Compositions of Micronized Solabegron and Methods of Use Thereof

Abstract

Disclosed herein are compositions and methods for treating overactive bladder. In some embodiments, the composition comprises an effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof. In some embodiments, the micronized solabegron particles have a particle size of about 0.1 microns to 30 microns. In some embodiments, the pharmaceutical composition is administered twice a day.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application Serial No. 63 / 168,817, entitled “COMPOSITIONS OF MICRONIZED SOLABEGRON AND METHODS OF USE,” filed March 31, 2021, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0002] Disclosed herein are solid, orally administrable pharmaceutical compositions and methods for treating overactive bladder comprising administering such pharmaceutical compositions to a subject in need thereof.

[0003] In some embodiments, the pharmaceutical composition comprises about 75 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to 30 microns. In some embodiments, the excipient is selected from the group consisting of a filler, a disintegrant, a binder, a wetting agent, a lubricant, and a glidant, or a combination thereof. In some embodiments, the excipient is selected from the group consisting of mannitol, poloxamer 188, methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and polyvinyl alcohol, or a combination thereof. In some embodiments, the excipient is selected from the group consisting of sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, sodium carboxymethylcellulose, white wax, magnesium stearate, and carnauba wax, or a combination thereof. In some embodiments, the excipient is selected from the group consisting of colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from the group consisting of antimuscarinics, alpha adrenergic receptor blockers, botulinum toxins, purinergic agents, cannabinoids, transient receptor potential (TRP) protein inhibitors, prostaglandins, transcutaneous tibial nerve stimulators, sacral nerve stimulators, 5-alpha reductase inhibitors, phosphodiesterase-5 inhibitors, and combinations thereof. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from trospium or tolterodine. In some embodiments, the pharmaceutical composition is a tablet, capsule, granule, or powder.In some embodiments, the pharmaceutical composition is an immediate release composition, a modified release composition, or a combination thereof.

[0004] The embodiments herein describe a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 75 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to 30 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the one or more symptoms of overactive bladder are selected from increased frequency of urgency, nocturia, increased urination frequency, and urinary incontinence, and combinations thereof. In some embodiments, the method includes administering to the subject one or more additional therapeutic agents selected from the group consisting of antimuscarinic agents, alpha adrenergic receptor blockers, botulinum toxins, purinergic agents, cannabinoids, transient receptor potential (TRP) protein inhibitors, prostaglandins, transcutaneous tibial nerve stimulators, sacral nerve stimulators, 5-alpha reductase inhibitors, phosphodiesterase-5 inhibitors, beta-3 adrenergic receptor agonists, and combinations thereof.In some embodiments, the additional therapeutic agent is an antimuscarinic agent.In some embodiments, the antimuscarinic agent is trospium or tolterodine.

[0005] The present invention also relates to a method of treating irritable bowel syndrome and similar gastrointestinal disorders in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 50 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to 30 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0006]

[0023] Embodiments of the present invention also relate to a method of treating inflammatory bowel disease in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 50 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to 30 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0007] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof, wherein said pharmaceutical composition achieves a target AUC of about 17,000 ng.hr / mL to about 23,000 ng.hr / mL. 48 In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered twice daily. In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered once daily.

[0008] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof, wherein said pharmaceutical composition achieves a target AUC of about 14,000 ng.hr / mL to about 29,000 ng.hr / mL. 48 In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered twice daily. In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered once daily. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the dissolution profile of the non-micronized 75 mg solabegron tablet composition. [Diagram 2] FIG. 2 shows the dissolution profile of the non-micronized 100 mg solabegron tablet composition. [Diagram 3] FIG. 3 shows the composition profile of non-micronized 125 mg solabegron tablet. [Figure 4] FIG. 4 shows the dissolution profile of the non-micronized 175 mg solabegron tablet composition. [Diagram 5] 5A and 5B show an exemplary dissolution profile of a micronized 125 mg solabegron tablet composition (A) and the corresponding values ​​at different time points (B). [Figure 6] 6A and 6B show an exemplary dissolution profile of a micronized 175 mg solabegron tablet composition (A) and the corresponding values ​​at different time points (B). [Figure 7] FIG. 7 shows a comparison of the dissolution profiles of non-micronized and micronized 125 mg solabegron tablets. [Figure 8] FIG. 8 shows a comparison of the dissolution profiles of non-micronized and micronized 175 mg solabegron tablets. [Figure 9]9A and 9B show efficacy data for micronized solabegron used in the Phase 2b clinical trial of Example 5. [Figure 10] Figure 10 shows a comparison of the clinical efficacy of non-micronized solabegron 125 mg versus micronized solabegron 125 mg. Clinically meaningful improvements are 15%-20% improvement over the current beta-3 therapeutic drug Myrbetriq. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] As used herein, the term "about" immediately preceding a numerical value means a range of plus or minus 10% of that numerical value, for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc., unless the context of this disclosure indicates otherwise or is inconsistent with such an interpretation.

[0011] The term "agonist," as used herein, refers to a compound whose presence produces the same biological activity of a receptor that results from the presence of a naturally occurring ligand for that receptor.

[0012] As used herein, the terms "administer," "administering," or "administration" refer to the direct administration of a compound (e.g., solabegron) or a pharma- ceutically acceptable salt of the compound (e.g., solabegron), or a composition comprising solabegron or a pharma- ceutically acceptable salt thereof, to a subject.

[0013] As used herein, the term "bid" means twice a day (from the Latin bis in die).

[0014] The transitional term "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes elements, steps, or ingredients not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to those materials or steps specified and that do not materially affect the basic and novel characteristics of the claimed invention. In embodiments or claims in which the term "comprising" is used as a transitional phrase, such embodiments can also be envisioned by replacing the term "comprising" with the term "consisting of" or "consisting essentially of."

[0015] The term "derivatives" as used herein refers to pharma- ceutically acceptable solvates, pharma- ceutically acceptable salts dissolved in pharma- ceutically acceptable solvents, and metabolites.

[0016] The term "effective amount" as used herein refers to an amount that results in measurable inhibition of at least one symptom or parameter of a particular disorder or pathological process. As used herein, the term "therapeutically effective amount" of a composition of the present application is an amount that confers a therapeutic effect on the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject sees or feels an effect, or the physician observes a change).

[0017] The term "immediate release" as used herein refers to a pharmaceutical composition that releases an active ingredient over a short period of time.

[0018] The term "modified release" as used herein refers to a pharmaceutical composition that does not immediately release the active ingredient, for example, releases the active ingredient at a sustained or controlled rate over an extended period of time, releases the active ingredient after a lag time after administration, or can be optionally used in combination with an immediate release composition. Modified release includes sustained release, extended release, and delayed release. The term "extended release" or "sustained release" as used herein refers to a dosage form that makes the drug available for an extended period of time after administration. The term "delayed release" as used herein refers to a dosage form that releases the drug at a time other than immediately after administration.

[0019] As used herein, the phrase "overactive bladder" or "OAB" refers to a group of medical symptoms consisting of urgency, frequency, nocturia, involuntary urination, increased frequency of urination, and urinary incontinence. A patient with OAB may have one or more of these symptoms.

[0020] The phrase "pharmaceutical acceptable" refers to molecular entities and compositions that are generally considered safe and non-toxic. In particular, pharmaceutical acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of the present application are physiologically acceptable, compatible with other ingredients, and typically do not cause allergic or similar unpleasant reactions (e.g., upset stomach, dizziness, etc.) when administered to a subject. Preferably, the term "pharmaceutical acceptable" as used herein means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more particularly in humans.

[0021] As used herein, the phrase "pharmaceutically acceptable salts" includes salts of the compounds of the present application that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the present application or in compounds identified according to the methods of the present application. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate tartrate, pantothenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoic acid)). Certain compounds of the present application may form pharma-ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0022] The terms "subject", "individual" or "patient" as used herein are used interchangeably and are intended to include humans and non-human animals as used herein. Non-human animals include all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, with mammals such as non-human primates, sheep, dogs, cats, cows, and horses being preferred. For example, preferred subjects include humans in need of treatment. The method is particularly suitable for treating humans with diseases or disorders as described herein.

[0023] The term "therapeutic agent" as used herein means an agent utilized to treat, combat, ameliorate, prevent or ameliorate an unwanted condition or disease in a subject.

[0024] The terms "treat", "treated" or "treating" as used herein refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to protect (partially or totally) against or delay (e.g., attenuate or postpone onset) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result, such as a partial or total restoration or inhibition of decline of a parameter, value, function or outcome that was or will become abnormal. For purposes of this application, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent or intensity or rate of onset of a condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delay in onset or slowing of progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state, and remission (whether partial or total), whether or not it leads to immediate relief of actual clinical symptoms, or enhancement or amelioration of the condition, disorder or disease. Treatment aims to elicit a clinically significant response without excessive side effects.

[0025] "Weight percent" disclosed herein can be weight to weight percent or weight to volume percent, depending on the composition.

[0026] Overactive bladder (OAB) is a condition characterized by sudden, involuntary contractions of the bladder's detrusor muscle. The result is a sudden, irresistible need to urinate (urgency) even when the bladder is only filled with a small amount of urine. The main symptom is a sudden, irresistible need to urinate (urgency) with or without urinary incontinence, often accompanied by frequency (urinating eight or more times a day) and nocturia (waking up one or more times at night to urinate). Overactive bladder accompanied by urinary leakage (the inability to control the urge to urinate) is also called urge incontinence.

[0027] As used herein, the term "urgency" is considered the hallmark symptom of OAB and refers to a sudden, compelling desire to urinate that is difficult to postpone.

[0028] The term "urination frequency" or "urination frequency" as used herein refers to the number of times a subject urinates, with more than eight urinations per day being considered abnormal. This frequency is typically monitored by recording urination episodes in a voiding diary. The number of episodes varies with sleep, fluid intake, and medications, with up to seven episodes being considered normal consistent with other factors.

[0029] As used herein, the term "nocturia" refers to a condition in which a person experiences interruption of sleep due to the urge to urinate and is influenced by similar lifestyle and medical factors as the urination frequency component. Individual arousal events are not considered abnormal.

[0030] The term "urge incontinence" as used herein, as described above, is a form of urinary incontinence characterized by the involuntary loss of urine without apparent reason, despite a sense of urgency to urinate. Urge incontinence can be measured by pad tests, which are often used for research purposes. The goal of treating urge incontinence is to reduce the number of instances of urine leakage.

[0031] As used herein, the term "voided volume" is used as a measure of bladder capacity. Anatomically, functional bladder capacity increases with age, from childhood [(age + 2 years) × 30 mL] to adulthood (300-600 mL). The goal of treatment for OAB is to increase bladder capacity or voided volume. Increased voided volume is a good indicator of the effectiveness of treatment. For example, the goal of OAB treatment is to reduce voiding frequency. This is one of the recognized endpoints of OAB treatment. Thus, an increase in voided volume with the same intake will result in a decrease in voiding frequency (i.e., voiding frequency).

[0032] Normally, the kidneys produce urine, which is then drained into the bladder. During urination, urine passes from the bladder through the urethra. When the bladder is full, afferent nerve signals sent to the brain trigger the desire to urinate, and these nerve signals coordinate the relaxation of the pelvic floor muscles and the muscles of the urethra (urethral sphincter). The bladder muscles contract, pushing urine out (voiding). Overactive bladder occurs because the bladder muscles begin to contract involuntarily, even when there is only a small amount of urine in the bladder. These involuntary contractions create a sense of an urgent need to urinate. When the bladder holds about 300 ml of urine, it sends signals to the nerves to stimulate the bladder muscles, allowing the body to regulate urination. Voluntary control of the sphincter muscle at the opening of the bladder allows urine to remain in the bladder for longer. A normal adult bladder can hold up to 600 ml of urine. In people with OAB, bladder capacity is typically small (<200 ml).

[0033] The goals of treating OAB include reducing the frequency of urgency, reducing nocturia, reducing voiding frequency, reducing urinary incontinence, increasing voiding volume, reducing post-void residual volume, improving patient-reported outcomes, and combinations of these.

[0034] Disclosed herein are pharmaceutical compositions of micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, and methods for treating overactive bladder.

[0035] Solabegron (3'-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino]biphenyl-3-carboxylic acid) is a beta-3 adrenergic receptor agonist and has the following structure: [ka]

[0036] Further described in U.S. Patent No. 6,251,925, U.S. Patent No. 8,642,661, U.S. Patent No. 9,907,767, and PCT Application No. US2015 / 38583.

[0037] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of micronized solabegron or a pharma- ceutically acceptable salt thereof. In embodiments, the micronized solabegron is amorphous, zwitterionic or free base. In embodiments, the pharma- ceutically acceptable salt thereof includes, but is not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate. , benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoic acid)), various amino acids, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, amines such as diethanolamine, organic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. Solabegron can exist in any physical form known to those skilled in the art, such as nanoparticles, crystalline solids, amorphous solids, polymorphs, ionic solids such as cations, anions, and zwitterions, pharma- ceutically acceptable salts, hydrates, solvates, stereoisomers, and suspensions. Crystalline solids have an ordered arrangement of components held together by uniform intermolecular forces, whereas the components of amorphous solids are not ordered. A hydrate is a substance that incorporates at least one water molecule in a crystalline matrix. A solvate is a substance that incorporates at least one solvent molecule in a crystalline matrix. Polymorphs exhibit different crystal structures for molecules with the same molecular formula and arrangement of bonded atoms. Stereoisomers are isomeric molecules that have the same molecular formula and arrangement of bonded atoms (configuration) but differ only in the three-dimensional orientation of the atoms in space. In some embodiments, the solabegron is an amorphous solid form of solabegron. In some embodiments, the solabegron is solabegron hydrochloride.In some embodiments, solabegron is a zwitterionic form of solabegron.

[0038] Without wishing to be bound by theory, it has been observed that reducing the particle size of solabegron active pharmaceutical ingredient (API) to 30 microns in a tablet formulation improves the pharmacokinetics, including increasing the AUC(24 hr), compared to tablets with solabegron particle size greater than 30 microns. This observation was unexpected and surprising, and demonstrates the effect on pharmacokinetics of reducing the particle size (micronization) of solabegron in a pharmaceutical composition.

[0039] Micronized solabegron composition In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof. Micronized solabegron particles may have an average particle size of about 0.1 microns to about 30 microns, about 0.1 microns to about 25 microns, about 0.1 microns to about 20 microns, about 0.1 microns to about 10 microns, about 0.1 microns to about 8 microns, about 0.1 microns to about 6 microns, about 0.1 microns to about 4 microns, about 0.1 microns to about 2 microns, about 0.1 microns to about 1 micron, about 1 micron to about 10 microns, about 1 micron to about 9 microns, about 1 micron to about 8 microns, about 1 micron to about 7 microns, about 1 micron to about 6 microns, about 1 micron to about 5 microns, about 1 micron to about 4 microns, about 2 microns to about 10 microns, about 3 microns to about 10 microns, about 4 microns to about 10 microns, about 4 microns to about 8 microns, about 5 microns to about 10 microns, or about 6 microns to about 10 microns, or any value between these ranges.In some embodiments, the micronized solabegron particles are about 0.1 microns, about 0.2 microns, about 0.3 microns, about 0.4 microns, about 0.5 microns, about 0.60 microns, about 0.70 microns, about 0.80 microns, about 0.90 microns, about 1 micron, about 2.0 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, about 8.0 microns, about 9 microns, about 10 microns, about 11 microns, about 12 microns, about 13 microns, about 14 microns, about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, about and an upper limit of about 0.9 microns, about 0.8 microns, about 0.7 microns, about 0.6 microns, about 0.5 microns, about 0.4 microns, about 0.3 microns, about 0.2 microns, and about 0.1 microns. Specific examples include particle sizes of about 0.1 microns to about 10 microns, about 4 microns to about 8 microns, about 0.1 microns, about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, about 8 microns, about 9 microns, about 10 microns, about 11 microns, about 12 microns, about 13 microns, about 14 microns, about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, about 30 microns, and particle sizes in the ranges between these values.

[0040] In some embodiments, at least 99% of the solabegron particles, at least 98% of the solabegron particles, at least 97% of the solabegron particles, at least 96% of the solabegron particles, at least 95% of the solabegron particles, at least 94% of the solabegron particles, at least 93% of the solabegron particles, at least 90% of the solabegron particles, at least 85% of the solabegron particles, at least 80% of the solabegron particles, at least 75% of the solabegron particles, at least 70% of the solabegron particles, at least 60% of the solabegron particles, at least 50% of the solabegron particles, or at least 10% of the solabegron particles in the pharmaceutical composition are between about 0.1 microns and 30 microns, between about 0.1 microns and about 25 microns. microns, about 0.1 microns to about 20 microns, about 0.1 microns to about 10 microns, about 0.1 microns to about 8 microns, about 0.1 microns to about 6 microns, about 0.1 microns to about 4 microns, about 0.1 microns to about 2 microns, or about 0.1 microns to about 1 micron, about 1 micron to about 10 microns, about 1 micron to about 9 microns, about 1 micron to about 8 microns, about 1 micron to about 7 microns, about 1 micron to about 6 microns, about 1 micron to about 5 microns, about 1 micron to about 4 microns, about 2 microns to about 10 microns, about 3 microns to about 10 microns, about 4 microns to about 10 microns, about 5 microns to about 10 microns, or about 6 microns to about 10 microns, or any value between these ranges. Specific examples include about 0.1 microns to about 10 microns, about 4 microns to about 8 microns, about 0.1 microns, about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, about 8 microns, about 9 microns, about 10 microns, about 11 microns, about 12 microns, about 13 microns, about 14 microns, about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, about 30 microns, and ranges between these values.

[0041] In some embodiments, at least 90% of the solabegron particles (D90) in the pharmaceutical composition have a particle size of about 0.1 microns to about 30 microns, about 0.1 microns to about 25 microns, about 0.1 microns to about 20 microns, about 0.1 microns to about 10 microns, about 0.1 microns to about 8 microns, about 0.1 microns to about 6 microns, about 0.1 microns to about 4 microns, about 0.1 microns to about 2 microns, or about 0.1 microns to about 1 micron, about 1 micron to about 10 microns, about 1 micron to about 9 microns, about 1 micron to about 8 microns, about 1 micron to about 7 microns, about 1 micron to about 6 microns, about 1 micron to about 5 microns, about 1 micron to about 4 microns, about 2 microns to about 10 microns, about 3 microns to about 10 microns, about 4 microns to about 10 microns, about 5 microns to about 10 microns, or about 6 microns to about 10 microns, or any value between these ranges. In some embodiments, at least 90% of the solabegron particles (D90) in the pharmaceutical composition are about 0.1 microns, about 0.2 microns, about 0.3 microns, about 0. microns, about 0.5 mg / kg microns, about 0.60 microns, about 0.70 microns, about 0.80 microns, about 0.90 microns, about 1 micron, about 2.0 microns, about 5 microns, about 8.0 microns, about 10 microns, about 13 microns, about 15 microns, about 18 microns, about 20 microns, about 23 mg / kg microns, about 25 microns, about 28 microns, and about 30 microns; and upper limits of about 30 microns, about 28 microns, about 23 microns, about 20 microns, about 18 microns, about 15 microns, about 13 microns, about 10 microns, about 8 microns, about 5 microns, about 3 microns, about 1 micron, about 0.9 microns, about 0.8 microns, about 0.7 microns, about 0.6 microns, about 0.5 microns, about 0.4 microns, about 0.3 microns, about 0.2 microns, and about 0.1 microns.Specific examples include about 0.1 microns to about 10 microns, about 4 microns to about 8 microns, about 0.1 microns, about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, about 8 microns, about 9 microns, about 10 microns, about 11 microns, about 12 microns, about 13 microns, about 14 microns, about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, about 30 microns, and ranges between these values.

[0042] In some embodiments, at least 50% of the solabegron particles (D50) in the pharmaceutical composition have a particle size of about 0.1 microns to about 10 microns, about 0.1 microns to about 9 microns, about 0.1 microns to about 8 microns, about 0.1 microns to about 7 microns, about 0.1 microns to about 6 microns, about 0.1 microns to about 5 microns, about 0.1 microns to about 4 microns, about 0.1 microns to about 3 microns, about 0.1 microns to about 2 microns, or about 0.1 microns to about 1 micron, about 1 micron to about 5 microns, about 1 micron to about 4 microns, about 1 micron to about 3 microns, about 2 microns to about 5 microns, about 2 microns to about 4 microns, about 3 microns to about 4 microns, or any value between these ranges. In some embodiments, at least 50% of the solabegron particles (D50) in the pharmaceutical composition are about 0.1 microns, about 0.2 microns, about 0.3 microns, about 0.4 microns, about 0.5 mg / kg micron, about 0.60 microns, about 0.70 microns, about 0.80 microns, about 0.90 microns, about 1 micron, about 2.0 microns, about 5 microns, about 8.0 microns, about 10 microns, about 13 microns, about 15 microns, about 18 microns, about 20 microns, about 23 mg / kg microns , about 25 microns, about 28 microns, and lower limits of about 30 microns; and upper limits of about 30 microns, about 28 microns, about 23 microns, about 20 microns, about 18 microns, about 15 microns, about 13 microns, about 10 microns, about 8 microns, about 5 microns, about 3 microns, about 1 micron, about 0.9 microns, about 0.8 microns, about 0.7 microns, about 0.6 microns, about 0.5 microns, about 0.4 microns, about 0.3 microns, about 0.2 microns, and about 0.1 microns.Specific examples include about 0.1 microns to about 10 microns, about 4 microns to about 8 microns, about 0.1 microns, about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, about 8 microns, about 9 microns, about 10 microns, about 11 microns, about 12 microns, about 13 microns, about 14 microns, about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, about 30 microns, and ranges between these values.

[0043] In some embodiments, micronized solabegron has a D95 of about 7 microns to about 10 microns; a D90 of about 6 microns to about 8 microns; a D50 of about 3 microns to about 4 microns; a D10 of about 0.8 microns to about 1.3 microns, and any combination thereof.

[0044] In some embodiments, micronized solabegron has a D95 of about 7 microns to about 10 microns, and a D90 of about 6 microns to about 8 microns.

[0045] In some embodiments, micronized solabegron has a D95 of about 7 microns to about 10 microns, and a D50 of about 3 microns to about 4 microns.

[0046] In some embodiments, micronized solabegron has a D95 of about 7 microns to about 10 microns, and a D10 of about 0.8 microns to about 1.3 microns, and any combination thereof.

[0047] In some embodiments, micronized solabegron has a D90 of about 6 microns to about 8 microns, and a D50 of about 3 microns to about 4 microns.

[0048] In some embodiments, micronized solabegron has a D90 of about 6 microns to about 8 microns, and a D10 of about 0.8 microns to about 1.3 microns.

[0049] In some embodiments, micronized solabegron has a D50 of about 3 microns to about 4 microns, and a D10 of about 0.8 microns to about 1.3.

[0050] In some embodiments, the micronized solabegron has the following particle size distributions, or combinations thereof: TIFF2024513830000003.tif72151

[0051] In some embodiments, the micronized solabegron has the following particle size distribution: TIFF2024513830000004.tif72146

[0052] In some embodiments, the micronized solabegron has the following particle size distribution: TIFF2024513830000005.tif67140

[0053] In some embodiments, the micronized solabegron has the following particle size distribution: TIFF2024513830000006.tif69139

[0054] In some embodiments, the effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg.

[0055] In some embodiments, the effective amount of micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, present in the composition is about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, or about 50 mg to about 60 mg, or any value between these ranges.

[0056] In some embodiments, the effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 75 mg to 125 mg. In some embodiments, the effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 100 mg to 125 mg. In some embodiments, the effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 100 mg. In some embodiments, the effective amount of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 125 mg.

[0057] In some embodiments, the effective amount of micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, present in the composition is about 20 wt% to about 60 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or any value between these ranges, of the total weight of the composition.

[0058] Non-micronized solabegron composition Non-micronized solabegron is solabegron having an average particle size of greater than 30 microns, greater than 40 microns, greater than 50 microns, greater than 60 microns, greater than 70 microns, greater than 80 microns, greater than 90 microns, greater than 100 microns, and any value between these ranges. In some embodiments, non-micronized solabegron has a D90 of greater than 30 microns, greater than 40 microns, greater than 50 microns, greater than 60 microns, greater than 70 microns, greater than 80 microns, greater than 90 microns, greater than 100 microns, and any value between these ranges.

[0059] An example of non-micronized solabegron has the following particle size distribution: TIFF2024513830000007.tif30140

[0060] In some embodiments, the composition comprises non-micronized solabegron. In some embodiments, the effective amount of non-micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof present in the composition is about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg.

[0061] In some embodiments, the effective amount of non-micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, present in the composition is about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, or about 50 mg to about 60 mg, or any value between these ranges.

[0062] In some embodiments, the effective amount of non-micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, present in the composition is about 20 wt% to about 60 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 40 wt%, about 20 wt% to about 30 wt%, about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or any value between these ranges, of the total weight of the composition.

[0063] Additional medications In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from the group consisting of antimuscarinics, alpha adrenergic receptor blockers, botulinum toxins, purinergic agonists, cannabinoids, transient receptor potential (TRP) protein inhibitors, prostaglandins, transcutaneous tibial nerve stimulators, sacral nerve stimulators, 5-alpha reductase inhibitors, phosphodiesterase-5 inhibitors, beta-3 adrenergic receptor agonists, and combinations thereof.

[0064] In some embodiments, the antimuscarinic agent may be selected from tolterodine, oxybutynin, trospium, solifenacin, darifenacin, propiverine, fesoterodine, and pharmaceutically acceptable salts thereof. In some embodiments, the antimuscarinic agent is tolterodine or trospium. In some embodiments, the antimuscarinic agent is tolterodine. In some embodiments, the antimuscarinic agent is trospium.

[0065] In some embodiments, the alpha adrenergic receptor blocker may be selected from tamsulosin, alfuzosin, and silodosin, and pharma- ceutically acceptable salts thereof.

[0066] In some embodiments, the 5-alpha reductase inhibitor may be selected from finasteride, dutasteride, epristeride, alphatradiol, and pharmaceutically acceptable salts thereof.

[0067] In some embodiments, the phosphodiesterase-5 inhibitor may be selected from sildenafil, tadalafil, vardenafil, udenafil, avanafil, and pharma- ceutically acceptable salts thereof.

[0068] In some embodiments, the beta-3 adrenergic receptor agonist may be selected from mirabegron, amibegron, ritobegron, vibegron, L-742,791, L-796,568, TRK-380, LY-368,842, Ro40-2148, and pharma- ceutically acceptable salts thereof.

[0069] Pharmaceutically acceptable excipients In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient. Examples of the pharma-ceutically acceptable excipient that may be present in the composition include, but are not limited to, fillers / vehicles, solvents / cosolvents, preservatives, antioxidants, suspending agents, surfactants, antifoaming agents, buffers, chelating agents, sweeteners, flavoring agents, binders, bulking agents, disintegrants, diluents, lubricants, fillers, wetting agents, glidants, and combinations thereof.

[0070] Exemplary fillers that may be present in the pharmaceutical composition in some embodiments include cellulose and cellulose derivatives such as microcrystalline cellulose; starches such as dry starch, hydrolyzed starch, and starch derivatives such as corn starch; cyclodextrins; sugars such as powdered sugar, and sugar alcohols such as lactose, mannitol, sucrose, and sorbitol; inorganic fillers such as aluminum hydroxide gel, precipitated calcium carbonate, carbonates, magnesium aluminosilicate, calcium phosphate dibasic; and sodium chloride, silicon dioxide, titanium dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, alumina, kaolin, talc, or combinations thereof. The filler can be present in the composition at about 20 wt% to about 65 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 40 wt%, about 45 wt% to about 65 wt%, about 50 wt% to about 65 wt%, or about 55 wt% to about 65 wt%, based on the total weight of the composition, or any value between these ranges.

[0071] In some embodiments, exemplary disintegrants that may be present in the pharmaceutical composition include starch, alginic acid, cross-linked polymers such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starch glycolate, clay, cellulose, starch, gums, or combinations thereof. The disintegrant may be present in the composition at about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 7 wt%, about 1 wt% to about 6 wt%, or about 1 wt% to about 5 wt%, or any value between these ranges, based on the total weight of the composition.

[0072] In some embodiments, the pharmaceutical composition comprises a binder, including but not limited to celluloses such as hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; starches such as corn starch, pregelatinized starch, and hydroxypropyl starch; waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate; synthetic polymers such as polymethacrylates, polyvinylpyrrolidone; and povidone, dextrin, pullulan, agar, gelatin, tragacanth, macrogol, or combinations thereof. The binder can be present in the composition at about 0.5 wt% to about 5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 2 wt%, or about 0.5 wt% to about 1 wt%, or any value between these ranges, based on the total weight of the composition.

[0073] In some embodiments, the pharmaceutical composition comprises a wetting agent, including, but not limited to, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, poloxamer, poloxamer 188, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates, cetyl alcohol, glycerin fatty acid esters (e.g., triacetin, glycerin monostearate, etc.), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and combinations thereof. The humectant can be present in the composition at about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 4 wt%, or about 0.1 wt% to about 5 wt%, or any value between these ranges, based on the total weight of the composition.

[0074] In some embodiments, the pharmaceutical composition comprises a lubricant, including, but not limited to, stearic acid, magnesium stearate, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal salts and alkaline earth metal salts, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (PEG), methoxypolyethylene glycol, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof. The lubricant can be present in the composition at about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or any value between these ranges, based on the total weight of the composition.

[0075] In some embodiments, the pharmaceutical composition comprises a lubricant, including but not limited to colloidal silicon dioxide, talc, sodium lauryl sulfate, natural starch, and combinations thereof. The lubricant may be present in the composition at about 0.05 wt% to about 1 wt%, about 0.05 wt% to about 0.9 wt%, about 0.05 wt% to about 0.8 wt%, about 0.05 wt% to about 0.5 wt%, or about 0.05 wt% to about 0.1 wt%, or any value between these ranges, based on the total weight of the composition.

[0076] In some embodiments, exemplary buffering agents that may be present in the composition include gluconate, lactate, citrate, acetate, phosphate, benzoate, carbonate, or combinations thereof. The buffering agent may be present in an amount sufficient to buffer the pH of the solution and minimize degradation of the active ingredient. Some buffering agents adjust the solubility of the active ingredient in the liquid dosage form. The pH can be adjusted with a combination of two or more of these buffering agents, for example, citric acid and sodium benzoate. The buffering agent may be present in the composition at about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 7 wt%, about 1 wt% to about 6 wt%, or about 1 wt% to about 5 wt%, or any value between these ranges, based on the total weight of the composition.

[0077] In some embodiments, exemplary preservatives that may be present in the composition include sodium benzoate, paraoxybenzoic acid esters, methyl, ethyl, butyl, and propyl paraben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride (BKC), benzethonium chloride, phenol, phenyl mercaptan nitrate, thimerosal, or combinations thereof. Preservatives may be included in the liquid dosage form. The preservative may be in an amount sufficient to extend the shelf life or storage stability, or both, of the liquid dosage form. The preservative may be present in the composition at about 0.05 wt% to about 1 wt%, about 0.05 wt% to about 0.9 wt%, about 0.05 wt% to about 0.8 wt%, about 0.05 wt% to about 0.5 wt%, or about 0.05 wt% to about 0.1 wt%, or any value between these ranges, based on the total weight of the composition.

[0078] In some embodiments, non-limiting examples of flavoring agents that may be present in the composition include synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plant leaves, flowers, fruits, etc., or any combination thereof. These include cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, cassia oil, etc., or combinations thereof. Also useful as flavorings are citrus oils such as vanilla, lemon, orange, grape, lime, grapefruit, etc., fruit essences such as apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, strawberry flavor, tutti fruity flavor, mint flavor, or combinations thereof. The flavoring agent can be present in the composition at about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, based on the total weight of the composition, or any value between these ranges.

[0079] In some embodiments, exemplary antioxidants that may be present in the composition include flavonoids, anthocyanidins, anthocyanins, proanthocyanidins, or combinations thereof. The antioxidants may be present in the composition at about 0.05 wt% to about 1 wt%, about 0.05 wt% to about 0.9 wt%, about 0.05 wt% to about 0.8 wt%, about 0.05 wt% to about 0.5 wt%, or about 0.05 wt% to about 0.1 wt%, or any value between these ranges, based on the total weight of the composition.

[0080] In some embodiments, exemplary sweeteners that may be present in the composition include sorbitol, saccharin, acesulfame, such as acesulfame potassium, sucralose, xylitol, maltitol, sucrose, aspartame, fructose, neotame, glycerin, sodium saccharinate, dipotassium glycyrrhizinate, acesulfame K, mannitol, invert sugar, or combinations thereof. In some cases, sweeteners, such as one or more sucralose-containing or saccharin-containing components, may be added to the pharmaceutical composition to modify the taste of the pharmaceutical composition. Sweeteners may be present in the composition at about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or any value between these ranges, based on the total weight of the composition.

[0081] In some embodiments, the pharmaceutical composition comprises polysorbate 20, polysorbate 60, polysorbate 80, vitamin E TPGS, Cremophor, Solutol, poloxamer 121, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338, poloxamer 407, poloxamer 407, Labrasol®, Labrafils®, Gelucire® 50 / 13, Gelucire® 44 / 14, Gelucire® 48 / 16, lauroglycol, propylene glycol, polyethylene glycol, PEG 300, PEG 400, PEG 5 ... 1000, Soluplus®, SDS, SLS, polyoxyl stearates, sorbitan ester sucrose esters, stearic acid, cetyl alcohol, cetylpyridinium chloride, docusate sodium, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, lecithin, oleic acid, and combinations thereof. In some embodiments, the surfactant may be present in the composition at about 0.1 wt% to about 30 wt%, about 0.1 wt% to about 25 wt%, about 0.1 wt% to about 20 wt%, about 0.1 wt% to about 15 wt%, about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 5 wt%, or any value between these ranges, based on the total weight of the composition. Specific examples include about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 20 wt%, about 25 wt%, or about 30 wt%.

[0082] In some embodiments, the pharmaceutical composition is a tablet and includes a topcoat, such as a hydroxypropyl methylcellulose coating or a polyvinyl alcohol coating, available under the trade name Opadry™, such as Opadry White, Opadry II, etc. The topcoat can be present in the composition at about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 7 wt%, about 1 wt% to about 6 wt%, or about 1 wt% to about 5 wt%, or any value between these ranges, based on the total weight of the composition.

[0083] In some embodiments, the pharmaceutical composition comprises micronized solabegron, or a pharma- ceutically acceptable salt or derivative thereof, according to any embodiment described herein, and an excipient selected from the group consisting of mannitol, poloxamer 188, methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and polyvinyl alcohol, or a combination thereof. In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof according to any embodiment described herein, mannitol, poloxamer 188, methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and polyvinyl alcohol. In some embodiments, the pharmaceutical composition comprises about 20 wt% to about 40 wt% micronized solabegron hydrochloride, about 45 wt% to about 65 wt% mannitol, about 1 wt% to about 10 wt% croscarmellose sodium, about 0.5 wt% to about 5 wt% methylcellulose, about 0.1 wt% to about 1 wt% poloxamer 188, about 0.1 wt% to about 5 wt% magnesium stearate, about 0.05 wt% to about 1 wt% colloidal silicon dioxide, and about 1 wt% to about 10 wt% Opadry II.

[0084] In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof according to any embodiment described herein, and an excipient selected from the group consisting of sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, sodium carboxymethylcellulose, white wax, magnesium stearate, and carnauba wax, or a combination thereof. In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof according to any embodiment described herein, sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, sodium carboxymethylcellulose, white wax, magnesium stearate, and carnauba wax.

[0085] In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof according to any embodiment described herein, and an excipient selected from the group consisting of colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide, or a combination thereof. In some embodiments, the pharmaceutical composition comprises micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof according to any embodiment described herein, colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide.

[0086] In some embodiments, the compositions disclosed herein may be formulated as tablets, capsules, granules, or powders. In some embodiments, the compositions may be tablets, bilayer tablets, capsules, multiparticulates, drug-coated spheres, matrix tablets, or polynuclear tablets.

[0087] To obtain micronized solabegron particles, methods known in the art can be used. For example, the solabegron particles of the composition according to the present invention are dispersed in a liquid dispersion medium in which the solabegron particles are poorly soluble, and mechanical means are applied in the presence of a grinding medium to reduce the particle size of the composition to the desired effective average particle size. The particles can be reduced in size in the presence of one or more nonionic surface stabilizers. Alternatively, the particles can be contacted with one or more nonionic surface stabilizers after attrition. Other compounds, such as diluents, can be added to the composition during the size reduction process. The dispersion can be produced in a continuous or batch mode.

[0088] The mechanical means applied to reduce the particle size of the compositions according to the invention may conveniently take the form of a dispersion mill. Suitable dispersion mills include ball mills, attritor mills, vibratory mills, jet mills, Fitz mills, and media mills such as sand mills and bead mills.

[0089] In some embodiments, tablet can be prepared using reagents and techniques readily available in the art and / or exemplary methods as described herein.Compressed tablet can be prepared by compressing the active compound in free-flowing form such as powder or granules, optionally mixed with binder, lubricant, inert diluent, glidant, surface active agent or dispersant, with the material for forming core in suitable machine.Core tablet can be immediate release or delayed release.

[0090] Immediate Release and Modified Release Compositions In some embodiments, the micronized and non-micronized solabegron compositions disclosed herein are immediate release pharmaceutical compositions, modified release pharmaceutical compositions, or combinations thereof. In some embodiments, the immediate release pharmaceutical compositions release solabegron in a short time after administration, typically less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, less than about 90 minutes, less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, or less than about 10 minutes.

[0091] In some embodiments, the in vitro dissolution rate of the immediate release pharmaceutical composition as measured by USP Apparatus Type II (paddle speed 50 rpm) at 37° C. is about 55%-65% of solabegron released in about 10 minutes, about 65%-75% of solabegron released in about 15 minutes, about 70%-80% of solabegron released in about 20 minutes, about 75%-85% of solabegron released in about 30 minutes, about 80%-90% of solabegron released in about 45 minutes, or about 85%-95% of solabegron released in about 60 minutes. In some embodiments, the dissolution medium comprises about 900 ml of a solution comprising 0.01 N hydrochloric acid and 2% (w / v) poloxamer 188.

[0092] In some embodiments, the immediate release pharmaceutical composition can be prepared using a pharmaceutical process, i.e., by direct compression or by granulation and final tableting. This process can include first forming a core containing micronized solabegron, followed by forming a topcoat. The core can be formed by dispersing micronized solabegron with one or more excipients, such as mannitol, poloxamer 188, methylcellulose, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide.

[0093] In some embodiments, the immediate release pharmaceutical composition of the micronized solabegron tablet comprises: [Table 1]

[0094] In some embodiments, the immediate release composition of the micronized solabegron tablet comprises: [Table 2]

[0095] In some embodiments, the immediate release composition may comprise about 20 wt% to about 40 wt% micronized solabegron according to any embodiment described herein, about 45 wt% to about 65 wt% filler, about 1 wt% to about 10 wt% disintegrant, about 0.5 wt% to about 5 wt% binder, about 0.1 wt% to about 1 wt% wetting agent, about 0.1 wt% to about 5 wt% lubricating oil, about 0.05 wt% to about 1 wt% slip agent, and about 1 wt% to about 10 wt% film coat.

[0096] In some embodiments, the immediate release composition may comprise about 27 wt% to about 31 wt% micronized solabegron according to any embodiment described herein, about 53 wt% to about 60 wt% filler, about 3 wt% to about 6 wt% disintegrant, about 2 wt% to about 3.5 wt% binder, about 0.4 wt% to about 1 wt% wetting agent, about 0.4 wt% to about 1 wt% lubricating oil, about 0.1 wt% to about 0.6 wt% slip agent, and about 3 wt% to about 4.5 wt% film coat.

[0097] In some embodiments, the immediate release composition comprises about 20 wt% to about 40 wt% micronized solabegron according to any embodiment described herein, about 45 wt% to about 65 wt% mannitol, about 1 wt% to about 10 wt% croscarmellose sodium, about 0.5 wt% to about 5 wt% methylcellulose, about 0.1 wt% to about 1 wt% poloxamer 188, about 0.1 wt% to about 5 wt% magnesium stearate, about 0.05 wt% to about 1 wt% colloidal silicon dioxide, and about 1 wt% to about 10 wt% Opadry II.

[0098] In some embodiments, the immediate release composition may comprise about 25 wt% to about 35 wt% micronized solabegron according to any embodiment described herein, about 45 wt% to about 60 wt% mannitol, about 3 wt% to about 7 wt% croscarmellose sodium, about 2 wt% to about 4 wt% methylcellulose, about 0.3 wt% to about 1 wt% poloxamer 188, about 0.5 wt% to about 2 wt% magnesium stearate, about 0.1 wt% to about 0.5 wt% colloidal silicon dioxide, and about 2 wt% to about 5 wt% Opadry II.

[0099] In some embodiments, the immediate release composition may comprise about 29 wt% to about 31 wt% micronized solabegron according to any embodiment described herein, about 50 wt% to about 60 wt% mannitol, about 3 wt% to about 5 wt% croscarmellose sodium, about 2 wt% to about 3 wt% methylcellulose, about 0.4 wt% to about 0.8 wt% poloxamer 188, about 0.5 wt% to about 1.5 wt% magnesium stearate, about 0.05 wt% to about 0.5 wt% colloidal silicon dioxide, and about 2 wt% to about 4 wt% Opadry II.

[0100] In some embodiments, the immediate release composition may comprise about 20 wt% to about 40 wt% non-micronized solabegron according to any embodiment described herein, about 0.1 wt% to about 25 wt% surfactant, about 45 wt% to about 65 wt% filler, about 1 wt% to about 10 wt% disintegrant, about 0.5 wt% to about 5 wt% binder, about 0.1 wt% to about 1 wt% wetting agent, about 0.1 wt% to about 5 wt% lubricating oil, about 0.05 wt% to about 1 wt% slip agent, and about 1 wt% to about 10 wt% film coat.

[0101] In some embodiments, the modified release composition can release micronized solabegron at a sustained or controlled rate over an extended period of time, or release solabegron after a lag time after administration. For example, solabegron is released from the composition 4 hours after administration, 8 hours after administration, 12 hours after administration, 16 hours after administration, or 24 hours after administration. Modified release compositions include sustained release compositions, extended release compositions, and delayed release compositions. In some embodiments, the modified release composition can release about 10% solabegron in about 2 hours, about 20% solabegron in about 2 hours, about 40% solabegron in about 2 hours, about 50% solabegron in about 2 hours, about 10% solabegron in about 3 hours, about 20% solabegron in about 3 hours, about 40% solabegron in about 3 hours, about 5 ... solabegron, about 10% solabegron in about 4 hours, about 20% solabegron in about 4 hours, about 40% solabegron in about 4 hours, about 50% solabegron in about 4 hours, about 10% solabegron in about 6 hours, about 20% solabegron in about 6 hours, about 40% solabegron in about 6 hours, or about 50% solabegron in about 6 hours.

[0102] In some embodiments, the modified release composition may comprise a matrix selected from microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropyl methylcellulose and hydroxypropylcellulose, alkylcelluloses such as polyethylene oxide methylcellulose, ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylates, polyvinyl acetate, and mixtures thereof.

[0103] In some embodiments, the modified release composition may be a tablet. The tablet may include a core of micronized solabegron and a delayed release material compressed and coated onto the core. In some embodiments, the delayed release material includes heteropolysaccharide gums (e.g., xanthan gum), homopolysaccharide gums (e.g., locust bean gum), and sugars (e.g., lactose, dextrose, mannitol, etc.). In certain embodiments, the gum(s) are wet granulated with any sugar(s) to form agglomerated particles, including, for example, a mixture of xanthan gum, locust bean gum, and dextrose. In some embodiments, the delayed release material includes hydroxypropylmethylcellulose, polymethacrylate-based copolymers, hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, etc.

[0104] In some embodiments, the compression coating delays the release of solabegron from the dosage form until the dosage form reaches at least the mid-small intestine after oral administration to a human. In certain embodiments, the initial release of solabegron from the dosage form does not occur until after the dosage form enters the distal small intestine. In certain alternative embodiments, the initial release of solabegron from the dosage form does not occur until after the dosage form enters the ileocecal junction. In certain embodiments, the initial release of solabegron from the dosage form does not occur until after the dosage form enters the ascending colon. In certain embodiments, the initial release of solabegron from the dosage form does not occur until after the dosage form enters the hepatic flexure. In certain embodiments, the initial release of solabegron from the dosage form does not occur until after the dosage form enters the transverse colon.

[0105] In some embodiments, the micronized solabegron pharmaceutical composition disclosed herein achieves a target area under the curve (hereinafter AUC) of about 5,000 ng.hr / mL to about 35,000 ng.hr / mL, about 10,000 ng.hr / mL to about 35,000 ng.hr / mL, about 15,000 ng.hr / mL to about 35,000 ng.hr / mL, about 20,000 ng.hr / mL to about 35,000 ng.hr / mL, about 15,000 ng.hr / mL to about 20,000 ng.hr / mL, or any value between these ranges over a 24 hour period. Specific examples include about 5,000 ng.hr / mL, about 10,000 ng.hr / mL, about 15,000 ng.hr / mL, about 17,000 ng.hr / mL, about 20,000 ng.hr / mL, about 25,000 ng.hr / mL, or about 35,000 ng.hr / mL over a 24 hour period. In some embodiments, a pharmaceutical composition comprising micronized solabegron achieves an AUC that is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% greater than a similarly administered composition prepared from non-micronized solabegron without a surfactant.

[0106] Some embodiments describe a pharmaceutical composition comprising 75 mg to 125 mg of solabegron, the solabegron being a combination of micronized solabegron having a particle size of about 0.1 microns to 30 microns and non-micronized solabegron having a particle size greater than 30 microns, wherein when the pharmaceutical composition is administered to a subject, the pharmaceutical composition has an AUC 48 or an AUC of approximately 80% to 125% of 22,239 ng hr / mL 48 Achieve this.

[0107] In some embodiments, the pharmaceutical composition comprises 75 mg to 125 mg of solabegron, wherein the solabegron is a combination of micronized solabegron having a particle size of about 0.1 microns to 30 microns and non-micronized solabegron having a particle size greater than 30 microns, and when the pharmaceutical composition is administered to a subject, the pharmaceutical composition has an AUC 24 , or an AUC of approximately 80% to 125% of the AUC of 20,920 ng hr / mL 24 Achieve this.

[0108] In some embodiments, the pharmaceutical composition comprises 75 mg to 125 mg of solabegron in accordance with one or more embodiments described herein, and when the pharmaceutical composition is administered to a subject, the pharmaceutical composition has an AUC 48 or an AUC of approximately 80% to 125% of the AUC of approximately 22,239 ng hr / mL 48 Achieve this.

[0109] In some embodiments, the pharmaceutical composition comprises 75 mg to 125 mg of solabegron in accordance with one or more embodiments described herein, and when the pharmaceutical composition is administered to a subject, the pharmaceutical composition has an AUC 24 , or an AUC of approximately 80% to 125% of 20,920 ng hr / mL 24 Achieve this.

[0110] In some embodiments, a pharmaceutical composition comprises 75 mg to 125 mg of micronized solabegron according to any embodiment described herein, and when said pharmaceutical composition is administered to a subject, the pharmaceutical composition achieves an AUC that is about 40% greater than the AUC achieved from the same dose of non-micronized solabegron.

[0111] In some embodiments, the micronized solabegron pharmaceutical composition disclosed herein has a target C max Specific examples include about 1.0 μg / mL, about 1.5 μg / mL, about 2.0 μg / mL, about 2.1 μg / mL, about 2.5 μg / mL, about 3.0 μg / mL, about 4.0 μg / mL, or about 5.0 μg / mL. In some embodiments, a pharmaceutical composition comprising micronized solabegron achieves at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% greater C compared to a similarly administered composition prepared from non-micronized solabegron without a surfactant. max Achieve this.

[0112] In some embodiments, pharmaceutical compositions comprising micronized and non-micronized solabegron and one or more surfactants may achieve pharmacokinetics similar to those of the micronized solabegron pharmaceutical compositions disclosed herein. In some embodiments, pharmaceutical compositions comprising micronized and non-micronized solabegron and one or more surfactants achieve a target area under the curve (hereinafter AUC) of about 5,000ng.hr / mL to about 35,000ng.hr / mL, about 10,000ng.hr / mL to about 35,000ng.hr / mL, about 15,000ng.hr / mL to about 35,000ng.hr / mL, about 20,000ng.hr / mL to about 35,000ng.hr / mL, about 15,000ng.hr / mL to about 20,000ng.hr / mL, or any value between these ranges over a 24 hour period. Specific examples include about 5,000 ng.hr / mL, about 10,000 ng.hr / mL, about 15,000 ng.hr / mL, about 17,000 ng.hr / mL, about 20,000 ng.hr / mL, about 25,000 ng.hr / mL, or about 35,000 ng.hr / mL over a 24 hour period.

[0113] In some embodiments, pharmaceutical compositions comprising micronized and non-micronized solabegron and one or more surfactants have a target C value of about 1 μg / mL to about 5.0 μg / mL, about 1 μg / mL to about 4.0 μg / mL, about 1 μg / mL to about 3.0 μg / mL, about 1 μg / mL to about 2.0 μg / mL, or about 1 μg / mL to about 1.5 μg / mL, or any value between these ranges. max Specific examples include about 1.0 μg / mL, about 1.5 μg / mL, about 2.0 μg / mL, about 2.1 μg / mL, about 2.5 μg / mL, about 3.0 μg / mL, about 4.0 μg / mL, or about 5.0 μg / mL.

[0114] Treatment method

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron according to any embodiment described herein. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 30 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 10 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 4 microns to about 8 microns.

[0115]

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron according to any embodiment described herein, wherein treating the overactive bladder relieves one or more of the symptoms of the overactive bladder as measured by an increase in urination volume, the one or more symptoms of the overactive bladder being selected from the group consisting of urgency, frequency, nocturia, and urge incontinence, or a combination thereof. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 30 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 10 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 4 microns to about 8 microns.

[0023] Embodiments of the present invention also relate to a method of treating irritable bowel syndrome and similar gastrointestinal disorders in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron according to any of the embodiments described herein. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 30 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 10 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 4 microns to about 8 microns.

[0116]

[0023] Embodiments of the present invention also relate to a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron according to any embodiment described herein. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 30 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 0.1 microns to about 10 microns. In some embodiments, the micronized solabegron comprises at least 90% of the solabegron particles having a particle size of about 4 microns to about 8 microns.

[0117]

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder or one or more symptoms thereof, comprising orally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of about 75 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 30 microns. In some embodiments, at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, administration of the pharmaceutical composition is orally, twice daily.

[0118] In some embodiments, the symptoms of overactive bladder are selected from increased frequency of urgency, nocturia, increased frequency of urination, urinary incontinence, and combinations thereof.

[0119] In some embodiments, treatment of overactive bladder is measured by a reduction in frequency of urgency, a reduction in urination frequency, a reduction in incontinence episodes, a reduction in urge incontinence, percent dryness (zero incontinence episodes), a percent change from baseline in urge incontinence, an increase in voided volume, post-void residual volume, patient-reported outcomes, and combinations thereof.

[0120] An embodiment of the present invention relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 30 microns. In some embodiments, at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered orally twice daily.

[0121] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 100 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, administration of the pharmaceutical composition is orally twice daily.

[0122]

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject an immediate release pharmaceutical composition comprising a therapeutically effective amount of about 100 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 30 microns. In some embodiments, 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, administration of the immediate release pharmaceutical composition is twice daily.

[0123] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective in treating overactive bladder or symptoms thereof compared to a similarly dosed pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0124] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective in treating urinary incontinence than a similarly dosed pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0125] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective at reducing urination frequency compared to a similar dose of a pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0126] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective in reducing the frequency of urge incontinence compared to a similarly dosed pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0127] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective at increasing percent dryness compared to a similarly dosed pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0128] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron is more effective in reducing the frequency of urgency compared to a similarly dosed pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron without a surfactant. In some embodiments, the pharmaceutical composition is an immediate release composition comprising about 100 mg of micronized solabegron and is orally administered twice daily.

[0129] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof, wherein said pharmaceutical composition achieves a target AUC of about 17,000 ng.hr / mL to about 23,000 ng.hr / mL. 48 In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered twice daily. In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered once daily.

[0130] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof, wherein said pharmaceutical composition achieves a target AUC of about 14,000 ng.hr / mL to about 29,000 ng.hr / mL. 48In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered twice daily. In some embodiments, the therapeutically effective amount is about 100 mg of micronized solabegron administered once daily.

[0131] The present invention also relates to a method of treating irritable bowel syndrome and similar gastrointestinal disorders in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 50 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 30 microns. In some embodiments, 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0132] Embodiments of the present invention also relate to a method of treating inflammatory bowel disease in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of about 50 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to about 30 microns. In some embodiments, 90% of the solabegron particles have a particle size of about 0.1 microns to about 10 microns. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, administration of the pharmaceutical composition is twice daily. In some embodiments, the inflammatory bowel disease includes Crohn's disease and ulcerative colitis.

[0133]

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron. In some embodiments, the composition comprises a therapeutically effective amount of about 50 mg to about 125 mg of non-micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the non-micronized solabegron pharmaceutical composition further comprises one or more surfactants. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0134] Embodiments of the present invention also relate to a method of treating irritable bowel syndrome and similar gastrointestinal disorders in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron. In some embodiments, the composition comprises a therapeutically effective amount of about 50 mg to about 125 mg of non-micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the non-micronized solabegron pharmaceutical composition further comprises one or more surfactants. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0135] The present invention also relates to a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron. In some embodiments, the composition comprises a therapeutically effective amount of about 50 mg to about 125 mg of non-micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the non-micronized solabegron pharmaceutical composition further comprises one or more surfactants. In some embodiments, the pharmaceutical composition is an immediate release composition. In some embodiments, the pharmaceutical composition is administered twice daily.

[0136] In some embodiments, the compositions disclosed herein may be administered once, as needed, once a day, twice a day, three times a day, once a week, twice a week, every other week, every other day, etc., for one or more administration cycles. An administration cycle may include administration for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. After this cycle, the next cycle may be initiated about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. A treatment regimen may include 1, 2, 3, 4, 5, or 6 cycles, each cycle being about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks apart. It will be understood that the specific dose level and frequency of administration for a particular subject may vary and will depend on a variety of factors including the subject's species, age, body weight, general health, sex and diet, mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition.

[0137] In some embodiments, when the composition is administered twice daily, the period between administration of the first and second doses is about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, or about 18 hours.

[0138] In some embodiments, the bid administration of an immediate release solid oral dosage form comprising about 100 mg of micronized solabegron has a time interval between administrations of 5 to 15 hours. In another embodiment, the bid administration of an immediate release solid oral dosage form comprising about 100 mg of micronized solabegron has a time interval between administrations of 6 to 16 hours. In another embodiment, the bid administration of an immediate release solid oral dosage form comprising about 100 mg of micronized solabegron has a time interval between administrations of 5 to 10 hours. In another embodiment, the bid administration of an immediate release solid oral dosage form comprising about 100 mg of micronized solabegron has a time interval between administrations of 6 to 12 hours.

[0139] In some embodiments, the pharmaceutical composition disclosed herein is administered once a day. In some embodiments, the pharmaceutical composition comprises 100 mg of micronized solabegron and is administered once a day. In some embodiments, the pharmaceutical composition is an immediate release composition, a modified release composition, or a combination thereof.

[0140] An embodiment of the present invention also relates to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of micronized solabegron or a pharma- ceutical acceptable salt or derivative thereof, said pharmaceutical composition having a target AUC of about 5,000 ng.hr / mL to about 35,000 ng.hr / mL and a C of about 1 μg / mL to about 5.0 μg / mL. max In some embodiments, the pharmaceutical composition achieves a target AUC of about 17,000 ng.hr / mL. In other embodiments, the pharmaceutical composition achieves a C of 2.1 μg / mL. max In some embodiments, the pharmaceutical composition comprises about 100 mg of micronized solabegron and is administered twice daily. In some embodiments, the pharmaceutical composition comprises about 100 mg of micronized solabegron and is administered once daily.

[0141]

[0023] Embodiments of the present invention also relate to a method of treating overactive bladder or one or more symptoms thereof in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of non-micronized solabegron or a pharma- ceutically acceptable salt or derivative thereof and one or more surfactants, wherein the pharmaceutical composition achieves a target AUC of about 5,000 ng.hr / mL to about 35,000 ng.hr / mL and a Cmax of about 1 μg / mL to about 5.0 μg / mL. In some embodiments, the pharmaceutical composition achieves a target AUC of about 17,000 ng.hr / mL. In other embodiments, the pharmaceutical composition achieves a Cmax of 2.1 μg / mL. In some embodiments, the pharmaceutical composition comprises about 100 mg of non-micronized solabegron and is administered twice daily. In some embodiments, the pharmaceutical composition comprises about 100 mg of non-micronized solabegron and is administered once daily.

[0142] The pharmaceutical composition of the present application can be administered by any suitable means, for example, orally, sublingually, or buccally, for any of the uses described herein.The composition can be administered, for example, in a form suitable for immediate release or sustained release.Immediate release or sustained release can be achieved by using a suitable pharmaceutical composition containing the compound of the present invention, or, especially in the case of sustained release, by using a device such as a subcutaneous implant or an osmotic pump.The composition of the present invention can also be administered liposomally.

[0143] In some embodiments, the method of treating overactive bladder or a symptom thereof may further comprise administering a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents may be administered before, simultaneously with, or after administration of a pharmaceutical composition comprising solabegron. In some embodiments, the one or more additional therapeutic agents may be present in the same composition with solabegron. In some embodiments, the one or more additional therapeutic agents may be antimuscarinic agents, alpha adrenergic receptor blockers, botulinum toxins, purinergic agonists, cannabinoids, transient receptor potential (TRP) protein inhibitors, prostaglandins, transcutaneous tibial nerve stimulators, 5-alpha reductase inhibitors, phosphodiesterase-5 inhibitors, beta-3 adrenergic receptor agonists, and combinations thereof. In some embodiments, the additional therapeutic agent is trospium or tolterodine.

[0144] Working Example Example 1: Micronized Solabegron Tablet Formulation Table 3 shows the 125 mg and 175 mg tablet compositions of micronized solabegron. [Table 3]

[0145] A formulation comparison of non-micronized and micronized solabegron tablets is shown in Table 4. The excipients used in the micronized formulation were identical to the non-micronized solabegron formulation, except for two minor differences listed below. The differences in excipients used in the micronized formulation did not affect the in vitro tablet performance. 1. The poloxamer P188 and Lutrol F68 in the micronized formulation are standard particle size materials as opposed to the "micro" materials previously used. Because poloxamer makes up only 1% of the formulation, this change did not alter processability or dissolution performance. 2. Instead of Opadry White® OY-S-28876, use low TiO 2Opadry II (white), 85F18546 was formulated into a micronized formulation. Low TiO 2 Opadry II was selected for its excellent resistance to scratching during processing. [Table 4]

[0146] Example 2: Dissolution Profiles of Micronized and Non-Micronized Solabegron The dissolution of various solabegron tablets was measured using USP Apparatus 2 according to the current USP standards for dissolution. <711> The parameters are shown in Table 5. [Table 5]

[0147] The dissolution profiles of all tablet formulations are shown in Figures 1 to 6.

[0148] Example 3: Comparison of dissolution profiles of micronized and non-micronized 125 mg solabegron tablets The dissolution of 125 mg micronized and 125 mg non-micronized solabegron tablets was measured using a USP Type 2 apparatus with the parameters listed in Table 5. Table 6 shows the dissolution rates at various time points and is graphically depicted in Figure 7. The dissolution profiles of the micronized and non-micronized tablets were similar except for a slight difference in the dissolution rate at 10 minutes. [Table 6]

[0149] Example 4: Comparison of dissolution profiles of micronized and non-micronized 175 mg solabegron tablets The dissolution of 175 mg micronized solabegron tablets and 175 mg non-micronized solabegron tablets was measured using USP Type 2 apparatus with the parameters listed in Table 5. Table 7 shows the dissolution rates at various time points and is graphically depicted in Figure 8. The dissolution profiles of micronized and non-micronized tablets were similar at all intervals. [Table 7]

[0150] Example 5: Evaluation of the efficacy of micronized solabegron tablets This study is a phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and tolerability of solabegron tablets (solabegron D90 approximately 4.22-7.65 microns) administered twice daily for 12 weeks in adult women. Eligible female subjects with at least 6 months of overactive bladder symptoms (urinary frequency, urgency, and primarily urge incontinence) were selected for the study. Eligible subjects who met pre-specified criteria were randomized 1:1:1 to receive micronized solabegron immediate-release tablets, low or high dose, or matching placebo. The objectives of this study are: (a) to evaluate the efficacy of micronized solabegron immediate-release tablets, 125 mg or 175 mg, administered twice daily to adult female subjects with OAB; and (b) to evaluate the safety and tolerability of micronized solabegron immediate-release tablets, 125 mg or 175 mg, administered twice daily to adult female subjects with OAB.

[0151] The primary efficacy endpoint of the study was the change from baseline in the mean number of micturitions per 24 hours at week 12 in the MITT (primary analysis) population. Treatment with micronized solabegron 125 mg twice daily reduced the mean number of micturitions from baseline at week 12 by nearly 4 micturitions per 24 hours (-3.86). The comparison of the micronized solabegron 125 mg group with the placebo group was statistically significant (placebo-corrected reduction = -0.82; p = 0.0134). In contrast, the mean reduction in micturition in the placebo group exceeded the mean reduction from baseline in the solabegron 175 mg group at week 12 (placebo-corrected increase; p = 0.0428). The results of the MITT (primary analysis) population using LOCF are summarized in Table 8 and Figures 9A and 9B. [Table 8]

[0152] Additionally, the micronized solabegron 125 mg and 175 mg groups were associated with a 72% and 67% reduction, respectively, in urge incontinence episodes from baseline to week 12. Statistically significant differences compared with placebo were evident for the solabegron 125 mg and 175 mg groups at week 8.

[0153] There was a statistically significant difference in mean change from baseline in urgency ratings between the 125 mg and 175 mg micronized solabegron groups compared to the placebo group at week 12. There were also statistically significant differences between the 175 mg solabegron group and the placebo group at weeks 4 and 8.

[0154] A statistically significant reduction from baseline in the mean number of urgency episodes per 24 hours was demonstrated in the micronized solabegron 125 mg group compared to the placebo group at weeks 8 and 12. The reduction in urgency episodes from baseline was slightly higher in the PP analysis, with a significant reduction demonstrated in the micronized solabegron 125 mg and micronized solabegron 175 mg groups at week 8 and in the micronized solabegron 125 mg group at week 12 compared to the placebo group.

[0155] A statistically significant reduction from baseline in % dryness was also demonstrated by the micronized solabegron 125 mg and 175 mg groups.

[0156] Example 6: Comparison of Pharmacokinetics and Clinical Efficacy of Micronized and Non-Micronized Solabegron Tablets A phase 2 proof-of-concept study conducted with non-micronized solabegron (Ohlstein, et. al., "A multicenter, double-blind, randomized, placebo-controlled trial of the β3-adrenoceptor agonist solabegron for overactive bladder", European Urology, 62(5): 834-840 June 5, 2012) and a comparison with the phase 2 study (Example 9) confirm that micronization of solabegron in the pharmaceutical composition had an unexpectedly significant and meaningful impact on its pharmacokinetics in patients with OAB.

[0157] As shown in Table 9 and FIG. 10, the 125 mg micronized solabegron tablets (D90 4.22-7.65 microns) in the Example 5 study demonstrated increased mean AUC (24 hr) and mean Cmax compared to the non-micronized tablets. [Table 9]

[0158] Surprisingly, treatment with micronized solabegron tablets increased exposure (AUC) by approximately 40%.

[0159] The higher exposure levels achieved by the micronized formulation may reduce the amount (dose) of solabegron that needs to be administered to a patient. For example, based on the data presented in Table 9, for a 125 mg micronized solabegron formulation, a 100 mg dose of solabegron is predicted to have better exposure than a 125 mg dose of non-micronized solabegron (Table 10). [Table 10]

Claims

1. 1. A pharmaceutical composition comprising about 100 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of said micronized solabegron has a particle size of about 0.1 microns to 30 microns, and said pharmaceutical composition is an immediate release composition.

2. 2. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of a filler, a disintegrant, a binder, a wetting agent, a lubricant, and a glidant, or a combination thereof.

3. 3. The pharmaceutical composition of claim 1, wherein the excipient is selected from the group consisting of mannitol, poloxamer 188, methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and polyvinyl alcohol, or a combination thereof.

4. 3. The pharmaceutical composition of claim 1, wherein the excipient is selected from the group consisting of sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, sodium carboxymethylcellulose, white wax, magnesium stearate, and carnauba wax, or a combination thereof.

5. 3. The pharmaceutical composition of claim 1, wherein the excipient is selected from the group consisting of colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide, or a combination thereof.

6. 10. The pharmaceutical composition of claim 1, further comprising one or more additional therapeutic agents selected from trospium or tolterodine.

7. 10. The pharmaceutical composition of claim 1, wherein the composition is a tablet, capsule, granule or powder.

8. A pharmaceutical composition comprising a therapeutically effective amount of about 100 mg to about 125 mg of micronized solabegron or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, wherein at least 90% of the solabegron particles have a particle size of about 0.1 microns to 30 microns, said pharmaceutical composition being an immediate release composition, for use in treating overactive bladder or one or more symptoms thereof in a subject in need thereof, and which is administered orally.

9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is administered twice daily.

10. 9. The pharmaceutical composition of claim 8, wherein the one or more symptoms are selected from increased frequency of urinary urgency, nocturia, increased urination frequency, and urinary incontinence, and combinations thereof.

11. 9. The pharmaceutical composition of claim 8, wherein the treatment further comprises administration to the subject of one or more additional therapeutic agents selected from the group consisting of antimuscarinics, alpha adrenergic receptor blockers, botulinum toxins, purinergic agonists, cannabinoids, transient receptor potential (TRP) protein inhibitors, prostaglandins, transcutaneous tibial nerve stimulators, sacral nerve stimulators, 5-alpha reductase inhibitors, phosphodiesterase-5 inhibitors, beta-3 adrenergic receptor agonists, and combinations thereof.

12. 12. The pharmaceutical composition of claim 11, wherein the additional therapeutic agent is an antimuscarinic agent.

13. 13. The pharmaceutical composition of claim 12, wherein the antimuscarinic agent is trospium or tolterodine.

14. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition has a target AUC of about 17,000 ng.hr / mL to about 23,000 ng.hr / mL. ４８ A pharmaceutical composition which achieves the above object.

15. 15. The pharmaceutical composition of claim 14, wherein the amount of micronized solabegron is about 100 mg.

16. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is administered twice daily.

17. The pharmaceutical composition of claim 14, wherein the amount of micronized solabegron is about 125 mg.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is administered twice daily.

19. The pharmaceutical composition of claim 1, wherein the micronized solabegron has a particle size of about 0.1 microns to 10 microns.

20. A pharmaceutical composition according to claim 1 for use in treatment.

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