Compressed oral dosage form of ibutamoren

Abstract

The present disclosure relates to pharmaceutical solids and compositions comprising ibutamoren or a pharmaceutically acceptable salt thereof, and methods of administration to pediatric subjects for the treatment of growth hormone deficiency.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 422,329, filed November 3, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Growth hormone deficiency (GHD), which leads to short stature (height-for-chronological age -2 SD), is a worldwide disorder. Current treatment for children with short stature due to growth hormone deficiency typically continues for many years from childhood diagnosis until final height is achieved. Establishing a new growth trajectory with treatment typically requires more than one year of treatment. These children then often require more than 10 years of treatment before reaching optimal adult height. Furthermore, results from a 6-month treatment evaluation in newly diagnosed children can vary significantly due to differences in the underlying etiology of GH deficiency and the pattern and rate of catch-up growth at the time of treatment initiation. Children with GHD are typically treated with daily subcutaneous injections of GH, which is painful, inconvenient, and distressing for some children, especially younger ones.

[0003] Therefore, developing an effective once-daily oral treatment that does not rely on injections for the treatment of GHD in children would be beneficial in terms of ease of treatment, patient convenience, and long-term compliance.

[0004] The present disclosure addresses these and other unmet needs. Summary of the Invention

[0005] In some aspects, the present disclosure provides a pharmaceutical solid comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount greater than 10% by weight of the pharmaceutical solid, and the weight of the pharmaceutical solid is less than about 20 mg.

[0006] In some embodiments, the ibutamoren or a pharmaceutically acceptable salt thereof is ibutamoren mesylate.

[0007] In some embodiments, the pharmaceutical solid is a tablet, a mini-tablet, a sprinkle, or a bead.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a plurality of pharmaceutical solids disclosed herein.

[0009] In some embodiments, the composition is in the form of a capsule containing 1 to 12 tablets disclosed herein. In some embodiments, the tablets are mini-tablets. In some embodiments, the tablets are mini-tablets having a diameter of less than 3 mm.

[0010] In some embodiments, the present disclosure provides a method for treating growth hormone deficiency, the method comprising administering to a subject in need thereof one or more pharmaceutical forms disclosed herein, or a pharmaceutical composition disclosed herein.

[0011] In some embodiments, the subject is a human child between the ages of 2 and 20. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows a flow chart outlining a process for manufacturing pharmaceutical tablets of the present disclosure comprising ibutamoren mesylate. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide those of ordinary skill in the art with general definitions for many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0014] As used herein, the verb "comprise" and variations thereof as used in the description and claims are used in their open-ended sense, meaning that the items that follow the word are included, but not items not specifically mentioned are excluded. The present disclosure may suitably "comprise," "consist of," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0015] Unless specifically stated otherwise or clear from context, the term "or," as used herein, is understood to be inclusive. Unless specifically stated otherwise or clear from context, as used herein, the terms "a," "an," and "the" are understood to be singular or plural.

[0016] Throughout this specification, the terms "about" and / or "approximately" may be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean those values ​​that are close to the recited value. Additionally, the phrases "less than about [value]" or "greater than about [value]" should be understood in light of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0017] As used herein, "D90" refers to the 90th percentile of particle size determined by sieving analysis, i.e., the percentage of drug particles retained on a mesh screen during a sieving process using a screen of a particular mesh size. For example, if D90=100 μm, then 90% of the drug particles will remain on a 100 μm mesh screen during the sieving process. Similarly, "D80" refers to the 80th percentile of particle size, "D70" refers to the 70th percentile of particle size, "D60" refers to the 60th percentile of particle size, "D50" refers to the 50th percentile of particle size, "D40" refers to the 40th percentile of particle size, "D30" refers to the 30th percentile of particle size, "D20" refers to the 20th percentile of particle size, and "D10" refers to the 10th percentile of particle size.

[0018] As used herein, "substantially" or "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The precise tolerance for deviation from absolute completeness may depend in some cases on the specific context. Generally speaking, however, the proximity to completeness would result in the same overall result as would be obtained if absolute and complete completeness were obtained. The use of "substantially" is equally applicable when used in a negative connotation, referring to the complete or nearly complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free" of other active agents is either completely devoid of the other active agents or nearly completely devoid of the other active agents to the extent that the effect is the same as if the other active agents were completely absent. In other words, a composition that is "substantially free" of a component or element or other active agent may still contain such material as long as there is no measurable effect.

[0019] The term "treatment" refers to one or more of alleviating, alleviating, delaying, reducing, ameliorating, improving, or managing at least one symptom of a condition in a subject. The term "treatment" can also refer to one or more of arresting the progression of a symptom, delaying the onset of a symptom (i.e., the period before a symptom becomes clinically manifest), or reducing the risk of onset or worsening of a symptom.

[0020] The term "therapeutically effective" as applied to a dose or amount refers to the amount of a compound or pharmaceutical preparation sufficient to result in a desired clinical benefit after administration to a subject (e.g., a human child) in need thereof.

[0021] As used herein, "prepubertal" refers to children with a bone age of <8 years for girls and <9 years for boys. Bone age can be determined using well-known methods such as the atlas matching method of Greulich and Pyle or the weighted scoring system of Tanner and Whitehouse. Other examples of bone age include <7 years for females and <8 years for males.

[0022] As used herein, "peripubertal" refers to a child who has begun to experience puberty as clinically assessed by Tanner staging. Tanner stage 1 is prepubertal, and any stage passed before the end of puberty (Tanner stage 4) is considered peripubertal.

[0023] As used herein, "short stature" refers to a child's height being below the 2.3 percentile (which is approximately height for chronological age -2 SD) for the child's chronological age. Other examples include being below the 5th, 4th, 3rd, 2nd, and 1st percentile for the child's chronological age.

[0024] As used herein, "growth retardation" or "reduced height velocity" refers to height velocity recorded over at least six months that is less than the 25th percentile for age and sex. Other examples include height velocity that is less than the 24th, 23rd, 22nd, 21st, 20th, 19th, 18th, 17th, 16th, 15th, 14th, 13th, 12th, 11th, 10th, 9th, 8th, 7th, 6th, 5th, 4th, 3rd, 2nd, and 1st percentile for age and sex over at least six months of recording.

[0025] As used herein, "sufficient GH secretory capacity" refers to a patient who is considered to have sufficient GH secretory capacity if the subject meets the following conditions: o(i) have peak GH concentrations of <10 μg / L (or <7 μg / L) in response to standard provocation tests; o(ii) have a peak serum GH of ≥ 5 μg / L in response to a single dose of ibutamoren mesylate (e.g., 0.8 mg / kg);

[0026] As used herein, "equivalent growth potential compared to rhGH" refers to a patient who is considered to have equivalent growth potential compared to chronic subcutaneous rhGH injections (equivalent growth potential compared to rhGH) if the subject meets the following conditions: o(i) have a peak serum GH of ≥ 5 μg / L in response to a single dose of ibutamoren mesylate (e.g., 0.8 mg / kg); o(ii) have baseline serum IGF-I >30 μg / L;

[0027] All weight percentages (i.e., "weight %," "wt.%," and "w / w") referred to herein are measured relative to the total weight of the solid pharmaceutical form or pharmaceutical composition, unless otherwise specified.

[0028] Pharmaceutical solids In some embodiments, the present disclosure provides a pharmaceutical solid comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount greater than 10% by weight of the pharmaceutical solid, and the weight of the pharmaceutical solid is less than about 20 mg.

[0029] Ibutamoren is a non-peptide ghrelin agonist and growth hormone secretagogue with the following structure: [ka] Its chemical name is N-[l(R)-[(l,2-dihydro-l-methanesulfonylspiro[3H-indol-3,4'-piperzin]-l'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide.

[0030] Ibutamoren mesylate, N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperzin]-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate, known as MK-0677 and LUM-201, is being evaluated in multiple clinical trials.

[0031] In some embodiments, the pharmaceutical solid of the present disclosure contains ibutamoren or a pharmaceutically acceptable salt thereof in an amount greater than 10%, greater than 12.5%, greater than 15%, greater than 17.5%, greater than 20%, greater than 22.5%, greater than 25%, greater than 27.5%, greater than 30%, greater than 32.5%, greater than 35%, greater than 37.5%, greater than 40%, greater than 42.5%, or greater than 45% by weight of the pharmaceutical solid. In some embodiments, the ibutamoren or pharmaceutically acceptable salt thereof is present in an amount of 10% or more by weight of the pharmaceutical solid. In some embodiments, the ibutamoren or pharmaceutically acceptable salt thereof is present in an amount of 20% or more by weight of the pharmaceutical solid. In some embodiments, the ibutamoren or pharmaceutically acceptable salt thereof is present in an amount of 30% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 40% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 50% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 60% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 70% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 80% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 85% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 90% or more by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 10% to about 90% by weight of the pharmaceutical solid.In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 15% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 20% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 25% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 30% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 35% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 40% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 45% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 50% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 55% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 60% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 65% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 70% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 75% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 80% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 85% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 50% to about 80% by weight of the pharmaceutical solid.In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 55% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 60% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 65% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 70% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 75% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 30% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 35% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 40% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of about 45% to about 50% by weight of the pharmaceutical solid. In some embodiments, the pharmaceutically acceptable salt is ibutamoren mesylate.

[0032] In some embodiments, the weight of a pharmaceutical solid of the present disclosure is less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than 4 mg, less than 3 mg, or less than 2 mg. In other embodiments, the weight of a pharmaceutical solid of the present disclosure is in the range of about 1.0 mg to about 20 mg, or in the range of about 2 mg to about 17 mg. In some embodiments, the weight of a pharmaceutical solid of the present disclosure is less than about 19 mg. In some embodiments, the weight of a pharmaceutical solid of the present disclosure is less than about 18 mg. In some embodiments, the pharmaceutical solid of the present disclosure has a weight of about 5 mg to about 20 mg, e.g., about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some embodiments, the pharmaceutical solid is a tablet weighing about 12 mg to about 20 mg. In some embodiments, the pharmaceutical solid is a tablet weighing about 12 mg to about 18 mg.

[0033] In another embodiment, each solid, tablet, mini-tablet, etc. contains a different dose of ibutamoren or a pharmaceutically acceptable salt thereof. In a particular embodiment, the ibutamoren is ibutamoren mesylate.

[0034] In certain embodiments, tablets or minitablets contain from about 1 to about 20 mg, e.g., 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, or 22 mg of ibutamoren mesylate, including all values ​​and subranges therebetween. In some embodiments, tablets or minitablets contain about 4 to about 15 mg of ibutamoren mesylate, e.g., 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, or 15.5 mg, including all values ​​and subranges therebetween. In some embodiments, tablets or minitablets with a 50% weight drug load contain about 4.7 mg of ibutamoren mesylate. In some embodiments, tablets or minitablets with a 70% weight drug load contain about 7.11 mg of ibutamoren mesylate. In some embodiments, a tablet or minitablet with an 85% drug load by weight contains about 10.36 mg of ibutamoren mesylate.

[0035] The pharmaceutical solids of the present disclosure can be in any suitable form known in the art. In some embodiments, the pharmaceutical solids can be designed into a desired shape, such as a tablet, sprinkles, beads, etc. In some embodiments, the pharmaceutical solids are tablets. In some embodiments, the tablets are mini-tablets. In some embodiments, the tablets or mini-tablets are not prepared by wet granulation. In some embodiments, the solids or mini-tablets are prepared by roller compaction of drug particles. In some embodiments, the pharmaceutical solids are a bead or multiple beads. In some embodiments, the pharmaceutical solids can be orally administered by mixing with soft foods such as applesauce, pudding, yogurt, etc.

[0036] In certain embodiments, after roller compaction, the solid is prepared and compressed into a mini-tablet form, which is then further incorporated into an additional dosage form, such as a capsule, or administered directly to a subject as one or more mini-tablets, depending on the drug dose required by the subject.

[0037] In some embodiments, the pharmaceutical solid is a tablet having a diameter of about 5 mm or less, eg, about 4.5 mm or less, about 4 mm or less, about 3.5 mm or less, about 3.0 mm or less, about 2.5 mm or less, or about 2 mm. In some embodiments, the tablets have a diameter in the range of about 1 mm to about 5 mm, e.g., about 1 mm, about 1.5 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3.0 mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, including all values ​​and subranges therebetween. In some embodiments, the tablets have a diameter of less than about 3 mm and are referred to as mini-tablets. In some embodiments, the tablets have a diameter of less than about 2.5 mm and are referred to as minitablets. In some embodiments, the minitablets have a diameter ranging from about 2 mm to about 3 mm. In some embodiments, the minitablets have a diameter of 2 mm. In some embodiments, the minitablets have a diameter of 2.5 mm. In some embodiments, the minitablets have a diameter of 2 mm. The tablets and minitablets disclosed herein can have any shape convenient to one of skill in the art, such as spherical, round, oval, triangular, etc. In some embodiments, the tablets are round, oval, or triangular. In some embodiments, the tablets are round. In some embodiments, the tablets are round and convex. In some embodiments, the tablets are round and concave.

[0038] In some embodiments, the tablets disclosed herein are compressed tablets and may be compressed by a tablet press (rotary or single punch) or other techniques known in the art. In some embodiments, the tablets comprise drug-containing granules disclosed herein. In some embodiments, the compressed tablets comprise drug-containing granules and one or more extragranular pharmaceutical excipients. In some embodiments, the compressed tablets comprise drug-containing granules and an extragranular binder, a disintegrant, and a lubricant. In some embodiments, the compressed tablets comprise drug-containing granules and an extragranular disintegrant, a lubricant, and an optional binder. In some embodiments, the tablets are compressed with roller-compacted drug-containing granules disclosed herein and an extragranular binder, a disintegrant, and / or a lubricant.

[0039] In some embodiments, the one or more extragranular pharmaceutical excipients include a binder, a disintegrant, and a lubricant. In some embodiments, the amount of binder ranges from about 1% w / w to about 5% w / w, the amount of disintegrant ranges from about 1% w / w to about 5% w / w, and the amount of lubricant ranges from about 0.5% w / w to about 2% w / w, each relative to the tablet weight. In some embodiments, the amount of binder ranges from about 2% w / w to about 4% w / w, the amount of disintegrant ranges from about 2.5% w / w to about 3.5% w / w, and the amount of lubricant ranges from about 0.25% w / w to about 1.0% w / w, each relative to the tablet weight.

[0040] Suitable binders for the extragranular material include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums (e.g., acacia sodium alginate, polyvinylpyrrolidone), cellulose polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, etc.), and veegum, and combinations thereof. Examples of polyvinylpyrrolidones include povidone, copovidone, and crospovidone. In some embodiments, the binder is pregelatinized starch.

[0041] Suitable disintegrants for the extragranular material include, but are not limited to, starch, clay, cellulose, algin, gum, or cross-linked polymer (e.g., cross-linked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, white sugar, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and the like. In some embodiments, the one or more disintegrants are lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, or combinations and mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0042] Suitable lubricants for extragranular materials include, but are not limited to, magnesium stearate, calcium stearate, talc, colloidal silica, etc. In some embodiments, the lubricant comprises stearic acid and / or a stearate salt, such as magnesium stearate. In some embodiments, the lubricant is magnesium stearate.

[0043] In some embodiments, the binder is pregelatinized starch, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0044] In some embodiments, the present disclosure provides a pharmaceutical tablet (e.g., a compressed pharmaceutical tablet or compressed pharmaceutical mini-tablet) comprising a drug-containing granule comprising about 10% to about 90% by weight of ibutamoren mesylate, about 2% to about 50% by weight of a binder, about 1% to about 35% by weight of a filler, about 0.5% to about 5% by weight of a disintegrant, and about 0.1% to about 1% by weight of a lubricant, wherein the tablet has a friability of less than 1% and a hardness of greater than about 0.7 Kp when compressed using a tablet press equipped with tooling less than 3 mm.

[0045] In some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0046] In some embodiments, the present disclosure provides tablets having a composition with a drug loading (DL) of 10% to 90% according to the table below.

[0047] [Table 1]

[0048] Tablets must have sufficient hardness and low friability to ensure tablet strength and structural integrity during packaging, shipping, and end-use. However, maintaining adequate hardness and friability can be difficult when compressing mini- and mini-tablets (e.g., tablets having a diameter of less than 5 mm), especially when the compressed drug-containing granules contain high drug loading levels (e.g., ≥50 wt% ibutamoren mesylate). As described herein, it has been unexpectedly discovered that roller-compacted drug-containing granule blends, compared to non-compacted granules, have an increased proportion of large granules (e.g., granules retained on 40-, 60-, and 80-mesh sieves), increased blend density, and improved flowability, even at drug loading levels greater than 50 wt%. These surprising and unexpected properties have resulted in roller-compacted blends of drug-containing granules that provide sufficient hardness and low friability when compressed into mini- and mini-tablets containing about 10 wt% to about 90 wt% ibutamoren mesylate.

[0049] The ability to prepare small tablets and mini-tablets, as disclosed herein, is important for improving compliance and providing flexible dosing regimens in the treatment of children aged 2 to 20 years.

[0050] In some embodiments, the tablets disclosed herein have a hardness of greater than 0.7 Kp when compressed at a compression force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablets have a hardness of greater than 1.5 Kp when compressed at a compression force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablets have a hardness of greater than 3.0 Kp when compressed at a compression force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablet has a hardness of about 0.5 kP to about 6 kP, e.g., about 0.5 kP, about 1 kP, about 1.5 kP, about 2 kP, about 2.5 kP, about 3 kP, about 3.5 kP, about 4 kP, about 4.5 kP, about 5 kP, about 5.5 kP, or about 6 kP, including all values ​​and subranges therebetween. In some embodiments, the drug load in the tablet is about 70% to about 90% by weight of the tablet, and the tablet has a hardness of about 3.2 kP to about 5.5 kP when prepared on a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 90% by weight of the tablet, and the tablet has a hardness of about 4.5 kP to about 5.5 kP when prepared on a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 70% by weight of the tablet, and the tablet has a hardness of about 3.2 kP to about 4.2 kP when prepared on a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 50% by weight of the tablet, and the tablet has a hardness of about 1.5 kP to about 2.5 kP when prepared on a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 30% by weight of the tablet, and the tablet has a hardness of about 1.0 kP to about 2.0 kP when prepared on a 2.5 mm tablet press. In some embodiments, the compression force is less than or equal to 20 kN, 19 kN, 18 kN, 17 kN, 16 kN, 15 kN, 14 kN, 13 kN, 12 kN, 11 kN, or 10 kN, including all values ​​and subranges therebetween. In some embodiments, compression is performed using a tablet press.

[0051] In some embodiments, the tablets disclosed herein have a friability of less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.3%, or less than about 0.20%. In some embodiments, the tablets have a friability of less than about 1%. In some embodiments, the tablets have a friability of less than about 0.75%. In some embodiments, the tablets have a friability of less than about 0.5%. In some embodiments, the tablets have a friability of less than about 0.3%.

[0052] The pharmaceutical tablets (e.g., minitablets) of the present disclosure may be uncoated or coated with one or more coating layers. In some embodiments, the coating comprises Eudragit® E PO, Eudragit® E 100, Eudragit® E 12,5, or Opadry® amb II. In some embodiments, the coating comprises Opadry® amb II film coating, a polyethylene glycol (PEG)-free polyvinyl alcohol (PVA)-based coating. In some embodiments, the coating comprises Eudragit® E PO, a functional copolymer comprising N,N-dimethylaminoethyl methacrylate, methacrylate, and butyl methacrylate monomers. In some embodiments, the coating applied to the tablets or minitablets comprises an aminoalkyl methacrylate copolymer. In some embodiments, the coating is a taste-masking layer. In some embodiments, the coating is applied to the tablet at a weight gain of about 1% to about 30%, based on the total weight (dry polymer weight) of the pharmaceutical solids, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, including all values ​​and subranges therebetween. In some embodiments, the coating is applied to the tablet at a weight gain of about 5% to about 25%, based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablet at a weight gain of about 8% to about 20%, e.g., about 8%, about 10%, about 12%, about 16%, or about 20%, based on the total weight of the pharmaceutical solids, including all values ​​and subranges therebetween. In some embodiments, the coating is applied to the tablet at a weight gain of about 8%, based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablet at a weight gain of about 10%, based on the total weight of the pharmaceutical solids.In some embodiments, the coating is applied to the tablet to provide a weight gain of about 12% based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablet to provide a weight gain of about 16% based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablet to provide a weight gain of about 20% based on the total weight of the pharmaceutical solids. The coating can be applied by any method known in the art, including spraying a polymer or polymers onto the tablets or minitablets described above. In some embodiments, the coating is applied using a fluidized bed coater or modified coating pan.

[0053] In some embodiments, the pharmaceutical solid of the present disclosure comprises drug-containing granules or drug particles as described below. In some embodiments, the pharmaceutical solid is a tablet comprising drug-containing granules or drug particles as described below. In some embodiments, the tablet is a mini-tablet comprising drug-containing granules or drug particles as described below. In some embodiments, the tablet or mini-tablet is not prepared by wet granulation or direct compression. In some embodiments, the solid or mini-tablet is prepared by roller compaction of drug particles or drug-containing granules as follows:

[0054] Drug-containing granules of the present disclosure In some embodiments, the pharmaceutical solids disclosed herein comprise drug-containing granules or drug particles. In some embodiments, the drug-containing granules comprise ibutamoren or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-containing granules comprise ibutamoren or a pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients disclosed herein. In some embodiments, the drug-containing granules comprise ibutamoren or a pharmaceutically acceptable salt thereof and a binder, a filler, a disintegrant, and / or a lubricant. In some embodiments, the ibutamoren salt is ibutamoren mesylate. In some embodiments, the drug-containing granules are roller-compacted drug-containing granules.

[0055] In some embodiments, the drug-containing granules of the present disclosure have a bulk density of less than 1 g / cc, less than 0.9 g / cc, less than 0.8 g / cc, less than 0.7 g / cc, less than 0.6 g / cc, or less than 0.5 g / cc, including all values ​​and subranges therebetween. In some embodiments, the drug-containing granules have a bulk density of less than 0.6 g / cc. In some embodiments, the drug-containing granules have a bulk density of less than 0.5 g / cc.

[0056] In some embodiments, the drug-containing granules of the present disclosure have a tap density of less than 1 g / cc, less than 0.90 g / cc, less than 0.8 g / cc, less than 0.75 g / cc, less than 0.7 g / cc, less than 0.65 g / cc, or less than 0.6 g / cc, including all values ​​and sub-ranges therebetween. In some embodiments, the drug-containing granules have a tap density of less than 0.75 g / cc. In some embodiments, the drug-containing granules have a tap density of less than 0.6 g / cc.

[0057] In some embodiments, the drug-containing granules of the present disclosure have a bulk density of less than about 0.6 g / cc and a tapped density of less than about 0.75 g / cc. In some embodiments, the drug-containing granules of the present disclosure have a bulk density of less than about 0.5 g / cc and a tapped density of less than about 0.6 g / cc.

[0058] The flow characteristics of a drug-containing granule can be estimated by calculating the Hauser ratio, which, as used herein, is the ratio of tapped density to bulk density. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.0 to about 1.4. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.15 to about 1.4. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.0 to about 1.25. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.0 to about 1.2. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.15 to about 1.25, for example, when the drug load of ibutamoren mesylate is about 60% to about 90% by weight of the pharmaceutical solid. In some embodiments, the roller-compacted drug-containing granules have a Hausner ratio of about 1.20, for example, when the drug load of ibutamoren mesylate is about 90% by weight of the pharmaceutical solid. The correlation between flowability and Hausner ratio is shown in Table 3 below.

[0059] The compressibility of the drug-containing granules may be estimated by calculating the Carr's index from the following formula:

number

[0060] In some embodiments, the roller-compacted drug-containing granules have a curl index of about 10% to about 30%. In some embodiments, the roller-compacted drug-containing granules have a curl index of about 15% to about 30%. In some embodiments, the roller-compacted drug-containing granules have a curl index of about 10% to about 20%. In some embodiments, the roller-compacted drug-containing granules have a curl index of about 15% to about 20%. In some embodiments, the roller-compacted drug-containing granules have a curl index of about 15% to about 20% when the drug load of ibutamoren mesylate is about 70% to about 90% by weight of the pharmaceutical solid. In some embodiments, the roller-compacted drug-containing granules have a curl index of about 16% when the drug load of ibutamoren mesylate is about 90% by weight of the pharmaceutical solid. The correlation between compressibility and curl index is shown in Table 3 below.

[0061] Without being bound by any particular theory, it has been surprisingly and unexpectedly discovered that roller-compacted blends of drug-loaded granules containing 10 wt% to 90 wt% ibutamoren mesylate have unique and beneficial properties compared to pre-compacted blends (e.g., the initial blend in Figure 1). In particular, roller-compacted blends (e.g., the RC milled blend in Figure 1) were found to produce drug granules with lower density and larger particle size, such that the density decreased and particle size increased as the drug loading level within the granules increased (Tables 2A and 2B).

[0062] This result is contrary to what would be expected. For example, increasing drug loading typically decreases the density of the granules and decreases the particle size of the granules. Smaller particle sizes (high amounts of fine particles) make it more difficult to compress the drug granules, i.e., to compress them into tablets or mini-tablets, resulting in less desirable pharmaceutical tablet properties, such as hardness and friability, required for tablet storage and transportation as required by the pharmaceutical industry.

[0063] Unlike the prior art, the granules of the present invention allow for high drug loading at large particle sizes, and are therefore easy to compress into tablets with desirable hardness and friability. In the present invention, it was discovered that all drug-loaded granules processed by roller compaction had an increased proportion of larger particles compared to the pre-compacted blends (Tables 2A and 2B). Unexpectedly, the resulting shift in particle size distribution (PSD) toward larger particles was most pronounced in granules loaded with about 70% to about 90% ibutamoren mesylate by weight, with a D50 of over 400 μm compared to about 170 μm for the pre-compacted drug-containing granules at these drug loads.

[0064] The unexpected density increase, particularly at high drug loading levels, combined with a shift to a larger PSD, improved the flowability of the material, enabling compression into mini- and mini-tablets containing ≥50% or ≥70% by weight of ibutamoren mesylate, which were previously difficult to prepare with suitable properties. Indeed, for highly drug-loaded, readily compressible tablets, one embodiment of the present invention is a combination of a pharmaceutical solid, such as a mini-tablet, containing at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% by weight of ibutamoren mesylate drug, with a pharmaceutical solid, such as a tablet, wherein the tablet weighs less than about 30 mg, 20 mg, 15 mg, or 12 mg.

[0065] In some embodiments, the pharmaceutical solid comprises drug-containing granules having a D50 of greater than about 175 μm. In some embodiments, when ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount greater than 50% by weight of the solid, the drug-containing granules have a D50 of greater than about 175 μm.

[0066] In some embodiments, the pharmaceutical solid comprises drug-containing granules having a D50 of greater than about 400 μm. In some embodiments, when ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount greater than 70% by weight of the solid dosage form, the drug-containing granules have a D50 of greater than about 400 μm. In some embodiments, when ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 70% by weight to about 90% by weight of the solid dosage form, the drug-containing granules have a D50 of greater than about 400 μm.

[0067] In some embodiments, the drug-containing granules are compressed drug-containing granules. In some embodiments, the compressed drug-containing granules have a D50 that is at least about 1.5 times greater than that of non-compressed drug granules having the same composition. In some embodiments, the compressed drug-containing granules have a D50 that is at least about 2 times greater than that of non-compressed drug granules having the same composition. In some embodiments, the compressed drug-containing granules have a D50 that is at least about 2.5 times greater than that of non-compressed drug granules having the same composition.

[0068] In some embodiments, the drug-containing granules comprise ibutamoren or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the mesylate salt.

[0069] In some embodiments, the drug-containing granules further comprise one or more binders, fillers, and / or lubricants. In some embodiments, the drug-containing granules further comprise a binder, filler, and lubricant.

[0070] In some embodiments, the drug-containing granules comprise a binder in an amount ranging from about 2% w / w to about 60% w / w, a bulking agent in an amount ranging from about 1% w / w to about 40% w / w, a disintegrant in an amount ranging from about 1% w / w to about 5% w / w, and a lubricant in an amount ranging from about 0.5% w / w to about 2% w / w.

[0071] In some embodiments, the drug-containing granules comprise a binder in an amount ranging from about 2% w / w to about 30% w / w, a bulking agent in an amount ranging from about 1% w / w to about 20% w / w, a disintegrant in an amount ranging from about 1% w / w to about 2% w / w, and a lubricant in an amount ranging from about 0.5% w / w to about 1.5% w / w.

[0072] Suitable binder materials include, but are not limited to, starch (including cornstarch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums (e.g., acacia sodium alginate, polyvinylpyrrolidone), cellulose polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, etc.), and veegum, and combinations thereof. Examples of polyvinylpyrrolidones include povidone, copovidone, and crospovidone.

[0073] Bulking agents, also known as diluents, include materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, sugars, or combinations thereof. Any suitable sugars can be used in the compositions of the present invention. As used herein, "sugars" includes sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldose, and ketose. Exemplary disaccharides include, but are not limited to, sucrose, isomalt, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, fructooligosaccharides, inulin, galactooligosaccharides, and mannanoligosaccharides. In some embodiments, the sugar is sorbitol, mannitol, or xylitol. In some embodiments, the sugar is mannitol.

[0074] Disintegrants include, but are not limited to, starch, clay, cellulose, algin, gum, or crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, white sugar, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and the like. In some embodiments, the one or more disintegrants are lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, or combinations and mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0075] Suitable lubricants for pharmaceutical solids of the present disclosure include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. In some embodiments, the lubricant comprises stearic acid and / or a stearate salt, such as magnesium stearate. In some embodiments, the pharmaceutical solid (e.g., minitablets) comprises about 0.1% to 5%, e.g., about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5%, of lubricant based on the total weight of the pharmaceutical solid, including all values ​​and sub-ranges therebetween.

[0076] In some embodiments, the drug-containing granules comprise a binder, a filler, a disintegrant, and a lubricant, hi some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0077] In some embodiments, the drug-containing granules are processed by roller compaction, for example, according to the manufacturing parameters disclosed herein.

[0078] Pharmaceutical Composition The mini-tablet, bead, and sprinkle formulations prepared according to the roller compaction manufacturing methods described herein offer significant advantages, including dosing flexibility and patient compliance, when treating pediatric patient populations with GH deficiency. For example, the small size of compressed tablets containing about 10% to about 90% by weight of ibutamoren mesylate, which can be prepared by the roller compaction methods disclosed herein, allows for the provision of compositions (e.g., capsules, sachets, etc.) with different doses of ibutamoren, which, for example, allows for increased dosing flexibility and compliance in children with a wide range of body weights, ultimately leading to more beneficial outcomes in treating pediatric patient populations.

[0079] Thus, in some embodiments, the pharmaceutical compositions disclosed herein comprise a plurality of mini-tablets, e.g., 1 to 30 mini-tablets, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 mini-tablets, including all subranges therebetween. In some embodiments, the mini-tablets are contained in a capsule or sachet for oral administration. In some embodiments, the mini-tablets are contained in a capsule for oral administration. In some embodiments, the capsule is a hard gelatin or hydroxypropyl methylcellulose (HPMC) capsule. In some embodiments, the capsule contains 2 to 30 mini-tablets, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 mini-tablets, including all subranges therebetween. In some embodiments, the capsule contains 3 to 12 mini-tablets, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mini-tablets, including all subranges therebetween. In some embodiments, the capsule contains 3, 4, or 12 mini-tablets. In some embodiments, the capsule contains 3 mini-tablets. In some embodiments, the capsule contains 4 mini-tablets. In some embodiments, the capsule contains 5 mini-tablets. In some embodiments, the capsule contains 6 mini-tablets. In some embodiments, the capsule contains 7 mini-tablets. In some embodiments, the capsule contains 8 mini-tablets. In some embodiments, the capsule contains 9 mini-tablets. In some embodiments, the capsule contains 10 mini-tablets. In some embodiments, the capsule contains 11 mini-tablets. In some embodiments, the capsule contains 12 mini-tablets.

[0080] In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 10% ibutamoren mesylate by weight of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 20% ​​ibutamoren mesylate by weight of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 30% ibutamoren mesylate by weight of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 50% ibutamoren mesylate by weight of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 70% ibutamoren mesylate by weight of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 mini-tablets, each comprising 90% ibutamoren mesylate by weight of the tablet.

[0081] The pharmaceutical compositions disclosed herein may include multiple sprinkles. For example, 100 or more sprinkles may be incorporated into a pharmaceutical composition. In another embodiment, the amount of sprinkles in the pharmaceutical composition may range from 10 to 50 sprinkles, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 sprinkles, including all subranges therebetween. In some embodiments, the sprinkles are contained in a capsule or sachet for oral administration. In some embodiments, the sprinkles are contained in a capsule for oral administration. In some embodiments, when the sprinkles are contained in a capsule, the capsule is opened and the sprinkles are added to soft food for oral administration. In some embodiments, the capsule is a hard gelatin or hydroxypropyl methylcellulose (HPMC) capsule. In some embodiments, the capsule contains between 10 and 50 sprinkles, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 sprinkles, including all subranges therebetween.

[0082] In certain embodiments, the pharmaceutical compositions described herein may be included in the form of a kit. In certain embodiments, the kit may include one or more pharmaceutical solids and / or one or more pharmaceutical compositions. In certain embodiments, the kit may include one or more tablets in a capsule.

[0083] In another embodiment, the pharmaceutical solid and / or one or more pharmaceutical compositions contain ibutamoren mesylate in a dosage range of about 4 mg to about 6 mg, about 6 mg to about 8 mg, and / or about 9 mg to about 11 mg. In a specific embodiment, the kit includes a capsule containing one or more tablets having a dosage of ibutamoren mesylate in a range of about 4 mg to about 6 mg, about 6 mg to about 8 mg, and / or about 9 mg to about 11 mg. In another embodiment, the kit includes at least one capsule containing 1 to 6 tablets having a dosage of ibutamoren mesylate in a range of about 4 mg to about 6 mg, and / or at least one capsule containing 2 to 12 tablets having a dosage of ibutamoren mesylate in a range of about 6 mg to about 8 mg, and / or at least one capsule containing 2 to 10 tablets having a dosage of ibutamoren mesylate in a range of about 9 mg to about 11 mg.

[0084] Treatment method Methods for treating growth hormone (GH) deficiency in children are described in U.S. Patent Nos. 10,898,472, 10,105,352, and 9,763,919, the contents of which are incorporated herein by reference in their entireties. However, challenges remain regarding dosage flexibility and patient compliance in addition to the need for improved efficacy in the pediatric patient population in need of treatment.

[0085] As discussed above, pharmaceutical compositions including the disclosed pharmaceutical compositions (e.g., mini-tablet, bead, and sprinkle formulations) prepared according to the roller compaction manufacturing methods described herein offer significant advantages in treating growth hormone deficiency in pediatric patients.

[0086] Thus, in some embodiments, the present disclosure provides a method of treating growth hormone deficiency, the method comprising administering to a subject in need thereof one or more pharmaceutical solids disclosed herein, or a pharmaceutical composition disclosed herein.

[0087] In some embodiments, the subject is a human subject. In some embodiments, the subject is a human subject aged 0 to 20 years, e.g., 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years. In some embodiments, the subject is a human subject aged 2 to 20 years. In some embodiments, the subject is a human subject aged 3 to 13 years. In some embodiments, the human subject is an infant, i.e., a child aged 0 to 1 years.

[0088] In some embodiments, one or more solid pharmaceutical forms or compositions are administered orally once daily (qd).

[0089] In some embodiments, the present disclosure provides a method of treating growth hormone deficiency (GHD) in a child, the method comprising administering to a child known to have short stature and adequate GH secretory capacity a therapeutically effective amount of one or more pharmaceutical forms disclosed herein or a pharmaceutical composition disclosed herein.

[0090] In some embodiments, the child is severely GH deficient, as identified by an inability to increase peak GH to >5 μg / L and / or having a baseline IGF-I of <30 μg / L.

[0091] In some embodiments, the present disclosure provides a method of treating growth hormone deficiency (GHD) in a child, the method comprising administering a therapeutically effective amount of one or more solid pharmaceutical forms, such as mini-tablets, or pharmaceutical compositions, such as capsules, disclosed herein to a child known to have short stature and equivalent growth potential compared to rhGH, wherein the child has equivalent growth potential compared to rhGH if they have: (i) peak serum GH≧5 μg / L in response to a single oral dose of ibutamoren mesylate, (ii) baseline serum IGF-I>30 ng / mL.

[0092] In some embodiments, the child is known to have growth retardation, hi some embodiments, the child is known to have equivalent growth potential compared to recombinant growth hormone (rhGH).

[0093] In some embodiments, the child is pre-pubertal. In some embodiments, the child is periphormetic.

[0094] In some embodiments, treatment continues for more than 6 months. For example, treatment with the disclosed methods can be maintained for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. Further, treatment for at least 2.5, 3, 3.5, 4, 4.5, or 5 years, or until growth potential is lost, is also included.

[0095] In one embodiment of the present invention, the method comprises administering one or more pharmaceutical solids disclosed herein, or a pharmaceutical composition described herein, to a subject in need thereof.

[0096] As described above, the pharmaceutical solids of the present invention provide desirable tablet and pharmaceutical dosage form properties. The pharmaceutical granules of the present invention can be compressed, i.e., compressed into tablets or mini-tablets, and have desirable pharmaceutical tablet properties and a high drug load of ibutamoren mesylate. Indeed, for high drug load, easily compressible tablets, one embodiment of the present invention also includes a method of administering a pharmaceutical solid (e.g., a mini-tablet) containing at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of the ibutamoren mesylate drug amount, and the weight of the pharmaceutical solid, such as a tablet, is also less than about 30 mg, 20 mg, 15 mg, or 12 mg.

[0097] The combination of high drug load and small tablet size allows for both compliance from pediatric patient populations and flexibility in administering ibutamoren mesylate to pediatric patient populations that may vary greatly in weight. Thus, in one embodiment of the present invention, pharmaceutical dosage forms such as solids and tablets (e.g., mini-tablets) can have different doses that can be mixed and adjusted for administration to pediatric patients of any weight, such as the weight of a 2-year-old or an 18-year-old. In one embodiment, these methods can include dosage forms that can contain different doses in different tablets or mini-tablets. In another embodiment, the different doses can be contained in different capsules, with the capsules containing tablets or mini-tablets of the same or different doses.

[0098] In certain embodiments, each pharmaceutical solid or tablet contains about 1 mg to about 15 mg of ibutamoren mesylate, or about 3 mg to about 15 mg of ibutamoren mesylate, or about 4 mg to about 6 mg of ibutamoren mesylate, or about 6 mg to about 8 mg of ibutamoren mesylate, or about 9 mg to about 11 mg of ibutamoren mesylate. In certain embodiments, each pharmaceutical solid or tablet contains about 1.0 mg, 1.5 mg, 2.0 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 2.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, or 15 mg of ibutamoren mesylate.

[0099] In another embodiment, a plurality of solid pharmaceutical forms or tablets are administered to a subject. In another specific embodiment, a plurality of solid pharmaceutical forms or tablets can be administered ad libitum, such as by mixing them with food and administering them directly to a subject without food. In another embodiment, a plurality of solid pharmaceutical forms or tablets can be administered in a dosage form in which the solid pharmaceutical forms or tablets are encapsulated. In certain embodiments, the dosage form can be a capsule. In certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 solid pharmaceutical forms or tablets are incorporated into a capsule for administration to a subject.

[0100] In another embodiment, multiple solid pharmaceutical forms or tablets may be administered based on the drug loading of the solid pharmaceutical forms or tablets and the subject's body weight, for example, as shown in Table 6.

[0101] In certain embodiments, the solid pharmaceutical form or tablet may be administered to a subject one, two, three, four, five, or six times daily.

[0102] In certain embodiments, the solid pharmaceutical form or tablet is administered to a subject once daily. In other embodiments, the total daily dose of ibutamoren mesylate for a subject ranges from about 8 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 75 mg, from about 30 mg to about 60 mg, and from about 40 mg to about 50 mg.

[0103] In certain embodiments, the therapeutic dose administered to a subject ranges from about 0.1 mg / kg of subject body weight / day to about 4.0 mg / kg of subject body weight / day, or from about 0.6 mg / kg of subject body weight / day to about 3.5 mg / kg of subject body weight / day. In other embodiments, the therapeutic dose ranges from about 0.8 mg / kg of ibutamoren mesylate to about 3.2 mg / kg of subject body weight / day, or from about 0.8 mg / kg of ibutamoren mesylate to about 3.2 mg / kg of subject body weight / day. g / kg / day, about 1.9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, about 2.2 mg / kg / day, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, or about 3.2 mg / kg / day.

[0104] In some embodiments, the subject is administered a dose of about 0.8 mg / kg / day to about 3.2 mg / kg / day, e.g., about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, about 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.9 mg / kg / day, about 2. In some embodiments, the subject is administered about 0 mg / kg / day, about 2.1 mg / kg / day, about 2.2 mg / kg / day, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, or about 3.2 mg / kg / day of ibutamoren mesylate, including all values ​​and subranges therebetween. In some embodiments, the subject is administered about 0.8 mg / kg / day, about 1.6 mg / kg / day, about 2.4 mg / kg / day, or 3.2 mg / kg / day of ibutamoren mesylate. In some embodiments, the subject is administered about 0.8 mg / kg / day of ibutamoren mesylate. In some embodiments, the subject is administered about 1.6 mg / kg / day of ibutamoren mesylate. In some embodiments, the subject is administered about 3.2 mg / kg / day of ibutamoren mesylate.

[0105] In some embodiments, the subject is administered about 0.1 mg / kg / day to about 1.5 mg / kg / day of ibutamoren mesylate, e.g., about 0.1 mg / kg / day, about 0.2 mg / kg / day, about 0.3 mg / kg / day, about 0.4 mg / kg / day, about 0.5 mg / kg / day, about 0.6 mg / kg / day, about 0.7 mg / kg / day, about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, about 1.4 mg / kg / day, or about 1.5 mg / kg / day, including all values ​​and subranges therebetween. In some embodiments, the subject is administered about 0.6 mg / kg / day to about 1.0 mg / kg / day of ibutamoren mesylate. In some embodiments, the subject is administered about 0.8 mg / kg / day of ibutamoren mesylate.

[0106] In some embodiments, a subject is administered 1-2 capsules per day, based on body weight, each containing up to 12 mini-tablets. In some embodiments, a subject is administered 1-2 capsules per day, based on body weight, each containing 2-12 mini-tablets. In some embodiments, a subject is administered 1-2 capsules per day, based on body weight, each containing up to 10 mini-tablets. In some embodiments, a subject is administered 1-2 capsules per day, based on body weight, each containing 2-10 mini-tablets.

[0107] In some embodiments, a 0.8 mg / kg / day dose of ibutamoren mesylate is provided by administering 2 to 12 mini-tablets daily to a subject, each mini-tablet being a 50% drug load mini-tablet containing approximately 4.7 mg of ibutamoren mesylate. In some embodiments, the dose is administered in one capsule or two capsules, each containing two, three, or six mini-tablets.

[0108] In some embodiments, a 0.8 mg / kg / day dose of ibutamoren mesylate is provided by administering to a subject up to two capsules per day containing two, three, or six mini-tablets, each mini-tablet being a 50% drug-loaded mini-tablet containing approximately 4.7 mg of ibutamoren mesylate.

[0109] In some embodiments, a 1.6 mg / kg / day dose of ibutamoren mesylate is provided by administering 3 to 16 mini-tablets daily to a subject, each mini-tablet being a 70% drug load mini-tablet containing approximately 7.11 mg of ibutamoren mesylate. In some embodiments, the dose is administered in one capsule or two capsules, each containing 3, 4, or 12 mini-tablets.

[0110] In some embodiments, a 1.6 mg / kg / day dose of ibutamoren mesylate is provided by administering to a subject up to two capsules per day containing 3, 4, or 12 mini-tablets, each mini-tablet being a 70% drug-loaded mini-tablet containing approximately 7.11 mg of ibutamoren mesylate.

[0111] In some embodiments, a 3.2 mg / kg / day dose of ibutamoren mesylate is provided by administering 3 to 20 mini-tablets daily to a subject, each mini-tablet being an 85% drug load mini-tablet containing approximately 10.36 mg of ibutamoren mesylate. In some embodiments, the dose is administered in one capsule or two capsules, each containing 3, 4, or 10 mini-tablets.

[0112] In some embodiments, a 3.2 mg / kg / day dose of ibutamoren mesylate is provided by administering to a subject up to two capsules per day containing 3, 4, or 10 mini-tablets, each mini-tablet being an 85% drug-loaded mini-tablet containing approximately 10.36 mg of ibutamoren mesylate.

[0113] In some embodiments, the subject to be treated is growth hormone naive (treatment naive). In some embodiments, the subject or child to be treated may have received previous GH therapy that has been discontinued, so long as the subject or child meets the criteria for adequate GH secretory capacity as identified above.

[0114] In some embodiments, the present disclosure provides a method of treating a disease or condition associated with abnormally reduced growth hormone (GH) secretion in a subject with sufficient GH secretory capacity, the method comprising administering to the subject one or more pharmaceutical solids disclosed herein, or a pharmaceutical composition disclosed herein.

[0115] In some embodiments, treating the disease or condition comprises increasing endogenous GH secretion in the subject.

[0116] In some embodiments, the disease or condition is Turner syndrome, childhood chronic kidney disease (PCKD), Prader-Willi syndrome (PWS), lipodystrophy (e.g., HIV lipodystrophy), muscle wasting disease, small for gestational age (SGA), idiopathic short stature (ISS), short stature homeobox-containing gene (SHOX) deficiency, Noonan syndrome, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

[0117] In some embodiments, the muscle wasting disease is sarcopenia, cachexia, hypothalamic amenorrhea, or relative energy deficiency in sports (RED-S) syndrome.

[0118] Preparation method The present disclosure also provides methods for preparing the pharmaceutical solids and compositions thereof disclosed herein.

[0119] In some embodiments, the present disclosure provides a compressed pharmaceutical tablet prepared by: (a) blending a mixture of ibutamoren or a pharmaceutically acceptable salt thereof with a first portion of a binder, a filler, a disintegrant, and a lubricant; (b) compressing the blended mixture of step (a) using a roller compactor, thereby forming a compacted material; (c) sieving the compacted material of step (b) through one or more screens to produce drug-containing granules; (d) blending the drug-containing granules of step (c) with a second portion of a disintegrant, a lubricant, and a binder to obtain a final blend; (e) compressing the final blend of step (d) into compressed tablets; and (f) Optionally, the compressed tablets are coated with a coating described herein (e.g., Eudragit® E PO).

[0120] In some embodiments, the ibutamoren salt is ibutamoren mesylate.

[0121] The binder, filler, disintegrant, and lubricant can be any of the options described herein in any disclosed amounts or ranges, hi some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0122] In some embodiments, the blending in step (a) occurs for about 1 minute to about 30 minutes. In some embodiments, the blending in step (a) occurs for about 5 minutes to about 15 minutes. In some embodiments, the blending occurs in a blender, such as a V-blender.

[0123] The roller compactor in step (b) can be operated at any suitable screw speed, roller speed, and compaction pressure sufficient to prepare a compacted material of the present disclosure, as determined by one of ordinary skill in the art based on factors including, but not limited to, the size and model of the compactor, and the composition of the blended mixture. In some embodiments, the roller compactor in step (b) is operated at a screw feeder speed of about 20 rpm to about 60 rpm, a roller speed of about 3 rpm to about 9 rpm, and a compaction pressure of about 10 bar to about 30 bar. In some embodiments, the roller compactor in step (b) is operated at a screw feeder speed of about 40 rpm, a roller speed of about 6 rpm, and a compaction pressure of about 20 bar. In some embodiments, the roller compactor comprises a granulator operated at 75 rpm to 125 rpm. In some embodiments, the granulator is operated at about 95 rpm.

[0124] In some embodiments, the first portion of binder is about 25% to about 75% by weight of the total amount of binder added. In some embodiments, the first portion of lubricant is about 25% to about 75% by weight of the total amount of lubricant added. In some embodiments, the first portion of binder is about 50% by weight of the total amount of binder added. In some embodiments, the first portion of lubricant is about 50% by weight of the total amount of lubricant added.

[0125] In some embodiments, one or more of the binder, filler, disintegrant, and lubricant in step (a) are screened through a mesh sieve prior to roller compaction, hi some embodiments, the sieve is a 20 mesh or 40 mesh sieve.

[0126] In some embodiments, the screening in step (c) comprises screening the roller-compacted material through a coarse screen and / or a fine screen. In some embodiments, the screening in step (c) comprises screening the roller-compacted material through a coarse screen and a fine screen. In some embodiments, the coarse screen has a size of 1.6 mm. In some embodiments, the fine screen has a size of 1.0 mm. In some embodiments, the roller compactor is equipped with a coarse screen and a fine screen.

[0127] In some embodiments, one or more of the binder, disintegrant, and second portion of lubricant are screened through a mesh sieve prior to blending in step (d). In some embodiments, the sieve is a 20 mesh or a 40 mesh sieve.

[0128] In some embodiments, the second portion of disintegrant is about 50% by weight of the total amount of disintegrant added. In some embodiments, the second portion of lubricant is about 50% by weight of the total amount of lubricant added. [Example]

[0129] The following examples are provided to illustrate the present disclosure and should not be construed as limiting the disclosure.

[0130] Example 1. Preparation of drug-containing granules Final blends of drug-containing granules of the present disclosure containing 10%, 20%, 30%, 50%, 70%, 85%, and 90% by weight of ibutamoren mesylate were prepared by a manufacturing method involving roller compaction (see FIG. 1 ) and the processing parameters shown in Table 1.

[0131] [Table 2]

[0132] Example 2. Characteristics of drug-containing granules The particle size distributions by density and sieve analysis were compared for drug-containing granules containing 10%, 20%, 30%, 50%, 70%, 85%, and 90% by weight of ibutamoren mesylate, prepared as described in Example 1 (Tables 2A and 2B). The tables below compare the initial blend before roller compaction (pre-RC) with the milled blend after roller compaction (see Figure 1) (hereinafter also referred to as post-RC).

[0133] [Table 3]

[0134] [Table 4]

[0135] As shown in Tables 2A and 2B, the drug-containing granules produced by roller compaction exhibit significant compressibility as the drug loading increases. The general trend observed is a decrease in densification as the drug loading of ibutamoren mesylate increases, but a shift in the particle size distribution (PSD) toward larger particle sizes in the post-RC blends compared to the pre-RC blends.

[0136] Table 3 shows the calculation of Hausner ratio and Carr index for estimation of flowability and compressibility index of powder blends / granules respectively. Table 4 provides guidance for flowability properties of powder blends / granules.

[0137] [Table 5]

[0138] [Table 6]

[0139] The above data demonstrate that ibutamoren mesylate exhibits unique compression characteristics at both low (10%) and high (90%) drug loads, resulting in roller-compacted granule / powder blends with sieve analysis (particle size distribution) and densities (bulk and tapped) suitable for compression. In all drug load preparations, the roller compaction process resulted in an increased amount of large granules (i.e., granules retained on 40-, 60-, and 80-mesh sieves) along with improved densification (increased bulk density) of the blend compared to before roller compaction. Without being bound by any particular theory, controlling granule size distribution and avoiding excessive fines are important for proper flow and minimal powder segregation during compression. Density measurements of granules before and after roller compaction were performed according to USP <616> In all cases, blend densification was observed, but with increasing drug loading, densification decreased (90% < 85% < 70% < 50% < 30% < 20% < 10%), and increasing drug loading improved the flow and compressibility properties of the blends.

[0140] Example 3. Preparation of compressed tablets The final blend of drug-containing granules and extragranular excipients (binder, disintegrant, and / or lubricant) described above and in Figure 1 was compressed into tablets using a rotary tablet press. Tablets were produced by pressing the blend containing drug-containing granules and extragranular excipients into the center of a die using two punches that fit into the upper and lower parts of the die. Both punches travel between two large wheels (pressure rolls), which press the punches together to form a tablet at a specific compression force. The distance between the upper and lower punches and the compression force determine the thickness and hardness of the tablet while maintaining a constant tablet weight.

[0141] Example 4. Properties of compressed tablets The properties, including hardness and friability, of the tablets produced according to Example 3 are provided in Table 5.

[0142] [Table 7]

[0143] Tablets of each ibutamoren mesylate drug load were successfully compressed using 2.5 mm round tooling. All tablet batches exhibited a friability of less than 1% and hardness ranging from 0.8 kP to 5.2 kP before coating. Data showed that tablet hardness generally increased with increasing drug load. After compression, all batches were successfully coated with a 20% weight gain.

[0144] Compression of the compactable blends into tablets using 2.5 mm tooling (see Figure 1) was unaffected by the drug load of ibutamoren mesylate. All tablets were prepared within the USP weight variation limit of 10% and with a friability of 1.0% or less. At each drug load, tablet hardness was sufficient to withstand the fluid-bed coating process. Minitablet dissolution of 85% or greater (Q = 80%) was achieved in 30 minutes (NLT) at each drug load.

[0145] Example 5. Efficacy study in pediatric growth hormone (GH)-deficient subjects Summary: A study is being conducted to determine whether the mini-tablets disclosed herein can be used to treat GHD in children. The disclosed mini-tablets will be compared to rhGH injections according to the following protocol: Bone age will be determined using the atlas matching method of the Greulich and Pyle protocol, and subjects will be randomly assigned to receive mini-tablets providing one of three oral daily doses of ibutamoren mesylate or daily injections of recombinant human growth hormone (rhGH).

[0146] The study will involve treatment for up to 24 months. Subjects will undergo a physical examination, blood and urine samples to assess response to treatment.

[0147] Participants: Children of both sexes aged 3 to 12 years who have been diagnosed with idiopathic PGHD according to standard diagnostic criteria and who have sufficient GH secretory capacity. ·Having a lower HT-SDS ≤ -2.0 or HT-SDS ≥ 2SD below the mean parent HT-SDS. · Have a baseline height velocity of <5.5 cm / year based on at least 6 months of growth. · Have a bone age that is ≥ 6 months behind chronological age. Prepubertal status as evidenced by Tanner stage I breast development in girls and a testicular volume <4.0 mL in boys.

[0148] Treatment Groups and Doses (Table 6): 0.8 mg / kg / day of ibutamoren mesylate administered orally once daily in mini-tablets 1.6 mg / kg / day of ibutamoren mesylate administered orally once daily in mini-tablets 3.2 mg / kg / day of ibutamoren mesylate administered orally once daily in mini-tablets 34 μg / kg / day of rhGH administered subcutaneously once daily (active drug comparison)

[0149] Primary outcomes included: Annual height velocity (AHV) measured using a height gauge Comparison of AHV and rhGH measured after 6 months of administration of a disclosed mini-tablet containing ibutamoren mesylate

[0150] Secondary outcomes may include: Determination of bone age changes - X-ray measurements of the left hand and wrist using the atlas of Greulich and Pyle Pharmacokinetic evaluation Changes in weight, BMI, and other parameters Height Standard Deviation Score (SDS) and Height Velocity Standard Deviation Score (HV-SDS)

[0151] Conclusion: Subjects diagnosed with GHD and treated with the mini-tablets of the present disclosure demonstrate improved outcomes at each dose of ibutamoren mesylate administered, as determined by AHV and other measured parameters, compared to subjects receiving subcutaneous rhGH.

[0152] [Table 8]

[0153] summary Generally, high drug load formulations are difficult to prepare using roller compaction processes. At low drug loads, blending properties can be adjusted and processability improved by selecting appropriate excipients in appropriate amounts, but at high drug loads, this option is limited. Thus, the physical properties of a drug substance that exhibits comparable blending and tableting properties at low and high drug loads present a challenge that is addressed by the pharmaceutical solids and manufacturing methods disclosed herein.

[0154] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0155] equivalent While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the disclosure should be determined by reference to the claims, their full scope of equivalents, and the specification, and such variations.

Claims

1. A pharmaceutical solid comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount of 10% by weight or more of the pharmaceutical solid, and the weight of the pharmaceutical solid is less than about 20 mg.

2. 2. The pharmaceutical solid of claim 1, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount of about 10% to about 90% by weight of the pharmaceutical solid.

3. 2. The pharmaceutical solid of claim 1, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount of more than 50% by weight of the pharmaceutical solid.

4. 2. The pharmaceutical solid of claim 1, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount of more than 80% by weight of the pharmaceutical solid.

5. The pharmaceutical solid according to any one of claims 1 to 4, wherein the pharmaceutical solid comprises a drug-containing granule containing the ibutamoren or a pharmaceutically acceptable salt thereof.

6. 6. The pharmaceutical solid of claim 5, wherein the drug-containing granules have a bulk density of less than 0.6 g / cc.

7. 6. The pharmaceutical solid of claim 5, wherein the drug-containing granules have a bulk density of less than 0.5 g / cc.

8. The pharmaceutical solid according to any one of claims 5 to 7, wherein the drug-containing granules have a tap density of less than 0.78 g / cc.

9. The pharmaceutical solid according to any one of claims 5 to 7, wherein the drug-containing granules have a tap density of less than 0.6 g / cc.

10. 10. The pharmaceutical solid according to any one of claims 5 to 9, wherein the drug-containing granules have a D50 of greater than about 175 μm.

11. 10. The pharmaceutical solid according to any one of claims 5 to 9, wherein the drug-containing granules have a D50 of greater than about 400 μm.

12. The pharmaceutical solid according to any one of claims 5 to 11, wherein the drug-containing granules are compressed drug-containing granules.

13. 13. The pharmaceutical solid of claim 12, wherein the compressed drug-containing granules have a D50 that is at least about two times greater than a non-compressed drug granule having the same composition.

14. The pharmaceutical solid according to any one of claims 5 to 13, wherein the drug-containing granule comprises the ibutamoren or a pharmaceutically acceptable salt thereof, as well as a binder, a filler, a disintegrant, and a lubricant.

15. 15. The pharmaceutical solid of claim 14, wherein the amount of the binder ranges from about 2% w / w to about 60% w / w, the amount of the filler ranges from about 1% w / w to about 40% w / w, the amount of the disintegrant ranges from about 1% w / w to about 5% w / w, and the amount of the lubricant ranges from about 0.5% w / w to about 2% w / w.

16. 15. The pharmaceutical solid of claim 14, wherein the amount of the binder ranges from about 2% w / w to about 30% w / w, the amount of the filler ranges from about 1% w / w to about 20% w / w, the amount of the disintegrant ranges from about 1% w / w to about 2% w / w, and the amount of the lubricant ranges from about 0.5% w / w to about 1.5% w / w.

17. The pharmaceutical solid according to any one of claims 14 to 16, wherein the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

18. The pharmaceutical solid according to any one of claims 5 to 17, wherein the drug-containing granules are processed by roller compaction.

19. The pharmaceutical solid according to any one of claims 1 to 18, wherein the ibutamoren is ibutamoren mesylate.

20. The pharmaceutical solid according to any one of claims 1 to 19, wherein the pharmaceutical solid is a tablet, a sprinkle, or a bead.

21. 21. The pharmaceutical solid according to claim 20, wherein the pharmaceutical solid is a tablet.

22. 22. The pharmaceutical solid of claim 20 or 21, wherein the diameter of the pharmaceutical solid or tablet is less than about 3 mm.

23. 22. The pharmaceutical solid according to claim 20 or 21, wherein the tablet has a diameter of about 2.5 mm.

24. The pharmaceutical solid according to any one of claims 20 to 23, wherein the tablet is a compressed tablet.

25. 25. The pharmaceutical solid of claim 24, wherein the tablet is compressed with the drug-containing granules prepared by roller compaction.

26. 26. The pharmaceutical solid according to any one of claims 20 to 25, wherein the tablet is not prepared by wet granulation or direct compression.

27. The pharmaceutical solid according to any one of claims 20 to 26, wherein the tablet is a coated tablet.

28. 28. The pharmaceutical solid of claim 27, wherein the coating is applied to the tablet to provide a weight gain of about 8% to about 20% by weight based on the total weight of the tablet.

29. 29. The pharmaceutical solid according to claim 27 or 28, wherein the coating comprises a taste-masking layer.

30. 30. The pharmaceutical solid according to any one of claims 27 to 29, wherein the coating comprises an aminoalkyl methacrylate copolymer.

31. The pharmaceutical solid according to any one of claims 27 to 30, wherein the coating comprises N,N-dimethylaminoethyl methacrylate / methacrylate / butyl methacrylate copolymer (Eudragit® E PO).

32. 27. The pharmaceutical solid according to any one of claims 20 to 26, wherein the tablet is an uncoated tablet and has a hardness of greater than 0.7 Kp when compressed using a tablet tool size of 2.5 mm.

33. 27. The pharmaceutical solid according to any one of claims 20 to 26, wherein the tablet is an uncoated tablet and has a hardness of greater than 1.5 Kp when compressed using a tablet tool size of 2.5 mm.

34. 27. The pharmaceutical solid according to any one of claims 20 to 26, wherein the tablet is an uncoated tablet and has a hardness of greater than 3.0 Kp when compressed using a tablet tool size of 2.5 mm.

35. 35. The pharmaceutical solid according to any one of claims 20 to 26 and 32 to 34, wherein the tablet is an uncoated tablet and has a friability of less than 1%.

36. The pharmaceutical solid according to any one of claims 20 to 35, wherein the tablet further comprises a binder, a disintegrant and a lubricant.

37. 37. The pharmaceutical solid of claim 36, wherein the amount of the binder is in the range of about 1% w / w to about 5%, the amount of the disintegrant is in the range of about 1% w / w to about 5%, and the amount of the lubricant is in the range of about 0.5% w / w to about 2%, each relative to the weight of the tablet.

38. 37. The pharmaceutical solid of claim 36, wherein the amount of the binder is in the range of about 2% w / w to about 4%, the amount of the disintegrant is in the range of about 2.5% w / w to about 3.5%, and the amount of the lubricant is in the range of about 0.25% w / w to about 1.0%, each relative to the weight of the tablet.

39. The pharmaceutical solid according to any one of claims 36 to 38, wherein the binder is pregelatinized starch, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

40. 40. The pharmaceutical solid of any one of claims 20 to 39, wherein the tablet weighs less than about 20 mg, the tablet has a friability of less than 1%, and the tablet has a hardness of greater than 1.5 Kp when compressed using a 2.5 mm tablet tool size.

41. 41. The pharmaceutical solid of claim 40, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount of more than 60% by weight of the tablet.

42. 41. The pharmaceutical solid of claim 40, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount of more than 80% by weight of the tablet.

43. 43. The pharmaceutical solid according to any one of claims 40 to 42, wherein the tablet further comprises a binder, a disintegrant, and a lubricant, each of which, relative to the weight of the tablet, comprises the binder in an amount ranging from about 1% w / w to about 5%, the disintegrant in an amount ranging from about 1% w / w to about 5%, and the lubricant in an amount ranging from about 0.5% w / w to about 2%.

44. 44. The pharmaceutical solid of claim 43, wherein the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

45. A pharmaceutical composition comprising a plurality of solid pharmaceutical forms according to any one of claims 1 to 44.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the composition is in the form of a capsule containing the plurality of pharmaceutical tablets.

47. 47. The pharmaceutical composition of claim 45 or 46, wherein the composition is in the form of a capsule containing 2 to 12 of the pharmaceutical tablets.

48. 48. A method for treating growth hormone deficiency, said method comprising administering to a subject in need thereof one or more pharmaceutical forms according to any one of claims 1 to 44 or a pharmaceutical composition according to any one of claims 45 to 47.

49. 49. The method of claim 48, wherein the subject is a human between the ages of 2 and 20.

50. 49. The method of claim 48, wherein the subject is a human between the ages of 3 and 13.

51. 51. The method of any one of claims 48 to 50, wherein the one or more tablets or compositions are administered orally once daily.

52. 52. The method of claim 51, wherein each tablet contains from about 1 mg to about 15 mg of ibutamoren mesylate, or from about 3 mg to about 15 mg of ibutamoren mesylate, or from about 4 mg to about 6 mg of ibutamoren mesylate, or from about 6 mg to about 8 mg of ibutamoren mesylate, or from about 9 mg to about 11 mg of ibutamoren mesylate.

53. 53. The method of claim 52, wherein each tablet contains about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, or 15.0 mg of ibutamoren mesylate.

54. 54. The method of any one of claims 48 to 53, wherein the subject is administered a plurality of solid pharmaceutical forms or tablets.

55. 55. The method of claim 54, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 tablets are loaded into a capsule for administration.

56. 55. The method of claim 54, wherein the subject is administered multiple capsules per day.

57. 57. The method of any one of claims 54-56, wherein the subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 tablets per day.

58. 54. The method of any one of claims 48-53, wherein the therapeutic dose administered to the subject ranges from about 0.1 mg dose / kg of subject body weight / day to about 4.0 mg dose / kg of subject body weight / day, or from about 0.6 mg dose / kg of subject body weight / day to about 3.5 mg dose / kg of subject body weight / day.

59. The therapeutic dose may range from about 0.8 mg / kg / day to about 3.2 mg / kg / day of ibutamoren mesylate, or about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, about 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.

59. The method of claim 58, wherein the amount of the compound administered is about 9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, about 2.2 mg / kg / day, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, or about 3.2 mg / kg / day.

60. 60. The method of any one of claims 48-59, wherein the total daily dose of ibutamoren mesylate for the subject ranges from about 8 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 75 mg, from about 30 mg to about 60 mg, and from about 40 mg to about 50 mg.

61. 48. A method for treating a disease or condition associated with an abnormal decrease in growth hormone (GH) secretion in a subject with sufficient GH secretory capacity, said method comprising administering to said subject in need thereof one or more pharmaceutical forms according to any one of claims 1 to 44 or a pharmaceutical composition according to any one of claims 45 to 47.

62. 62. The method of claim 61, wherein treating the disease or condition comprises increasing endogenous GH secretion in the subject.

63. 63. The method of claim 61 or 62, wherein the disease or condition is Turner syndrome, childhood chronic kidney disease (PCKD), Prader-Willi syndrome (PWS), lipodystrophy (e.g., HIV lipodystrophy), muscle wasting disease, small for gestational age (SGA), idiopathic short stature (ISS), short stature homeobox-containing gene (SHOX) deficiency, Noonan syndrome, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

64. 64. The method of claim 63, wherein the muscle wasting disease is sarcopenia, cachexia, hypothalamic amenorrhea, or relative energy deficiency in sports (RED-S) syndrome.

65. 65. The method of any one of claims 61 to 64, wherein the subject is a human between 2 and 20 years of age.

66. 65. The method of any one of claims 61 to 64, wherein the subject is a human between 3 and 13 years of age.

67. 67. The method of any one of claims 61 to 66, wherein the one or more tablets or compositions are administered orally once daily.

68. 68. The method of claim 67, wherein each tablet contains from about 1 mg to about 15 mg of ibutamoren mesylate, or from about 3 mg to about 15 mg of ibutamoren mesylate, or from about 4 mg to about 6 mg of ibutamoren mesylate, or from about 6 mg to about 8 mg of ibutamoren mesylate, or from about 9 mg to about 11 mg of ibutamoren mesylate.

69. 69. The method of claim 68, wherein each tablet contains about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, or 15.0 mg of ibutamoren mesylate.

70. 70. The method of any one of claims 61 to 69, wherein the subject is administered a plurality of solid pharmaceutical forms or tablets.

71. 71. The method of claim 70, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 tablets are loaded into a capsule for administration.

72. 71. The method of claim 70, wherein the subject is administered multiple capsules per day.

73. 73. The method of any one of claims 70-72, wherein the subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 tablets per day.

74. 70. The method of any one of claims 61-69, wherein the therapeutic dose administered to the subject ranges from about 0.1 mg dose / kg of subject body weight / day to about 4.0 mg dose / kg of subject body weight / day, or from about 0.6 mg dose / kg of subject body weight / day to about 3.5 mg dose / kg of subject body weight / day.

75. The therapeutic dose may range from about 0.8 mg / kg / day to about 3.2 mg / kg / day of ibutamoren mesylate, or about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, about 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.

75. The method of claim 74, wherein the amount of the compound administered is about 9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, about 2.2 mg / kg / day, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, or about 3.2 mg / kg / day.

76. 76. The method of any one of claims 61-75, wherein the total daily dose of ibutamoren mesylate for the subject ranges from about 8 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 75 mg, from about 30 mg to about 60 mg, and from about 40 mg to about 50 mg.

77. A kit comprising one or more pharmaceutical solids and / or one or more pharmaceutical compositions according to any one of claims 1 to 47.

78. 78. The kit of claim 77, wherein the kit provides various doses in the pharmaceutical solid or pharmaceutical composition.

79. 79. The kit of claim 78, wherein the kit comprises tablets having a dose of ibutamoren mesylate ranging from about 2 mg to about 6 mg, from about 6 mg to about 8 mg, and / or from about 9 mg to about 11 mg.

80. 80. The kit of claim 79, wherein the kit comprises a capsule containing one or more tablets having a dose of ibutamoren mesylate ranging from about 4 mg to about 6 mg, from about 6 mg to about 8 mg, and / or from about 9 mg to about 11 mg.

81. 81. The kit of claim 80, wherein at least one capsule contains 1 to 6 tablets having a dose of ibutamoren mesylate ranging from about 4 mg to about 6 mg, and / or at least one capsule contains 3 to 12 tablets having a dose of ibutamoren mesylate ranging from about 6 mg to about 8 mg, and / or at least one capsule contains 3 to 10 tablets having a dose of ibutamoren mesylate ranging from about 9 mg to about 11 mg.

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