performed by a dry granulation process. In one embodiment, the dry granulation is performed by roller compaction.

[0179] In one embodiment, the method further comprises the step of compressing the composition into a solid composition. In one embodiment, the composition is compressed into a tablet.

[0180] Therefore, in one embodiment, the composition according to the present disclosure is compressed into a tablet. Compressing with sufficient force provides a tablet in which the cracks between the particles are small, which reduces the water penetration rate and ensures proper erosion of the tablet. Those skilled in the art know how to achieve appropriate compression to ensure a slow water penetration rate and how to optimize the compression force based on the materials or equipment used.

[0181] In one embodiment, the PEO, HPMC and / or HPMC-AS and the active ingredients are as described herein.

[0182] excipient

[0183] The compositions according to the present disclosure may comprise one or more additional excipients.An excipient is a pharmacologically inactive substance formulated with the active ingredient of a drug.

[0184] In one embodiment, the pharmaceutical composition according to the present invention comprises one or more excipients. The one or more excipients can be used as solid carriers, diluents, flavoring agents, solubilizers, lubricants, glidants, suspending agents, adhesives, fillers, preservatives, antiadherents, wetting agents, tablet disintegrants, adsorbents, and / or encapsulation / coating materials.

[0185] In one embodiment, the one or more additional excipients are selected from one or more of a binder, a filler, a lubricant, a controlled release excipient, a stabilizer, a plasticizer, an antioxidant, and a preservative.

[0186] In one embodiment, the composition comprises a filler, for example a filler selected from the group consisting of calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, isomalt, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose (MCC), polydextrose, sodium alginate, sorbitol, talc and xylitol.

[0187] In one embodiment, the composition comprises a binder, for example, a binder selected from the group consisting of gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, chitosan, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, hypromellose, methylcellulose, poloxamer, polydextrose, polyethylene oxide, povidone, sodium alginate, sucrose, starch, pregelatinized starch, and maltodextrin.

[0188] In one embodiment, the composition comprises a lubricant, for example a lubricant selected from 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, silicon dioxide and zinc stearate.

[0189] Preservatives can be antimicrobial agents or antioxidants. Preservatives can also be light filters or light blockers, such as TiO 2 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: antimicrobial agents, antioxidants, light filters, or light blocking agents.

[0190] In one embodiment, the composition comprises a controlled release excipient, for example, a controlled release excipient selected from 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.

[0191] Any other excipients suitable for the purposes of the present invention and known to those skilled in the art are deemed to be included in the present invention.

[0192] Sustained release preparations

[0193] tablet

[0194] In one embodiment, the present disclosure relates to a pharmaceutical formulation or pharmaceutical composition comprising a composition described herein.

[0195] Thus, in one embodiment, the composition described herein is a pharmaceutical composition. In one embodiment, the composition described herein is a pharmaceutical formulation.

[0196] The terms pharmaceutical formulation, pharmaceutically safe formulation and pharmaceutically acceptable formulation are used interchangeably.

[0197] In one embodiment, the pharmaceutical formulation or pharmaceutical composition described herein provides sustained release of triiodothyronine or a pharmaceutically acceptable salt thereof.

[0198] Tablets are a pharmaceutical dosage form that contains a mixture of one or more active substances and excipients, compressed or compacted into a solid dosage form. Tablets are simple and convenient to use. They provide a precisely measured dose of active ingredient in a convenient, portable package. Manufacturing processes and technologies can provide tablets with special properties, such as extended release or fast dissolving formulations. Tablets are easy to weigh and have high physical integrity.

[0199] Tablets can be manufactured by methods known in the art, such as, but not limited to, vacuum compression molding (VCM), wet granulation, dry granulation, direct compression (DCT), hot melt extrusion and calendaring, roller compaction, or a combination thereof. In one embodiment, the tablets are prepared as described herein.

[0200] 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.

[0201] In one embodiment, the pharmaceutical formulation is a monolithic dosage form, such as, for example, a cylindrical monolithic tablet.

[0202] In one embodiment, the pharmaceutical formulation is a tablet having a total weight of 50 mg to 800 mg.

[0203] In one embodiment, the pharmaceutical formulation is a tablet having a total weight of 50 mg to 250 mg, such as 100 mg to 200 mg, such as 150 mg.

[0204] In another embodiment, the volume / weight ratio of the tablet is from 100 to 200, such as from 130 to 170, such as from 140 to 160, such as 150.

[0205] In one embodiment, the pharmaceutical formulation is a cylindrical tablet, wherein one dimension of the tablet measures from 2 mm to 4 mm, such as 3 mm, and another dimension measures from 6 mm to 20 mm, such as 8 mm.

[0206] According to the present disclosure, the pharmaceutical formulation may include a coating. The coating may be formed of a material that can provide protection and stability to the formulation. The coating may include other excipients described herein.

[0207] Thus, in one embodiment, the pharmaceutical formulation further comprises a coating. In another embodiment, the coating material comprises one or more polymers. In another embodiment, the coating material comprises one or more of the group consisting of polyacrylates, polyacrylate derivatives, and copolymers thereof. In another embodiment, the coating material comprises one or more cellulose derivatives. In another embodiment, the coating material comprises shellac.

[0208] In one embodiment, the pharmaceutical formulation is orally available.

[0209] In one embodiment, the pharmaceutical formulation is a solid dosage form. In one embodiment, the formulation is an orally acceptable solid dosage form.

[0210] In one embodiment, the pharmaceutical preparation is a single unit oral dosage form. In another embodiment, the pharmaceutical preparation is a multiple unit oral dosage form.

[0211] In one embodiment, the dosage unit is selected from coated or uncoated tablets, coated or uncoated mini-tablets, coated or uncoated micro-tablets, and coated or uncoated spheres or thermoformed solid oral dosage forms.

[0212] 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.

[0213] In a sustained release composition, a variety of factors will potentially affect the release rate of the active ingredient. The release rate can be determined by evaluating the dissolution curve of the production batch. The in vitro drug dissolution data generated by the dissolution testing experiment can be associated with the in vivo pharmacokinetic data through in vitro-in vivo correlation (IVIVC).

[0214] Medical Uses

[0215] In one aspect, the present disclosure relates to a composition or pharmaceutical formulation as described herein for use as a medicament.

[0216] In one aspect, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in the modulation of hormone or endocrine signaling.

[0217] In one embodiment, the natural level of hormone or endocrine signaling oscillates within a 24 hour period. In one embodiment, the natural level of hormone or endocrine signaling increases or decreases between 12 am and 7 am.

[0218] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in treating hypothyroidism and / or for preventing or reducing the occurrence of side effects associated with hypothyroidism treatment.

[0219] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in treating bone damage, cartilage damage, myxedema, goiter and / or for treating stroke.

[0220] Hypothyroidism can be caused by a variety of reasons, such as autoimmune disease, radiation therapy, surgery to remove part or all of the thyroid gland, treatment with other medications, congenital disorders, or pregnancy. It can also occur in people with cancer, or it can be caused by other medications, so it is called drug-induced hypothyroidism.

[0221] Thus, in one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for treating hypothyroidism, wherein the hypothyroidism is caused by one or more selected from the group consisting of: autoimmune disease, radiation therapy, surgical removal of part or all of the thyroid gland (thyroidectomy), treatment with other medications, congenital disease, and pregnancy.

[0222] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for treating hypothyroidism, wherein the hypothyroidism is drug-induced hypothyroidism.

[0223] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for treating hypothyroidism in a wide range of cancer patients who exhibit low thyroid hormone levels. In another embodiment, the cancer patient is treated with a checkpoint inhibitor. In a further embodiment, the checkpoint inhibitor is selected from CTLA-4 and / or a-PDL1.

[0224] One advantage of the invention disclosed herein is that it provides physiological hormone levels according to the natural oscillation of the circadian rhythm and safely returns to baseline levels.

[0225] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation for reducing and / or preventing side effects of hypothyroidism treatment. In another embodiment, the side effects are selected from one or more of cardiovascular disease, high blood pressure, mineral metabolism complications, depression, dyspnea, headache, tremor, feeling nervous or irritable, muscle weakness, increased appetite, diarrhea, menstrual cycle disorders, weight loss, feeling hot, rash, and sleep disorders.

[0226] In one embodiment, the pharmaceutical compositions or pharmaceutical formulations described herein are to be administered to a patient suffering from side effects of hypothyroidism treatment.

[0227] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in treating or preventing a neurodegenerative disease, such as Alzheimer's disease or Huntington's disease.

[0228] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for stimulating chondrocyte maturation and promoting the progression of endochondral ossification during cartilage fracture or injury.

[0229] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in the treatment of stroke following ischemic brain injury or accident.

[0230] In one embodiment, the disclosure relates to a composition or pharmaceutical formulation as described herein for use in an underweight patient, wherein the composition or formulation comprises 10 μg to 75 μg of triiodothyronine or a pharmaceutically acceptable salt thereof.

[0231] In one embodiment, the present disclosure relates to a composition or pharmaceutical formulation, wherein the composition or formulation comprises 2.5 μg to 25 μg of triiodothyronine or a pharmaceutically acceptable salt thereof, for use in children under 18 years of age, underweight patients, or patients requiring more than one dose as described herein.

[0232] Application time and parameters

[0233] In one embodiment, the composition or pharmaceutical formulation described herein is to be administered between 18:00 and 00:00, such as between 20:00 and 22:00, such as at 21:00.

[0234] 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.

[0235] In one embodiment, a composition or pharmaceutical formulation described herein is administered prior to a major sleep period, such as within 3 hours prior to a major sleep period, such as within 2 hours prior to a major sleep period, such as within 1 hour prior to a major sleep period, such as within 30 minutes prior to a major sleep period.

[0236] In one embodiment, a composition or pharmaceutical formulation described herein will be administered once daily.

[0237] In one embodiment, a composition or pharmaceutical formulation described herein is administered more than once per day.

[0238] In one embodiment, a composition or pharmaceutical formulation described herein is administered on an empty stomach.

[0239] In one embodiment, the compositions or pharmaceutical formulations described herein provide triiodothyronine T compared to an equivalent amount of triiodothyronine administered as an immediate release formulation. max increase.

[0240] In one embodiment, the T is compared to an equivalent amount of triiodothyronine administered as an immediate release formulation. 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.

[0241] In one embodiment, the compositions or pharmaceutical formulations described herein provide a C of triiodothyronine between 150 ng / dL and 400 ng / dL, such as between 200 ng / dL and 350 ng / dL. max . Example

[0242] Example 1: Preparation

[0243] Purpose

[0244] To illustrate the preparation of a sustained-release formulation.

[0245] Materials and methods

[0246] Preparations containing ibuprofen as a T3 substitute:

[0247] The preparation of formulations A, B, C, E and F is described in detail below:

[0248] Methocel TM (Hydroxypropyl methylcellulose, HPMC, Methocel K100M) or (hydroxypropyl methylcellulose acetate succinate, HPMC_AS, Aqoat-AS-LF) and polyethylene oxide (PEO Polyox TM NF80) mixed.

[0249] 5 mg of ibuprofen (Sigma-Aldrich) was mixed with PEO (molecular weight 200 kDa) alone or with 5-10% Methocel TM or 5-10% The PEO (molecular weight 200 kDa) was uniformly mixed and melted by using a vacuum melt extruder ( The size of the cylindrical tablets was 8 mm in diameter and 3 mm in height (volume / weight=11), and the total weight of the tablets was 150 mg.

[0250] Preparations containing T3:

[0251] The preparation of Formulations D, G, H and I is described in detail below:

[0252] Will (Hydroxypropyl methylcellulose acetate succinate, HPMC-AS) was mixed with PEO with a molecular weight of 200 kDa.

[0253] T3 was purchased as API from T3 TOCRIS (Cat No. 6666). For Formulation D, 50 μg of T3 was uniformly mixed using an aliquot of diluent to ensure uniform mixing using a vacuum melt extruder ( The homogeneity of VCM) with PEO of molecular weight 200 kDa and 10% Aqoat. The size of cylindrical tablets is 8 mm in diameter, 3 mm in height, volume / weight=1, and the total weight of tablets is 150 mg.

[0254] Formulations G, H and I were prepared by a dry granulation method using roller compaction. Three different amounts of T3 (40 μg, 30 μg and 20 μg) were used, and the total weight of the matrix and the amount of HPMC-AS were varied as described in Table 1.

[0255] Table 1: Prepared formulations

[0256]

[0257] a VCM: Use Vacuum compression molding is performed. b DGRC - Dry granulation using roller compaction. c Dimensions and weight: Cylindrical dimensions are height (mm) x diameter (mm), weight is expressed in mg.

[0258] d Ibuprofen

[0259] Example 2: Dissolution experiment of T3 substitute

[0260] Purpose

[0261] To study the dissolution profile of sustained-release formulations containing API analogs.

[0262] Materials and methods

[0263] Dissolution method:

[0264] Experiments were performed to measure the cumulative drug release (%) over time using ibuprofen as a T3 substitute.

[0265] Dissolution experiments were carried out in USP apparatus 2 (Erweka DT 70, Heusenstamm, Germany) with a dedicated insert and a 250-mL container. Tablets were studied in duplicate (n=2). 2 liters of 0.1M phosphate buffer (pH 6.8) were prepared. The USP bath was preheated. 250ml of 0.1M phosphate buffer (pH 6.8) was added to each of the six dissolution containers. Then, the container was allowed to reach 37 degrees (15 minutes). FaSSGF culture medium was added to a beaker and simulated intestinal fluid, and a phosphate buffer of pH 6.8 simulated intestinal fluid. At pH 6.8, a dissolution experiment was carried out until 24 hours at 37 ± 0.1 ° C with a paddle stirring rate of 50 rpm (2 times for each formulation). Take out sample (1mL) when time is 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours and 5 hours, take out sample of 0.5ml from each container, and put it directly into HPLC bottle. After 24 hours, also take sample and analyze, and terminate the experiment. After terminating the experiment, sample is run in HPLC under the situation of untreated. Also prepare the standard curve of 250-1ug / ml in triplicate.

[0266] Ibuprofen was quantified by high performance liquid chromatography (HPLC) using the Ultimate 3000 HPLC system from Dionex (Sunnyvale, USA). Separation was performed on a reverse phase Kinetex 100A XB-C18 column (4.6×100 mm, 5 μm) from Denmark, with the mobile phase consisting of A) 0.1% acetic acid and B) acetonitrile containing 0.1% acetic acid. The gradient of solvent B was continuously mixed with solvent A in the following order: 50% B at 0 minutes, 80% B at 2 minutes, 100% B at 3 minutes, 55% B at 7 minutes, and 50% B at 10 minutes. A volume of 10 μl was eluted at a flow rate of 1.0 ml / min, and the effluent was detected at a wavelength of 230 nm after about 2.9 minutes. The concentration of ibuprofen was then calculated using the average value of the peak areas obtained from the standard curve. The standard curve was linear in the range of 1-250 μg / ml.

[0267] result

[0268] The results showed that formulations A, B, C, E and F delayed the drug release of ibuprofen as a T3 substitute ( Figure 1 ). The dissolution profiles of formulations A, B, C, E and F were similar to those described, for example, in Bowerbank et al., 2019. 9 This is delayed compared to published values ​​for the immediate release liothyronine product described in US 9,526,701. The dissolution profile of Formulation A showed a delay of 1-2 hours and the dissolution profiles of Formulations B, C, E and F showed a delay of 3-4 hours compared to the immediate release liothyronine product.

[0269] in conclusion

[0270] Compared to existing immediate-release liothyronine formulations, the formulations according to the present disclosure have delayed drug release.

[0271] Example 3: IVIVC relevance of T3 substitutes

[0272] Purpose

[0273] It was demonstrated that formulations according to the present disclosure are able to provide sustained release that matches the natural variations in hormone levels.

[0274] method

[0275] The in vitro in vivo correlation (IVIVC) approach uses in vitro dissolution data to derive blood drug concentrations using the pharmacokinetic parameters of the test product. The convolution approach starts with the dissolution results or profiles and develops an in vivo or drug concentration-time estimate profile. Thus, using the dissolution rate data obtained for Formulations AC containing the T3 surrogate ibuprofen, we used the data from Qureshi et al., 2010 10The well-validated method described models the expected curves of T3 at different doses. Briefly, these curves were converted into discrete dose segments. The bioavailability of T3 was 95%, the half-life (t1 / 2) was estimated to be 4 hours after correction for the baseline (120 ng / dL), and the volume of distribution (Vd) in a 75 kg euthyroid individual was 0.2 L / kg body weight (BW). Then, the different pharmacokinetic parameters were calculated.

[0276] result

[0277] Figure 2 The convoluted predicted total T3 serum plasma profiles (IVIC) for formulation C at different T3 doses are shown. Table 2 shows the different predicted pharmacokinetic parameters for formulations AC assuming a T3 dose of 50 μg.

[0278] The predictive value of IVIVC correlation showed a delayed release and returned to baseline after 24 hours. This is consistent with Bowerbank et al., 2019 9 This is in contrast to the immediate release data published in US 9,526, 701. Furthermore, the predicted values ​​are consistent with the expected physiological values ​​and diurnal variation of T3.

[0279] Table 2: Pharmacokinetic (PK) parameters estimated from IVIVC correlations based on the dissolution profiles of Formulations AC, E and F containing the T3 surrogate ibuprofen.

[0280]

[0281] a Hypothetical dose of T3.

[0282] in conclusion

[0283] The formulations of IVIVC according to the present disclosure showed delayed release and returned to baseline within 24 hours.

[0284] Example 4: Correlation between dissolution rate of T3 and IVIVC

[0285] Purpose

[0286] It was demonstrated that the formulation according to the present disclosure was able to provide a sustained release of triiodothyronine that matched the natural variation in T hormone levels.

[0287] Materials and methods

[0288] The dissolution rates of Formulations D, G, H and I were performed under the same conditions as described in Example 2. The amount of T3 was quantified using an ELISA kit (EliKine(TM) Triiodothyronine (T3) ELISA Kit, Tebu-bio) according to the manufacturer's instructions.

[0289] IVIVC correlation was performed as described in Example 3, updating the mathematical model based on the additional drug release obtained during the dissolution rate testing.

[0290] result

[0291] The results showed that Formulation D delayed the drug release of T3 ( Figure 3 ). The dissolution rate was comparable to that observed in Formulation C containing the T3 substitute.

[0292] The predicted values ​​of IVIVC correlation showed a delayed release profile and returned to baseline after 24 hours based on expected physiological values ​​of T3 and circadian variation ( Figure 4 A).

[0293] When the dose of T3 was changed, different tablets (formulations G, H and I) with adjusted amount of matrix showed adequate dissolution profiles, such as Figure 4 As shown in B. Figure 4 The IVIVC correlation shown in C-4F confirms the delayed release profile and returns to baseline after 24 h according to the expected physiological values ​​of T3 and the circadian cycle variation (e.g. Figure 6 shown).

[0294] Table 3: Pharmacokinetic (PK) parameters estimated from IVIVC correlations based on the dissolution profiles of formulations D and GI containing T3.

[0295]

[0296] a Actual T3 Dosage.

[0297] in conclusion

[0298] The formulation according to the present invention provides a delayed release of triiodothyronine that is adapted to the natural circadian rhythm properties and returns safely to baseline.

[0299] The formulations disclosed herein can be used to provide different dosages depending on the patient's needs.

[0300] Example 5: Effect of size and amount of substrate

[0301] Purpose

[0302] Study how the size and amount of the matrix affects the release of the active ingredient.

[0303] Materials and methods

[0304] Preparations containing the proxy molecule ibuprofen:

[0305] According to Example 1, a formulation containing 5 mg of ibuprofen according to Formulation A (containing only PEO in the matrix) was prepared using the VCM method and the dissolution rate was studied as in Example 2. Two formulations were prepared:

[0306] Disc: Total weight 942 mg, 3 mm high x 20 mm diameter.

[0307] Small cylinder: total weight 301 mg, size 3 mm high x 8 mm diameter

[0308] result

[0309] Dissolution curve (such as Figure 5 ) show that the formulations according to the present disclosure with different geometries and amounts of matrices are able to delay drug release within an appropriate range.

[0310] in conclusion

[0311] The matrices of different geometries and amounts provide adequate sustained release of the T3 substitute.

[0312] Example 6: Formulation parameter study

[0313] Purpose

[0314] The release of ibuprofen (IBU) from different tablets prepared using direct compression and vacuum compression molding at five different compression forces was studied.

[0315] Materials and methods

[0316] Six different 8mm tablet compacting preparations are prepared and tested in triplicate using standard dissolution USP2 apparatus. The dissolution of tablets is carried out at 50rpm in a USP2 container containing 250mL of 0.1M phosphate buffer (pH 6.8). Sampling is performed at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes and 300 minutes, and HPLC is used to analyze ibuprofen content. The water penetration of the analysis tablet is used, and imaging is performed by ultraviolet imaging.

[0317] result

[0318] The compression pressure range tested was -1-7.5N, i.e. 20-150 tons / m2. The results showed that under the stated compression force and temperature limits, at a melt temperature of 85-145°C, tablet hardness or tablet mass deviation had no effect on the overall performance of the tablet.

[0319] Example 7: Study of Melatonin Release

[0320] Purpose

[0321] The release of melatonin was studied using formulations according to the present disclosure.

[0322] Materials and methods

[0323] Two melatonin tablets were prepared using geometric blending and direct compression according to the following parameters:

[0324] Preparation J : 200 mg tablet, 3×8 mm, 5 mg melatonin, 19.5 mg HPMC-AS, 175 mg PEO (n=3)

[0325] Formulation K: 500mg, 3×10mm, 5mg melatonin, 49.5mg HPMC-AS, 445.5mg PEO

[0326] As described in Example 2, triplicate tablets of each formulation (n=3) were tested for release in the intestinal environment and assayed for melatonin using HPLC. 10 The release rates were convolved into in vivo serum profiles using IVIVC using the method described in and the following assumed parameters: oral bioavailability (BA) was assumed to be 15%, half-life (T 1 / 2 ) = 45 minutes, the distribution volume (Vd) of 75 kg body weight (BW) is 1602 L, as shown in the literature 16 As reported.

[0327] result

[0328] Figure 7 A and Figure 7 B shows the release rate and convoluted plasma profile, respectively. The calculated pharmacokinetic parameters are shown in the following table:

[0329] Table 4: Pharmacokinetic (PK) parameters estimated from IVIVC correlations based on the dissolution profiles of melatonin-containing formulations J and K.

[0330]

[0331] in conclusion

[0332] The formulation according to the present invention provides a delayed release of melatonin adapted to the natural circadian rhythm properties and safely returns to baseline.

[0333] The formulations disclosed herein can provide different formulations according to the needs of the patient.

[0334] References

[0335] 1. J.,Sierra-Cote,M.C.,Zapata-Bravo,E.et al.Prevalenceof hyperthyroidism,hypothyroidism,and euthyroidism in thyroid eye disease:asystematic review of the literature.Syst Rev 9,201(2020).

[0336] 2.Hegedüs L,Bianco AC,Jonklaas J,Pearce SH,Weetman AP,PerrosP.Primary hypothyroidism and quality of life.Nat Rev Endocrinol.2022Apr;18(4):230-242.

[0337] 3.CarléA,Faber J,Steffensen R,Laurberg P,Nygaard B.HypothyroidPatients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3+L-T4 Combination Treatment-Data Using a Blind,Randomized,Clinical Study.EurThyroid J.2017 Jul;6(3):143-151.

[0338] 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 IsDelayed but Parallels Thyrotropin Levels,The Journal of ClinicalEndocrinology&Metabolism,Volume 93,Issue 6,1 June 2008,Pages2300–2306.

[0339] 5.Taylor PN,Albrecht D,Scholz A,Gutierrez-Buey G,Lazarus JH,Dayan CM,Okosieme OE.Global epidemiology of hyperthyroidism and hypothyroidism.Nat RevEndocrinol.2018 May;14(5):301-316.

[0340] 6.Camilla Virili,Alessandro Antonelli,Maria Giulia Santaguida,Salvatore Benvenga,Marco Centanni,Gastrointestinal Malabsorption ofThyroxine,Endocrine Reviews,Volume 40,Issue 1,February 2019,Pages 118–136,

[0341] 7.Alexandra M.Dumitrescu,Erin C.Hanlon,Marilyn Arosemena,Olga Duchon,Matthew Ettleson,Mihai Giurcanu,and Antonio C.Bianco.Thyroid.Feb 2022.196-205.

[0342] 8.Virili C,Brusca N,Capriello S and Centanni M(2021)LevothyroxineTherapy in Gastric Malabsorptive Disorders.Front.Endocrinol.11:621616.

[0343] 9.Bowerbank SL,Carlin MG,Dean JR.Dissolution Testing of Single-andDual-Component Thyroid Hormone Supplements.Separations.2019;6(1):18.

[0344] 10.Qureshi SA.In Vitro-In Vivo Correlation(IVIVC)and Determining DrugConcentrations in Blood from Dissolution Testing–A Simple and PracticalApproach.The Open Drug Delivery Journal,2010,Volume 4

[0345] 11.Jonklaas J,Burman KD,Wang H,Latham KR.Single-dose T3administration:kinetics and effects on biochemical and physiologicalparameters.Ther Drug Monit.2015;37(1):110-118.

[0346] 12.Gamble KL,Berry R,Frank SJ,Young ME.Circadian clock control ofendocrine factors.Nat Rev Endocrinol.2014 Aug;10(8):466-75.

[0347] 13.Dumitrescu AM,Hanlon EC,Arosemena M,Duchon O,Ettleson M,GiurcanuM,Bianco AC.Extended Absorption of Liothyronine from Poly-Zinc-Liothyronine:Results from a Phase 1,Double-Blind,Randomized,and Controlled Study inHumans.Thyroid.2022 Feb;32(2):196-205.

[0348] 14.Handbook of granulation technology,2nd ed.International StandardBook Number-10:0-8247-2647-2.Taylor and Francis,2005.

[0349] 15.van Tassell et al.,“Pharmacokinetics of L-Triiodothyronine inPatients Undergoing Thyroid Hormone Therapy Withdrawal,”Thyroid,vol.29,no.10,pp.1371–1379,Oct.2019,doi:10.1089 / thy.2019.0101.

[0350] 16. et al.“Clinical pharmacokinetics of melatonin:asystematic review”.European Journal of Clinical Pharmacology 71,901-909(2015).

Claims

1. A composition comprising: a. an active ingredient capable of regulating hormone or endocrine signal transduction or a pharmaceutically acceptable salt thereof, b. a total amount of 0.1 wt % to 20 wt % of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and / or hydroxypropyl methylcellulose (HPMC), and c. Polyethylene oxide (PEO) in an amount of 80 wt% to 99.9 wt%.

2. The composition according to claim 1, wherein the active ingredient is triiodothyronine or a pharmaceutically acceptable salt thereof.

3. The composition according to claim 1, wherein the active ingredient or a pharmaceutically acceptable salt thereof is selected from: thyroid hormone or thyroid hormone modulator, such as triiodothyronine or triiodothyronine; dopamine reuptake inhibitor; serotonin reuptake inhibitor; renin inhibitor; angiotensin inhibitor; angiotensin receptor antagonist; angiotensin converting enzyme inhibitor; renin-angiotensin-aldosterone pathway inhibitor; prolactin releaser; melatonin receptor agonist, 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 agonist; fibroblast growth factor 21 analog; fibroblast growth factor 21 receptor agonist; adiponectin receptor agonist; leptin analog; leptin receptor agonist and vasopressin receptor agonist.

4. A composition according to any one of the preceding claims, wherein the active ingredient or a pharmaceutically acceptable salt thereof is capable of modulating the level of an endocrine factor or hormone.

5. A composition according to any one of the preceding claims, wherein the active ingredient is a hormone or an endocrine factor.

6. A composition according to any one of the preceding claims, wherein the natural signaling level of the hormone or endocrine signaling; or the natural level of the hormone or endocrine factor oscillates with a period of 24 hours.

7. A composition according to any one of the preceding claims, wherein the natural signaling level of the hormone or endocrine signaling; or the natural level of the hormone or endocrine factor increases or decreases at night or in the early morning.

8. A composition according to any one of the preceding claims, wherein the natural level of the endocrine factor or hormone increases or decreases between 12 am and 7 am.

9. A composition according to any one of claims 1 to 5, wherein the natural signaling level of the hormone or endocrine signaling; or the natural level of the hormone or endocrine factor increases or decreases 1 to 6 hours after the onset of the main sleep cycle, such as 1 to 5 hours, 1 to 4 hours or 1 to 3 hours after the onset of the main sleep cycle.

10. A composition according to any preceding claim, wherein the active ingredient is present in an amount less than 10 wt% of the composition, such as less than 5 wt% of the composition, such as less than 2 wt% of the composition.

11. The composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is thyroid hormone.

12. The composition according to claim 11, wherein the active ingredient is triiodothyronine or a pharmaceutically acceptable salt thereof.

13. The composition of claim 12, wherein the composition is substantially free of triiodothyronine or a pharmaceutically acceptable salt thereof.

14. A composition according to any one of claims 2 and 12 to 13, wherein triiodothyronine or a pharmaceutically acceptable salt thereof is present in an amount of 1 μg to 100 μg, such as about 2 μg to 70 μg, such as about 5 μg to 50 μg.

15. The composition according to any one of claims 2 and 12 to 14, wherein triiodothyronine or a pharmaceutically acceptable salt thereof is present in an amount of 5 μg to 50 μg, such as 5 μg to 7 μg, such as 7 μg to 9 μg, such as 9 μg to 11 μg, such as 11 μg to 13 μg, such as 13 μg to 15 μg, such as 15 μg to 17 μg, such as 19 μg to 21 μg, such as 21 μg to 23 μg, such as 23 μg For example, 25 μg to 27 μg, for example 27 μg to 29 μg, for example 29 μg to 31 μg, for example 31 μg to 33 μg, for example 33 μg to 35 μg, for example 35 μg to 37 μg, for example 37 μg to 39 μg, for example 39 μg to 41 μg, for example 41 μg to 43 μg, for example 43 μg to 45 μg, for example 45 μg to 47 μg, for example 47 μg to 50 μg.

16. The composition of any one of claims 2 and 12 to 15, wherein the triiodothyronine or a pharmaceutically acceptable salt thereof is radiolabeled.

17. The composition according to claim 11, wherein the active ingredient is thyroxine or a pharmaceutically acceptable salt thereof.

18. A composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is a dopamine reuptake inhibitor or a pharmaceutically acceptable salt thereof, such as bupropion, wellbutrin, forfivo or aplezin.

19. A composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is a serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof, such as sertraline, fluoxetine, citalopram, escitalopram, paroxetine or fluvoxamine.

20. The composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is a melatonin receptor agonist or a pharmaceutically acceptable salt thereof, such as melatonin.

21. The composition according to any one of claims 1 and 3 to 10 and 20, wherein the active ingredient is melatonin or a pharmaceutically acceptable salt thereof.

22. A composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is a renin inhibitor capable of lowering blood pressure or a pharmaceutically acceptable salt thereof, such as aliskiren.

23. The composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is an angiotensin inhibitor capable of lowering blood pressure or a pharmaceutically acceptable salt thereof.

24. The composition according to any one of claims 1 and 3 to 10, wherein the active ingredient is a prolactin-releasing agent capable of inducing prolactin secretion or a pharmaceutically acceptable salt thereof.

25. A composition according to any preceding claim, wherein the active ingredient is not methotrexate.

26. A composition according to any of the preceding claims, wherein the HPMC-AS is present in an amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, such as about 10%.

27. The composition of claim 26, wherein the composition does not comprise HPMC, e.g. wherein the composition is substantially free of HPMC.

28. A composition according to any of the preceding claims, wherein the hydroxypropyl methylcellulose is present in an amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, such as about 10%.

29. The composition of claim 28, wherein the composition does not comprise HPMC-AS, e.g., wherein the composition is substantially free of HPMC-AS.

30. A composition according to any of the preceding claims, wherein the HPMC_AS and / or hydroxypropyl methylcellulose is present in a total amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, such as about 10%.

31. according to the composition described in any one of the preceding claims, the mean molecular weight of wherein said PEO is 10kDa to 2000kDa, for example 50kDa to 1000kDa, for example 100kDa to 500kDa, for example 150kDa to 300kDa.

32. A composition according to any one of the preceding claims, wherein PEO is present in an amount of about 80% to 99%, such as about 85% to 95%, such as about 88% to 92%, such as about 90%.

33. compositions according to any one of the preceding claims, wherein said PEO is with about 85% to 95%, for example 85% to 86%, for example 86% to 87%, for example 87% to 88%, for example 88% to 89%, for example 89% to 90%, for example 90% to 91%, for example 91% to 92%, for example 92% to 93%, for example 93% to 94%, for example the amount of 94% to 95wt% exists.

34. A composition according to any preceding claim, wherein the components a), b) and c) are in a single matrix.

35. A composition according to any of the preceding claims, wherein the weight ratio between PEO and the total amount of HPMC and / or HPMC-AS is from about 8:2 to about 9:0.

1.

36. A composition according to any one of the preceding claims, wherein the composition is a uniform dispersion of the active ingredient; the HPMC and / or HPMC-AS; and the PEO.

37. The composition of any preceding claim, wherein the homogeneous dispersion is prepared from a melt dispersion.

38. A composition according to any one of the preceding claims, wherein the composition is compressed into a tablet.

39. A composition according to any one of the preceding claims, wherein the composition is not easily penetrated by water.

40. The composition of any preceding claim, further comprising one or more additional polymers, each independently selected from the group consisting of ionic, non-ionic, water-insoluble polymers and water-soluble polymers.

41. A composition according to any one of the preceding claims, wherein the one or more other polymers are each independently selected from polysaccharides, polyacrylates and polysiloxanes and derivatives thereof.

42. A composition according to any of the preceding claims, wherein the one or more additional polymers are each independently selected from polyoxyethylene glucomannan, galactan, dextran, polygalacturonic acid, polyhydroxyalkanoate, polyxylan, polygalactomannan, rhamnogalacturonan, polyxyloglucan, arabinogalactan, starch, alginate, xanthan gum, carrageenan, agar, dextran, pectin, cellulose, polyvinyl alcohol, polyvinyl butyral, polyvinyl pyrrolidone, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose stearate, carboxymethylcellulose, carbomer, polyacrylic acid, poly(methacrylic) acid, poly(methyl methacrylate), polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxyphenylvalerate, polylactic acid, polyglycolic acid, polyacrylamide, and derivatives or copolymers thereof.

43. A composition according to any one of the preceding claims, further comprising one or more additional excipients.

44. A composition according to any one of the preceding claims, wherein the one or more additional excipients are selected from the group consisting of binders, fillers, lubricants, controlled release excipients, stabilizers, antioxidants and preservatives.

45. The composition of any one of claims 1 to 43, wherein the composition does not comprise a lubricant.

46. ​​A composition according to any one of the preceding claims, wherein the composition is a pharmaceutical formulation.

47. A pharmaceutical formulation comprising a composition according to any one of the preceding claims.

48. A composition according to any one of the preceding claims, wherein the composition is a solid dosage form, such as an orally acceptable solid dosage form.

49. The composition according to any one of the preceding claims, wherein the composition is selected from the group consisting of tablets, mini-tablets and micro-tablets.

50. A composition according to any one of the preceding claims, wherein the composition is a monolithic tablet.

51. A composition according to any one of the preceding claims, wherein the composition is a monolithic cylindrical tablet.

52. A composition according to any one of the preceding claims, wherein the composition is a tablet having a total weight of 50 to 800 mg, such as 50 to 250 mg, such as 100 to 200 mg, such as 150 mg.

53. A composition according to any one of the preceding claims, wherein the tablet has a volume / weight ratio of 100 to 200, such as 130 to 170, such as 140 to 160, such as 150.

54. A composition according to any preceding claim, wherein the cylindrical tablet has one dimension measuring 2 to 4 mm, such as 3 mm, and another dimension measuring 6 to 10 mm, such as 8 mm.

55. The composition of any preceding claim, further comprising a coating.

56. A composition according to any one of the preceding claims, wherein the coating material comprises one or more polymers.

57. A composition according to any one of the preceding claims, wherein the one or more polymers of the coating are selected from one or more of acrylates, cellulose and derivatives thereof.

58. The composition of any of the preceding claims, wherein the composition is a single unit oral dosage form.

59. A composition according to any one of the preceding claims, wherein the composition is a multiple unit oral dosage form.

60. A composition according to any one of the preceding claims, wherein the composition is contained within a capsule, such as a hard shell capsule, such as a hard shell capsule further comprising an outer coating.

61. A composition according to any of the preceding claims, wherein the dosage unit is selected from coated or uncoated tablets, coated or uncoated mini-tablets, coated or uncoated micro-tablets, and coated or uncoated spheres.

62. A composition according to any one of the preceding claims, wherein the composition is a sustained release composition.

63. A composition according to any one of claims 1 to 62, wherein the composition is contained in a pharmaceutical composition.

64. A pharmaceutical composition comprising the composition according to any one of claims 1 to 62.

65. A method of making a composition comprising the steps of: a. preparing a melt-homogeneous dispersion comprising i) PEO, ii) hydroxypropyl methylcellulose and / or HPMC-AS and iii) an active ingredient or a pharmaceutically acceptable salt thereof, and b. Cooling the melt to obtain a solid composition.

66. A method of making a composition comprising the steps of: a. mixing powders of the active ingredient or a pharmaceutically acceptable salt thereof, HPMC and / or HPMC-AS and PEO, and b. Compacting the mixture to obtain a uniform dispersion of the components in the matrix.

67. A method according to any one of claims 65 to 66, wherein the method further comprises the step of compressing the composition into a solid composition.

68. The method according to any one of claims 65 to 67, wherein the method further comprises the step of compressing the composition into a tablet.

69. The method of any one of claims 65 to 68, wherein the composition, the PEO, the HPMC and / or HPMC-AS and the active ingredient or a pharmaceutically acceptable salt thereof are according to any one of claims 1 to 62.

70. A composition obtained by the method according to any one of claims 65 to 69.

71. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use in a method of modulating hormone or endocrine signaling in an individual in need thereof.

72. The composition or pharmaceutical composition of claim 71, wherein the natural level of the hormone or endocrine signaling oscillates over a 24 hour period.

73. The composition or pharmaceutical composition of any one of claims 71 to 72, wherein the natural level of the hormone or endocrine signaling increases or decreases between 12 am and 7 am.

74. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use as a medicament.

75. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use in the treatment of hypothyroidism.

76. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use in the treatment of bone damage, cartilage damage and / or for the treatment of stroke.

77. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use in treating hypothyroidism in a wide range of cancer patients presenting with low thyroid hormone levels.

78. A composition or pharmaceutical composition for use according to any one of claims 75 or 77, wherein the hypothyroidism is drug-induced hypothyroidism.

79. A composition or pharmaceutical composition for use according to any one of claims 75 or 77-78, wherein the hypothyroidism is caused by one or more selected from autoimmune diseases, radiation therapy, treatment with other drugs, surgical removal of part or all of the thyroid gland, congenital diseases and pregnancy.

80. A composition according to any one of claims 1 to 63 and 70 or a pharmaceutical composition according to claim 64 for use in reducing and / or preventing side effects of hypothyroidism treatment.

81. A composition or pharmaceutical composition for use according to claim 80, wherein the side effect is selected from cardiovascular disease, hypertension, complications of mineral metabolism, depression, dyspnea, headache, tremor, feeling nervous or irritable, muscle weakness, increased appetite, diarrhea, menstrual cycle disorders, weight loss, feeling hot, rash and sleep disorders.

82. A composition or pharmaceutical composition for use according to any one of claims 75 to 81, wherein the composition or formulation is to be administered to a patient suffering from one or more side effects of hypothyroidism treatment.

83. A composition or pharmaceutical composition for use according to any one of claims 75 to 82, wherein the composition or formulation is to be administered to a patient suffering from one or more side effects caused by hypothyroidism treatment.

84. A composition or pharmaceutical composition for use according to any one of claims 75 to 83, wherein the composition or the preparation is applied between 18:00 and 00:00, such as between 20:00 and 22:00, such as at 21:

00.

85. according to the composition of the purposes described in any one in claim 75 to 84 or pharmaceutical composition, described composition or described preparation are used during dinner or after dinner, for example, within 3 hours after dinner, for example, within 2 hours after dinner, for example, within 1 hour after dinner, for example, within 30 minutes after dinner.

86. A composition or pharmaceutical composition for use according to any one of claims 75 to 85, wherein the composition or formulation is administered before the main sleep cycle, such as within 3 hours before the main sleep cycle, such as within 2 hours before the main sleep cycle, such as within 1 hour before the main sleep cycle, such as within 30 minutes before the main sleep cycle.

87. A composition or pharmaceutical composition for use according to any one of claims 75 to 86, which is administered once a day.

88. A composition or pharmaceutical composition for use according to any one of claims 75 to 87, which is administered on an empty stomach.

89. A composition or pharmaceutical composition for use according to any one of claims 75 to 88, which provides an increase in triiodothyronine T compared to an equivalent amount of triiodothyronine administered as an immediate release formulation. max increase.

90. A composition or pharmaceutical composition for use according to any one of claims 75 to 89, wherein the T of triiodothyronine is 2.0 t / cm3 compared to an equivalent amount of triiodothyronine administered as an immediate release formulation. max An increase of 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.

91. A composition or pharmaceutical composition for use according to any one of claims 75 to 90, wherein the formulation provides a C of triiodothyronine between 150 ng / dL and 400 ng / dL, such as between 200 ng / dL and 350 ng / dL. max .

92. Use of a composition or pharmaceutical formulation according to any one of the preceding claims in the preparation of a medicament.

93. Use of a composition or pharmaceutical formulation according to any one of the preceding claims in the preparation of a medicament for the treatment of hypothyroidism.

94. Use of a composition or pharmaceutical formulation according to any one of the preceding claims for the preparation of a medicament for reducing and / or preventing side effects of hypothyroidism treatment.

95. A method of treating a disease, the method comprising administering to a subject in need thereof a composition or pharmaceutical formulation according to any one of the preceding claims.

96. A method of treating hypothyroidism, the method comprising administering to a subject in need thereof a composition or pharmaceutical formulation according to any one of the preceding claims.

97. A method of treating, reducing or preventing side effects of hypothyroidism treatment, the method comprising administering to a subject in need thereof a composition or formulation according to any one of the preceding claims.

98. The method according to any one of the preceding claims, further comprising the steps of: a) measuring the subject's thyroid hormone levels, b) comparing the measured level in a) with a reference value, and c) selecting a composition according to any one of the preceding claims or having an appropriate dose of triiodothyronine according to the thyroid hormone level measured in step a).

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