Compressible oral formulations of ibmuren

Abstract

The present disclosure relates to pharmaceutical solid forms and pharmaceutical compositions comprising ibmuren or a pharmaceutically acceptable salt thereof, and methods for administration to a pediatric subject to treat growth hormone deficiency.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 422,329, filed on November 3, 2022, which is incorporated herein by reference in its entirety. Technical background

[0003] Growth hormone deficiency (GHD) resulting in short stature (-2SD height for chronological age) in children is a worldwide condition. Current treatment of children with growth hormone deficiency and short stature typically lasts for many years from childhood diagnosis until final height is reached. Generally, 1 year or more of treatment is required to establish a new growth trajectory during treatment. Thereafter, typically 10 years or more of treatment is required to achieve the best adult height for these children. Additionally, due to the underlying causes of GH deficiency and differences in the pattern and rate of catch - up growth at the start of treatment, the results obtained from 6 - month treatment evaluations in newly diagnosed children can vary widely. Children with GHD are typically treated by daily subcutaneous injection of GH, which can be painful, inconvenient, and distressing in some children (especially young children).

[0004] Accordingly, the development of non - injectable therapies (e.g., once - daily oral treatment) that are effective for treating pediatric GHD would be beneficial in terms of simplicity of treatment, patient convenience, and long - term adherence. Thus, it would be beneficial to develop non - injection - based therapies (such as once - daily oral treatment) that are effective in treating pediatric GHD in terms of simplicity of treatment, patient convenience, and long - term adherence.

[0005] This disclosure addresses these and other unmet needs. Summary of the invention

[0006] In some aspects, the present disclosure provides a pharmaceutical solid form comprising ibomolen or a pharmaceutically acceptable salt thereof, wherein the amount of ibomolen or its pharmaceutically acceptable salt is greater than 10% by weight of the pharmaceutical solid form, and wherein the weight of the pharmaceutical solid form is less than about 20 mg.

[0007] In some embodiments, ibomolen or its pharmaceutically acceptable salt is ibomolen mesylate.

[0008] In some embodiments, the pharmaceutical solid form is a tablet, a microtablet, a sprinkle, or a bead.

[0009] In some embodiments, the present disclosure provides a pharmaceutical composition comprising more than one pharmaceutical solid form disclosed herein.

[0010] In some embodiments, the composition is in the form of a capsule that contains 1 to 12 tablets as disclosed herein. In some embodiments, the tablets are microtablets. In some embodiments, the tablets are microtablets having a diameter of less than 3 mm.

[0011] In some embodiments, the present disclosure also provides a method for treating growth hormone deficiency, the method comprising administering to a subject in need thereof one or more of the pharmaceutical forms or pharmaceutical compositions disclosed herein.

[0012] In some embodiments, the subject is a human child between 2 and 20 years of age. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 A flow chart is provided that outlines a method for manufacturing a pharmaceutical tablet of the present disclosure that contains ibmolexate mesylate. DETAILED DESCRIPTION

[0014] DEFINITIONS

[0015] 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 one of ordinary skill in the art with a general definition of 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 and Marham, The Harper Collins Dictionary of Biology (1991). Unless otherwise indicated, as used herein, the following terms have the meanings given to them below.

[0016] As used herein, the verb “comprise” and its conjugations as used in this specification and the claims are used in its non-limiting sense, meaning including the item(s) after the word, but not excluding items not expressly mentioned. The present disclosure may suitably “comprise” the steps, elements, and / or reagents described in the claims, “consist of” the steps, elements, and / or reagents described in the claims, or “consist essentially of” the steps, elements, and / or reagents described in the claims.

[0017] Unless expressly stated or obvious from the context, as used herein, the term "or" is understood to be inclusive. Unless expressly stated or obvious from the context, as used herein, the terms "a / an" and "the" are understood to be singular or plural.

[0018] Throughout this specification, the terms "about" and / or "approximately" may be used in connection with numerical values and / or ranges. The term "about" is understood to mean those values that are close to the stated value. Additionally, the phrases "less than about [a value]" or "greater than about [a value]" should be understood based on the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0019] As used herein, "D90" refers to the 90% value of the particle size as determined by sieve analysis, i.e., the percentage of drug particles retained on the sieve during the sieving process using a sieve with a specific mesh size. For example, if D90 = 100 μm, then 90% of the drug particles are retained on the 100-μm sieve during the sieving process. Similarly, "D80" refers to the 80% value of the particle size, "D70" refers to the 70% value of the particle size, "D60" refers to the 60% value of the particle size, "D50" refers to the 50% value of the particle size, "D40" refers to the 40% value of the particle size, "D30" refers to the 30% value of the particle size, "D20" refers to the 20% value of the particle size, and "D10" refers to the 10% value of the particle size.

[0020] As used herein, "substantially" or "substantial" means the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, substance, or result. For example, an object that is "substantially" enclosed would mean that the object is completely enclosed or nearly completely enclosed. In some cases, the exact allowable degree of deviation from absolute completeness may depend on the specific context. However, generally speaking, complete proximity would be such that it has the same overall result as if absolute and total completion were achieved. When used in a negative sense, the use of "substantially" applies equally, meaning the complete or nearly complete lack of an action, characteristic, property, state, structure, substance, or result. For example, a composition that is "substantially free" of other active agents either has no other active agents at all, or has very few other active agents, and the effect is the same as if it had no other active agents at all. In other words, a composition that is "substantially free" of a certain ingredient or element or another active agent may still contain that substance, as long as it has no measurable effect.

[0021] The term "treatment" means alleviating, attenuating, delaying, reducing, reversing, improving, or controlling one or more of at least one symptom of a disorder in a subject. The term "treatment" may also mean arresting, delaying the onset (i.e., the period before the clinical manifestation of a disorder), or reducing the risk of development or worsening of a disorder, one or more of which.

[0022] The term "therapeutically effective" as applied to a dose or amount means an amount of a compound or pharmaceutical formulation that is sufficient to produce the desired clinical benefit upon administration to a subject in need (e.g., a human child).

[0023] As used herein, "prepubertal" refers to a child with a bone age of <8 years in girls and <9 years in boys. Bone age can be determined using well-known methods such as the Greulich and Pyle atlas matching method or the Tanner and Whitehouse scoring system. Other examples of bone age include <7 years in females and <8 years in males.

[0024] As used herein, "peripubertal" refers to a child who has started to experience puberty and is clinically evaluated by Tanner staging. Tanner stage 1 is prepubertal, and thereafter until the completion of puberty (Tanner stage 4) is considered peripubertal.

[0025] As used herein, "short stature" refers to a child whose height is below the 2.3rd percentile of his / her actual age (about -2SD height for actual age). Other examples include below the 5th, 4th, 3rd, 2nd, and 1st percentile of his / her actual age.

[0026] As used herein, "growth retardation" or "slow rate of height gain" refers to a rate of height gain that is below the 25th percentile for age and gender as recorded over at least 6 months. Other examples include below 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 gender as recorded over at least 6 months.

[0027] As used herein, a subject is considered to have sufficient GH secretory potential if the subject meets the following criteria:

[0028] ○ (i) has a peak GH of <10 μg / L (or <7 μg / L) in response to a standard stimulation test; and

[0029] ○ (ii) has a peak serum GH of ≥5 μg / L in response to a single dose of ibomolen mesylate (e.g., 0.8 mg / kg).

[0030] As used herein, "growth potential equal to rhGH" means that a patient is considered to have growth potential equal to long-term subcutaneous injection of rhGH (growth potential equal to rhGH) if the subject meets the following conditions:

[0031] ○ (i) has a peak serum GH of ≥ 5 μg / L in response to a single dose of ibutamoren mesylate (e.g., 0.8 mg / kg); and

[0032] ○ (ii) has a baseline serum IGF-I of > 30 μg / L.

[0033] Unless otherwise indicated, all weight percentages mentioned herein (i.e., "weight %" and "wt.%" and "w / w") are measured relative to the total weight of the solid drug form or the pharmaceutical composition.

[0034] Solid forms of the drug

[0035] In some embodiments, the present disclosure provides a solid drug form comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein the amount of ibutamoren or a pharmaceutically acceptable salt thereof is greater than 10 weight % of the solid drug form, and wherein the weight of the solid drug form is less than about 20 mg.

[0036] Ibutamoren is a non-peptide agonist of ghrelin and a growth hormone secretagogue, and has the following structure:

[0037]

[0038] And the chemical name is: N-[l(R)-[(l,2-dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidine]-l'-yl)carbonyl]-2-(phenyl-methoxy)ethyl]-2-amino-2-methylpropanamide.

[0039] The mesylate salt of ibutamoren, N-[1(R)-[(1,2-dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidine]-yl)carbonyl]-2-(phenylmethoxy)ethyl]-2-amino-2-methylpropanamide mesylate, is known as MK-0677 and LUM-201, and has been evaluated in several clinical studies.

[0040] In some embodiments, the pharmaceutical solid forms of the present disclosure comprise ibmoleucine 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%, greater than 45%, greater than 47.5%, greater than 50%, greater than 52.5%, greater than 55%, greater than 57.5%, greater than 60%, greater than 62.5%, greater than 65%, greater than 67.5%, greater than 70%, greater than 72.5%, greater than 75%, greater than 77.5%, greater than 80%, greater than 82.5%, greater than 85%, greater than 87.5%, greater than 90%, greater than 92.5% or greater than 95% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 10% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 20% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 30% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 40% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 50% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 60% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 70% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 80% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 85% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount greater than or equal to 90% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount of about 10% to about 90% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount of about 15% to about 90% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount of about 20% to about 90% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount of about 25% to about 90% by weight of the pharmaceutical solid form. In some embodiments, ibmoleucine or a pharmaceutically acceptable salt thereof is present in an amount of about 30% to about 90% by weight of the pharmaceutical solid form.In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 35 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 40 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 45 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 50 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 55 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 60 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 65 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 70 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 75 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 80 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 85 wt% to about 90 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 50 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 55 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 60 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 65 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 70 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 75 wt% to about 80 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 30 wt% to about 50 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 35 wt% to about 50 wt% in the form of a pharmaceutical solid. In some embodiments, ibmoleen or a pharmaceutically acceptable salt thereof is present in an amount of about 40 wt% to about 50 wt% in the form of a pharmaceutical solid.In some embodiments, ibmolex or a pharmaceutically acceptable salt thereof is present in an amount of about 45 wt% to about 50 wt% in the form of a pharmaceutical solid. In some embodiments, the pharmaceutically acceptable salt is the mesylate salt of ibmolex.

[0041] In some embodiments, the weight of the pharmaceutical solid form 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 another embodiment, the weight of the pharmaceutical solid form of the present disclosure is in the range of about 1.0 mg to about 20 mg, in the range of about 2 mg to about 17 mg. In some embodiments, the weight of the pharmaceutical solid form of the present disclosure is less than about 19 mg. In some embodiments, the weight of the pharmaceutical solid form of the present disclosure is less than about 18 mg. In some embodiments, the pharmaceutical solid form of the present disclosure has a weight of about 5 mg to about 20 mg, such as 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 form is a tablet having a weight of about 12 mg to about 20 mg. In some embodiments, the pharmaceutical solid form is a tablet having a weight of about 12 mg to about 18 mg.

[0042] In another embodiment, each solid form, tablet, microtablet, etc. contains a different dose of ibmolex or a pharmaceutically acceptable salt thereof. In a specific embodiment, ibmolex is ibmolex mesylate.

[0043] In a specific embodiment, the tablet or minitablet contains from about 1 to about 20 mg of ibmolexan mesylate, such as 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, including all values and subranges therebetween. In some embodiments, the tablet or minitablet contains from about 4 to about 15 mg of ibmolexan mesylate, such as 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, a tablet or minitablet having a drug loading of 50 wt% contains about 4.7 mg of ibmolexan mesylate. In some embodiments, a tablet or minitablet having a drug loading of 70 wt% contains about 7.11 mg of ibmolexan mesylate. In some embodiments, a tablet or minitablet having a drug loading of 85 wt% contains about 10.36 mg of ibmolexan mesylate.

[0044] The pharmaceutical solid forms of the present disclosure can be any suitable form known in the art. In some embodiments, the pharmaceutical solid form can be designed in any shape as needed, including tablets, sprays or beads. In some embodiments, the pharmaceutical solid form is a tablet. In some embodiments, the tablet is a minitablet. In some embodiments, the tablet or minitablet is not prepared by wet granulation. In some embodiments, the solid form or minitablet is prepared by roller compaction on the drug particles. In some embodiments, the pharmaceutical solid form is beads or a plurality of beads. In some embodiments, the pharmaceutical solid form can be orally administered by mixing with soft foods (such as applesauce, pudding, yogurt, etc.).

[0045] In one specific embodiment, the solid form is prepared after roller compaction and pressed into the form of a minitablet. The minitablet form can then be further incorporated into additional dosage forms (such as capsules) or directly administered to the subject as one or more minitablets according to the drug dosage required by the subject.

[0046] In some embodiments, the pharmaceutical solid form is a tablet having a diameter less than or equal to about 5 mm, such as 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 tablet has a diameter in the range of about 1 mm to about 5 mm, such as 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, and about 4.9 mm (including all values and subranges therebetween). In some embodiments, the tablet has a diameter of less than about 3 mm and is referred to as a mini-tablet. In some embodiments, the tablet has a diameter of less than about 2.5 mm and is referred to as a mini-tablet. In some embodiments, the mini-tablet has a diameter in the range of about 2 mm to about 3 mm. In some embodiments, the mini-tablet has a diameter of 2 mm. In some embodiments, the mini-tablet has a diameter of 2.5 mm. In some embodiments, the mini-tablet has a diameter of 2 mm. The tablets and mini-tablets disclosed herein can have any shape convenient to those skilled in the art, such as spherical, circular, oval, and triangular. In some embodiments, the tablet is circular, oval, or triangular. In some embodiments, the tablet is circular. In some embodiments, the tablet is circular and convex. In some embodiments, the tablet is circular and concave.

[0047] In some embodiments, the tablets disclosed herein are compression tablets, which can be compressed by a tablet press (rotary or single punch) or any other technique known in the art. In some embodiments, the tablet contains the pharmaceutical granules disclosed herein. In some embodiments, the compression tablet contains pharmaceutical granules and one or more extra-granular pharmaceutical excipients. In some embodiments, the compression tablet contains pharmaceutical granules and extra-granular binder, disintegrant, and lubricant. In some embodiments, the compression tablet contains pharmaceutical granules and extra-granular disintegrant, lubricant, and an optional binder. In some embodiments, the tablet is compressed from the pharmaceutical granules disclosed herein and extra-granular binder, disintegrant, and / or lubricant processed by roller compaction together.

[0048] In some embodiments, one or more extragranular pharmaceutical excipients include binders, disintegrants, and lubricants. In some embodiments, the amount of the binder ranges from about 1% w / w to about 5% 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, each based on the weight of the tablet. In some embodiments, the amount of the binder ranges from about 2% w / w to about 4% w / w, the amount of the disintegrant ranges from about 2.5% w / w to about 3.5% w / w, and the amount of the lubricant ranges from about 0.25% w / w to about 1.0% w / w, each based on the weight of the tablet.

[0049] Suitable binders for extragranular materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrin, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums such as gum arabic, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, etc.), and Veegum, and combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and crospovidone. In some embodiments, the binder is pregelatinized starch.

[0050] Suitable disintegrants for extragranular materials include, but are not limited to, starches, clays, celluloses, algins, gums, or crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, etc. In some embodiments, one or more disintegrants are lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modified starch, sodium carboxymethyl starch crosslinked, crosslinked polyvinylpyrrolidone, sodium starch glycolate, or combinations and mixtures thereof. In some embodiments, the disintegrant is sodium carboxymethyl starch crosslinked.

[0051] Suitable lubricants for extragranular materials include, but are not limited to, magnesium stearate, calcium stearate, talc, colloidal silica, etc. In some embodiments, the lubricant includes stearic acid and / or a stearate salt, such as magnesium stearate. In some embodiments, the lubricant is magnesium stearate.

[0052] In some embodiments, the binder is pregelatinized starch, the disintegrant is sodium carboxymethyl starch crosslinked, and the lubricant is magnesium stearate.

[0053] In some embodiments, the present disclosure provides a pharmaceutical tablet (e.g., a compressed pharmaceutical tablet or a compressed pharmaceutical microtablet), the pharmaceutical tablet comprising drug-containing granules, the drug-containing granules comprising from about 10 wt% to about 90 wt% ibmolexan tosylate, from about 2 wt% to about 50 wt% binder; from about 1 wt% to about 35 wt% filler, from about 0.5 wt% to about 5 wt% disintegrant and from about 0.1 wt% to about 1 wt% lubricant; wherein when compressed using a tablet press with a tool smaller than 3 mm, the tablet has a friability of less than 1% and a hardness of greater than about 0.7 Kp.

[0054] In some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0055] In some embodiments, the present disclosure provides tablets having a composition with a drug loading (DL) of 10% to 90% according to the following table:

[0056]

[0057] * Removed during processing, not found in the final product

[0058] Tablets should have sufficient hardness and low friability to ensure the strength and structural integrity of the tablets during packaging, transportation, and final use. However, when compressing small tablets and microtablets (e.g., those with a diameter less than 5 mm), especially when the drug-containing granules being compressed contain a high drug loading level (e.g., ≥50 wt% ibmolexan tosylate), it can be challenging to maintain sufficient hardness and friability. As described herein, it has surprisingly been found that compared to uncompacted granules, even when the drug loading level exceeds 50 wt%, the roll-compounded blend of drug-containing granules exhibits an increased proportion of large granules (e.g., granules retained on 40, 60, and 80 mesh sieves), increased blend densification, and improved flowability. These surprising and unexpected properties enable the roll-compounded blend of drug-containing granules to provide sufficient hardness and low friability when compressed into small tablets and microtablets (comprising from about 10 wt% to about 90 wt% ibmolexan tosylate).

[0059] The ability to prepare small tablets and microtablets is important for improving compliance and providing flexible dosing regimens for treating children from 2 to 20 years old as disclosed herein.

[0060] In some embodiments, the tablets disclosed herein have a hardness greater than 0.7 Kp when compressed at a compression force of less than or equal to 25 kN, less than or equal to 20 kN, less than or equal to 15 kN, or less than or equal to 10 kN. In some embodiments, the tablets have a hardness greater than 1.5 Kp when compressed at a compression force of less than or equal to 25 kN, less than or equal to 20 kN, less than or equal to 15 kN, or less than or equal to 10 kN. In some embodiments, the tablets have a hardness greater than 3.0 Kp when compressed at a compression force of less than or equal to 25 kN, less than or equal to 20 kN, less than or equal to 15 kN, or less than or equal to 10 kN. In some embodiments, the tablets have a hardness of from about 0.5 kP to about 6 kP, such as 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 loading in the tablets is from about 70 wt% to about 90 wt% of the tablets, and when prepared using a 2.5 mm compression tool, the tablets have a hardness of from about 3.2 kP to about 5.5 kP. In some embodiments, the drug loading in the tablets is about 90 wt% of the tablets, and when prepared using a 2.5 mm compression tool, the tablets have a hardness of from about 4.5 kP to about 5.5 kP. In some embodiments, the drug loading in the tablets is about 70 wt% of the tablets, and when prepared using a 2.5 mm compression tool, the tablets have a hardness of from about 3.2 kP to about 4.2 kP. In some embodiments, the drug loading in the tablets is about 50 wt% of the tablets, and when prepared using a 2.5 mm compression tool, the tablets have a hardness of from about 1.5 kP to about 2.5 kP. In some embodiments, the drug loading in the tablets is about 30 wt% of the tablets, and when prepared using a 2.5 mm compression tool, the tablets have a hardness of from about 1.0 kP to about 2.0 kP. 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 carried out using a tablet press.

[0061] 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%.

[0062] The pharmaceutical tablets (e.g., minitablets) of the present disclosure can be uncoated or coated with one or more coatings. In some embodiments, the coating comprises E PO, E 100, E 12,5 or amb II. In some embodiments, the coating comprises an amb II film coating, which is a polyethylene glycol (PEG)-free polyvinyl alcohol (PVA)-based coating. In some embodiments, the coating comprises E PO, which is a functional copolymer comprising dimethylaminoethyl methacrylate, methacrylate and butyl methacrylate monomers. In some embodiments, the coating applied to the tablet or microtablet 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 to obtain a weight gain of about 1% to about 30%, such as 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) based on the total weight (dry polymer weight) of the drug solid form. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 5% to about 25%. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 8% to about 20%, such as about 8%, about 10%, about 12%, about 16% or about 20% (including all values and subranges therebetween) based on the total weight of the drug solid form. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 8%. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 10%. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 12%. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 16%. In some embodiments, the coating is applied to the tablet to obtain a weight gain of about 20%. The coating can be applied by any known method in the art, including spraying one or more polymers on top of the above-mentioned tablets or microtablets. In some embodiments, a fluidized bed coater or an improved coating pan is used to apply the coating.

[0063] In some embodiments, the drug solid form of the present disclosure comprises drug-containing particles or drug particles as described below. In some embodiments, the drug solid form is a tablet comprising drug-containing particles or drug particles as described below. In some embodiments, the tablet is a microtablet comprising drug-containing particles or drug particles as described below. In some embodiments, the tablet or microtablet is not prepared by wet granulation or direct compression. In some embodiments, the solid form or microtablet is prepared by roller compaction on the drug particles or drug-containing particles as described below.

[0064] The drug-containing particles of the present disclosure

[0065] In some embodiments, the pharmaceutical solid forms disclosed herein comprise drug-containing granules or drug particles. In some embodiments, the drug-containing granules comprise ibmoleucine or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-containing granules comprise ibmoleucine or a pharmaceutically acceptable salt thereof and one or more of the pharmaceutical excipients disclosed herein. In some embodiments, the drug-containing granules comprise ibmoleucine or a pharmaceutically acceptable salt thereof; and a binder, a filler, a disintegrant, and / or a lubricant. In some embodiments, the ibmoleucine salt is ibmoleucine mesylate. In some embodiments, the drug-containing granules are roll-compressed drug-containing granules.

[0066] 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.

[0067] In some embodiments, the drug-containing granules of the present disclosure have a tapped 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 subranges therebetween). In some embodiments, the drug-containing granules have a tapped density of less than 0.75 g / cc. In some embodiments, the drug-containing granules have a tapped density of less than 0.6 g / cc

[0068] 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.

[0069] The flow characteristics of the drug-containing granules can be estimated by calculating the Hauser ratio, which, as used herein, is the ratio of the tapped density to the bulk density. In some embodiments, the roller-compressed drug-containing granules have a Hauser ratio of from about 1.0 to about 1.4. In some embodiments, the roller-compressed drug-containing granules have a Hauser ratio of from about 1.15 to about 1.4. In some embodiments, the roller-compressed drug-containing granules have a Hauser ratio of from about 1.0 to about 1.25. In some embodiments, the roller-compressed drug-containing granules have a Hauser ratio of from about 1.0 to about 1.2. In some embodiments, for example, when the drug loading of ibupomeren mesylate is from about 60 wt% to about 90 wt% of the solid form of the drug, the roller-compressed drug-containing granules have a Hauser ratio of from about 1.15 to about 1.25. In some embodiments, for example, when the drug loading of ibupomeren mesylate is about 90 wt% of the solid form of the drug, the roller-compressed drug-containing granules have a Hauser ratio of about 1.20. The correlation between flowability and the Hauser ratio is provided in Table 3 below.

[0070] The compressibility of the drug-containing granules can be estimated by calculating Carr's index using the following formula: where ρ B is the bulk density of the freely settling granules, and ρ T is the tapped density of the granules.

[0071] In some embodiments, the roller-compressed drug-containing granules have a Carr's index of from about 10% to about 30%. In some embodiments, the roller-compressed drug-containing granules have a Carr's index of from about 15% to about 30%. In some embodiments, the roller-compressed drug-containing granules have a Carr's index of from about 10% to about 20%. In some embodiments, the roller-compressed drug-containing granules have a Carr's index of from about 15% to about 20%. In some embodiments, when the drug loading of ibupomeren mesylate is from about 70 wt% to about 90 wt% of the solid form of the drug, the roller-compressed drug-containing granules have a Carr's index of from about 15% to about 20%. In some embodiments, when the drug loading of ibupomeren mesylate is about 90 wt% of the solid form of the drug, the roller-compressed drug-containing granules have a Carr's index of about 16%. The correlation between compressibility and Carr's index is provided in Table 3 below.

[0072] Without being bound by any particular theory, it has surprisingly and unexpectedly been found that, compared to the pre-compression blend (e.g., Figure 1 the initial blend), the roller-compressed blend of drug-loaded granules containing 10 wt% to 90 wt% of ibupomeren mesylate has unique and beneficial properties. In particular, it has been found that the roller-compressed blend (e.g., Figure 1The drug particles produced by the RC milling blend) have low densification and large particle size, including lower densification and larger particle size as the drug loading level in the particles increases. (Tables 2A and 2B).

[0073] This finding is contrary to expectations. For example, when the drug loading increases, generally the particles become less dense and the particle size of the particles decreases. As the particle size decreases (a large number of fine particles), the drug particles become more difficult to press, i.e., into tablets or microtablets, and thus have the desired drug tablet properties such as hardness and friability required for tablet storage and transportation in the pharmaceutical field.

[0074] Different from the prior art, the particles of the present invention allow high drug loading and large particle size, and thus are easy to press into tablets with the desired hardness and friability. The present invention finds that compared with the blend before compaction, all the drug-loaded particles processed by roller compaction show an increased percentage of larger particles (Tables 2A and 2B). Unexpectedly and necessarily, for the particles loaded with about 70 wt% to about 90 wt% of ibuprofen mesylate, the transformation of the particle size distribution (PSD) to larger particles is the most obvious, which has a D50 greater than 400 μm, in contrast, the drug-containing particles before compaction at these drug loading levels have a D50 of about 170 μm.

[0075] The combination of the unexpected increase in densification and the transformation to a larger PSD (especially at high drug loading levels) provides improved material fluidity and enables the pressing of small tablets and microtablets containing ≥50 wt% or ≥70 wt% of ibuprofen mesylate, while it has been challenging to prepare small tablets and microtablets with suitable properties before. In fact, for high drug loading and easily pressable tablets, one embodiment of the present invention is a solid drug form (such as a microtablet) containing at least 10 wt%, at least 20 wt%, at least 30 wt%, at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt% or at least 90 wt% of the drug amount of ibuprofen mesylate, in combination with a solid drug form such as a tablet where the tablet weight is less than about 30 mg, 20 mg, 15 mg or 12 mg.

[0076] In some embodiments, the solid drug form contains drug-containing particles with a D50 greater than about 175 μm. In some embodiments, when ibuprofen or a pharmaceutically acceptable salt thereof is present in an amount greater than 50 wt% of the solid dosage form, the drug-containing particles have a D50 greater than about 175 μm.

[0077] In some embodiments, the pharmaceutical solid form comprises drug-containing particles having a D50 greater than about 400 μm. In some embodiments, the drug-containing particles have a D50 greater than about 400 μm when ibmolex or a pharmaceutically acceptable salt thereof is present in an amount greater than 70% by weight of the solid dosage form. In some embodiments, the drug-containing particles have a D50 greater than about 400 μm when ibmolex or a pharmaceutically acceptable salt thereof is present in an amount in the range of about 70% to about 90% by weight of the solid dosage form.

[0078] In some embodiments, the drug-containing particles are compacted drug-containing particles. In some embodiments, the D50 of the compacted drug-containing particles is at least about 1.5 times that of the uncompacted drug particles having the same composition. In some embodiments, the D50 of the compacted drug-containing particles is at least about 2 times that of the uncompacted drug particles having the same composition. In some embodiments, the D50 of the compacted drug-containing particles is at least about 2.5 times that of the uncompacted drug particles having the same composition.

[0079] In some embodiments, the drug-containing particles comprise ibmolex or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is mesylate.

[0080] In some embodiments, the drug-containing particles further comprise one or more binders, fillers, and / or lubricants. In some embodiments, the drug-containing particles further comprise binders, fillers, and lubricants.

[0081] In some embodiments, the drug-containing particles comprise an amount of binder in the range of about 2% w / w to about 60% w / w, an amount of filler in the range of about 1% w / w to about 40% w / w, an amount of disintegrant in the range of about 1% w / w to about 5% w / w, and an amount of lubricant in the range of about 0.5% w / w to about 2% w / w.

[0082] In some embodiments, the drug-containing particles comprise an amount of binder in the range of about 2% w / w to about 30% w / w, an amount of filler in the range of about 1% w / w to about 20% w / w, an amount of disintegrant in the range of about 1% w / w to about 2% w / w, and an amount of lubricant in the range of about 0.5% w / w to about 1.5% w / w.

[0083] Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums such as gum arabic, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, etc.), and Veegum, and combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and cross-linked polyvinylpyrrolidone.

[0084] Fillers (which may also be referred to as diluents) include materials such as, for example, silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, and sugars or combinations thereof. Any suitable sugar can be used in the compositions of the present invention. As used herein, "sugars" used in the present invention include sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitols, and hexitols. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldoses, and ketoses. Exemplary disaccharides include, but are not limited to, sucrose, isomaltulose, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, fructooligosaccharides, inulin, galactooligosaccharides, and mannanooligosaccharides. In some embodiments, the sugar is sorbitol, mannitol, or xylitol. In some embodiments, the sugar is mannitol.

[0085] Disintegrants include, but are not limited to, starches, clays, celluloses, alginates, gums, or cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, etc. In some embodiments, one or more disintegrants are lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modified starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, or combinations and mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0086] Suitable lubricants for the solid pharmaceutical forms of the present disclosure include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. In some embodiments, the lubricant includes stearic acid and / or stearates, such as magnesium stearate. In some embodiments, the solid pharmaceutical form (e.g., microtablets) contains from about 0.1% to 5% of the lubricant, such as 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% based on the total weight of the solid pharmaceutical form, including all values and subranges therebetween.

[0087] In some embodiments, the drug-containing granules comprise a binder, a filler, a disintegrant, and a lubricant. In some embodiments, the binder is pre-gelatinized starch, the filler is mannitol, the disintegrant is sodium carboxymethylcellulose cross-linked, and the lubricant is magnesium stearate.

[0088] In some embodiments, the drug-containing granules are processed by roller compaction, such as by the manufacturing parameters disclosed herein.

[0089] Pharmaceutical composition

[0090] Mini-tablets, beads, and spray-dried formulations prepared according to the roller compaction manufacturing methods described herein provide significant advantages, including dosing flexibility and patient compliance in treating pediatric patient populations with GH deficiency. For example, due to the small size of the compressed tablets containing from about 10 wt% to about 90 wt% ibomolen mesylate that can be prepared by the roller compaction methods disclosed herein, compositions (e.g., capsules, sachets, etc.) with different doses of ibomolen can be provided, which increases dosing flexibility (e.g., in children across a wide weight range) and compliance, and ultimately results in more beneficial outcomes in treating pediatric patient populations.

[0091] Thus, in some embodiments, the pharmaceutical compositions disclosed herein comprise a plurality of microtablets, e.g., in the range of 1 to 30 microtablets, such as 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 microtablets, including all sub-ranges therebetween. In some embodiments, the microtablets are contained in a capsule or sachet for oral administration. In some embodiments, the microtablets 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 microtablets, such as 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 microtablets, including all sub-ranges therebetween. In some embodiments, the capsule contains 3 to 12 microtablets, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 microtablets, including all sub-ranges therebetween. In some embodiments, the capsule contains 3, 4, or 12 microtablets. In some embodiments, the capsule contains 3 microtablets. In some embodiments, the capsule contains 4 microtablets. In some embodiments, the capsule contains 5 microtablets. In some embodiments, the capsule contains 6 microtablets. In some embodiments, the capsule contains 7 microtablets. In some embodiments, the capsule contains 8 microtablets. In some embodiments, the capsule contains 9 microtablets. In some embodiments, the capsule contains 10 microtablets. In some embodiments, the capsule contains 11 microtablets. In some embodiments, the capsule contains 12 microtablets.

[0092] In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 10% by weight of ibmoximod mesylate of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 20% by weight of ibmoximod mesylate of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 30% by weight of ibmoximod mesylate of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 50% by weight of ibmoximod mesylate of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 70% by weight of ibmoximod mesylate of the tablet. In some embodiments, the capsules disclosed herein contain 3 to 12 microtablets, and each microtablet comprises 90% by weight of ibmoximod mesylate of the tablet.

[0093] The pharmaceutical compositions disclosed herein may comprise a plurality of sprays. For example, 100 or more sprays may be incorporated into the pharmaceutical composition. In another embodiment, the amount of sprays in the pharmaceutical composition may range from 10 to 50 sprays, 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 sprays, including all sub-ranges therebetween. In some embodiments, the sprays are contained in a capsule or sachet for oral administration. In some embodiments, the sprays are contained in a capsule for oral administration. In some embodiments, when the sprays are contained in a capsule, the capsule is opened and the sprays 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 10 to 50 sprays, 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 sprays, including all sub-ranges therebetween.

[0094] In a specific embodiment, the pharmaceutical compositions described herein may be included in the form of a kit. In a specific embodiment, the kit may comprise one or more solid forms of the drug and / or one or more pharmaceutical compositions. In a specific embodiment, the kit may include one or more tablets in a capsule.

[0095] In another embodiment, the solid form of the drug and / or one or more pharmaceutical compositions comprise a dose of ibmuran mesylate in the 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 contains a capsule, and the capsule contains one or more tablets with a dose of ibmuran mesylate in the 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 contains at least one capsule, and the capsule contains 1 - 6 tablets with a dose of ibmuran mesylate in the range of about 4 mg to about 6 mg; and / or at least one capsule, and the capsule has 2 to 12 tablets with a dose of ibmuran mesylate in the range of about 6 mg to about 8 mg; and / or at least one capsule, and the capsule has 2 to 10 tablets with a dose of ibmuran mesylate in the range of about 9 mg to about 11 mg.

[0096] Therapeutic method

[0097] Methods for treating pediatric growth hormone (GH) deficiency 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 entirety. However, in addition to the need to improve efficacy, there remain challenges with dosing flexibility and patient compliance in the pediatric patient population in need of treatment.

[0098] As described above, pharmaceutical compositions comprising the disclosed pharmaceutical compositions (e.g., microtablets, beads, and spray formulations) prepared according to the roller compaction manufacturing method described herein provide significant advantages in treating growth hormone deficiency in pediatric patients.

[0099] Accordingly, in some embodiments, the present disclosure provides methods for treating growth hormone deficiency, the methods comprising administering to a subject in need thereof one or more of the pharmaceutical solid forms or pharmaceutical compositions disclosed herein.

[0100] In some embodiments, the subject is a human subject. In some embodiments, the subject is a human subject from 0 to 20 years old, such as 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 old. In some embodiments, the subject is a human subject from 2 to 20 years old. In some embodiments, the subject is a human subject from 3 to 13 years old. In some embodiments, the human subject is an infant, i.e., a child from 0 to 1 year old.

[0101] In some embodiments, the one or more solid pharmaceutical forms or compositions are administered orally once daily (qd).

[0102] In some embodiments, the present disclosure provides a method for treating growth hormone deficiency (GHD) in a child, the method comprising administering to a child known to be short of stature and having sufficient GH secretion potential a therapeutically effective amount of one or more of the pharmaceutical forms or pharmaceutical compositions disclosed herein.

[0103] In some embodiments, the child is a child with severe GH deficiency as identified by the inability to increase peak GH to >5 μg / L and / or by having a baseline IGF-I of <30 μg / L.

[0104] In some embodiments, the present disclosure provides a method of treating growth hormone deficiency (GHD) in children, the method comprising: administering to a child known to have short stature and having growth potential comparable to rhGH, a therapeutically effective amount of one or more solid pharmaceutical forms (such as minitablets) or pharmaceutical compositions (such as capsules) disclosed herein, wherein the child has growth potential comparable to rhGH when the child: (i.) has a peak serum GH of ≧5 μg / L in response to a single oral dose of ibmolexate mesylate; and (ii.) has a baseline serum IGF-I of >30 ng / mL.

[0105] In some embodiments, the child is known to have growth retardation. In some embodiments, the child has growth potential comparable to recombinant growth hormone (rhGH).

[0106] In some embodiments, the child is prepubertal. In some embodiments, the child is peripubertal.

[0107] In some embodiments, the treatment is maintained for more than 6 months. For example, treatment according to the disclosed method 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 examples include treatment for at least 2.5, 3, 3.5, 4, 4.5, 5 years or until growth potential is exhausted.

[0108] In one embodiment of the invention, the method comprises administering to a subject in need thereof one or more of the solid pharmaceutical forms disclosed herein or the pharmaceutical compositions described herein.

[0109] As described above, the solid pharmaceutical forms herein provide advantageous tablet and pharmaceutical dosage form properties. The pharmaceutical granules of the invention can be compressed, i.e., pressed into tablets or minitablets, having the desired pharmaceutical tablet properties and having a high ibmolexate mesylate drug loading. In fact, for tablets with high drug loading and easy compressibility, one embodiment of the invention further comprises a method of administering a solid pharmaceutical form (such as a minitablet) comprising at least 10 wt%, at least 20 wt%, at least 30 wt%, at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt% or at least 90 wt% of the amount of ibmolexate mesylate drug, wherein the weight of the solid pharmaceutical form such as a tablet is also less than about 30 mg, 20 mg, 15 mg or 12 mg.

[0110] The combination of high drug loading and small tablet size allows for compliance in the pediatric patient population and flexibility in administering ibmolexan mesylate to pediatric patients with a wide range of possible weights. Thus, one embodiment of the present invention allows for a pharmaceutical dosage form, such as a solid dosage form and a tablet (such as a microtablet), to have different doses that can be mixed and matched to be administered to pediatric patients of any weight (such as the weight of a 2-year-old or an 18-year-old). In one embodiment, the method may include dosage forms containing various doses in different tablets or microtablets. In another embodiment, the various doses may be in different capsules, where the capsules contain tablets or microtablets of the same or different doses.

[0111] In a specific embodiment, each pharmaceutical solid form or tablet contains from about 1 mg to about 15 mg of ibmolexan mesylate, or from about 3 mg to about 15 mg of ibmolexan mesylate, or from about 4 mg to about 6 mg of ibmolexan mesylate, or from about 6 mg to about 8 mg of ibmolexan mesylate, or from about 9 mg to about 11 mg of ibmolexan mesylate. In a specific embodiment, each pharmaceutical solid form 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 ibmolexan mesylate.

[0112] In another embodiment, more than one solid pharmaceutical form or tablet is administered to a subject. In another specific embodiment, more than one solid pharmaceutical form or tablet can be freely administered, such as mixed in food or administered directly to the subject without food. In another embodiment, more than one solid pharmaceutical form or tablet can be administered in a dosage form that encapsulates the solid pharmaceutical form or tablet. In a specific embodiment, the dosage form can be a capsule. In a specific embodiment, 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.

[0113] In another embodiment, more than one solid pharmaceutical form or tablet can be administered based on the drug loading of the solid pharmaceutical form or tablet and the weight of the subject, for example, as provided in Table 6.

[0114] In a specific embodiment, the solid pharmaceutical form or tablet can be administered to the subject once, twice, three times, four times, five times, or six times a day.

[0115] In a specific embodiment, the solid pharmaceutical form or tablet is administered to the subject once daily. In another embodiment, the total daily dose of ibmoleucine mesylate administered to the subject is in the range of about 8 mg to about 120 mg, about 10 mg to about 100 mg, about 20 mg to about 75 mg, about 30 mg to about 60 mg, and about 40 mg to about 50 mg.

[0116] In a specific embodiment, the therapeutic dose administered to the subject is in the range of about 0.1 mg dose / kg subject body weight / day to about 4.0 mg dose / kg subject body weight / day or about 0.6 mg dose / kg subject body weight / day to about 3.5 mg dose / kg subject body weight / day. In another embodiment, the therapeutic dose is in the range of about 0.8 mg / kg / day to about 3.2 mg / kg / day of ibmoleucine mesylate, or the amount is 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 2.0 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.

[0117] In some embodiments, ibmoleucine mesylate is administered to a subject at about 0.8 mg / kg / day to about 3.2 mg / kg / day, such as 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 2.0 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, including all values and subranges therebetween. In some embodiments, ibmoleucine mesylate is administered to a subject at about 0.8 mg / kg / day, about 1.6 mg / kg / day, about 2.4 mg / kg / day or 3.2 mg / kg / day. In some embodiments, ibmoleucine mesylate is administered to a subject at about 0.8 mg / kg / day. In some embodiments, ibmoleucine mesylate is administered to a subject at about 1.6 mg / kg / day. In some embodiments, ibmoleucine mesylate is administered to a subject at about 3.2 mg / kg / day.

[0118] In some embodiments, ibmoleucine mesylate is administered to a subject at about 0.1 mg / kg / day to about 1.5 mg / kg / day, such as 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, ibmoleucine mesylate is administered to a subject at about 0.6 mg / kg / day to about 1.0 mg / kg / day. In some embodiments, ibmoleucine mesylate is administered to a subject at about 0.8 mg / kg / day.

[0119] In some embodiments, one or two capsules are administered to a subject in a day based on body weight, and each capsule contains up to 12 micropills. In some embodiments, one or two capsules are administered to a subject in a day based on body weight, and each capsule contains 2 to 12 micropills. In some embodiments, one or two capsules are administered to a subject in a day based on body weight, and each capsule contains up to 10 micropills. In some embodiments, one or two capsules are administered to a subject in a day based on body weight, and each capsule contains 2 to 10 micropills.

[0120] In some embodiments, a dose of 0.8 mg / kg / day of ibmolexan mesylate is provided by administering 2 to 12 micropills / day to a subject, wherein each micropill is a 50% drug-loaded micropill containing approximately 4.7 mg of ibmolexan mesylate. In some embodiments, the dose is administered via 1 or 2 capsules, each capsule containing 2, 3, or 6 micropills.

[0121] In some embodiments, a dose of 0.8 mg / kg / day of ibmolexan mesylate is provided by administering up to 2 capsules / day to a subject, the capsules containing 2, 3, or 6 micropills, wherein each micropill is a 50% drug-loaded micropill containing approximately 4.7 mg of ibmolexan mesylate.

[0122] In some embodiments, a dose of 1.6 mg / kg / day of ibmolexan mesylate is provided by administering 3 to 16 micropills / day to a subject, wherein each micropill is a 70% drug-loaded micropill containing approximately 7.11 mg of ibmolexan mesylate. In some embodiments, the dose is administered via 1 or 2 capsules, each capsule containing 3, 4, or 12 micropills.

[0123] In some embodiments, a dose of 1.6 mg / kg / day of ibmolexan mesylate is provided by administering up to 2 capsules / day to a subject, the capsules containing 3, 4, or 12 micropills, wherein each micropill is a 70% drug-loaded micropill containing approximately 7.11 mg of ibmolexan mesylate.

[0124] In some embodiments, a dose of 3.2 mg / kg / day of ibmolexan mesylate is provided by administering 3 to 20 micropills / day to a subject, wherein each micropill is an 85% drug-loaded micropill containing approximately 10.36 mg of ibmolexan mesylate. In some embodiments, the dose is administered via 1 or 2 capsules, each capsule containing 3, 4, or 10 micropills.

[0125] In some embodiments, a dose of 3.2 mg / kg / day of ibmolexan mesylate is provided by administering up to 2 capsules / day to a subject, the capsules containing 3, 4, or 10 mini-tablets, where each mini-tablet is an 85% drug-loaded mini-tablet containing approximately 10.36 mg of ibmolexan mesylate.

[0126] In some embodiments, the subject to be treated has never been treated with growth hormone (treatment-naive). In some embodiments, the subject or child to be treated may have received interrupted prior GH treatment, provided that the child meets the criteria for sufficient GH secretory potential as determined above.

[0127] In some embodiments, the present disclosure provides a method for treating a disease or disorder associated with abnormal reduction of growth hormone (GH) secretion in a subject having sufficient GH secretory potential, the method comprising administering to the subject one or more of the pharmaceutical solid forms disclosed herein or the pharmaceutical compositions disclosed herein.

[0128] In some embodiments, treating the disease or disorder comprises increasing endogenous GH secretion in the subject.

[0129] In some embodiments, the disease or disorder is Turner syndrome, pediatric 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).

[0130] In some embodiments, the muscle wasting disease is sarcopenia, cachexia, hypothalamic amenorrhea, or relative energy deficiency in sport (RED-S) syndrome.

[0131] Preparation method

[0132] The present disclosure also provides methods for preparing the pharmaceutical solid forms and their compositions disclosed herein.

[0133] In some embodiments, the present disclosure provides compressed pharmaceutical tablets prepared by the following steps:

[0134] (a) blending a mixture of ibmolexan or a pharmaceutically acceptable salt thereof with a first portion of binder, filler, disintegrant, and lubricant;

[0135] (b) compacting the blended mixture of step (a) using a roller press to form a compacted material;

[0136] (c) Screening the compacted material of step (b) through one or more sieving steps to produce drug-containing particles;

[0137] (d) Blending the drug-containing particles of step (c) with the disintegrant, lubricant, and binder of the second portion to provide a final mixture;

[0138] (e) Compressing the final blend of step (d) into compressed tablets; and

[0139] (f) Optionally coating the compressed tablets with a coating described herein (e.g., E PO).

[0140] In some embodiments, the ibmolex salt is ibmolex mesylate.

[0141] The binder, filler, disintegrant, and lubricant can be any of the options described herein in any amount or range disclosed. In some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0142] In some embodiments, the blending of step (a) is carried out for about 1 minute to about 30 minutes. In some embodiments, the blending of step (a) is carried out for about 5 minutes to about 15 minutes. In some embodiments, the blending is carried out in a mixer (e.g., a V-type mixer).

[0143] The roll press of step (b) can be operated at any suitable screw speed, roll speed, and compaction pressure sufficient to prepare the 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, model, and composition of the blend mixture. In some embodiments, the roll press of step (b) operates at a screw feeder speed of about 20 rpm to about 60 rpm, a roll 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 roll press of step (b) operates at a screw feeder speed of about 40 rpm, a roll speed of about 6 rpm, and a compaction pressure of about 20 bar. In some embodiments, the roll press includes a granulator operating between 75 rpm and 125 rpm. In some embodiments, the granulator operates at about 95 rpm.

[0144] In some embodiments, the binder of the first portion is about 25 wt% to about 75 wt% of the total amount of binder added. In some embodiments, the lubricant of the first portion is about 25% to about 75% of the total amount of lubricant added. In some embodiments, the binder of the first portion is about 50 wt% of the total amount of binder added. In some embodiments, the lubricant of the first portion is about 50% of the total amount of lubricant added.

[0145] In some embodiments, one or more of the binder, filler, disintegrant, and lubricant in step (a) are sieved through a wire mesh screen prior to roller compaction. In some embodiments, the screen is a 20-mesh or 40-mesh screen.

[0146] In some embodiments, the screening in step (c) includes screening the roller-compacted material through a coarse screen and / or a fine screen. In some embodiments, the screening in step (c) includes 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 coarse screen and the fine screen are mounted on the roller press.

[0147] In some embodiments, prior to the mixing in step (d), one or more of the second portion of the binder, disintegrant, and lubricant are sieved through a wire mesh screen. In some embodiments, the screen is a 20-mesh or 40-mesh screen.

[0148] In some embodiments, the second portion of the disintegrant is about 50 wt% of the total amount of disintegrant added. In some embodiments, the second portion of the lubricant is about 50% of the total amount of lubricant added.

[0149] Example

[0150] The following examples are provided to illustrate the present disclosure and should not be construed as limiting the invention.

[0151] Example 1: Preparation of Drug-Containing Granules

[0152] Final blends of the drug-containing granules of the present disclosure containing 10 wt%, 20 wt%, 30 wt%, 50 wt%, 70 wt%, 85 wt%, and 90 wt% ibmolexan mesylate were prepared by a manufacturing method including roller compaction (see Figure 1 ) and the process parameters provided in Table 1.

[0153] Table 1. Manufacturing information for test batches of low (10%) to high (90%) drug-containing granules produced by roller compaction.

[0154]

[0155] Example 2: Properties of Drug-Containing Granules

[0156] The density and particle size distribution of the drug-containing granules having 10 wt%, 20 wt%, 30 wt%, 50 wt%, 70 wt%, 85 wt%, and 90 wt% ibmolexan mesylate prepared as described in Example 1 were compared by sieve analysis (Tables 2A and 2B). In the following table, the initial blend before roller compaction (before RC) is compared with the milled blend after roller compaction (seeFigure 1 ) were compared, and the roll-compacted and then milled blend is also referred to hereinafter as RC post.

[0157] Table 2A. Comparison of density and sieving analysis of drug-loaded granules containing 10% to 30% ibuprofen mesylate.

[0158]

[0159] Table 2B. Comparison of density and sieving analysis of drug-loaded granules containing 50% to 90% ibuprofen mesylate.

[0160]

[0161] As shown in Table 2A and Table 2B, the drug-loaded granules produced by roll compaction showed significant compaction with increasing drug loading. The overall trend observed was that with increasing ibuprofen mesylate drug loading, densification decreased. However, the particle size distribution (PSD) of the RC post blend shifted to larger particle sizes relative to the pre-RC blend.

[0162] Table 3 lists the calculations of the Hausner ratio and Carr index used to estimate the flowability and compressibility indices of the powder blend / granules. Table 4 lists the guidelines for the characterization of powder blend / granule flowability.

[0163] Table 3. Hausner ratio and Carr index data for ibuprofen mesylate powder blend / granules

[0164] Hausner ratio (after roller compaction) Carr index % (after roller compaction) 10% DL (NB1787:45) 1.38 27.4 20% DL (NB1787:29) 1.30 23.1 30% DL (NB1787:54) 1.35 26.2 50% DL (NB1787:37) 1.36 26.6 70% DL (NB1787:62) 1.24 19.6 85% DL (NB1787:72) 1.25 20.0 90% DL (NB1787:01) 1.19 15.8

[0165] Table 4. Guidelines for the characterization of powder flow characteristics for compaction.

[0166] Flow properties Hausner ratio Carr index (%) Excellent / very free flow 1.00-1.11 ≤10 Good / free flow 1.12-1.18 11-15 Fair 1.19-1.25 16-20 Passable 1.26-1.34 21-25 Poor / sticky 1.35-1.45 26-31 Very poor / very sticky 1.45-1.59 32-37 Very, very poor / nearly non-flowing ＞1.60 ＞38

[0167] The above data indicate that ibmoleucine mesylate exhibits unique compaction characteristics at both low (10%) and high (90%) drug loadings, resulting in roller-compacted granule / powder blends with suitable sieve analysis (particle size distribution) and density (bulk and tapped) for compaction. For all drug-loaded formulations, the roller compaction process showed an increase in the amount of large particles (i.e., particles retained on 40, 60, and 80 mesh sieves) compared to before roller compaction, accompanied by densification of the blend (increase in bulk density). Without being bound by any particular theory, controlling the particle size distribution and avoiding a large amount of fines is important for minimizing the segregation of powders with suitable flow during the compaction process. The density measurements of the particles before and after roller compaction were measured according to USP <616>. In all cases, densification of the blend was noted, however, as the drug loading increased, the densification decreased (90% < 85% < 70% < 50% < 30% < 20% < 10%), and as the drug loading increased, the blend exhibited improved flowability and compressibility characteristics.

[0168] Example 3: Preparation of Compressed Tablets

[0169] The final blend of drug-containing granules and extra-granular excipients (binders, disintegrants, and / or lubricants) described above and Figure 1 was compressed into tablets using a rotary tablet press. Tablets were prepared by compressing a blend containing drug-containing granules and extra-granular excipients through the center of a die by two punches, which were fitted into the top (upper) and bottom (lower) of the die. Both punches moved between two large wheels (pressure rollers), which pushed the punches together to form tablets with a specific tableting force. The distance between the upper and lower punches and the tableting force determined the thickness and hardness of the tablets while keeping the tablet weight constant.

[0170] Example 4: Properties of Compressed Tablets

[0171] The properties of the tablets produced according to Example 3, including their hardness and percentage friability, are provided in Table 5.

[0172] Table 5. Properties of the Compressed Tablets of the Present Disclosure.

[0173]

[0174] Tablets of each ibmoleucine mesylate drug loading were successfully compressed using a 2.5 mm round tool. All tablet batches exhibited less than 1% friability and hardness in the range of 0.8 kP to 5.2 kP before coating. According to the data, the tablet hardness generally increased as the drug loading increased. After compression, all batches were successfully coated with a 20% weight gain.

[0175] The compacted blend was compressed into tablets using a 2.5 mm tool (see Figure 1)It is not affected by the drug loading of ibmolexan mesylate. All tablets were prepared within the USP weight change limit of 10% and a friability range not exceeding 1.0%. At each drug loading, the tablet hardness was sufficient to withstand the fluidized bed coating process. At each drug loading, a minimum dissolution of not less than (NLT) 85% (Q = 80%) of the minitablets was achieved at 30 minutes.

[0176] Example 5: Efficacy Study in Patients with Growth Hormone (GH) Deficiency in Children

[0177] Overview: A study was conducted to determine whether the minitablets disclosed herein can be used to treat childhood GHD. The disclosed minitablets were compared with rhGH injections according to the following protocol. Bone age was determined using the radiographic matching method of the Greulich and Pyle protocol: Subjects were randomly assigned to receive minitablets providing one of three oral daily doses of ibmolexan mesylate or daily injections of recombinant human growth hormone (rhGH).

[0178] The study included treatment for up to 24 months. Subjects underwent physical examinations, blood, and urine collections to evaluate the response to treatment.

[0179] Participants:

[0180] · Male and female children aged 3 to 12 years diagnosed with idiopathic PGHD by standard diagnostic criteria, with sufficient GH secretory potential.

[0181] · HT-SDS ≤ -2.0 or HT-SDS ≥ 2 SD below the parental mean HT-SDS.

[0182] · Based on growth over at least 6 months, the baseline height growth rate < 5.5 cm / year.

[0183] · Bone age was delayed relative to chronological age by ≥ 6 months.

[0184] · Prepubertal status, as demonstrated by Tanner stage I breast development in girls and testicular volume < 4.0 mL in boys.

[0185] Treatment Groups and Dosing (Table 6):

[0186] · 0.8 mg / kg / day of ibmolexan mesylate administered orally once daily via minitablets

[0187] · 1.6 mg / kg / day of ibmolexan mesylate administered orally once daily via minitablets

[0188] · 3.2 mg / kg / day of ibmolexan mesylate administered orally once daily via minitablets

[0189] · Administer 34 μg / kg / day rhGH (active comparator) subcutaneously once daily

[0190] The primary outcomes included:

[0191] · Annual height velocity (AHV) measured with a stadiometer as standing height

[0192] · AHV measured 6 months after administration of the disclosed microtablets containing ibmolexate mesylate compared to rhGH

[0193] The secondary outcomes may include:

[0194] · Determination of bone age change - measured by X-ray of the left hand and wrist using the Greulich and Pyle atlas

[0195] · Pharmacokinetic evaluation

[0196] · Changes in body weight, body mass index, and other parameters

[0197] · Height standard deviation score (SDS) and height velocity standard deviation score (HV-SDS)

[0198] Conclusion: Subjects diagnosed with GHD and treated with the disclosed microtablets showed improved outcomes at each dose of ibmolexate mesylate administered compared to subjects treated subcutaneously with rhGH, as determined by AHV and other measured parameters.

[0199] Table 6. Summary of dose change calculations and selection of capsule strength – treatment dose based on subject body weight.

[0200]

[0201] Summary

[0202] Overall, high drug-loading formulations are challenging formulations using a roller compaction process. At lower drug loadings, blend properties can be adjusted to improve processability by selecting a suitable amount of appropriate excipients, but at high drug loadings, this selection is limited. Thus, drug substance physical properties that exhibit equivalent blend and tablet properties at low and high drug loadings present challenges that are addressed by the drug solid forms and preparation methods disclosed herein.

[0203] Incorporated by reference

[0204] All publications and patents mentioned herein are hereby incorporated by reference in their entirety 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) shall govern.

[0205] Equivalent solutions

[0206] Although specific embodiments of the present disclosure have been discussed, the foregoing specification is illustrative and not restrictive. Upon review of this specification and the following claims, various variations of the present disclosure will become apparent to those skilled in the art. The full scope of the present disclosure should be determined by reference to the claims, along with the full scope of their equivalents, and the specification, along with such variations.

Claims

1. A pharmaceutical solid form comprising ibmoleen or a pharmaceutically acceptable salt thereof, wherein the amount of ibmoleen or its pharmaceutically acceptable salt is greater than or equal to 10% by weight of the pharmaceutical solid form, and the weight of the pharmaceutical solid form is less than about 20 mg.

2. The pharmaceutical solid form according to claim 1, wherein the amount of ibmoleen or its pharmaceutically acceptable salt is from about 10% by weight to about 90% by weight of the pharmaceutical solid form.

3. The pharmaceutical solid form according to claim 1, wherein the amount of ibmoleen or its pharmaceutically acceptable salt is greater than 50% by weight of the pharmaceutical solid form.

4. The pharmaceutical solid form according to claim 1, wherein the amount of ibmoleen or its pharmaceutically acceptable salt is greater than 80% by weight of the pharmaceutical solid form.

5. The pharmaceutical solid form according to any one of claims 1-4, wherein the pharmaceutical solid form comprises drug-containing particles, and the drug-containing particles comprise ibmoleen or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

13. The pharmaceutical solid form according to claim 12, wherein the D50 of the compacted drug-containing particles is at least about 2 times that of the uncompacted drug particles having the same composition.

14. The pharmaceutical solid form according to any one of claims 5-13, wherein the drug-containing particles comprise the ibmoleen or a pharmaceutically acceptable salt thereof; and a binder, a filler, a disintegrant, and a lubricant.

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

16. The pharmaceutical solid form according to claim 14, wherein the amount of the binder is in the range of about 2% w / w to about 30% w / w, the amount of the filler is in the range of about 1% w / w to about 20% w / w, the amount of the disintegrant is in the range of about 1% w / w to about 2% w / w, and the amount of the lubricant is in the range of about 0.5% w / w to about 1.5% w / w.

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

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

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

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

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

22. The pharmaceutical solid form according to claim 20 or 21, wherein the pharmaceutical solid form or the tablet has a diameter of less than about 3 mm.

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

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

25. The pharmaceutical solid form according to claim 24, wherein the tablet is compressed from the drug-containing granules prepared by roller compaction.

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

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

28. The pharmaceutical solid form according to claim 27, wherein the coating is applied to the tablet to obtain a weight increase of about 8% to about 20% based on the total weight of the tablet.

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

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

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

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

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

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

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

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

37. The pharmaceutical solid form according to 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 based on the weight of the tablet.

38. The pharmaceutical solid form according to 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 based on the weight of the tablet.

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

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

41. The pharmaceutical solid form according to claim 40, wherein the amount of ibmoleucine or a pharmaceutically acceptable salt thereof is greater than 60% by weight of the tablet.

42. The pharmaceutical solid form according to claim 40, wherein the amount of ibmoleucine or a pharmaceutically acceptable salt thereof is greater than 80% by weight of the tablet.

43. The pharmaceutical solid form according to any one of claims 40-42, wherein the tablet further comprises a binder, a disintegrant, and a lubricant, and 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 based on the weight of the tablet.

44. The pharmaceutical solid form according to 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 more than one solid pharmaceutical form according to any one of claims 1-44.

46. The pharmaceutical composition according to claim 45, wherein the composition is in the form of a capsule containing more than one pharmaceutical tablet.

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

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

49. The method according to claim 48, wherein the subject is a human from 2 to 20 years old.

50. The method according to claim 48, wherein the subject is a human from 3 to 13 years old.

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

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

53. The method according to 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 ibmoximod mesylate.

54. The method according to any one of claims 48 - 53, wherein more than one solid pharmaceutical form or tablet is administered to the subject.

55. The method according to claim 54, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 tablets are filled in a capsule for administration.

56. The method according to claim 54, wherein more than one capsule is administered to the subject in a day.

57. The method according to any one of claims 54 - 56, wherein 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 are administered to the subject per day.

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

59. The method according to claim 58, wherein the therapeutic dose is in the range of from about 0.8 mg / kg / day to about 3.2 mg / kg / day of ibmoleucine mesylate, or an amount of 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 2.0 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. The method according to any one of claims 48 - 59, wherein the total daily dose of ibmoleucine mesylate administered to the subject is in the range of 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. A method for treating a disease or disorder associated with an abnormally reduced secretion of growth hormone (GH) in a subject having sufficient GH secretory potential, the method comprising administering to a subject in need thereof one or more pharmaceutical forms according to any one of claims 1 - 44, or a pharmaceutical composition according to any one of claims 45 - 47.

62. The method according to claim 61, wherein treating the disease or disorder comprises increasing the endogenous GH secretion of the subject.

63. The method according to claim 61 or 62, wherein the disease or disorder is Turner syndrome, pediatric chronic kidney disease (PCKD), Prader - Willi syndrome (PWS), lipodystrophy (e.g., HIV - associated 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. The method according to claim 63, wherein the muscle - wasting disease is sarcopenia, cachexia, hypothalamic amenorrhea or relative energy deficiency in sport (RED - S) syndrome.

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

66. The method according to any one of claims 61 - 64, wherein the subject is a human from 3 years to 13 years of age.

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

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

69. The method according to claim 68, wherein each tablet comprises 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 ibomolen mesylate.

70. The method according to any one of claims 61 - 69, wherein more than one solid pharmaceutical form or tablet is administered to the subject.

71. The method according to claim 70, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 tablets are filled in a capsule for administration.

72. The method according to claim 70, wherein more than one capsule is administered to the subject in a day.

73. The method according to any one of claims 70 - 72, wherein 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 are administered to the subject per day.

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

75. The method according to claim 74, wherein the therapeutic dose is in the range of from about 0.8 mg / kg / day to about 3.2 mg / kg / day of ibomolen mesylate, or an amount of 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 2.0 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. The method according to any one of claims 61 - 75, wherein the total daily dose of ibomolen mesylate administered to the subject is in the range of 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, the kit comprising one or more solid forms of a drug and / or one or more of the pharmaceutical compositions according to claims 1 - 47.

78. The kit according to claim 77, wherein the kit provides different doses in the solid form of the drug or the pharmaceutical composition.

79. The kit according to claim 78, wherein the kit comprises tablets having an ibomolen mesylate dose in the range of 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. The kit according to claim 79, wherein the kit comprises capsules, the capsules comprising one or more tablets having an ibomolen mesylate dose in the range of 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. The kit according to claim 80, wherein at least one capsule comprises 1 - 6 tablets having an ibomolen mesylate dose in the range of from about 4 mg to about 6 mg; and / or at least one capsule has 3 - 12 tablets having an ibomolen mesylate dose in the range of from about 6 mg to about 8 mg; and / or at least one capsule has 3 - 10 tablets having an ibomolen mesylate dose in the range of from about 9 mg to about 11 mg.

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