Composition and method for oral delivery of sustained-release crystalline PRX-3140

Abstract

This disclosure relates to a novel crystalline form of the compound of formula I, commonly known as PRX-3140:##STR00001##(6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidine-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide potassium salt or potassium 7-isopropyl-6-oxo-5-(3-piperidine-1-yl-propylcarbamoyl)-6,7-dihydro-thieno[2,3-b]pyridine-4-oleate), a particle dispersal system for the crystalline compound, a method for preparing such compositions, and its therapeutic use. This disclosure also relates to a method for treating diabetes and lowering mean daily blood glucose by the use of PRX-3140. Crystalline PRX-3140 compositions are described in U.S. Patents No. 11,725,016 and No. 11,993,609.

Description

Technical Field

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 471,059, filed on June 5, 2023, and U.S. Provisional Patent Application No. 63 / 543,114, filed on October 9, 2023, which are hereby incorporated by reference in their entirety.

Background Art

[0002] The present disclosure generally relates to novel crystalline forms of a compound of formula I, which is PRX-3140: ##STR00001## (also called potassium 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide or potassium 7-isopropyl-6-oxo-5-(3-piperidin-1-yl-propylcarbamoyl)-6,7-dihydro-thieno[2,3-b]pyridine-4-olate), particulate sustained release delivery systems of crystalline compounds, methods of preparing such compositions, and their therapeutic use. The present disclosure also relates to methods of treating diabetes and reducing mean blood glucose per day by the use of PRX-3140. Crystalline PRX-3140 compositions are described in U.S. Pat. Nos. 11,725,016 and 11,993,609. Sustained release PRX-3140 formulations and uses of the present disclosure are described in Patent Applications Nos. 63 / 471,059 and 63 / 543,114. The compositions described herein enable the crystalline PRX-3140 potassium salt compound to be administered by a non-invasive route to a patient, such as oral sustained release administration.

Chem.

[0003] The compounds of this disclosure, referred to in the literature as PRX-3140, PRX-03140, PRX-3140 potassium salt, or PRX-3140 acid in solution (the potassium ion dissociates in aqueous or physiological solution), are selective partial agonists for 5-hydroxytryptamine receptor 4 (5-HT4) and ligands for Sigma-1 and Sigma-2 receptors. PRX-3140 is a highly selective and potent (Ki=22~37nM) 5-HT4R agonist in radioligand binding assays, exhibiting affinity differences of more than 100-fold compared to all other 5-HT receptors tested. PRX-3140 acts as a partial agonist in cell lines expressing any of the human 5-HT4aR, 5-HT4bR, or 5-HT4eR isoforms, stimulating cAMP production to 30%~60% compared to 5-HT. PRX-3140 also demonstrates binding to both Sigma-1 and Sigma-2 receptors (Ki = 79–100 nM and 99–160 nM, respectively) in radioligand binding assays, but does not demonstrate significant affinity to more than 50 other receptors tested, including GPCRs, ion channels, and receptor tyrosine kinases. Specific ligand binding to the receptor is defined as the difference between total binding and determined nonspecific binding in the presence of excess unlabeled ligand. The inhibition constant (Ki) was calculated from the Cheng-Prusoff formula (Ki = IC50 / (1 + (L / KD)), where L = concentration of radioligand in the assay, Kd = affinity of radioligand to the receptor, and Hill coefficient = 1).

[0004] PRX-3140 is being developed for Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems, including post-traumatic stress disorder (PTSD). Extensive preclinical studies have been completed, including in vitro and in vivo pharmacological, safety pharmacological, genotoxicity, and single-dose and repeated-dose toxicity studies in two species, rats and beagle dogs. Early-stage clinical studies, including safety, tolerability, and pharmacokinetics of PRX-3140, demonstrate high oral bioavailability of the compound up to 250 milligrams, as well as safety and efficacy. In addition to its high oral bioavailability, PRX-3140 achieves a brain / serum distribution ratio of 0.93 at 1 hour post-oral administration in preclinical studies. PRX-3140 demonstrates high CNS permeability without inducing significant distal gastrointestinal motility observed with gastrointestinally active 5-HT4 agonists (e.g., cisapride, tegaserod).

[0005] Oral administration of drugs such as PRX-3140 is generally preferred over intravenous administration for reasons of patient comfort and compliance. However, many drugs are absorbed in varying ways when delivered orally. For the past decade, considerable effort has been made to produce drug particles ranging from 100 nanometers to several hundred microns in size, for their improved solubility and ability to be absorbed more efficiently. Through several experiments, the inventors have surprisingly discovered a novel solid form of PRX-3140, including a fine particle crystalline form of PRX-3140 potassium salt. This crystalline form has unexpectedly good properties, is more suitable for formulation processing, storage, and industrial production, and has better bioavailability. Compared to the known solid forms of PRX-3140 described in U.S. Patent No. 7,488,736, followed by U.S. Patent No. 7,982,040, the fine particle crystalline form of PRX-3140 potassium salt of the present invention has at least one or more superior properties and achieves unexpected effects. Specific improvements include, for example, higher solubility in water, faster dissolution rate, better stability, lower hygroscopicity, better fluidity, and better processing and handling characteristics. Preferably, the new solid form in the present invention has improved stability.

[0006] There is a strong need for formulations that provide sustained blood levels of PRX-3140 to avoid the rapid release or delivery of PRX-3140 in subjects that may be associated with patient side effects. Furthermore, there is a strong need to ensure that the full dose of PRX-3140 is available to patients by ensuring that the drug passes through the stomach without being broken down in its acidic environment. Examples of controlled-release and sustained-release formulations include U.S. Patent Nos. 6,984,404, 7,829,105, 7,846,459, 8,377,479, 8,394,812, 8,389,008, 8,501,232, 9,040,091, 9,554,996, 11,202,788, 11,291,673, and U.S. Patent Application Publication No. 2022 / 0175702. In particular, there is a need for treatments for patients with Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems (including acquired stress disorder (PTSD)) where treatments with reduced interactions with other drugs or their metabolism are required. Further factors that reduce the risk of clinical success with once-daily formulations in Alzheimer's disease include a high prevalence of gastrointestinal complications affecting gastrointestinal parameters, including transit time, pH, bacterial composition, and other functions of the GI system. These complications include nausea, vomiting, and very frequent diarrhea.

[0007] Diabetes mellitus is an inflammatory metabolic disorder characterized by chronically high blood glucose levels (hyperglycemia) due to insufficient insulin activity. Insulin, produced by pancreatic beta cells, promotes glucose utilization for energy storage, protein synthesis, and glycogen formation. Glycogen stores glucose and can be converted back as needed. Under normal conditions, insulin is secreted in response to glucose at basal and increased rates, maintaining metabolic equilibrium through the conversion of glucose to glycogen. Diabetes mellitus encompasses type 1 (insulin-dependent, IDDM) and type 2 (insulin-independent, NIDDM) diabetes. In type 1, there is an insulin deficiency and insulin replacement therapy is required. In type 2, there is initially insulin resistance, which can be managed with diet, lifestyle changes, and oral medications, but insulin may later be required to control hyperglycemia and prevent complications associated with hyperglycemia and inflammation. Three cytokines thought to be involved in pancreatic beta cell inflammation in IDDM are interferon-gamma (IFN-γ) and the innate inflammatory cytokines TNF-α and IL-1β. Further evidence also suggests that cortisol and other glucocorticoids, which normally suppress insulin release, are regulated by sigma-1 receptors, resulting in improved diabetes control. Therefore, there is a need for methods to alleviate inflammation and diabetes, including improving average daily blood glucose levels. Surprisingly, oral PRX-3140 has been found to lower blood glucose levels in a dose-dependent manner. There is a strong need for formulations that provide sustained blood levels of PRX-3140, avoiding the rapid release or delivery of PRX-3140 in subjects that may be associated with patient side effects. Furthermore, there is a strong need to ensure that the full dose of PRX-3140 is available to patients by ensuring that the drug passes through the stomach without being broken down in its acidic environment. In particular, there is a need for treatment of diabetic patients with hyperglycemia, with reduced interaction effects with other drugs or their metabolism. Further effects of improved insulin levels and blood glucose levels include improved response to glucocorticoid therapy and weight control, including obesity. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 11,725,016 [Patent Document 2] Strength Specification No. 11,993,609 [Patent Document 3] U.S. Patent No. 7,488,736 [Patent Document 4] U.S. Patent No. 7,982,040 [Patent Document 5] U.S. Patent No. 6,984,404 [Patent Document 6] U.S. Patent No. 7,829,105 [Patent Document 7] U.S. Patent No. 7,846,459 [Patent Document 8] U.S. Patent No. 8,377,479 [Patent Document 9] U.S. Patent No. 8,394,812 [Patent Document 10] U.S. Patent No. 8,389,008 [Patent Document 11] U.S. Patent No. 8,501,232 [Patent Document 12] U.S. Patent No. 9,040,091 [Patent Document 13] U.S. Patent No. 9,554,996 [Patent Document 14] U.S. Patent No. 11,202,788, [Patent Document 15] U.S. Patent No. 11,291,673 [Patent Document 16] U.S. Patent Application Publication No. 2022 / 0175702 Specification [Overview of the Initiative] [Means for solving the problem]

[0009] This disclosure addresses this need by providing crystalline PRX-3140 potassium salt preparations for composition, preparation and treatment of the compound. In one embodiment, this disclosure provides a novel method for preparing a sustained-release preparation of the compound of formula I: ##STR00001## shown in Figure 1. [ka] A sustained-release polymer selected from microcrystalline cellulose, hydroxypropyl methylcellulose with a number-average molecular weight of approximately 86,000 to 220,000 daltons, 80% polyvinyl acetate (weight-average molecular weight approximately 450,000 daltons) / polyvinylpyrrolidone (weight-average molecular weight approximately 55,000 daltons), and xanthan gum, wherein more than 90% of the compound of formula I is in crystalline form I, characterized by an X-ray powder diffraction pattern with major peaks at 22.3+ / -0.3°, 25.3+ / -0.3°, and 5.4+ / -0.3° 2-theta, and the release of the compound of formula I from the oral dosage form as defined by in vitro dissolution is up to 50% as measured by reversed-phase high-performance liquid chromatography (HPLC) at 2 hours and at least 50% as measured by HPLC at 12 hours, and the dissolution of the oral dosage form is measured from 0 to 2 hours by the United States Pharmacopeia (USP) II dissolution test (paddle method) or USP The process is carried out at 50 revolutions per minute in water or simulated gastric fluid at pH 1.2, and then at 2 hours later in simulated intestinal fluid at pH 6.8, following the general procedure of the basket method (I). In certain embodiments, the disclosure provides that the oral dosage form is in the form of a capsule or a tablet. In other embodiments, the tablet is coated. In further embodiments, the disclosure provides that the weight ratio of the oral dosage form of microcrystalline cellulose to at least one sustained-release polymer is about 1:3 to about 3:1. In another embodiment, the disclosure provides a sustained-release oral dosage form in which the weight ratio of microcrystalline cellulose to at least one sustained-release polymer is about 1:1 to about 3:1. In another embodiment, the disclosure provides a sustained-release oral dosage form according to any one of claims 1 to 6, comprising about 2% to about 10% by weight of the compound of formula I. In another embodiment, the disclosure provides a sustained-release oral dosage form comprising about 2% to about 5% by weight of the compound of formula I. In another embodiment, the disclosure provides a sustained-release oral dosage form comprising about 3.3% by weight of the compound of formula I. In another embodiment, the disclosure provides a sustained-release oral dosage form, the oral dosage form is Formula II:##STR00002## [ka] Formula III:##STR00003## [Chemical] It further comprises. In another embodiment, the present disclosure provides a sustained-release oral dosage form, wherein the oral dosage form, if present, contains less than 0.5% by weight of the compound of Formula II and, if present, less than 0.5% by weight of the compound of Formula III.

[0010] The present invention also describes a method of treating a disease in a human subject who needs treatment for the disease, which includes administering to the human at least once a day a therapeutically effective amount of a pharmaceutical composition comprising crystalline PRX-3140 potassium salt in order to achieve a steady-state average concentration (Cavg) of at least 1 ng / ml of PRX-3140 free acid in the blood. In some embodiments, the method of treating a disease in a human subject who needs treatment for the disease includes crystalline PRX-3140 potassium salt present in the pharmaceutical composition in an amount of 0.1 mg to about 250 mg. In some embodiments, the method of treating a disease in a human subject who needs treatment for the disease includes crystalline PRX-3140 potassium salt present in the pharmaceutical composition, and the disease is type 2 diabetes. In some embodiments, the method of treating a disease in a human subject who needs treatment for the disease includes crystalline PRX-3140 potassium salt present in the pharmaceutical composition, and the disease is type 1 diabetes. In some embodiments, the method for treating a disease in a human subject who needs treatment for the disease includes crystalline PRX-3140 potassium salt present in the pharmaceutical composition, and the disease is being treated with glucocorticoid therapy. In some embodiments, the method of treating a disease in a human subject who needs treatment for the disease includes crystalline PRX-3140 potassium salt present in the pharmaceutical composition, and the disease is obesity.

[0011] In some embodiments, the composition comprises a compound of formula I:##STR00001##, or a crystalline form of the potassium salt or polymorph or salt thereof, wherein crystalline form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 22.3+ / -0.3°, 25.3+ / -0.3°, and 5.4+ / -0.3°, and optionally further comprising at least one peak selected from 25.8+ / -0.3°, 15.9+ / -0.3°, and 29.9+ / -0.3°. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 21.6+ / -0.3°, 16.5+ / -0.3°, and 20.3°. The X-ray powder diffraction pattern may further include peaks at 21.3+ / -0.3°, 17.1+ / -0.3°, 16.3+ / -0.3°, 33.1+ / -0.3°, 45.6+ / -0.3°, and 13.7+ / -0.3° in the 2-theta. In some embodiments, crystalline form I is substantially characterized by the X-ray powder diffraction pattern shown in Figures 3A and 3B. In some embodiments, more than 90% by weight of the compound of formula I in the composition may be crystalline form I. In some embodiments, the compound of formula I:##STR00001## is form I and is present in an amount ranging from about 0.01% by mass to about 99.99% by mass of the composition. In some embodiments, the composition has an average diameter of about 1 mm, 0.5 mm, or less than 0.3 mm. In some embodiments, the compound is stable for at least 12 months at 5 and 60% relative humidity or 25 and 60% relative humidity. In further embodiments, the formation of decomposition products is less than 0.5% by weight per year at 5% and 60% relative humidity or 25% and 60% relative humidity.In further embodiments, the compound degradation products are formula II:##STR00002##.5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and formula III:##STR0000 3##.[7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide. In further embodiments, the composition may contain less than 0.5% by weight of formula II:##STR00002##.5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxatiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxatiino[6,5-b]pyridine-2,2,7(8H)-trione, and formula III:##STR00003##.[7-( If the composition contains methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)-N-(3-piperidylpropyl)carboxamide or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, the composition is white or light brown. Formula II:##STR00002## [ka] Formula III:##STR00003## [ka]

[0012] In certain embodiments, a particulate delivery system (PDS) is described comprising a crystalline form of the compound of formula I:##STR00001## and at least one pharmaceutically acceptable additive. In certain embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from two thetas at 22.3+ / -0.3°, 25.3+ / -0.3°, and 5.4+ / -0.3°. In certain embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from two thetas at 25.8+ / -0.3°, 15.9+ / -0.3°, and 29.9+ / -0.3°. In certain embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from two thetas at 21.6+ / -0.3°, 16.5+ / -0.3°, and 20.3°. In certain embodiments, the X-ray powder diffraction pattern further includes peaks at 25.8 ± 0.3 degrees, 15.9 ± 0.3 degrees, 29.9 ± 0.3 degrees, 21.6 ± 0.3 degrees, 16.5 ± 0.3 degrees, and 20.3 degrees in the 2-theta. In certain embodiments, the crystalline form of the compound of formula I is characterized substantially by the X-ray powder diffraction pattern shown in Figure 3A or Figure 3B. Furthermore, the crystalline form I in the matrix of the sustained-release polymer hydroxypropyl methylcellulose (Methocel K100M) and xanthan gum is characterized substantially by the X-ray powder diffraction patterns shown in Figures 13A and 13B, respectively. In certain embodiments, a particulate delivery system containing more than 90% by weight of the compound of formula I:##STR00001## is in form I. In certain embodiments, the particulate delivery system containing the crystalline compound of formula I:##STR00001## is in form I and is present in amounts ranging from about 0.01% to about 99.99% by mass, about 10% to about 90% by mass, or about 10% to about 50% by mass. In certain embodiments, the particulate delivery system is formulated for oral, parenteral, or topical delivery. In certain embodiments, the particulate delivery system is formulated for oral delivery as a tablet, caplet, capsule, or pill. In certain embodiments, the particulate delivery system has an average diameter of about 1 mm, 0.5 mm, or less than 0.3 mm.In certain embodiments, the pharmaceutically acceptable additive is a polymer, a water-soluble polymer, selected from starch, cellulose, or polyethylene glycol. In certain embodiments, the particulate delivery system comprises a second additive, selected from magnesium stearate, stearic acid, hydroxypropyl-beta-cyclodextrin, silicon dioxide, mannitol, hydroxypropyl methylcellulose, polyvinyl acetate / povidone, or xanthan gum. In further embodiments, the second additive is a sugar. In certain embodiments, the particulate delivery system is formulated for oral administration and may contain 0.01 mg to 200 mg of the compound. In certain embodiments, the particulate delivery system containing the compound is stable for at least 12 months at 5 and 60% relative humidity or 25 and 60% relative humidity. In further embodiments, the formation of degradation products is less than 0.5% by weight per year at 5 and 60% relative humidity or 25 and 60% relative humidity. In further embodiments, the compound degradation products are formula II:##STR00002##.5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and formula III:##STR0000 3##.[7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide.In further embodiments, the composition may contain less than 0.5% by weight of formula II:##STR00002##.5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxatino[6.5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxatino[6,5-b]pyridine-2,2,7(8H)-trione, and formula III:##STR00003##.[7-( If the composition contains methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)-N-(3-piperidylpropyl)carboxamide or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, the composition is white or light brown. In further embodiments, the sustained-release oral dosage form contains, if present, less than 0.5% by weight of the compound of formula II and, if present, less than 0.5% by weight of the compound of formula III.

[0013] The present invention also describes a method for producing a particulate delivery system (PDS) of the compounds of the Composition, comprising blending the Composition with an additive to form a mixture, processing the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the coarse particles to form particles having an average diameter of less than about 0.5 mm. In further embodiments, the present invention also describes a method for producing a particulate delivery system of the compounds of the Composition, comprising blending the Composition with a polymer to form a mixture, processing the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and jet milling the coarse particles to form particles having an average diameter of less than about 1 micrometer.

[0014] In certain embodiments, the Disclosure provides a method for treating Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems, comprising administering an effective amount of a composition of the Compound to a patient in need. In further embodiments, the Disclosure provides a method for treating post-traumatic stress disorder (PTSD), comprising administering an effective amount of a composition of the Compound to a patient in need.

[0015] In certain embodiments, the Disclosure provides a method for treating a subject with Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems, comprising administering to a subject a composition comprising a crystalline form of the compound of formula I:##STR00001##, wherein at least 90% by weight of the compound of formula I in the composition is in the crystalline form of the compound, characterized in form I having an X-ray powder diffraction pattern with major peaks at 22.3+ / -0.3°, 25.3+ / -0.3°, and 5.4+ / -0.3°, and the composition is prepared by blending the composition with additives to form a mixture, processing the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the coarse particles to form particles having an average diameter of less than about 500 micrometers.

[0016] In another aspect, the present disclosure relates to a method for producing a composition comprising a crystalline fine particle form I of PRX-3140 potassium salt, Blending crystalline fine particle form I of PRX-3140 potassium salt with additives to form a mixture. The above mixture is processed to form coarse particles having an average diameter in the range of approximately 0.1 mm to approximately 5 mm, and The above coarse particles are crushed to form particles having an average diameter in the range of approximately 0.1 micrometers to approximately 0.5 mm. This provides a method that includes [something].

[0017] In another embodiment, this disclosure is expressed as formula I:##STR00001## [ka] Provides the crystalline form of the compound, Form I is described by an X-ray powder diffraction pattern further including at least one peak selected from the 2-theta at 22.3+ / -0.3°, 25.3+ / -0.3°, 5.4+ / -0.3°, 25.8+ / -0.3°, 15.9+ / -0.3°, 29.9+ / -0.3°, 21.6+ / -0.3°, 16.5+ / -0.3°, and 20.3°. More than 90% by weight of the compound of formula I:##STR00001## is form I.

[0018] In another embodiment, the present disclosure provides a compound of formula I in crystalline form: ##STR00001## [ka] Crystal morphology I, characterized by its X-ray powder diffraction pattern, further includes at least one peak selected from two thetas at 22.3+ / -0.3°, 25.3+ / -0.3°, 5.4+ / -0.3°, 25.8+ / -0.3°, 15.9+ / -0.3°, 29.9+ / -0.3°, 21.6+ / -0.3°, 16.5+ / -0.3°, and 20.3°. Compound I: ##STR00001## is in form I if more than 90% by weight is The composition has an average diameter of less than approximately 500 μm. The compound is stable for at least 12 months at 5 and 60% relative humidity or 25 and 60% relative humidity.

[0019] In another embodiment, the Disclosure provides a method for producing a particulate delivery system of the compounds of the Composition, comprising blending the Composition with additives to form a mixture, processing the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the coarse particles to form particles having an average diameter of less than about 0.5 mm. In a further embodiment, the Invention also describes a method for producing a particulate delivery system of the compounds of the Composition, comprising blending the Composition with a polymer to form a mixture, processing the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and jet milling the coarse particles to form particles having an average diameter of less than about 1 micrometer.

[0020] In another set of embodiments, sustained-release (SR) oral dosage forms are described, comprising a crystalline form of compound I: ##STR00001## and at least one pharmaceutically acceptable additive. In certain embodiments, the SR dosage form contains more than 90% by weight of compound I: ##STR00001## in form I. In certain embodiments, the SR dosage form contains crystalline compound I: ##STR00001## in form I, present in amounts ranging from about 0.01% to about 99.99% by mass, about 10% to about 90% by mass, or about 10% to about 50% by mass. In certain embodiments, the SR dosage form is formulated for oral, parenteral, or topical delivery. In certain embodiments, the SR dosage form is formulated for oral delivery as a tablet, caplet, capsule, or pill. In certain embodiments, the pharmaceutically acceptable additive in the SR dosage form is a polymer, a water-soluble polymer, selected from starch, cellulose, gum, or polyethylene glycol. In certain embodiments, the SR dosage form comprises a second additive selected from magnesium stearate, stearic acid, hydroxypropyl-beta-cyclodextrin, silicon dioxide, mannitol, hydroxypropyl methylcellulose, polyvinyl acetate / povidone, or xanthan gum. In certain embodiments, the SR dosage form is formulated for oral administration and may contain 0.01 mg to 200 mg of the above compound. In certain embodiments, the SR dosage form contains the above compound and is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity. In further embodiments, the formation of degradation products is less than 0.5% by weight per year at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity.In further embodiments, the compound degradation products are formula II:##STR00002##:5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione and formula III:##STR0000 3##:7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide. In further embodiments, the SR dosage form is a composition containing an amount of formula II:##STR00002##:5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione and less than 0.5% by weight of formula III:##STR00003##: If the SR dosage form contains 7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)-N-(3-piperidylpropyl)carboxamide or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, the SR dosage form is white or light brown. In further embodiments, the SR dosage form has at least two solubility parameters of PRX-3140, selected from a solubility of less than 50% at 2 hours and a solubility of at least 50% at 12 hours, measured at 37 degrees Celsius in water or simulated gastric juice at pH 1.2 for 0-2 hours and in simulated intestinal juice at pH 6.8 after 2 hours.

[0021] In another embodiment, the disclosure provides a sustained-release composition comprising PRX-3140 and a sustained-release agent, wherein the compound is PRX-3140, a polymorph of PRX-3140, a salt of PRX-3140, or a combination thereof, and the sustained-release agent is selected from the group consisting of hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, or gum. In another embodiment, the sustained-release additive is selected from the group consisting of cellulose, gum, acrylic resin, or a combination thereof. In another embodiment, the sustained-release agent is hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or a combination thereof. In another embodiment, the sustained-release agent is hydroxypropylmethylcellulose, also known as HPMC or hypromellose. Furthermore, the crystalline morphology I in the matrix of the sustained-release polymer K100M HPMC and xanthan gum is substantially characterized by the X-ray powder diffraction patterns shown in Figures 13A and 13B.

[0022] In another embodiment, the sustained-release composition contains at least 1% w / w, at least 10% w / w, at least 20% w / w, at least 25% w / w, at least 30% w / w, at least 35% w / w, or at least 40% w / w of the sustained-release agent. In another embodiment, the sustained-release composition contains 1% to 99% w / w of the sustained-release agent. In another embodiment, the sustained-release composition contains 5% to 90% w / w of the sustained-release agent. In another embodiment, the sustained-release composition contains 5% to 70% w / w of the sustained-release agent. In another embodiment, the sustained-release composition contains 10% to 40% w / w of the sustained-release agent. In another embodiment, the sustained-release composition contains 15% to 40% w / w of the sustained-release agent. In another embodiment, the sustained-release agent contains 0.25% to 10% w / w, 0.5% to 8% w / w, or 1% to 4% w / w of the compound.

[0023] In another embodiment, the sustained-release composition is formulated for oral administration as a tablet or capsule containing at least 90% w / w, at least 95% w / w, or at least 99% w / w of the compound as PRX-3140 form I. In a particular embodiment, the particulate delivery system is formulated for oral administration as a tablet or capsule and may contain 0.01 mg to 200 mg of the compound as PRX-3140 potassium salt form I.

[0024] In another embodiment, the sustained-release composition is formulated for oral administration as a tablet or capsule, and the composition further comprises one or more additives including a binder, a lubricant, or a combination thereof. In another embodiment, the binder is monosaccharide, disaccharide, starch, polyhedric alcohol, mannitol, xylitol, sorbitol, lactose, polyethylene glycol, gums such as xanthan gum, alginic acid, polyvinylpyrrolidone, methylcellulose, polyvinyl acetate, hydroxypropyl methylcellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, anhydrous dicalcium phosphate, talc, dextrate, kaolin, mannitol, silicic acid, sorbitol, or a combination thereof. In another embodiment, the binder is microcrystalline cellulose. In another embodiment, the sustained-release composition formulated for oral administration as a tablet or capsule contains 1% to 99% w / w of the binder. In another embodiment, a sustained-release composition formulated for oral administration as a tablet or capsule contains 30% to 97% w / w of binder. In yet another embodiment, a sustained-release composition formulated for oral administration as a tablet or capsule contains 40% to 75% w / w of binder. In yet another embodiment, a sustained-release composition formulated for oral administration as a tablet or capsule contains 50% to 75% w / w of binder.

[0025] In another embodiment, the lubricant is stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laurate, agar, wax, or a combination thereof. In yet another embodiment, the lubricant is magnesium stearate.

[0026] In another embodiment, a sustained-release composition formulated for oral administration as a final dosage form such as a tablet or capsule further comprises an enteric coating encapsulating the tablet or capsule containing the compound and the sustained-release agent, the enteric coating comprising the sustained-release agent, a plasticizer, an anti-tackifying agent, or a combination thereof. In another embodiment, the enteric coating is 4% to 40% w / w of the sustained-release composition. In another embodiment, the enteric coating is 5% to 30% w / w of the composition. In another embodiment, the enteric coating is 5% to 25% w / w of a particle delivery system formulated for oral administration as a tablet or capsule, comprising 5% to 20% w / w of the enteric coating of the composition. In another embodiment, the final dosage form releases at least about 50% of the drug within about 1 hour, preferably at least about 80% of the drug within about 1 or 2 hours, after the end of the delay time provided by the enteric coating. In another embodiment, the enteric coating provides a delay time of about 1 to about 2 hours after oral administration. In another embodiment, the enteric coating releases at least 50% of the drug in the colon. In another embodiment, the enteric coating agent is polymethacrylate.

[0027] In another embodiment, the Disclosure provides a sustained-release composition comprising a tablet or capsule and an enteric coating enclosing the tablet or capsule, wherein the composition comprises PRX-3140 and a sustained-release agent, and the enteric coating comprises a delayed-release agent, a plasticizer, an anti-tackifier, or a combination thereof, wherein the compound is PRX-3140, a polymorph of PRX-3140, a salt of PRX-3140, or a combination thereof, and the sustained-release agent is selected from the group consisting of hydroxyalkylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. In another embodiment, the sustained-release composition comprises a tablet or capsule and an enteric coating enclosing the tablet or capsule, comprising a core containing a therapeutically effective amount of drug, the sustained-release material comprising 1 or more natural or synthetic gums, the gums comprising about 5% to about 50% by weight of the tablet or capsule, and the enteric coating delays the release of the drug from the dosage form such that at least 50% of the drug is released into the colon after oral administration to a human.

[0028] In another embodiment, the disclosure provides a sustained-release composition comprising a tablet or capsule and an enteric coating enclosing the tablet, wherein the tablet comprises PRX-3140 and hypromellose, the compound comprises at least 1% by weight of PRX-3140, and the enteric coating comprises a poly(meth)acrylate polymer and triethyl citrate.

[0029] In another embodiment, the enteric coating further comprises talc. In another embodiment, the tablet comprises at least 20% w / w of hypromellose relative to the total tablet weight. In another embodiment, the tablet comprises 1% to 40% w / w of the compound relative to the total tablet weight. In another embodiment, the enteric coating comprises 60% to 80% w / w of poly(meth)acrylate polymer relative to the total enteric coating weight. In another embodiment, the enteric coating comprises 10% w / w or less of triethyl citrate relative to the total enteric coating weight. In another embodiment, the enteric coating comprises 10% to 40% w / w of talc relative to the total enteric coating weight.

[0030] In another embodiment, the present disclosure provides a method for preparing a sustained-release composition, comprising combining and mixing PRX-3140, polymorphs of PRX-3140, salts of PRX-3140, and combinations thereof, a sustained-release agent, a binder, and a lubricant, and drying and compressing the compound, at least one sustained-release agent, at least one binder, and at least one lubricant to form a core tablet or a filled capsule.

[0031] In another embodiment, the method further comprises mixing at least one sustained-release agent, at least one plasticizer, and at least one anti-tack or anti-adhesion component to form a coating solution, and substantially coating a core tablet or filling capsule with the coating solution to form a functional coating.

[0032] In another embodiment, the present disclosure provides a method for administering a sustained-release composition, comprising administering the sustained-release composition orally to a subject requiring the administration of the sustained-release composition, wherein the sustained-release composition comprises PRX-3140 and a sustained-release agent, the compound being PRX-3140, a polymorph of PRX-3140, a salt of PRX-3140, or a combination thereof, and the sustained-release composition is formulated such that less than 50% of the compound dissolves within 2 hours after administration and at least 50% of the compound dissolves within 12 hours after administration.

[0033] In another embodiment, the present disclosure provides a method comprising administering a sustained-release composition to a subject requiring such administration, the method comprising orally administering the sustained-release composition to the subject requiring it, the sustained-release composition comprising PRX-3140 and a sustained-release agent, the compound being PRX-3140, a polymorph of PRX-3140, a salt of PRX-3140, or a combination thereof, the compound indicating a time to a maximum observable concentration of PRX-3140 acid in the subject's blood, serum, or plasma of at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, or at least 24 hours.

[0034] In another embodiment, the Disclosure provides a method for treating a subject requiring treatment, the subject having or at risk of having a disability, and the method comprises administering the subject a sustained-release composition of the Disclosure.

[0035] In another embodiment, the present disclosure provides a method for treating a subject requiring treatment, wherein the subject is disabled or at risk of being disabled, and the method comprises administering to the subject a sustained-release composition comprising PRX-3140 and a sustained-release agent, wherein the compound is PRX-3140, a polymorph of PRX-3140, a salt of PRX-3140, or a combination thereof, and the sustained-release agent is selected from the group consisting of hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, or gum.

[0036] In another embodiment, the sustained-release composition is administered once daily, twice daily, every two days, every three days, every four days, every five days, every six days, or every seven days. In yet another embodiment, a sustained-release composition of form I PRX-3140 potassium salt is administered to the subject in doses of 0.1 mg to about 250 mg, 1 mg to about 150 mg, 1 mg to about 100 mg, 1 mg to about 50 mg, or 1 mg to about 20 mg.

[0037] In yet another embodiment, the sustained-release dosage form described herein provides a Cmax of less than 50% of the IR "drug-containing capsule" dosage form of the plasma concentration curve / time curve of PRX-3140 acid, based on a single dose or steady state. In another embodiment, the present invention also relates to a method of treating a person in need of treatment, the method comprising administering a sustained-release dosage form containing a therapeutically effective amount of PRX-3140 or a pharmaceutically acceptable salt thereof in a sustained-release system, wherein the dosage form provides a Tmax greater than 50% of the IR "drug-containing capsule" dosage form of the plasma concentration curve / time curve of PRX-3140 acid, based on a single dose or steady state, and maintains a plateau of relatively constant serum levels of PRX-3140 that do not consistently increase or decrease between time points. In yet another embodiment of the present invention, the sustained-release dosage form described herein provides less than 50% of the variability % of the plasma concentration of the IR "drug-containing capsule" dosage form.

[0038] For the purposes of this invention, the term "Cmax" refers to the calculated mean of the maximum blood concentration of PRX-3140 achieved after a single or multiple dose administration of the dosage form according to the present invention in a patient. The term "Cmin," also known as trough concentration, is the calculated mean of the minimum blood concentration of PRX-3140 achieved after multiple doses of the dosage form according to the present invention, for example on days 3, 7, or 14, or after steady state is reached. Both parameters can be transformed using pharmacokinetic calculations before correlation analysis. The term "C-mean" is the calculated mean of all blood concentrations of PRX-3140 achieved during multiple doses of the dosage form according to the present invention, for example on days 3, 7, or 14, or after steady state is reached. For the purposes of this invention, the term "Tmax" is intended to refer to the elapsed time from administration of the dosage form until the Cmax of PRX-3140 is achieved. The term AUC (Area Under the Curve) or AUC24 after a once-daily dose is the calculated product of concentration and time, taking into account all concentrations observed at the dosing interval, for example, AUC24 over 24 hours. The term % variation, or variation from peak to trough, is calculated as the ratio of the steady-state Cmax to the steady-state Cmin after administration, according to the recommended dosing interval, e.g., 24 hours for once-daily administration.

[0039] For the purposes of this invention, the terms “mean” or “calculated mean,” when used to define pharmacokinetic values ​​(e.g., Tmax), refer to the arithmetic mean measured across a patient population. For the purposes of this invention, “sustained release” means that once a drug is released from a formulation, it is released at a controlled rate such that therapeutically beneficial blood levels of the drug (but below toxic levels) are maintained for a long period from the start of drug release, for example, over a period of about 2 to about 24 hours from the point of drug release after a delay time.

[0040] This disclosure also addresses diabetes by providing crystalline PRX-3140 potassium salt preparations relating to compositions of compounds, methods for preparation and treatment for diabetes and hyperglycemia. In one embodiment, a method is provided for lowering a patient's blood glucose, comprising administering to a subject an oral formulation administered once or more times daily, containing an amount of PRX-3140 sufficient to maintain an average plasma concentration of at least about 1 ng / ml of PRX-3140 acid for at least about 12 hours. In other embodiments, the average plasma concentration of PRX-3140 acid is about 1 ng / ml to about 900 ng / ml, about 10 ng / ml to about 900 ng / ml, or about 10 ng / ml to about 500 ng / ml. In further embodiments, the mean plasma concentration is at least about 25 ng / ml, at least about 50 ng / ml, at least about 75 ng / ml, at least about 85 ng / ml, at least about 100 ng / ml, at least about 150 ng / ml, at least about 170 ng / ml, at least about 175 ng / ml, at least about 200 ng / ml, at least about 225 ng / ml, at least about 250 ng / ml, at least about 300 ng / ml, at least about 350 ng / ml, at least about 400 ng / ml, at least about 450 ng / ml, at least about 500 ng / ml, at least about 550 ng / ml, or at least about 600 ng / ml. In other embodiments, the concentration of PRX-3140 is such that it produces a biological or therapeutic effect equivalent to that observed with a given concentration of PRX-3140, such as a decrease in blood glucose or a decrease in body weight. In further embodiments, the subject has diabetes or impaired glucose tolerance. Further embodiments provide a method for reducing the overall mean daily blood glucose concentration of a subject (e.g., a subject with type I, type II, or gestational diabetes) that requires a reduction in the overall mean daily blood glucose concentration, comprising administering to the subject a certain amount of an oral formulation containing enough PRX-3140 to maintain an average plasma concentration of at least about 1 ng / ml of PRX-3140 acid for at least about 12 hours.Another embodiment provides a method for lowering a subject's hemoglobin A1C (HbA1C) by a certain amount of oral formulation containing enough PRX-3140 to maintain an average plasma concentration of at least about 1 ng / ml of PRX-3140 acid for at least about 12 hours. In some embodiments, the methods disclosed herein further provide that PRX-3140 is co-administered with one or more oral antidiabetic agents. Such agents include, but are not limited to, metformin, sulfonylurea (SU), thiazolidinedione (TZD), or any combination thereof. In further embodiments, the methods disclosed herein provide that oral sustained-release PRX-3140 can be used to improve insulin levels and blood glucose levels, resulting in an improved response to glucocorticoid therapy and weight control, including obesity.

[0041] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. [Brief explanation of the drawing]

[0042] Novel features of the present invention are described in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description illustrating exemplary embodiments in which the principles of the present invention are utilized, and to the appended drawings.

[0043] [Figure 1]Figure 1 shows PRX-3140 (Formula I: ##STR00001##), 5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione (Formula II: ##STR00002##) and [7-(methylethyl)1, This is the chemical structure of 4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide (Formula III:##STR00003##).

[0044] [Figure 2] Figure 2 shows the synthesis of crystalline fine particle form I of PRX-3140 potassium salt.

[0045] [Figure 3] Figure 3 shows the XRD patterns of morphology I for (A) crystalline fine particle morphology I of Example 1 of PRX-3140 potassium salt and (B) crystalline fine particle morphology I of the scale-up batch of PRX-3140 potassium salt.

[0046] [Figure 4] Figure 4 shows the photostability experimental HPLC chromatogram of the crystalline fine particle form I of PRX-3140 potassium salt for (A) an unexposed crystalline fine particle form I of a control sample, and (B) a photostable exposed sample of the crystalline fine particle form I of PRX-3140 potassium salt.

[0047] [Figure 5]Figure 5 shows the peroxide decomposition products of crystalline fine particle form I of PRX-3140 potassium salt, formula II:##STR00002##.5-hydroxy-8-(methylethyl)-8-hydro-1,2-oxathiino[6,5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and formula III:# #STR00003##. Indicates [7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide.

[0048] [Figure 6] Figure 6 shows (A) the standard (control) HPLC chromatogram at 250 nm and (B) the standard (control) UV spectrum at 12.2 min of the forced decomposition experiment of crystalline fine particulate morphology I of PRX-3140 potassium salt in Example 3. Maximals are identified at 220, 250, and 320 nm.

[0049] [Figure 7] Figure 7 shows (A) the LC-UV chromatogram at 250 nm of the crystalline fine particle morphology I of the peroxide sample of PRX-3140 potassium salt from Example 4, with two major impurities at 9.6 min and 13.3 min; (B) the mass spectrum of the PRX-3140a peroxide sample at 9.6 min, with [M+H]+ at 258.1 m / z, [M+H+NH3]+ at 275.1 m / z, [M+Na]+ at 280.1 m / z, and [2M+Na]+ at 537.1 m / z; and (C) the mass spectrum of the PRX-3140b peroxide sample at 13.3 min, with [M+H]+ at 394.2 m / z and [2M+H]+ at 787.4 m / z.

[0050] [Figure 8] Figure 8 shows the 1H NMR of (A) the crude product of oxidation of PRX-3140 and (B) the potassium salt of unoxidized PRX-3140.

[0051] [Figure 9] Figure 9 shows (A) the UV chromatogram of the PRX-3140 30% peroxide sample at 250 nm, and (B) the standard (control) UV spectrum at 12.5 min, with maximum values ​​at 220, 250, and 320 nm.

[0052] [Figure 10] Figure 10 shows (A) the UV spectrum of PRX-3140a at 8.9 min and (B) the UV spectrum of PRX-3140b at 12.9 min.

[0053] [Figure 11] Figure 11 shows (A) the mass spectrum of the parent molecule at 12.5 min, [M+H]+ at 378.2 m / z; (B) the mass spectra of the H2O2 sample at 8.9 min and 70 V, [M+H]+ at 258.0 m / z, [M+H+NH3]+ at 275.1 m / z, [M+Na]+ at 280.1 m / z, and [2M+Na]+ at 537.1 m / z; and (C) the mass spectrum at 12.9 min, [M+H]+ at 394.2 m / z and [2M+H]+ at 787.4 m / z.

[0054] [Figure 12] Figure 12 shows HPLC chromatograms of PRX-3140:lecithin (50:50) at 250 nm for (A) the initial sample at time 0 and (B) the sample at day 90.

[0055] [Figure 13]Figure 13 shows the XRD patterns of (A) crystalline particulate matter form I (formulation 7) of PRX-3140 potassium salt mixed with hydroxypropyl methylcellulose K100M in Example 11, and (B) crystalline particulate matter form I (formulation 9) of PRX-3140 potassium salt mixed with xanthan gum in Example 11.

[0056] [Figure 14] Figure 14 is a graph showing the dissolution (average percentage dissolved over time) of PRX-3140 in the form of sustained-release capsules (uncoated) containing 10 mg of PRX-3140, compared to composition formulations 2 (50% E4M), 6 (30% E4M), 7 (30% K100M), 8 (30% Kollidon SR), and 9 (30% Xanthan Gum), as described in Example 14, measured according to the United States Pharmacopeia (USP) Method I (basket). The release of PRX-3140 upon dissolution of the compositions was measured using high-performance liquid chromatography (HPLC-UV) with UV detection for up to 24 hours.

[0057] [Figure 15] Figure 15 shows the mean serum concentrations of crystalline PRX-3140 potassium salt administered orally as a daily dose of either 100 mg of immediate-release (IR) "drug-containing capsules" or Formulation 7 sustained-release capsules from administration time (time 0) to 96 hours, as described in Example 15, on a semi-logarithmic scale.

[0058] [Figure 16] Figure 16 shows blood glucose levels (mg / dL) versus time on a linear scale in healthy adult patients at control levels (without PRX-3140), as described in Example 18.

[0059] [Figure 17] Figure 17 shows, on a linear scale, blood glucose levels (mg / dL) versus time in healthy adult patients who were orally administered crystalline PRX-3140 potassium salt as a daily morning dose of 10 mg sustained-release capsules, as described in Example 18. [Modes for carrying out the invention]

[0060] Detailed explanation I. Terminology Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0061] The terms "a" and "an" do not indicate a limit on quantity, but rather indicate the existence of at least one of the items being referred to. The term "or" means "and / or". The terms "equip," "have," "include," and "contain" should be interpreted as open-ended terms (i.e., "include, but not limited to").

[0062] Unless otherwise indicated herein, the notation of a range of values ​​is intended merely as a simplified way of referring individually to each distinct value contained within that range, and each distinct value is incorporated herein as if it were individually described herein. The endpoints of all ranges are contained within the range and can be combined independently.

[0063] All methods described herein may be performed in any order appropriate, unless otherwise indicated herein or unless it is clearly inconsistent with the context. The use of any example or illustrative language (e.g., "etc.") is intended solely to better illustrate the invention and, unless otherwise claimed, does not limit the scope of the invention. No language herein should be construed as indicating that any non-claimed element is essential to the practice of the invention as used herein. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of the present disclosure.

[0064] Furthermore, this disclosure encompasses all variations, combinations, and substitutions in which one or more limitations, elements, clauses, and descriptive terms from one or more enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in Markush group form, each subgroup of elements is also disclosed, and any element may be removed from a group.

[0065] It is understood that all compounds contain all possible isotopes of the atoms present in the compound. Isotopes are atoms that have the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11C, 13C, and 14C.

[0066] The open-ended term "to consist of" includes the intermediate term "essentially consisting of" and the closed term "consisting of." A significant change is any detectable change that is statistically significant, with p < 0.05 in a standard parametric test of statistical significance, such as Student's t-test.

[0067] As described herein, a controlled-release dosage is a mechanism for delivering a drug to a specific target in the body (targeted-release dosage) after its administration, either delayed (delayed-release dosage) or over a longer period (sustained-release dosage), as opposed to an immediate-release dosage. Sustained-release formulations are designed to release a drug at a predetermined rate to maintain a constant drug concentration over a specific period while minimizing side effects. This can be achieved through various formulations, including the use of polymers that hydrate and swell over a longer period compared to several minutes in immediate-release formulations. The definition of sustained-release is closer to "controlled-release" than "sustained." While these and other terms are sometimes treated as synonyms, the U.S. Food and Drug Administration actually defines most of them as distinct concepts. Controlled-release or sustained-release dosages and their variations are mechanisms used in tablets (pills) and capsules to dissolve a drug over time, with the advantage of releasing the drug into the bloodstream more slowly and steadily, while having the benefit of being ingested less frequently than the immediate-release (IR) formulation of the same drug. For example, orally administered extended or sustained-release morphine may allow certain chronic pain patients to take only one or two tablets per day, instead of needing to be re-administered every four to six hours, as is typical with immediate-release morphine tablets. II. Synthesis of PRX-3140 potassium salt in crystalline fine particle form I

[0068] This disclosure includes the following embodiments, which should not be construed as limiting. Rather, these embodiments are illustrative and are provided to illustrate the invention to those skilled in the art. Similar reference numbers refer to similar elements throughout.

[0069] It was unexpectedly discovered that crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt) can be obtained by dissolving 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt) using acetonitrile and the addition of potassium hydroxide in water, followed by heating and cooling. Unlike the conventional crystallization procedures in U.S. Patents No. 7,488,736 and 7,982,040, which use an aqueous solution of potassium tert-butoxide mixed with dichloromethane and ethyl acetate, this process unexpectedly provides a crystalline solid containing over 90% of the desired 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt).

[0070] In one embodiment, the present disclosure provides an industrially scalable process for producing the potassium salt of PRX-3140, comprising: (A) reductive amination of methyl 2-aminothiophene-3-carboxylate (3) using sodium triacetoxyborohydride in argon, anhydrous dichloromethane and formic acid with 2,2-dimethoxypropane, followed by post-treatment with potassium hydroxide; and (B) pyridine and butyronitrile using methyl malonyl chloride. The process involves acylation and cyclization of methyl 2-iso-propylaminothiophene-3-carboxylate (3) in a solution, followed by the addition of a sodium methoxide solution to obtain methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (5), amidation of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (5) using (C)3-piperidine-1-ylpropylamine (6), and the obtained crude The process involves acidifying PRX-3140 with hydrochloric acid to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide hydrochloride (8), and adding (D) 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide hydrochloride (8), MTBE, water, potassium hydroxide solution and sodium bicarbonate to obtain 4-hydroxy-7-iso Propyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide is obtained, then dissolved in acetonitrile, and potassium hydroxide is added in water to obtain crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide potassium salt (PRX-3140 potassium salt), thereby obtaining 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,The present invention provides a process comprising the step of preparing the potassium salt of [3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide. By grinding and sieving the powder, the crystalline fine particle form I of the potassium salt PRX-3140 is obtained.

[0071] The first step of the disclosed process is the crystallization of the input 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide and acetonitrile, as well as the addition of potassium hydroxide in water to obtain a crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt) solid and mother liquor, followed by separation and drying, the crystalline solid containing more than 90% of the desired PRX-3140 potassium salt. Crystallization can be carried out by heating the input to a first temperature to dissolve it in acetonitrile, and then cooling the solution to a second temperature to carry out crystallization. The solution can be held at the second temperature for several hours to allow sufficient crystallization. For example, the input material can be dissolved in acetonitrile at 45-50 degrees Celsius, and the resulting solution can then be cooled to 0-5 degrees Celsius and held at the second temperature for 0.5 hours to 10 days, preferably 2-4 hours. In some cases, a longer holding time at the second temperature may be required. The crystalline solid and mother liquor can be separated by filtration, decanting, suction, or any suitable method. The separated crystalline solid can be washed with a suitable solvent to remove impurities and dried with or without heat and / or reduced pressure to remove the solvent. Preferably, the crystalline solid is recovered by filtration, washed with a solvent, and dried in vacuum to a constant weight. The separated mother liquor can be concentrated in vacuum to obtain a solid or non-solid, and dried with or without heat and / or reduced pressure to remove the solvent. Preferably, the concentrated mother liquor is dried in vacuum to a constant weight.

[0072] Acetonitrile was unexpectedly found to be a particularly useful solvent for carrying out this process. Other solvents, such as MTBE, can also be used as a second solvent. Crystallization can be carried out by dissolving the introduced crystalline solid in the second solvent at a first temperature of 20–100 degrees Celsius, and then cooling the solution to the second temperature of 20–100 degrees Celsius. The solution can be held at the second temperature for several hours to allow sufficient crystallization. For example, the solid formed from the concentrated first mother liquor can be dissolved in acetonitrile at 30–70 degrees Celsius, preferably 40–60 degrees Celsius, and then the resulting solution is cooled to -10–20 degrees Celsius or 0–10 degrees Celsius and held at the second temperature for 0.5 hours to 10 days or 2 hours to 72 hours. In some cases, longer holding times at the second temperature may be required. The crystalline solid and mother liquor can be separated by filtration, decanting, aspiration, or any suitable method. The separated crystalline solid can be washed with a suitable solvent to remove impurities, and the solvent can be removed by drying with or without heat and / or reduced pressure. The separated mother liquor can be concentrated in a vacuum to obtain a solid, and the solvent can be removed by drying with or without heat and / or reduced pressure. Preferably, the mother liquor is separated from the crystalline solid by suction, concentrated, and dried in a vacuum to obtain a constant weight. III.Crystal form

[0073] In certain embodiments, this disclosure provides a crystalline fine particle form I of PRX-3140 potassium salt. This disclosure further provides pharmaceutical compositions of PRX-3140 potassium salt including the crystalline form described herein. The crystalline form of PRX-3140 potassium salt may offer bioavailability and stability advantages suitable for use as an active ingredient in pharmaceutical compositions. Variations in the crystalline structure of a pharmaceutical substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical formulation or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in various dosage forms or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or noncrystalline forms, the crystalline form may offer desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, the crystalline form of PRX-3140 potassium salt may offer advantages such as improving the manufacturing process of the active drug or the stability or shelf life of the compound or active ingredient formulation, and / or having appropriate bioavailability and / or stability as an active drug.

[0074] The use of specific solvents and fractional crystallization methods has been found to produce various polymorphs of the PRX-3140 potassium salt, including polymorph I, which may exhibit preferred properties of one or more than those described above. The preparation processes for the polymorphs described herein and the characterization of these polymorphs are described in more detail below.

[0075] In certain embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern substantially shown in Figure 3A or Figure 3B. Furthermore, the crystalline form I in the matrix of the sustained-release polymer hydroxypropyl methylcellulose (Methocel K100M) and xanthan gum is characterized by an X-ray powder diffraction pattern substantially shown in Figures 13A and 13B, respectively. In certain embodiments, the disclosure provides polymorph I of the potassium salt PRX-3140, wherein at least 90 wt% is the potassium salt PRX-3140. In some embodiments, polymorph I exhibits an X-ray diffraction (XRD) pattern substantially shown in Figure 3A. In some embodiments, polymorph I has an XRD pattern that includes at least two, at least three, at least four, at least five or at least six of the major peaks, as an XRD pattern substantially as shown in Figure 3A. The crystalline structures of the present invention are substantially pure, singular, and substantially free from any other crystalline or amorphous states. In the present invention, "substantially pure," when used in reference to a novel crystalline form, means that this novel crystalline form constitutes at least 80% by weight, more preferably at least 90% by weight, particularly at least 95% by weight, and particularly at least 99% by weight of the compound.

[0076] For example, the term “substantially shown” when referring to an XRD pattern includes patterns that are not necessarily identical to those shown herein but are within the limits of experimental error or deviation as considered by those skilled in the art. The relative intensity of XRD peaks may vary depending on particle size, sample preparation method, sample mounting procedure, and the specific instrument used. The crystalline morphology in this invention means that the compound is confirmed by the characterization of the X-ray powder diffraction pattern shown and has an intrinsic regular molecular arrangement or structure within the crystal lattice. It is well known to those skilled in the art that experimental error depends on instrument conditions, sample preparation, and sample purity. The 2-theta angles of the peaks in an XRD pattern usually vary slightly depending on the instrument and sample. The difference in peak angles may vary by 1 degree, 0.8 degrees, 0.5 degrees, 0.3 degrees, 0.1 degrees, etc., depending on different instruments, different samples, etc. Generally, the tolerance is + / -0.2 degrees. Therefore, the difference in peak angles cannot be used as the sole measure. The order of peak intensities may not be the sole or decisive factor, as the relative intensity of the peaks may vary depending on the sample, sample preparation, and other experimental conditions. The influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows for a specific shift. Therefore, those skilled in the art will understand that any crystal form having intrinsic peaks identical or similar to those of the powder X-ray diffraction pattern of the present invention falls within the scope of the present invention. "Single crystal form" refers to the single crystal form determined by powder X-ray diffraction.

[0077] Furthermore, instrument variations and other factors may affect the 2-theta values. Therefore, if a specified 2-theta angle is provided, it should be understood that the specified 2-theta angle may differ by a specified value, such as + / -0.5 degrees, + / -0.4 degrees, + / -0.3 degrees, + / -0.2 degrees, or + / -0.1 degrees. As used herein, “major peak” refers to an XRD peak with a peak intensity greater than the baseline, such as exceeding 100 or 500, depending on the baseline noise and the other test factors mentioned above.

[0078] In certain embodiments, the Disclosure provides a PRX-3140 compound of Formula I in a composition in which at least 90% by weight is in the crystalline form of a potassium salt. Crystalline form I may feature an X-ray powder diffraction pattern including major peaks at 22.3 ±0.3°, 25.3 ±0.3°, and 5.4 ±0.3°, and optionally further including at least one peak selected from the two thetas of 25.8 ±0.3°, 15.9 ±0.3°, and 29.9 ±0.3°. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from the two thetas of 21.6 ±0.3°, 16.5 ±0.3°, and 20.3°. The X-ray powder diffraction pattern may further include peaks at 21.3 ± 0.3 degrees, 17.1 ± 0.3 degrees, 16.3 ± 0.3 degrees, 33.1 ± 0.3 degrees, 45.6 ± 0.3 degrees, and 13.7 ± 0.3 degrees in the 2-theta. In some embodiments, crystalline form I is substantially characterized by the X-ray powder diffraction pattern shown in Figure 3A. Crystalline form I may be 90% by weight, 95% by weight, or more than 99% by weight of the compound of formula I in the composition. In some embodiments, the composition contains 0.01 mg to 200 mg of crystalline form I, or crystalline form I such as about 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg.

[0079] In some embodiments, a composition comprising a crystalline form of PRX-3140 potassium salt contains 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of PRX-3140 potassium salt (wt% / wt%) or (w / v) of the composition. In some embodiments, a composition comprising a crystalline form of PRX-3140 potassium salt contains 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of PRX-3140 potassium salt (wt% / wt%) or (w / v) of the composition.

[0080] The compounds and compositions disclosed herein can be administered to subjects requiring them by any route known in the art, including but not limited to oral, parenteral, topical, and intravascular delivery. Accordingly, the compositions disclosed herein are formulated to be compatible with the intended route of administration.

[0081] In some embodiments, the composition containing the crystalline form of PRX-3140 potassium salt further comprises additives. Such additives may be compatible with the intended route of administration. IV. Method for Manufacturing Particle Delivery Systems (PDS)

[0082] The Disclosure also relates to a method for producing a composition of the Disclosure comprising particles of crystalline form of PRX-3140 potassium salt encapsulated by an additive, The crystalline form of PRX-3140 potassium salt is blended with additives to form a mixture. The above mixture is processed to form coarse particles having an average diameter in the range of approximately 0.1 mm to approximately 5 mm, and The above coarse particles are crushed or milled to form particles having an average diameter of less than approximately 500 micrometers. This provides a method that includes [something].

[0083] In certain embodiments, the particles have an average diameter in the range of about 0.1 microns to about 0.1 mm. Particulate materials, also called “particles,” manufactured according to this disclosure may be desirable in the form of small particles ranging in size from nanometers to micrometers. Examples include pharmaceutical nanoparticles and fine particulate forms, including the crystalline form of PRX-3140 potassium salt. Numerous possibilities and combinations exist.

[0084] In one embodiment, a system for preparing the compositions of the present disclosure may include grinding a crystalline form of the PRX-3140 potassium salt in a mortar and pestle or a ball mill. In another embodiment, a system for preparing the compositions of the present disclosure may include, for example, a venturi nozzle or a "T-shaped" valve for introducing a cryogenic gas into a jet mill. While we do not wish to be bound by any particular theory, it has been observed that using a combination of cryogenic (generally below 0 degrees Celsius) dry gases before introduction into the jet mill can eliminate moisture-induced aggregation while simultaneously promoting brittle fracture of particles upon impact, working synergistically to result in a significant improvement in particle size reduction efficiency. Suitable cryogenic liquids for use in this method include liquid argon, liquid nitrogen, liquid helium, or any other liquefied gas with a temperature low enough to cause brittle fracture of particles. Cryogenic liquids can also prevent milling losses and thermal damage to the feed material caused by volatilization or overheating of components.

[0085] In one embodiment, the powder is placed in a temperature-controlled container such as a jacketed hopper or screw feeder, or is pre-frozen. The cryogenic liquid and gas inputs are opened, and the flow and temperature are set to the desired process conditions. A cryogenic gas feeding system, e.g., liquid nitrogen mixed with nitrogen gas, can be connected to a standard commercially available jet mill such as Trost Gem-T, Trost T-15, Fluid Air Aljet, Hosikawa Alpine AS Spiral Jet Mill, Sturtevant Micronizer, or a similar system, as the primary carrier gas in various gas feeding setups. Pre-operation setup of the system may include mounting a temperature probe or flow meter, such as a TSI Model 4040 flow meter or a similar system, on top of the gas input or cyclone (instead of an air relief bag), setting the carrier gas to different input pressures, and recording gas flow and temperature measurements (CFM). The milling process can be initiated by turning on the powder feeder, and after the powder has passed through the milling area, the jet-milled powder is collected in a cup or similar receiver unit (typically particles of about 1 to 10 microns), or from a bag above the cyclone, depending on the precise operating conditions. Particles with a diameter ranging from about less than 1 micron to about 10 microns can be produced by passing the powder through the jet mill multiple times, or through the cup, under similar operating conditions to obtain the desired particle size.

[0086] In certain embodiments, the particles may have an average diameter ranging from about 0.1 mm (100 microns) to about 3 mm. For example, the particles may have a diameter of less than about 2.06 mm (corresponding to a 10-mesh sieve), less than about 1.68 mm (corresponding to a 12-mesh sieve), less than about 1.40 mm (corresponding to a 14-mesh sieve), less than about 1.20 mm (corresponding to a 16-mesh sieve), less than about 1.00 mm (corresponding to an 18-mesh sieve), less than about 0.853 mm (corresponding to a 20-mesh sieve), less than about 0.710 mm (corresponding to a 25-mesh sieve), less than about 0.599 mm (corresponding to a 30-mesh sieve), or less than about 0.500 mm (corresponding to a 35-mesh sieve). In some embodiments, the particles may have a diameter of less than about 300 microns and may be able to pass through a 50-mesh sieve. In certain embodiments, the particles have a diameter of about 0.6 mm or less.

[0087] In certain embodiments, the release-controlled polymer is heated before being blended with the crystalline form of the PRX-3140 potassium salt.

[0088] In some embodiments, the Disclosure provides a method for producing compositions of the Disclosure, comprising particles of crystalline form of PRX-3140 potassium salt encapsulated by a controlled-release or sustained-release polymer, using a process that is at least partly a continuous manufacturing process. The crystalline form of PRX-3140 potassium salt is blended with a release-controlled polymer to form a mixture. Heat the above mixture to a temperature sufficient for extruding the mixture. The above mixture is extruded to form coarse particles having an average diameter in the range of approximately 0.1 mm to approximately 5 mm. Cooling the above-mentioned coarse particles, and The above coarse particles are processed (for example, by milling, grinding, or crushing) to form particles having an average diameter of less than approximately 0.1 mm. It may include.

[0089] In certain embodiments, the particles may have an average diameter ranging from about 0.1 mm (100 microns) to about 3 mm. For example, the particles may have a diameter of less than about 2.06 mm (corresponding to a 10-mesh sieve), less than about 1.68 mm (corresponding to a 12-mesh sieve), less than about 1.40 mm (corresponding to a 14-mesh sieve), less than about 1.20 mm (corresponding to a 16-mesh sieve), less than about 1.00 mm (corresponding to an 18-mesh sieve), less than about 0.853 mm (corresponding to a 20-mesh sieve), less than about 0.710 mm (corresponding to a 25-mesh sieve), less than about 0.599 mm (corresponding to a 30-mesh sieve), or less than about 0.500 mm (corresponding to a 35-mesh sieve). In some embodiments, the particles may have a diameter of less than about 300 microns and may be able to pass through a 50-mesh sieve. In certain embodiments, the particles may have a diameter of about 0.1 mm or less.

[0090] In certain embodiments, the controlled-release or sustained-release polymer may be heated before blending with the crystalline form of the PRX-3140 potassium salt.

[0091] V. Pharmaceutical Composition (Final Dosage Form) This disclosure further provides pharmaceutical compositions (sometimes referred to as “Final Dosage Form” or “FDF”) comprising the composition according to this disclosure, including the PDS from the previous section. In certain embodiments, the FDF includes immediate and sustained-release oral dosage forms, as well as other forms for the delivery of crystalline PRX-3140 potassium salt.

[0092] In some embodiments, the pharmaceutical composition may further contain at least one additive (e.g., a controlled-release polymer, a surfactant, and / or a metal salt), such as pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives may be those described, for example, in Remington's Pharmaceutical Sciences by E.W. Martin, and include cellulose, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. In some embodiments, the pharmaceutical composition may also contain pH buffers and wetting or emulsifying agents.

[0093] In some embodiments, the pharmaceutical composition may be formulated for oral administration. In these embodiments, the pharmaceutical composition may be in the form of, for example, tablets, capsules, or other oral dosage forms. Such oral dosage forms may be prepared by conventional means. The pharmaceutical composition may also be prepared as a liquid, for example, as a syrup or suspension. The liquid may contain a suspending agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), an emulsifier (lecithin or acacia), a non-aqueous vehicle (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and a preservative (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparation may also contain flavoring agents, coloring agents, and sweeteners. Alternatively, the composition may be provided as a dry product to be composed of water or another suitable vehicle.

[0094] For buccal and sublingual administration, the composition may take the form of tablets or lozenges according to conventional protocols.

[0095] This pharmaceutical composition can also be formulated for rectal administration as a suppository or retained enema containing a conventional suppository base such as PEG, cocoa butter, or other glycerides.

[0096] Conventional in vitro dissolution methods include those described in the United States Pharmacopeia (USP), the official public standard-setting body for all prescription and marketed drugs in the United States, as well as similar pharmacopoeias in Europe and Japan. Preferred methods include USP dissolution method I (basket) and method I (paddle) at 50 revolutions per minute (RPM). Therefore, it may be relevant to explain the extension of the degree of release by alternative dissolution methods, and in addition, the extended formulation may be further characterized by additional dissolution methods such as methods with different revolution speeds, different pH values, the use of dissolution media that simulate Gl conditions (e.g., fasting and feeding states, simulation of FaSSIP and FeSSlP media), and the use of additives to the dissolution media such as SLS to increase wettability or solubility, thereby reducing the overall dissolution time measured (increasing the dissolution rate).

[0097] In some embodiments, the pharmaceutical compositions described herein provide improved dissolution of the crystalline form of PRX-3140 potassium salt compared to the non-encapsulated crystalline form of PRX-3140 potassium salt and / or other dosage forms (e.g., more invasive dosage forms). For example, dissolution may increase by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200%, or by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000 times, as measured by a Vankel tablet dissolving device approved by the United States Pharmacopeia.

[0098] In some embodiments, the pharmaceutical compositions described herein provide improved oral bioavailability of the crystalline form of PRX-3140 potassium salt compared to the non-encapsulated crystalline form and / or other dosage forms (e.g., more invasive dosage forms). For example, absorption may increase by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200%, or by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000 times, as measured by, for example, in vivo pharmacokinetic studies in preclinical animal models or human clinical evaluations.

[0099] In some embodiments, the pharmaceutical compositions described herein are immediate-release formulations. In such embodiments, the pharmaceutical compositions provide a faster onset of action of the crystalline form of PRX-3140 potassium salt compared to the non-encapsulated crystalline form of PRX-3140 potassium salt and / or other dosage forms (e.g., more invasive dosage forms). For example, the onset of action may be shortened by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200%, or by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000 times, as measured by, for example, in vivo pharmacokinetic studies in preclinical animal models or human clinical evaluations.

[0100] In some embodiments, the pharmaceutical compositions described herein are sustained-release formulations. In such embodiments, the pharmaceutical compositions described herein provide a more rapid onset of action of the crystalline form of PRX-3140 potassium salt.

[0101] In some embodiments, the pharmaceutical compositions described herein have reduced absorption variability compared to non-encapsulated insoluble drugs and / or other dosage forms (e.g., more invasive dosage forms).

[0102] In some embodiments, the pharmaceutical compositions described herein are associated with improved patient compliance compared to other pharmaceutical compositions containing a crystalline form of PRX-3140 potassium salt (which may be in a different dosage form, e.g., a more invasive dosage form).

[0103] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral delivery. Compositions intended for oral use may be prepared in solid or fluid unit dosage forms. In at least some embodiments, the compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, lozenges, elixirs, suspensions, syrups, wafers, chewing gum, sugar-coated tablets, lozenges, and the like.

[0104] In some embodiments, the oral dosage form is a solid oral dosage form such as a tablet, caplet, or capsule. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, a gelatin-free capsule, a "cap-in-cap" capsule, an alginate capsule, a hydroxypropyl methylcellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule.

[0105] In some embodiments, an oral composition containing the crystalline form of the PRX-3140 potassium salt further comprises one or more additives. In some embodiments, an oral composition containing the crystalline form or polymorph of the PRX-3140 potassium salt further comprises one or more additives. Therefore, compositions designed for oral administration can be prepared using inert or active additives or using edible carriers disclosed herein.

[0106] In various embodiments, the compositions provided herein include one or more additives in amounts of about 1% to about 99.99% by weight, about 5% to about 95% by weight, about 5% to about 90% by weight, about 10% to about 80% by weight, about 15% to about 70% by weight, about 20% to about 60% by weight, about 30% to about 95% by weight, about 50% to about 90% by weight, about 60% to about 90% by weight, about 60% to about 80% by weight, or about 70% to about 80% by weight. In particular embodiments, the compositions provided herein include one or more additives in amounts of about 99.99% by weight, about 95% by weight, about 90% by weight, about 85% by weight, about 80% by weight, about 75% by weight, about 70% by weight, about 65% by weight, about 60% by weight, about 55% by weight, or about 50% by weight. In certain embodiments, the compositions provided herein include one or more additives in amounts of about 99.99%, about 99%, about 98% by weight, about 97% by weight, about 96% by weight, about 95% by weight, about 94% by weight, about 93% by weight, about 92% by weight, about 91% by weight, about 90% by weight, about 89% by weight, about 88% by weight, about 87% by weight, about 86% by weight, or about 85% by weight. In certain embodiments, the compositions provided herein include one or more additives in amounts of about 85% by weight, about 84% by weight, about 83% by weight, about 82% by weight, about 80% by weight, about 79% by weight, about 78% by weight, about 77% by weight, about 76% by weight, about 75% by weight, about 74% by weight, about 73% by weight, about 72% by weight, about 71% by weight, about 70% by weight, about 69% by weight, about 68% by weight, about 67% by weight, about 66% by weight, or about 65% by weight. In certain embodiments, the compositions provided herein include one or more additives in amounts of about 55% by weight, about 54% by weight, about 53% by weight, about 52% by weight, about 51% by weight, about 50% by weight, about 49% by weight, about 48% by weight, about 47% by weight, about 46% by weight, or about 45% by weight. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 30% by weight, about 29% by weight, about 28% by weight, about 27% by weight, about 26% by weight, about 25% by weight, about 24% by weight, about 23% by weight, about 22% by weight, about 21% by weight, or about 20% by weight.

[0107] Examples of additives that can be used in compositions formulated for oral administration are provided herein, but are not limited to, one or more of the following, or any combination thereof: bulking agents, binders, fillers, disintegrants, lubricants, flow enhancers, release regulators, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, etc.

[0108] Suitable binders for use in the pharmaceutical compositions provided herein include, but are not limited to, starches such as sucrose, corn starch, and potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, Methocel, Warocell HM, Luvitec, Luvicaparolactam, Avicel, SMCC, UNIPURE, gelatin, and natural binders such as acacia. The materials include synthetic rubber, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (e.g., numbers 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials marketed as AVICEL PH 101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pennsylvania), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Suitable anhydrous or low-moisture additives or additives include AVICEL PH 103 and Starch 1500 LM.

[0109] Examples of fillers suitable for use in pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, and lactose, salts such as calcium carbonate, calcium phosphate, sodium carbonate, and sodium phosphate, cellulosic bases such as starch, microcrystalline cellulose, powdered cellulose, and methylcellulose, carboxymethylcellulose dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0110] One or more binders or fillers in a composition typically make up about 10% to about 99% (wt% / wt%) of the composition or dosage form. In some embodiments, the binders and / or fillers in a composition constitute about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, and about 50% to 99% (wt% / wt%) of the composition.

[0111] To provide tablets that disintegrate upon exposure to an aqueous environment, a disintegrant can be used in the composition. Tablets with too much disintegrant may disintegrate during storage, while tablets with too little may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form a solid oral dosage form, neither too much nor too little, so as to adversely alter the release of the active ingredient. In some embodiments, the disintegrant is located deep within the oral solid dosage form to slow disintegration. The amount of disintegrant used varies depending on the type of formulation and is readily apparent to those skilled in the art.

[0112] A typical composition contains 0.5% to 15% (wt% / wt%) of a disintegrant. In some embodiments, the composition contains 1% to 5% (wt% / wt%) of a disintegrant. In other embodiments, the disintegrant is 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt% / wt%) of the composition.

[0113] Disintegrants that may be used in the pharmaceutical compositions provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, and mixtures thereof.

[0114] Lubricants that may be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, siloid silica gel (AEROSIL, manufactured by WRGrace Co., Baltimore, Maryland). This includes 200), synthetic silica solidification aerosol (sold by Degussa Co. of Plano, Texas), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Massachusetts), Q7-9120 (Dow Corning), and mixtures thereof. When used, lubricants are typically used in amounts less than 1% (wt% / wt%) of the composition or dosage form into which they are incorporated. In yet another embodiment, the lubricant is 0.1% to 3%, 0.5% to 1% (wt% / wt%) of the composition, etc.

[0115] Plasticizers may be added to control the flexibility or adaptability of oral dosage forms, such as capsule, caplet, or tablet shells, which may result in improved mechanical properties of pH-sensitive materials of coatings on oral dosage forms. Suitable plasticizers include, but are not limited to, petroleum (e.g., paraffinic process oils, naphthenic process oils, and aromatic process oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicone oils, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubber (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotamine, and glycerin or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical formulation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer may be 1% to 10%, 3% to 5% (wt% / wt%) of the composition, etc.

[0116] Examples of flow accelerators include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, and dibasic or tribasic compounds.

[0117] Examples of sweeteners or sweeteners include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, and acesulfame K.

[0118] Examples of flavorings include peppermint, methyl salicylate, peppermint, spear menthol, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, and cherry.

[0119] Compositions formulated for oral delivery disclosed herein, such as tablets, caplets, and capsules, may be coated with one or more enteric coating agents, release-controlling agents, or film-forming agents to control or delay the disintegration and absorption of the composition, which contains the crystalline form of the compound of formula I, in the gastrointestinal tract, thereby providing a longer-lasting effect. Thus, in some embodiments, tablets may be enteric-coated tablets, caplets may be enteric-coated caplets, or capsules may be enteric-coated capsules. Enteric-coated tablets, enteric-coated caplets, or enteric-coated capsules of this disclosure may be prepared by techniques known in the art.

[0120] The pharmaceutical formulations disclosed herein may include controlled-release agents. Examples of controlled-release agents suitable for use include, but are not limited to, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylate copolymers, cellulose phthalate acetate (CAP), cellulose succinate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate acetate (hypromellose succinate acetate), polyvinyl phthalate acetate (PVAP), methyl methacrylate-methacrylate copolymers, shellac, cellulose trimellitate acetate, sodium alginate, zein, synthetic waxes, microcrystalline waxes, paraffin waxes, carnauba waxes, and waxes including beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono- and di-tribenates, glyceryl monostearate, glyceryl distearate, long-chain alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and mixtures thereof. In some embodiments, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. In other embodiments, the release-controlled reagent is a digestible waxy substance such as hard paraffin wax.

[0121] In some embodiments, the composition may contain one or more pH-dependent polymers, such as acid-insoluble polymers. pH-dependent polymers become increasingly permeable above pH 5.0 but are impermeable below pH 5.0, whereas acid-insoluble polymers become soluble under neutral to weakly alkaline conditions. Such release-controlled polymers are intended for the upper small intestine and colon. Non-limiting examples of acid-insoluble polymers include cellulose phthalate acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose phthalate, algentates such as sodium alginate or potassium alginate, shellac, 80% polyvinyl acetate / polyvinylpyrrolidone, xanthan gum, and methylacrylic acid copolymer (commercially available as a powder or 30% aqueous dispersion from Rohm America Inc. in Piscataway, New Jersey under trade names EUDRAGIT®L and EUDRAGIT®S, or as a 30% dispersion from Eastman Chemical Co. in Kingsport, Tennessee under the trade name EASTACRYL®). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL, as well as EUDRAGIT® NE and NM, are also polymers useful for the purposes of this disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the preparation comprises EUDRAGIT® FS 30D. Those skilled in the art will understand that at least some of the acid-insoluble polymers listed herein are also biodegradable.

[0122] For time-delayed or delayed-release pharmaceutical formulations in oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, such as polymethacrylate pH-sensitive polymer-based coatings, can be used (e.g., as coating materials for enteric coatings of capsules, caplets, and tablets, i.e., as enteric coating agents). Commercial sources of delayed-release oral dosage forms are available, for example, DRCaps made from hypromellose (HPMC) by Capsugel (USA). Such delayed-release oral dosage forms are acid-resistant and can withstand the acidity found in the stomach for at least 30 minutes, at least 1 hour, at least 1.5 hours, or at least 2 hours, etc. Such delayed-release oral dosage forms can release at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the crystalline form of the compound of formula I in the intestines (small intestine, large intestine / colon, etc.).

[0123] In one aspect of this disclosure, enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules may be uncoated. Enteric-coated rigid uncoated capsules using endogenous enteric-coated capsule technology (e.g., EnTrinsic Drug Delivery available from Capsugel) are suitable for the purposes of this disclosure.

[0124] In various embodiments, enteric-coated tablets are hard tablets made from a free-flowing powder of the compound of formula I in crystalline form. In various embodiments, enteric-coated capsules are capsules made from a free-flowing powder of the compound of formula I in crystalline form. In various embodiments, enteric-coated tablets are hard tablets made from a free-flowing powder of the compound of formula I in crystalline form. In various embodiments, enteric-coated capsules are capsules made from a free-flowing powder of the compound of formula I in crystalline form.

[0125] In some embodiments, the enteric-coated capsule is a non-animal capsule such as hypromellose capsules (e.g., commercially available autogelling Vcaps, VCaps Plus, VCaps Enteric, other enteric-coated capsules made using Xcellodose, ENCODE colon delivery technology, and Capsugel's EnTrinsic(TM) drug delivery technology). Other technologies known and commercially available in the art for formulating oral solid dosage forms in enteric-coated form (e.g., Qualicaps, USA, Nutrascience, USA, etc.) are also available. In at least one embodiment, the capsule is an API-encapsulated capsule, meaning that a crystalline form of the compound of formula I or a salt thereof is filled into the capsule without a solvent. In such an API-encapsulated capsule or oral dosage form of “drug-containing capsule,” the crystalline form of the compound of formula I, which is the active ingredient, may be a free-flowing powder or a micronized powder. When dosage form I is contained within a capsule, in at least one embodiment, the capsule may be a seamless capsule or a banded capsule.

[0126] The dissolution of the oral dosage forms disclosed herein is tested by dissolution tests in accordance with the current methods of USP711. In some embodiments, the oral dosage forms disclosed herein are protected from the acidic environment of the stomach and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours, or at least 8 hours. In at least one embodiment, the oral dosage form does not release PRX-3140 for at least 6 hours. In another embodiment, the oral dosage form does not release PRX-3140 for at least 2 hours.

[0127] VI. Sustained-release pharmaceutical compositions This disclosure relates to novel sustained-release compositions of the compound PRX-3140, as well as its polymorphs and salts. The sustained-release compositions of this disclosure provide controlled release of a compound or drug over longer periods (e.g., at least 2 hours to about 72 hours, at least 4 hours to 24 hours, at least 6 hours to 48 hours, etc.). Approximately 2 hours after dose administration or ingestion, the sustained-release compositions of this disclosure provide long-term release in the intestines after the composition has passed the stomach, enabling uptake of the compound (PRX-3140 or its polymorphs or salts) from the subject's intestines and / or colon into the bloodstream. The release rate of PRX-3140 or its polymorphs or salts from the sustained-release compositions (e.g., enteric-coated delayed-release tablets) is slower than that observed for the reference product (capsules). The sustained-release compositions provide the subject with controlled, long-term exposure to the compound over a period of at least about 2 hours to about 270 hours per dose after administration. Therefore, by reducing the frequency of administration and / or the rate of uptake of the compound into the bloodstream, this disclosure offers the potential for improved or enhanced patient tolerance to the drug, as well as improved patient convenience and compliance. The slow, long-lasting (or sustained-release) release and uptake into the bloodstream of PRX-3140 or its polymorphs or salts also have the potential to offer reduced local and / or systemic side effects and toxicity, reduced drug accumulation, and / or a reduction in the total amount of drug for treatment compared to other dosage forms such as the reference product, as patients may be exposed to lower drug peak concentrations over time. Targeting the intestines (e.g., the duodenum and jejunum) and colon by delaying drug release to protect from the acidic environment of the stomach also increases the potential for improved bioavailability and tolerance to "food effects," as well as increased efficacy.

[0128] This disclosure provides PRX-3140, or a polymorph or salt thereof, and sustained-release compositions comprising a sustained-release system. The sustained-release system comprises (i) at least one sustained-release (SR) or release rate control agent (hereinafter interchangeably referred to as "sustained-release agent" or "SR agent"), (ii) at least one binder, and (iii) at least one lubricant.

[0129] In some embodiments, the sustained-release compositions of the Disclosure are in the form of solid dosage forms such as tablets, minitablets, beads, microbeads, granules, spherical particles, and polyparticles. The Disclosure provides that the sustained-release compositions of the Disclosure may be enterically coated for delayed release targeting the intestine and colon. Accordingly, in some embodiments, the sustained-release compositions are in the form of enterically coated delayed-release tablets, tablets containing enterically coated delayed-release tablets, capsules containing enterically coated delayed-release tablets, capsules containing beads, capsules containing spheres, and the like.

[0130] PRX-3140 or its polymorphs or salts can be uniformly dispersed in a sustained-release composition.

[0131] In certain embodiments, the sustained-release composition may contain PRX-3140 in w / w of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, and 100% PRX-3140 relative to the total PRX-3140 in the sustained-release composition. In other embodiments, a sustained-release composition containing PRX-3140 comprises, w / w, about 0.01% to about 40%, about 0.01% to about 20%, about 0.05% to about 15%, and about 0.1% to about 10% of PRX-3140 relative to the sustained-release composition. In at least one embodiment, a sustained-release composition containing PRX-3140 comprises, w / w, 0.01% to about 40% of PRX-3140 relative to the sustained-release composition. In various other embodiments, a sustained-release composition comprising PRX-3140 contains, in w / w, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, and about 20% of PRX-3140 relative to the sustained-release composition. In some embodiments, the PRX-3140 contained in the sustained-release composition is substantially pure. Such a sustained-release composition may contain less than 5%, less than 4%, less than 3%, less than 2.5%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% of PRX-3140. Such a sustained-release composition may contain less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of other impurities.

[0132] In certain embodiments, this disclosure provides crystalline forms of PRX-3140, including crystalline forms of PRX-3140 and crystalline forms of mixtures of PRX-3140 and PRX-3140 potassium salt. This disclosure further provides pharmaceutical compositions of PRX-3140, including the crystalline forms described herein. The crystalline forms of PRX-3140 may offer advantages in bioavailability and stability suitable for use as an active ingredient in pharmaceutical compositions. Modifications to the crystalline structure of a pharmaceutical raw material or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical product or active ingredient. Such modifications may affect preparations or formulations of pharmaceutical compositions in different dosage forms or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or noncrystalline forms, crystalline forms can provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, crystalline forms of PRX-3140 can offer advantages such as improving the manufacturing process of the active drug or the stability or shelf life of the drug product form of the compound or active ingredient, and / or having suitable bioavailability and / or stability as an active drug.

[0133] In some embodiments, the sustained-release composition comprises PRX-3140 potassium salt primarily as polymorphic form I. In certain embodiments, the sustained-release composition comprises PRX-3140 in w / w of the total PRX-3140 in the sustained-release composition as a single polymorphic form such as form I, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% of the total PRX-3140 in the sustained-release composition. For example, a sustained-release composition may contain PRX-3140 of form I as at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% w / w of total PRX-3140 in the sustained-release composition.

[0134] In at least one sustained-release composition, the composition contains a single polymorph of PRX-3140 potassium salt, such as Form I, at least 90% w / w of the total PRX-3140 in the sustained-release composition. For example, the sustained-release composition contains at least 90% w / w of PRX-3140 of Form I of the total PRX-3140 in the sustained-release composition. In another embodiment, the sustained-release composition contains at least 95% w / w of PRX-3140 of a single polymorph, such as Form I, of the total PRX-3140 in the sustained-release composition. In yet another embodiment, the sustained-release composition contains at least 96%, 97%, 98%, 99%, or 99.5% w / w of PRX-3140 of a single polymorph, such as Form I, of the total PRX-3140 in the sustained-release composition. For example, a sustained-release composition contains 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more of Form I PRX-3140 in the total PRX-3140 in the sustained-release composition by w / w. If a particular weight percentage of PRX-3140 is a single polymorph, the remainder of PRX-3140 in the sustained-release composition is any combination of amorphous PRX-3140 and / or one or more polymorphs of PRX-3140 other than the single polymorph. If polymorph PRX-3140 is defined as one particular form of PRX-3140, the remainder consists of amorphous PRX-3140 and / or one or more polymorphs other than the specified particular form. Examples of single polymorphic forms include form I of PRX-3140, and descriptions of single polymorphic forms characterized by one or more features, as described in the publication of the applicant's U.S. Patent Application No. 17 / 830,519.

[0135] In other embodiments, a sustained-release composition containing PRX-3140 comprises PRX-3140 in a single polymorph form, such as Form I, in w / w amounts of about 0.01% to about 20%, about 0.05% to about 15%, or about 0.1% to about 10% relative to the sustained-release composition. In at least one embodiment, a sustained-release composition containing PRX-3140 comprises PRX-3140 in a single polymorph form, such as Form I, in w / w amounts of about 0.01% to about 20% relative to the composition. In various other embodiments, a sustained-release composition comprising PRX-3140 comprises PRX-3140 in a single polymorph form, such as Form I, in wt% / wt% relative to the sustained-release composition, in amounts of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, or about 20%. In one embodiment, a sustained-release composition comprising PRX-3140 in a single polymorph form, such as Form I, further comprises PRX-3140 in a second polymorph form.

[0136] In one embodiment, the sustained-release composition contains polymorphic forms of PRX-3140 in amounts ranging from about 0.1 mg to about 200 mg per unit dose. In various embodiments, the sustained-release composition contains polymorphic forms of PRX-3140, such as Form I, or combinations thereof, in amounts of 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 50 mg, 75 mg, 100 mg, 200 mg, and 250 mg. For example, the sustained-release composition may contain Form I PRX-3140 in amounts of 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 50 mg, 75 mg, 100 mg, 200 mg, and 250 mg. In some embodiments, the sustained-release composition may contain PRX-3140 in polymorphic forms such as Form I, in amounts of 0.1 mg to 1 mg, 0.1 mg to 2 mg, 0.1 mg to 3 mg, 0.1 mg to 4 mg, 0.1 mg to 5 mg, 1 mg to 2 mg, 1 mg to 3 mg, 1 mg to 4 mg, 1 mg to 5 mg, 1 mg to 6 mg, 1 mg to 7 mg, 1 mg to 8 mg, 1 mg to 9 mg, 1 mg to 10 mg, 5 mg to 6 mg, 5 mg to 7 mg, 5 mg to 8 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 15 mg, 5 mg to 20 mg, 5 mg to 40 mg, 10 mg to 15 mg, 10 mg to 20 mg, or 10 mg to 40 mg.

[0137] The content of PRX-3140 or its polymorphs or salts in the sustained-release compositions of this disclosure varies depending on the dosage form of the sustained-release composition, the target disease, the severity of the disease, etc., but it generally corresponds to or is equivalent to about 0.01 mg to about 200 mg of PRX-3140. Those skilled in the art will recognize that when a sustained-release composition contains a salt of PRX-3140, the amount of PRX-3140 salt is equivalent based on the amount of PRX-3140 released.

[0138] In one embodiment, the Disclosure provides that the sustained-release composition of the Disclosure exhibits sustained release of the drug PRX-3140 or a polymorph or salt thereof from the sustained-release composition over a period of about 2 hours to about 72 hours. In some embodiments, the sustained-release composition of the Disclosure exhibits sustained release of the drug PRX-3140 or a polymorph or salt thereof from the sustained-release composition over a period of about 4 hours to about 24 hours or longer. In some embodiments, the sustained-release composition of the Disclosure sustainably releases PRX-3140 or a polymorph or salt thereof over a period of at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In some embodiments, the sustained-release PRX-3140 or a polymorph or salt thereof is released over a period of 6 hours to 48 hours. In some embodiments, PRX-3140 or its polymorph or salt is released from the sustained-release composition over a period ranging from about 2 hours to about 72 hours, approximately 2 hours after administration. In some embodiments, PRX-3140 or its polymorph or salt is released from the sustained-release composition over a period ranging from about 2 hours, about 3 hours, 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, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours and about 24 hours, approximately 24 hours, approximately 21 hours, about 22 hours and about 23 hours. In some embodiments, as shown in this disclosure, the rate of release of the compound (PRX-3140 or its polymorphs or salts) is slower, more sustained, or longer-lasting than the rate of release of the reference product, enteric-coated resistant delayed-release PRX-3140 capsules (as interchangeably used herein as “capsules” or “control”).

[0139] In dissolution tests of specific sustained-release compositions of this disclosure conducted according to the USP I method, the sustained-release compositions exhibit dissolution rates ranging from approximately 0% to 35% after 3 hours, approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to approximately 85% after 24 hours in a 50 RPM USP I dissolution test using simulated gastric fluid at 37 degrees Celsius or pH 1.2 as the test medium, and approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to approximately 85% after 24 hours.

[0140] A method for measuring the solubility of a composition (e.g., a sustained-release composition) may include measuring its solubility in water or an acidic phase (e.g., simulated gastric juice), followed by a buffer phase (e.g., simulated intestinal juice). The acidic phase may include placing 750 mL of 0.1 N hydrochloric acid into a container and assembling an apparatus (e.g., a paddle apparatus or a basket apparatus). The culture medium may be equilibrated to a temperature of 37 ± 0.5 degrees Celsius. A single dose unit may be placed in the apparatus, the container may be covered, and the apparatus may be operated at a specified speed. After 2 hours of operation in 0.1 N hydrochloric acid, an aliquot of the liquid may be taken out. The method may then proceed immediately as indicated under the buffer step. Analysis of the aliquot may be performed using an appropriate assay method. While operating the apparatus at a specified speed, 250 mL of 0.20 M tribasic sodium phosphate, equilibrated to 37 ± 0.5 degrees Celsius, may be added to the liquid in the container. The liquid may be adjusted to a pH of 6.8 ± 0.05 with 2N hydrochloric acid or 2N sodium hydroxide, if necessary. The apparatus may be left running for 45 minutes or for the specified time. At the end of the period, aliquots of the liquid may be taken out and analyzed using an appropriate assay method.

[0141] In some embodiments, the solubility is measured by the 50 RPM USP paddle method, for 0-2 hours in water or simulated gastric fluid at pH 1.2 at 37 degrees Celsius, and after 2 hours in simulated intestinal fluid at pH 6.8 at 37 degrees Celsius. The solubility refers to the percentage by weight of the dissolved composition. The solubility refers to the weight solubility of PRX-3140 or its polymorph or salt during the dissolution study. As a non-limiting example, if a tablet contains 4 mg of PRX-3140 and 1 mg of PRX-3140 dissolves in the solution during the dissolution study at 3 hours, the solubility at 3 hours is 25%. The solubility may be determined, for example, by high-performance liquid chromatography.

[0142] In some embodiments, the sustained-release composition has a solubility in the range of 5%-35%, 10%-15%, 20%-25%, 30%-35%, 5%-30%, 5%-25%, 5%-20%, 5%-15%, 5%-10%, 10%-15%, 15%-20%, 20%-25%, 25%-30%, or 30%-35% after 3 hours, measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0-2 hours, and then in simulated intestinal juice at pH 6.8 at 37 degrees Celsius after 2 hours.

[0143] In some embodiments, the sustained-release composition has a solubility of about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 25% or less, about 30% or less, about 35% or less, about 40% or less, about 45% or less, or about 50% or less after 2 hours, measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0 to 2 hours, and in simulated intestinal juice at pH 6.8 at 37 degrees Celsius after 2 hours. In some embodiments, the sustained-release composition has a solubility of about 30% or less (NMT), about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less after 3 hours.

[0144] In some embodiments, the sustained-release composition has a solubility of PRX-3140 or its polymorphs or salts in the range of less than 5% at 2 hours and more than 70% at 3 hours, measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0 to 2 hours, and then in simulated intestinal juice at pH 6.8 at 37 degrees Celsius after 2 hours.

[0145] In some embodiments, the sustained-release compositions have a solubility of PRX-3140 or its polymorphs or salts of less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 31%, less than 32%, less than 33%, less than 34%, less than 35%, less than 36%, less than 37%, less than 38%, less than 39%, and less than 40% after 7 hours, as measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0 to 2 hours, and then in simulated intestinal juice at pH 6.8 at 37 degrees Celsius after 2 hours.

[0146] In some embodiments, the sustained-release composition has a solubility of PRX-3140 or its polymorphs or salts in the range of less than 5% at 2 hours and more than 95% at 6 hours, measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0 to 2 hours, and in simulated intestinal juice at pH 6.8 at 37 degrees Celsius after 2 hours.

[0147] In some embodiments, the sustained-release composition has a solubility of PRX-3140 or its polymorphs or salts of less than 5% in 2 hours and about 20% or more (NLT), about 25% or more, about 30% or more, about 35% or more, or about 40% or more in 6 hours. In some embodiments, the sustained-release composition has a solubility of PRX-3140 or its polymorphs or salts of less than 5% in 2 hours and about 40% or more, about 45% or more, about 50% or more, about 55% or more, or about 60% or more in 9 hours. In some embodiments, the sustained-release composition has a solubility in the range of approximately 35% to approximately 55%, approximately 40% to approximately 55%, approximately 45% to approximately 55%, approximately 45% to approximately 55%, approximately 40% to approximately 55%, approximately 35% to approximately 50%, approximately 35% to approximately 45%, approximately 35% to approximately 40%, approximately 35% to approximately 40%, approximately 40% to approximately 45%, approximately 45% to approximately 50%, or approximately 50% to approximately 55% after 12 hours, as measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius for 0 to 2 hours, and approximately 45% to approximately 55% after 2 hours in simulated intestinal juice at pH 6.8 at 37 degrees Celsius.

[0148] In some embodiments, the sustained-release composition has a solubility of less than 20% of PRX-3140 or its polymorph or salt at 2 hours, and a solubility of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at 12 hours, as measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius, and at least about 2 hours in simulated intestinal juice at pH 6.8 at 37 degrees Celsius.

[0149] In some embodiments, the sustained-release composition has a solubility of PRX-3140 or its polymorphs or salts in the range of approximately 5% at 2 hours and approximately 55% to approximately 100%, approximately 60% to approximately 99%, approximately 75% to approximately 90%, approximately 80% to approximately 85%, approximately 55% to approximately 99%, approximately 65% ​​to approximately 99%, approximately 75% to approximately 99%, approximately 80% to approximately 99%, approximately 90% to approximately 95%, or approximately 75% to approximately 95% at 72 hours, as measured by the 50 RPM USP paddle method in water or simulated gastric juice at pH 1.2 at 37 degrees Celsius, and after 2 hours in simulated intestinal juice at pH 6.8 at 37 degrees Celsius.

[0150] In one embodiment, the sustained-release compositions of the Disclosure are formulated or prepared as solid dosage forms, including but not limited to tablets, minitablets, caplets, beads, microbeads, spheres, pellets, microspheres, granules, pills, tablets-containing tablets, capsules-containing tablets, capsules-containing granules, and the like. The sustained-release compositions of the Disclosure in solid dosage form provide sustained and controlled release of the drug, the active ingredient PRX-3140, or a polymorph or salt thereof, over a remarkably longer period than observed with other compositions containing PRX-3140 (e.g., at least about 4 hours to about 24 hours, at least about 2 hours to about 72 hours). In at least one embodiment, the sustained-release composition in solid dosage form is a tablet. Such a sustained-release composition may or may not be coated. In one embodiment, the Disclosure provides that the solid dosage forms of the Disclosure can be delivered orally.

[0151] In one embodiment, the Disclosure provides that an active ingredient (PRX-3140 or a polymorph or salt thereof) is dispersed in a sustained-release system. PRX-3140 or a salt or polymorph thereof may be uniformly or homogeneously dispersed. The sustained-release system includes, but is not limited to, at least one controlled-release agent such as a sustained-release agent that controls the release rate of the drug PRX-3140 or a salt or polymorph thereof, at least one binder, and at least one lubricant. In some embodiments, the sustained-release system is present in an amount ranging from about 1% to about 99.99% in the sustained-release composition of the Disclosure.

[0152] In some embodiments, the Xu Bing Da system is present in the sustained-release composition of the Disclosure in amounts ranging from about 0.1 mg to about 499.5 mg, about 25 mg to about 450 mg, about 50 to about 400 mg, or about 100 mg to about 300 mg. In at least one embodiment, the Xu Bing Da system is present in the sustained-release composition in amounts ranging from about 50 mg to about 199.5 mg. In another embodiment, the Xu Bing Da system is present in the sustained-release composition in amounts ranging from about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, or about 100 mg. In yet another embodiment, the extended-release benzoate is present in the extended-release composition in amounts of about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 195 mg, about 200 mg, about 210 mg, about 225 mg, about 300 mg, about 400 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 495 mg, or about 499.5 mg. In some embodiments, the extended-release benzoate is present in the extended-release composition in amounts of about 5 mg to 99.5 mg.

[0153] In some embodiments, the sustained-release compositions of the present disclosure generally have a ratio of PRX-3140 or its polymorph or salt to the sustained-release system of about 4:1 to about 0.1:100. In some embodiments, the ratio of PRX-3140 or its polymorph or salt to the sustained-release system is 2.5:1 to about 1:20.

[0154] The sustained-release agent present in the sustained-release composition of this disclosure may be any sustained-release agent known in the art for delaying the release of hydrophobic drugs such as PRX-3140 or its polymorphs or salts.

[0155] Examples of sustained-release agents include acrylic resins such as cellulose ethers, gums, acrylic acids, methacrylic acids, methyl acrylates, methyl methyl acrylates, and polymers and copolymers of these, polyvinylpyrrolidines, and protein-derived compounds. Examples of cellulosic ethers include hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose, e.g., numbers 2208, 2906, 2910), carboxyalkylcellulose, and carboxymethylcellulose. In some embodiments, at least one sustained-release agent is a pH-sustained-release agent such as an acid-insoluble polymer that becomes progressively soluble and permeable above pH 5.0 but remains impermeable below pH 5.0. Such controlled-release polymers target the upper small intestine and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose phthalate acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose phthalate, algentates, such as sodium alginate or potassium alginate, shellac, polyvinyl acetate / polyvinylpyrrolidone, xanthan gum, acrylate-methylacrylic acid copolymers (including those commercially available from Evonik or Rohm), Eudragit® sustained-release polymers (Eudragit® RL (high permeability), Eudragit® RS (low permeability), and Eudragit® NM (low permeability). The sustained-release agent includes 30D (low permeability), and either alone or in any combination thereof, achieves the desired permeability for sustained release. The viscosity of the sustained-release agent may be any viscosity suitable for the sustained release of PRX-3140 or its polymorphs or salts. In certain embodiments, the viscosity of at least the sustained-release agent is in the range of about 1,000 mPa·s to about 150,000 mPa·s. In some embodiments, the sustained-release system includes one or more SR / release rate control agents or combinations thereof having viscosities in the range of about 1,000 mPa·s to about 10,000 mPa·s, about 10,000 mPa·s to about 70,000 mPa·s, and about 70,000 mPa·s to about 150,000 mPa·s. In some embodiments, the present disclosure provides that the sustained-release system includes two or more sustained-release agents.Each sustained-release agent may have the same or different viscosities. For example, one sustained-release agent may have a viscosity in the range of about 1,000 mPa·s to about 10,000 mPa·s, while another sustained-release agent may have a viscosity in the range of about 10,000 mPa·s to about 70,000 mPa·s or about 70,000 mPa·s to about 150,000 mPa·s.

[0156] In some embodiments, the sustained-release agent is HPMC / hypromellose (e.g., numbers 2208, 2906, 2910). The hypromellose used in this disclosure has a number-average molecular weight (Mn) of about 86,000 to 220,000. In some embodiments, the hypromellose generally has a number-average molecular weight (Mn) of 10,000 to 250,000 or more. Hypromellose is commercially available from Dow Chemicals under the trade name Methocel(TM), for example, Methocel(TM) E4M (Mn 86,000, water viscosity 2% about 4,000 mPa·s). Methocel(TM) K100 (Mn=220,000, 2% viscosity, approx. 100,000 mPa·s), Methocel(TM) K15M (Mn=120,000, 2% viscosity, approx. 15,000 mPa·s), Methocel(TM) K4M (Mn=86,000, 2% viscosity, approx. 4,000 mPa·s). One grade of hypromellose can be used alone or in combination with another grade.

[0157] If a sustained-release composition is obtained that exhibits the release of PRX-3140 or its polymorph or salt for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours, then in some embodiments, the sustained-release agent, such as hypromellose, generally has a number-average molecular weight in the range of about 86,000 to about 220,000 daltons. In at least one embodiment, the number-average molecular weight is about 220,000 daltons.

[0158] The amount of sustained-release agent in the composition may be any amount effective in delaying the release of compound PRX-3140 or its polymorph or salt by about 2 hours after administration, protecting the compound from the acidic environment of the stomach, allowing the compound to pass through the stomach into the intestines, and extending such release for about 2 hours to about 72 hours. The amount of sustained-release agent in the composition may be any amount effective in providing a relatively slow release rate of compound PRX-3140 or its polymorph or salt compared to the reference product. In some embodiments, the amount of sustained-release agent in the composition may be any amount effective in delaying the release of compound PRX-3140, or a polymorph or salt thereof, for at least about 1 hour, at least about 1.1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 1.9 hours, at least about 2 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, at least about 2.4 hours, or at least about 2.5 hours after administration, compared to the reference product.

[0159] The sustained-release composition exhibits dissolution rates in the range of approximately 0% to 35% after 3 hours, approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to approximately 85% after 24 hours, in a dissolution test using the 50 RPM USP paddle method in simulated gastric fluid for 2 hours using water at 37 degrees Celsius or pH 1.2, and in simulated intestinal fluid for 24 hours using water at 37 degrees Celsius and pH 6.8, respectively. At least one sustained-release agent, such as hypromellose (HPMC), may generally be present in the sustained-release composition of this disclosure in amounts of approximately 0.1% to approximately 99%, approximately 0.1% to approximately 90%, approximately 5% to approximately 90%, approximately 5% to approximately 80%, approximately 5% to approximately 70%, and approximately 5% to approximately 60% w / w of the sustained-release composition. In some embodiments, the sustained-release agent (e.g., gum, acrylic resin, methacrylic acid, methyl acrylate, methyl methyl acrylate, polyvinylpyrrolidine, protein-derived compounds, hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyalkylcellulose, or carboxymethylcellulose) may be present in amounts of about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 20% to about 40%, about 20% to about 50%, or about 20% to about 60%. In some embodiments, the sustained-release agent may be present in amounts of at least about 10%, at least about 20%, at least about 30%, or at least about 40%. Such sustained-release compositions disclosed herein release PRX-3140 or its polymorphs or salts for a sustained period of at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. See Example 14 and Figure 14. In some embodiments, the compound in the sustained-release composition is released over a period of 6 to 48 hours.In some embodiments, the compound (e.g., PRX-3140 or its polymorphs or salts) is released over a period of 2 to 72 hours, using simulated gastric fluid for 2 hours with water at 37 degrees Celsius or pH 1.2, and simulated intestinal fluid for 24 hours with water at 37 degrees Celsius or pH 6.8, as tested by the USP I method.

[0160] As a non-limiting example, the ratio of PRX-3140 or its polymorph or salt to the sustained-release agent ranges from about 1:20 to about 20:1, about 1:10 to about 10:1, and about 1:5 to about 2:5 to prepare the sustained-release compositions of this disclosure. To prepare sustained-release tablets containing about 0.1 mg to about 200 mg of PRX-3140 or its salt, the drug-to-sustained-release agent ratio ranges from about 20:1 to about 1:20. In some embodiments, the drug-to-sustained-release agent ratio in sustained-release tablets containing about 0.1 mg to about 200 mg of PRX-3140 or its salt ranges from about 10:1 to about 1:10. In certain embodiments, the ratio of the therapeutic drug PRX-3140 or its polymorph or salt to the sustained-release agent is about 1:5. Those skilled in the art will recognize that the release rate of PRX-3140 or its polymorphs or salts can be adjusted for sustained release as desired by changing the viscosity grade of the sustained-release composition of this disclosure and the amount of the sustained-release agent disclosed herein.

[0161] The binders present in the sustained-release compositions of this disclosure may be any binder known in the art that can hold together the components in the sustained-release compositions of this disclosure or the components. Suitable binders for use in the sustained-release compositions provided herein include monosaccharides (such as sucrose, dextrose, and fructose), disaccharides, starches, e.g., corn starch, potato starch, or starches, e.g., starch paste, pregelatinized starch, and starch 1500, polyhedric alcohols, mannitol, xylitol, sorbitol, lactose, polyethylene glycol, e.g., PEG 6000, acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose (e.g., powdered cellulose and pregelatinized starch) and its derivatives (e.g., ethylcellulose, cellulose acetate, methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (e.g., numbers 2208, 2906, 2910), crystalline cellulose, microcrystalline cellulose (MCC), silicified microcrystalline cellulose, calcium carbonate and its salts, calcium phosphate, precipitated calcium phosphate, sodium carbonate, sodium phosphate, anhydrous discalcium phosphate, talc, dextrate, kaolin, mannitol, silicic acid, sorbitol and combinations or mixtures thereof. Preferred forms of crystalline and microcrystalline cellulose include, but are not limited to, materials commercially available as AVICEL® PH 101, AVICEL PH 103, AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa) and Pharmacel 101. Anhydrous or low-moisture additives are preferred. Suitable anhydrous or low-moisture additives or excipients include microcrystalline cellulose commercially available as AVICEL® PH 101, AVICEL® PH 103, and Pharmacel 101.In at least one embodiment, the binder is microcrystalline cellulose (such as AVICEL® PH 101) or silicified microcrystalline cellulose.

[0162] The sustained-release compositions of this disclosure may typically contain at least one binder in amounts ranging from about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, or about 20% to about 85% on a w / w basis relative to the weight of the sustained-release composition. In certain embodiments, the sustained-release compositions of this disclosure typically contain microcrystalline cellulose in amounts ranging from about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, or about 20% to about 85% on a w / w basis relative to the weight of the sustained-release composition.

[0163] Exemplary lubricants that can be used in sustained-release compositions provided herein include, but are not limited to, stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laurate, agar, wax, and combinations thereof. Additional lubricants include, for example, siloid silica gel (AEROSIL 200 manufactured by WRGrace Co. of Baltimore, Maryland), synthetic silica coagulation aerosol (sold by Degussa Co. of Plano, Texas), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Massachusetts), Q7-9120 (Dow Corning), and combinations thereof. In some embodiments, the lubricant is magnesium stearate. Magnesium stearate reduces friction between the die wall and the tablet mixture during tablet compression and ejection. It helps prevent tablets from sticking to the punch and die. Magnesium stearate also assists the flow of powder into the hopper and die. It has a particle size range of 450–550 microns and a density range of 1.00–1.80 g / mL. It is stable and does not polymerize in the tablet mixture. One lubricant, magnesium stearate, can also be used in formulations.

[0164] Typically, the sustained-release compositions of the present disclosure may contain at least one lubricant in amounts ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% on a w / w basis relative to the weight of the sustained-release composition. In certain embodiments, the sustained-release compositions of the present disclosure contain magnesium stearate in amounts ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% on a w / w basis relative to the weight of the sustained-release composition.

[0165] Specific exemplary embodiments of the sustained-release compositions of this disclosure include, but are not limited to, the following embodiments.

[0166] In some embodiments, at least one sustained-release agent (e.g., HPMC, cellulose phthalate acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose phthalate, sodium alginate, potassium alginate, shellac, polyvinyl acetate / polyvinylpyrrolidone, xanthan gum, or acrylate-methylacrylic acid copolymer) is present in the sustained-release composition in an amount ranging from about 0.1% to about 99%. At least one binder is present in the sustained-release composition in an amount ranging from about 1% to about 99%. At least one lubricant is present in the sustained-release composition in an amount ranging from about 0.01% to about 5%, the percentages being on a w / w basis relative to the weight of the sustained-release composition.

[0167] In some embodiments, at least one sustained-release agent is present in the sustained-release composition in an amount ranging from about 0.1% to about 90%. At least one binder is present in the sustained-release composition in an amount ranging from about 1% to about 99%. At least one lubricant is present in the sustained-release composition in an amount ranging from about 0.01% to about 5%, the percentages being on a w / w basis relative to the weight of the sustained-release composition.

[0168] In at least one embodiment, the sustained-release composition comprises at least one sustained-release agent in an amount ranging from about 5% to 60%, at least one binder in an amount ranging from about 10% to about 90%, and at least one lubricant in an amount ranging from about 0.01% to about 5%, the percentages being on a w / w basis relative to the weight of the sustained-release composition.

[0169] In some embodiments, at least one sustained-release agent is present in the sustained-release composition in an amount ranging from about 0.1% to about 10%. At least one binder is present in the sustained-release composition in an amount ranging from about 80% to about 99%. At least one lubricant is present in the sustained-release composition in an amount ranging from about 0.02% to about 2%, with the percentages being on a w / w basis relative to the weight of the sustained-release composition.

[0170] In at least one embodiment, the sustained-release composition comprises at least one sustained-release agent in an amount ranging from about 10% to 45%, at least one binder in an amount ranging from about 50% to about 80%, and at least one lubricant in an amount ranging from about 0.02% to about 2%, with the percentages being on a w / w basis relative to the weight of the sustained-release composition.

[0171] In certain embodiments, at least one sustained-release agent is present in the sustained-release composition in amounts of about 8%, about 9%, about 10%, about 12%, about 15%, about 18%, about 20%, about 22%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, and about 60%. At least one binder is present in the sustained-release composition in an amount of about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%, and at least one lubricant is present in an amount of about 0.02%, about 0.05%, about 0.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, and the percentages are on a w / w basis relative to the weight of the sustained-release composition.

[0172] In certain embodiments, at least one sustained-release agent is present in the sustained-release composition in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%. At least one binder is present in the sustained-release composition in an amount of about 29%, about 25%, about 30%, about 35%, about 39%, about 40%, about 45%, about 49%, about 50%, about 55%, about 60%, about 64%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%. At least one lubricant is present in the sustained-release composition in an amount of about 0.8%, about 0.9%, about 1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% on a w / w basis relative to the weight of the sustained-release composition, in each case.

[0173] In at least one embodiment, at least one sustained-release agent is present in the sustained-release composition in an amount of about 10%, about 20%, or about 40%. At least one binder is present in the sustained-release composition in an amount of about 55%, about 75%, about 80%, about 85%, or about 87%. At least one lubricant is present in the sustained-release composition in an amount of about 0.9% to about 1.1%. The percentages are on a w / w basis relative to the weight of the sustained-release composition.

[0174] In certain embodiments, the sustained-release compositions of the present disclosure include additional sustained-release agents, binders, lubricants, or any combination thereof.

[0175] The compositions and Xu Bing Da systems of this disclosure may further contain pharmaceutically acceptable additives. These pharmaceutically acceptable additives may be any additives conventionally used in the art of the preparation, such as fillers, stabilizers, flow promoters, surfactants, light-shielding agents, sweeteners, colorants, flavorings, antioxidants, preservatives, reducing agents, and chelating agents. The pharmaceutically acceptable additives are used in amounts conventionally used in the art of the preparation. Furthermore, two or more of these additives may be mixed in appropriate proportions.

[0176] Examples of fillers suitable for use in the sustained-release compositions of this disclosure include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars, e.g., dextrose, sucrose, lactose, salts, e.g., calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starch, microcrystalline cellulose, powdered cellulose, cellulose bases, e.g., methylcellulose, carboxymethylcellulose, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0177] Examples of stabilizers include sodium ascorbate tocopherol, tetrasodium edetate, cyclodextrin, nicotinamide, alkaline earth metal salts (e.g., calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium silicate, magnesium aluminate), and butylhydroxyanisole.

[0178] Examples of flow enhancers include, but are not limited to, colloidal silicon dioxide, cellulose, and dibasic or tribasic calcium phosphate. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Light-shielding agents include titanium dioxide. Light-shielding agents are desirable for photosensitive active ingredients such as PRX-3140 and its polymorphs and salts. Examples of antioxidants include butylhydroxytoluene (BHT), butylhydrodicyanizole (BHA), tocopherol, tocopherol esters (e.g., tocopherol acetate), ascorbic acid or its alkali or alkaline earth metal salts, lycopene, and beta-carotene. Examples of reducing agents include cystine and cysteine. Examples of chelating agents include EDTA or its alkali metal or alkaline earth metal salts. Colorants include, for example, food colors such as Food Coloring Yellow No. 5, US Food Coloring No. 6, Swedish Orange, Food Coloring Blue No. 2, Food Coloring Red No. 2, food lake color, yellow ferric oxide (yellow ferric oxide pigment), red ferric oxide (red ferric oxide pigment), black ferric oxide (black ferric oxide pigment), riboflavin, riboflavin organic acid esters, riboflavin phosphate or its alkali metal salts or alkali metal earth salts (slats), phenolphthalein, titanium dioxide, lycopene, and beta-carotene. Sweeteners include aspartame, acesulfame potassium, thaumatin, sodium saccharin, and dipotassium glycyrrhizinate. Examples of flavorings include menthol, peppermint oil, lemon oil, vanillin, and strawberry.

[0179] The shape of a sustained-release composition in solid dosage form, such as a tablet, is not particularly limited and can be any shape suitable for administration, for example, any shape suitable for oral administration, such as a sphere, ellipse, pear, cylindrical, cubic, regular and / or irregular shape. A tablet may have one of a variety of different shapes. For example, a tablet may be molded as a polyhedron, such as a cube, pyramid, or prism. Alternatively, it may have the geometric shape of a spatial figure having several non-planar faces, such as a cone, frustum of a cone, cylinder, sphere, or torus. In certain embodiments, a tablet has one or more main faces. For example, the tablet surface typically has opposing upper and lower surfaces formed by contact with the upper and lower punch surfaces of a compressor. In such embodiments, the tablet surface typically further includes a "belly band" located between the upper and lower surfaces and formed by contact with the die wall of the compressor.

[0180] In one embodiment, the disclosure provides that a sustained-release composition in the form of a sustained-release tablet has a tablet weight of about 60 to about 500 mg. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet weight of about 90 to about 110 mg. The sustained-release composition in the form of a sustained-release tablet has a tablet thickness of about 2.75 to about 3.75 mm. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet thickness of about 3 to about 3.5 mm.

[0181] The hardness of the tablets of the present invention may vary depending on various factors, including, for example, the relative amounts and specific types of components used, the tableting equipment used, and selected processing parameters. The compression and pressure used to prepare the tablets may affect the release profile of compound PRX-3140 or its polymorphs or salts to the test subject. The compression and pressure used to prepare the tablets of the present invention may vary depending on their surface area as well as the amount and particle size of compound PRX-3140 or its polymorphs or salts, sustained-release agents, binders, lubricants, and other additives contained in the tablets. The degree of hydration and solvation of the components in the composition is also important in determining the hardness of the tablets. In some embodiments, sustained-release compositions in the form of sustained-release tablets have a tablet hardness of about 4 kilopounds (Kp) to about 16 Kp. In some embodiments, sustained-release compositions in the form of sustained-release tablets have a hardness of about 10 to about 16 Kp. In some embodiments, sustained-release compositions in the form of sustained-release tablets have tablet hardnesses of about 4 Kp, about 4.5 Kp, about 5 Kp, about 5.5 Kp, about 6 Kp, about 6.5 Kp, about 7 Kp, about 7.5 Kp, about 8 Kp, about 8.5 Kp, about 9 Kp, about 9.5 Kp, about 10 Kp, about 10.5 Kp, about 11 Kp, about 11.5 Kp, about 12 Kp, about 12.5 Kp, about 13 Kp, about 13.5 Kp, about 14 Kp, about 14.5 Kp, about 15 Kp, about 15.5 Kp, and about 16 Kp. In some embodiments, sustained-release compositions in the form of sustained-release tablets have a tablet hardness of about 13 Kp. In at least one embodiment, sustained-release compositions in the form of sustained-release tablets have a tablet hardness of 5 Kp.

[0182] The abrasion rate of sustained-release tablets is typically 1.0% or less (NMT). In some embodiments, the sustained-release composition in the form of sustained-release tablets contains a light-shielding agent such as titanium dioxide. The sustained-release composition in the form of sustained-release tablets is a sustained-release composition of any color known in the art, for example, food coloring yellow No. 5, US food coloring No. 6, Swedish orange, food coloring blue No. 2, food coloring red No. 2, etc., food lake color, yellow ferric oxide (yellow ferric oxide pigment), red ferric oxide (red ferric oxide pigment), black ferric oxide (black ferric oxide pigment), riboflavin, riboflavin organic acid esters, riboflavin phosphate or its alkali metal salt or alkali metal earth salt (slats), phenolphthalein, titanium dioxide, lycopene, or beta-carotene. In some embodiments, the sustained-release composition in the form of sustained-release tablets is white or off-white. The sustained-release compositions, such as sustained-release tablets, described herein may be coated or not.

[0183] In another embodiment, the Disclosure provides the preparation of enteric-coated delayed-release solid dosage forms, such as enteric-coated delayed-release tablets, using the sustained-release compositions of the Disclosure. An advantageous embodiment of such enteric-coated compositions is that these sustained-release compositions, including enteric-coated delayed-release tablets, are formulated to minimize the release of PRX-3140 or its polymorphs or salts in the stomach, avoid the breakdown of PRX-3140 or its polymorphs or salts, and target the release of the active ingredient PRX-3140 or its polymorphs or salts into the small intestine, colon, or both. Targeting the intestine and colon increases the bioavailability of PRX-3140 or its polymorphs or salts. In some embodiments, the sustained-release compositions of the Disclosure deliver PRX-3140 or its polymorphs or salts into the duodenum or jejunum.

[0184] Those skilled in the art will recognize that the sustained-release compositions of this disclosure may function as sustained-release compositions on their own (see Examples 10 to 17), and may also function as “cores” (e.g., core tablets) used in the preparation of enteric-coated dosage forms (such as enteric-coated delayed-release tablets or enteric-coated delayed-release capsules) that provide delayed release of PRX-3140 or its polymorphs or salts targeting the small intestine, colon, or both.

[0185] Accordingly, in some embodiments, the sustained-release compositions of this disclosure in solid dosage form (e.g., as tablets) form a “core” composition (e.g., core tablet) for the preparation of enteric-coated delayed-release compositions. Such sustained-release compositions protect the acid-sensitive active ingredient PRX-3140 or its polymorphs or salts from the acidic environment of the stomach and allow dissolution at a pH greater than 5.5, generally in the intestines, e.g., the duodenum, jejunum and / or ileum and / or colon of the small intestine. The enteric coating protects the interconversion of active PRX-3140 to PRX-3140 in the stomach, and the drug PRX-3140 is subsequently released at a slower rate in the intestines, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours after administration, etc. The remarkably reduced interconversion of PRX-3140 based on the formulations disclosed herein provides unexpected benefits in the administration of PRX-3140 or its polymorphs or salts.

[0186] As a non-limiting example, the Disclosure provides sustained-release compositions of the Disclosure in the form of solid dosage forms, such as enteric-coated delayed-release tablets. The sustained-release compositions in the form of tablets function as a core (hereinafter referred to as the “core,” “core tablet,” or “tablet core,” and used interchangeably) substantially covered by at least one layer of a functional coating. In other words, the enteric-coated delayed-release tablets of the Disclosure have a core comprising (i) PRX-3140 or a salt or polymorph thereof, (ii) at least one sustained-release agent, and (iii) at least one lubricant, wherein the core is substantially covered by at least one layer of a functional coating.

[0187] In some embodiments, the functional coating comprises at least one controlled-release agent (e.g., a delayed-release agent targeting the intestine (e.g., duodenum) or colon or both). The disclosure provides that the functional coating may further comprise additional additives such as plasticizers and anti-tackifiers. Adding a delayed-release agent to the functional coating yielded remarkably favorable results, substantially reducing the conversion of PRX-3140 to PRX-3140. The remarkable advantages of coating a composition (e.g., a tablet) with a coating containing a delayed-release agent demonstrate that such a coating can more efficiently facilitate the delivery of PRX-3140. Furthermore, remarkably, coatings containing a delayed-release agent were found to result in a more consistent and slower release.

[0188] In certain embodiments, the functional coatings of the present disclosure include at least one controlled-release agent, e.g., a delayed-release agent, at least one plasticizer, and at least one anti-tack / anti-adhesion agent. In some embodiments, enteric-coated delayed-release tablets may be coated with at least two coatings, at least one of which is a functional coating comprising a delayed-release agent, at least one plasticizer, and at least one anti-tack / anti-adhesion agent.

[0189] Accordingly, in some embodiments, sustained-release compositions comprising PRX-3140 or a polymorph or salt thereof of the Disclosure include a core (e.g., a core tablet) substantially coated with at least one layer of a functional coating using a coating solution. The coating solution comprises at least one controlled-release agent, e.g., a delayed-release agent, at least one plasticizer, and at least one anti-tack / anti-adhesion agent. Those skilled in the art will recognize that the core tablets disclosed herein may be encapsulated in tablets, caplets, or capsules and further coated with the coating solutions disclosed herein to prepare other solid dosage forms such as tablet-containing tablets, tablet-containing caplets, and tablet-containing capsules. In such cases, the sustained-release compositions such as tablet-containing tablets, tablet-containing caplets, and tablet-containing capsules are substantially coated with at least one layer of the functional coating described herein. Thus, the coated tablets contained within other coated tablets, caplets, and capsules can release PRX-3140 or a polymorph or salt thereof in a pulsed manner.

[0190] Those skilled in the art will also recognize that, as with the core tablets described herein, other solid dosage forms of sustained-release compositions (e.g., mini-tablets, spheres, beads, granules, pellets, pills, etc.) can also be used as cores for the preparation of enteric-coated delayed-release tablets, caplets, and capsules. Examples of such sustained-release compositions include, but are not limited to, sustained-release enteric-coated tablets, enteric-coated mini-tablets, enteric-coated caplets, enteric-coated beads, enteric-coated spheres, enteric-coated granules, enteric-coated pellets, enteric-coated pills, enteric-coated tablet-containing tablets, enteric-coated tablet-containing capsules, etc., used for the delayed release of PRX-3140 or its polymorphs or salts into the small intestine, colon, or both. Enteric-coated delayed-release capsules can be prepared using commercially available delayed-release capsules, such as those available from Capsugel (e.g., VCaps® Plus or Enprotect® enteric-coated capsules), which are included in this disclosure. In some embodiments, enteric-coated delayed-release capsules may be non-animal capsules such as hypromellose capsules (e.g., commercially available autogelling Vcaps, VCaps Plus, VCaps Enteric, other enteric-coated capsules manufactured using Xcellodose, ENCODE colon delivery technology, and Capsugel's EnTrinsic™ drug delivery technology). Other technologies known and commercially available in the art for formulating oral solid dosage forms in enteric-coated forms (e.g., Qualicaps, USA, Nutrascience, USA, etc.) may also be utilized.

[0191] This disclosure provides that functional coating of a core may be performed using a coating solution comprising, but not limited to, at least one controlled release agent, such as a delayed release agent. In some embodiments, the functional coating solution may include plasticizers, anti-tack agents, etc. In some embodiments, functional coating of a core may be performed using a coating solution comprising, but not limited to, at least one controlled release agent, e.g., a delayed release agent, at least one plasticizer, and at least one anti-tack / anti-adhesion agent. The coating solutions provided herein may be applied as films, such as thin films, to a range of solid dosage forms, including particles, beads, spheres, granules, pellets, tablets, minitablets, pills, polyparticles, and capsules (having hard and soft shells) that encapsulate a core (e.g., immediate-release capsules), in order to prepare enteric-coated delayed-release solid dosage forms using the sustained-release compositions described herein.

[0192] If a sustained-release composition, such as an enteric-coated delayed-release tablet, exhibits dissolution rates in the range of approximately 0% to approximately 35% after 3 hours, approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to approximately 85% after 24 hours, using simulated gastric fluid at 37 degrees Celsius and pH 1.2 as the test medium, and simulated intestinal fluid at 37 degrees Celsius and pH 6.8 for 24 hours, then at least one layer of the functional coating provides a weight increase of approximately 1% to approximately 60%, approximately 2% to approximately 40%, approximately 5% to approximately 30%, and approximately 6% to approximately 20% relative to the weight of the core (e.g., core tablet).

[0193] If a sustained-release composition, such as an enteric-coated delayed-release tablet, exhibits a dissolution rate of approximately 5% or less after 2 hours, approximately 60% or more after 3 hours, approximately 95% or more after 6 hours, and approximately 100% after 12 hours in a 50 RPM USP paddle dissolution test using simulated gastric fluid at 37 degrees Celsius and pH 1.2 as the test medium, and simulated intestinal fluid at 37 degrees Celsius and pH 6.8 for 24 hours, then at least one layer of the functional coating provides a weight increase of approximately 1% to approximately 60%, approximately 2% to approximately 40%, approximately 5% to approximately 30%, and approximately 6% to approximately 20% relative to the weight of the core (e.g., core tablet).

[0194] If a sustained-release composition, such as an enteric-coated delayed-release tablet, exhibits a dissolution rate of approximately 10% or less after 3 hours, approximately 30% or more after 6 hours, approximately 50% or more after 9 hours, and approximately 80% or more after 14 hours in a dissolution test using the 50 RPM USP paddle method, with the test medium being simulated gastric fluid for 2 hours at 37 degrees Celsius using water or pH 1.2, and simulated intestinal fluid for 24 hours at 37 degrees Celsius using pH 6.8, then at least one layer of the functional coating provides a weight increase of approximately 1% to approximately 60%, approximately 2% to approximately 40%, approximately 5% to approximately 30%, and approximately 6% to approximately 20% relative to the weight of the core (e.g., core tablet).

[0195] The tablet weight also varies, among other things, depending on the dosage of compound PRX-3140 or its polymorph or salt, the type and amount of sustained-release agent used, and the presence, type and amount of additional materials. For the dosage of the compound, it may range from about 0.5 mg to about 200 mg, and the tablet weight may range from about 10 mg to about 2000 mg per tablet. In some embodiments, the tablet weight is in the range of 50 mg to 500 mg. In some embodiments, enteric-coated delayed-release tablets have tablet weights in the range of about 101 mg to 160 mg, 90 mg to 110 mg, or about 105 mg to about 120 mg. For time-delayed or delayed-release pharmaceutical preparations of the sustained-release compositions of this disclosure in the form of oral dosage forms, an acid-insoluble polymer (e.g., polymethacrylate) may be used as a delayed-release agent in the coating solution.

[0196] In the case of enteric-coated delayed-release preparations, acrylic acid polymers and copolymers formed from cellulose polymers such as glyceryl monostearate, glyceryl distearate, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, cellulose acetate, cellulose phthalate acetate, cellulose acetate trimellitate, and sodium carboxymethylcellulose, methacrylate-ethyl acrylate copolymer (1:1) (EUDRAGIT® L30D-55) and L100-55 (soluble at pH 5.5 or higher), preferably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, and other methacrylic resins commercially available under the trade name EUDRAGIT® (Evoniks, Rohm Pharma, Westerstadt, Germany). EUDRAGIT® 1,100D (soluble at pH 6.0 or higher), EUDRAGIT® S (soluble at pH 7.0 or higher as a result of a higher degree of esterification), and EUDRAGIT® NE, RL and RS (water-insoluble polymers with different degrees of permeability and swellability), vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl phthalate acetate, vinyl crotonate acetate copolymer, ethylene-vinyl acetate copolymer, polyvinyl acetate / polyvinylpyrrolidone, as well as azopolymers, enzymatically digestible polymers such as xanthan gum, chitosan, amylase and guar gum, zein and shellac.

[0197] In certain embodiments, the delayed-release agent is a pH-sensitive polymer such as polymethacrylate. In some embodiments, the delayed-release agent is methacrylate-ethyl acrylate copolymer (1:1) USP-NF (EUDRAGIT® L30D-55). In some embodiments, the delayed-release agent is methacrylate-ethyl acrylate copolymer (1:2).

[0198] This disclosure also provides that combinations or mixtures of different delayed-release agents may be used in a single layer of a functional coating. In some embodiments, multilayer (e.g., two or more layers) coatings using different delayed-release agents or polymers may also be applied to a core.

[0199] If a sustained-release composition in the form of an enteric-coated delayed-release dosage form (such as an enteric-coated delayed-release tablet) releases (obtains) PRX-3140 or a polymorph of its salt for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, or at least 72 hours, then a delayed-release agent, such as methacrylate-ethyl acrylate copolymer (1:1) USP-NF (EUDRAGIT® L30D-55), is present in at least one layer of the functional coating in an amount ranging from about 0.1% to about 35%, about 5% to about 35%, or about 8% to about 20% w / w relative to the weight of the core (e.g., core tablet).

[0200] If a sustained-release composition of this disclosure, such as a delayed-release tablet, exhibits dissolution rates in the range of approximately 0% to 35% after 3 hours, approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to approximately 85% after 24 hours in a 50 RPM USP paddle dissolution test using simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2 as the test medium, and simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8, then the delayed-release agent is present in at least one layer of the coating in an amount ranging from approximately 0.1% to approximately 30%, approximately 5% to approximately 25%, or approximately 8% to approximately 14% w / w of the weight of the core tablet. In some embodiments, the delayed-release agent is present in at least one layer of the coating in an amount ranging from approximately 0.1% to approximately 20% on a w / w basis relative to the weight of the core tablet.

[0201] If a sustained-release composition of this disclosure, such as a delayed-release tablet, exhibits dissolution rates of approximately 5% or less after 2 hours, approximately 70% or more after 3 hours, approximately 95% or more after 12 hours, and approximately 100% after 12 hours in a 50 RPM USP paddle dissolution test using water or pH 1.2 at 37 degrees Celsius for 2 hours as the test medium, and in simulated intestinal fluid using pH 6.8 at 37 degrees Celsius for 24 hours, the delayed-release agent is present in at least one layer of the coating in an amount ranging from approximately 0.1% to approximately 30%, approximately 5% to approximately 25%, or approximately 8% to approximately 14% w / w of the weight of the core tablet. In some embodiments, the delayed-release agent is present in at least one layer of the coating in an amount ranging from approximately 0.1% to approximately 20% on a w / w basis relative to the weight of the core tablet.

[0202] Such release of PRX-3140 or its polymorphic salts from the sustained-release compositions of this disclosure generally begins in the intestines about two hours after administration.

[0203] The addition of at least one plasticizer can control the softness or flexibility of sustained-release compositions prepared as solid dosage forms such as enteric-coated delayed-release tablets or capsules or caplet shells, and thus improve the mechanical properties of pH-sensitive materials of coatings on solid dosage forms.

[0204] Suitable plasticizers include petroleum (e.g., paraffinic process oils, naphthenic process oils, and aromatic process oils), squalene, squalane, vegetable oils (e.g., olive oil, camel oil, castor oil, tall oil, and peanut oil), mineral oil, silicone oil, dibasic acids or phthalates (e.g., dibutyl phthalate, diethyl phthalate, and dimethyl phthalate, and dioctyl phthalate), liquid rubber (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), and This includes hexyl urate, diethyl sebacate, and diisopropyl sebacate, citrate esters such as triethyl citrate, tributyl citrate, acetyl tributyl citrate, and acetyl triethyl citrate, triacetin, propylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, other polyethylene oxide sorbitan esters, phthalates, sorbitol, glycol salicylate, crotamine, glycerin, PLASACRYL(TM) T20, or mixtures thereof.

[0205] In some embodiments, at least one plasticizer in the functional coating is triethyl citrate. In some embodiments, at least one plasticizer (e.g., citrate ester, e.g., triethyl citrate) is present in an amount ranging from about 0.01% to about 5%, about 0.1% to about 4%, about 0.2% to about 2%, or about 0.5% to about 1.5% w / w of the weight of the core tablet.

[0206] This disclosure provides that at least one layer of a functional coating contains at least one anti-tack / anti-adhesion agent. The anti-tack / anti-adhesion agent is included in the coating solution for coating to prevent adhesion to the punched surface of tablets and to mechanical dispensing devices, tamping pins, etc. Exemplary anti-tack agents include talc, glyceryl monostearate, colloidal silicon dioxide, kaolin, or any combination thereof.

[0207] Adding talc as an anti-tackifying agent to functional coatings yielded surprisingly favorable results, substantially reducing the conversion of PRX-3140 to PRX-3140. The remarkable advantages of coating compositions (e.g., tablets) with talc-containing coatings demonstrate that such coatings can more efficiently facilitate the delivery of PRX-3140. Furthermore, surprisingly, coatings containing delayed-release agents were found to result in a more consistent and slower release.

[0208] The sustained-release composition (e.g., enteric-coated delayed-release tablets) contains at least one anti-tack agent present in an amount ranging from about 0.1% to about 10% w / w, 1% to about 8%, or about 2% to about 6% w / w of the core. Exemplary enteric-coated delayed-release capsules and tablets are provided herein and in Examples 16 and 17.

[0209] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet containing about 0.01% to about 40% or about 0.5 mg to about 200 mg of PRX-3140 or a polymorph or salt thereof, hypromellose, microcrystalline cellulose, and magnesium stearate. The core tablet is substantially encapsulated in at least one layer of a functional coating, the at least one layer of which contains a methacrylate-ethyl acrylate copolymer (ranging from 2:1 to 1:2), triethyl citrate, and talc.

[0210] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) about 0.01% to about 40% of PRX-3140 or a polymorph or salt thereof, (ii) about 0.1% to about 99% of hypromellose, (iii) about 1% to about 99% of microcrystalline cellulose, and (iv) about 0.01% to about 5% of magnesium stearate, wherein the core tablet is substantially encapsulated in at least one layer of a functional coating, the at least one layer of the functional coating comprising (i) about 5% to about 40% of methacrylate-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylate copolymer dispersion, 30% solids), the at least one layer of the functional coating contributing to a weight increase of about 2% to about 20% above the average core tablet weight. The amount is expressed as a weight percentage based on the weight of the core tablet. In some embodiments, the aforementioned sustained-release composition has a drug (PRX-3140 or its polymorph or salt) to sustained-release agent ratio of 1:5.

[0211] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) about 0.01% to about 40% of PRX-3140 or a polymorph or salt thereof, (ii) about 5% to about 60% of hypromellose, (iii) about 10% to about 90% of microcrystalline cellulose, and (iv) about 0.01% to about 5% of magnesium stearate, wherein the core tablet is substantially encapsulated in at least one layer of a functional coating, the at least one layer of the functional coating comprising (i) about 5% to about 40% of methacrylate-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylate copolymer dispersion, 30% solids), the at least one layer of the functional coating contributing to a weight increase of about 2% to about 20% above the average core tablet weight. The amount is expressed as a weight percentage based on the weight of the core tablet.

[0212] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) about 0.01% to about 40% of PRX-3140 or its polymorph or salt, (ii) about 5% to about 60% of hypromellose, (iii) about 10% to about 90% of microcrystalline cellulose, and (iv) about 0.01% to about 5% of magnesium stearate, wherein the core tablet is substantially encapsulated in at least one layer of a functional coating, the at least one layer of the functional coating comprising (i) about 0.1% to about 20% of methacrylate-ethyl acrylate copolymer (1:1) (polymethacrylate The methacrylic acid copolymer dispersion comprises (ii) approximately 0.01% to approximately 5% triethyl citrate and (iii) approximately 1% to approximately 10% talc, wherein at least one layer of the functional coating contributes to a weight increase of approximately 2% to approximately 20% above the average core tablet weight. The amount is expressed as a weight percentage based on the weight of the core tablet.

[0213] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) 0.5 mg, 1 mg, 2 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, or 40 mg of PRX-3140 or a polymorph or salt thereof, (ii) about 0.1% to about 99% or about 5% to about 60% of hypromellose, (iii) about 1% to about 99% or about 10% to about 90% of microcrystalline cellulose, and (iv) about 0.01% to about 5% of magnesium stearate, wherein the core tablet is substantially encapsulated in at least one layer of a functional coating, the at least one layer of the functional coating comprising (a) about 0.1% to about 20% of ethyl acrylate copolymer (1:1) (polymethacrylate The methacrylic acid copolymer dispersion, 30% solids, (b) approximately 0.01% to 5% triethyl citrate, and (c) approximately 1% to 10% talc, wherein at least one layer of the functional coating contributes to a weight increase of approximately 2% to 20% above the average core tablet weight. The amounts of all components in (ii) to (iv) and (a) to (c) are expressed as weight percentages relative to the weight of the core tablet. Such enteric-coated delayed-release tablets (i) provide sustained release of PRX-3140 or its polymorph or salt over at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, or at least 72 hours in a dissolution test using the 50 RPM USP paddle method, with water or pH 1.2 at 37 degrees Celsius as the test medium, and at least 8 hours at pH 6.8 at 37 degrees Celsius for 24 hours.

[0214] In some embodiments, such enteric-coated delayed-release tablets exhibit dissolution rates of approximately 0% to approximately 30% after 3 hours, approximately 30% to approximately 50% after 12 hours, and approximately 65% ​​to approximately 85% after 12 hours, in a dissolution test using the 50 RPM USP paddle method, with the test medium being simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2, and simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8.

[0215] In some embodiments, such enteric-coated delayed-release tablets exhibit the following dissolution rates in a 50 RPM USP paddle test, using simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2 as the test medium, and simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8: (i) a dissolution rate in the range of approximately 0% to 35% after 3 hours, approximately 35% to approximately 55% after 12 hours, and approximately 65% ​​to 85% after 24 hours; (ii) a dissolution rate of 30% or less after 3 hours, 50% or less after 12 hours, and 80% or more after 24 hours; or (iii) a dissolution rate of at least 20% to 30% after 24 hours.

[0216] In some embodiments, such enteric-coated delayed-release tablets exhibit dissolution rates of approximately 5% or less after 2 hours, approximately 70% or more after 3 hours, approximately 95% or more after 6 hours, and approximately 100% after 12 hours in a dissolution test using the 50 RPM USP paddle method, with the test medium being simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2, and simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8.

[0217] In some embodiments, such enteric-coated delayed-release tablets exhibit dissolution rates of approximately 5% or less after 2 hours, approximately 10% or less after 3 hours, approximately 30% or more after 6 hours, approximately 50% or more after 9 hours, and approximately 80% or more after 14 hours, when tested in a 50 RPM USP paddle method using simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2 as the test medium, and in simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8.

[0218] In some embodiments, such enteric-coated delayed-release tablets exhibit dissolution rates of approximately 10% or less after 3 hours, approximately 30% or more after 6 hours, approximately 50% or more after 9 hours, and approximately 80% or more after 14 hours in a dissolution test using the 50 RPM USP paddle method, with the test medium being simulated gastric fluid for 2 hours at 37 degrees Celsius with water or pH 1.2, and simulated intestinal fluid for 24 hours at 37 degrees Celsius with pH 6.8.

[0219] The functional coatings of the sustained-release compositions of this disclosure, including enteric-coated delayed-release tablets, may further contain pharmaceutically acceptable additives. These pharmaceutically acceptable additives may be any additives conventionally used in the art of the preparations, such as fillers, stabilizers, flow enhancers, surfactants, light-shielding agents, sweeteners, colorants, flavorings, antioxidants, preservatives, reducing agents, and chelating agents, as described herein. The pharmaceutically acceptable additives are used in amounts conventionally used in the art of the preparations. Furthermore, two or more of these pharmaceutically acceptable additives may be mixed and used in appropriate proportions. In one embodiment, this disclosure provides a sustained-release composition of compound PRX-3140 or a polymorph or salt thereof that provides a subject with sustained exposure to the compound at oral administration for approximately 2 to 270 hours per dose. In some embodiments, the sustained-release composition provides a subject with sustained exposure to released compound PRX-3140 or its polymorphs or salts for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 18 hours, at least 20 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 160 hours, at least 180 hours, at least 200 hours, at least 220 hours, at least 250 hours, and at least 270 hours.

[0220] VII. Pharmacokinetic Properties In one embodiment, a sustained-release composition of the present disclosure comprising compound PRX-3140 or a polymorph or salt thereof can provide enhanced pharmacokinetics in a subject when administered orally, compared to an immediate-release product or a "drug-containing capsule." Furthermore, the sustained-release composition may also have fewer side effects.

[0221] This disclosure provides pharmacokinetic (PK) parameters for single doses of sustained-release tablets in the form of enteric-coated delayed-release tablets. In non-limiting examples, in certain embodiments, a single oral dose of a sustained-release composition ingested by a subject (e.g., in the form of sustained-release tablets or capsules) can provide or achieve a mean plasma Cmax (ng / mL) of PRX-3140 acid in blood, serum, or plasma of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the Cmax of an equivalent single oral dose of an immediate-release capsule. In certain embodiments, a single-dose orally administered sustained-release tablet or capsule of the present disclosure can provide or achieve an average plasma Cmax (ng / mL) of at least about 45% of the Cmax of an equivalent single-dose orally administered immediate-release capsule.

[0222] This disclosure provides that a single oral dose of a sustained-release composition, such as an enteric-coated delayed-release tablet of this disclosure, ingested by a subject, can provide or achieve a mean plasma Tmax(hr) greater than that of an equivalent single oral dose of an IR dosage form. As a non-limiting example, the mean plasma Tmax(hr) of a single oral dose of an enteric-coated delayed-release tablet ingested by a fasted subject is greater than that of an equivalent single oral dose of an IR dosage form. Similarly, in certain embodiments, a single oral dose of a sustained-release composition of the Disclosure, for example in the form of an enteric-coated delayed-release tablet, may have an average plasma Tmax (hr) of at least 0.1, at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, at least 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 7.5, at least about 8, at least 8.5, at least 9 times, at least 9.5 and at least 10 times compared to the average plasma Tmax (hr) of an equivalent single oral dose of a reference product, the IR dosage form. Thus, the sustained-release compositions of the Disclosure reach their average plasma Cmax considerably later than the reference product, the IR dosage form (see Table 15). The average plasma concentrations over time after a single dose of the sustained-release compositions and the reference product, the IR dosage form, are shown in Table 12. In certain embodiments, the sustained-release compositions of this disclosure in the form of hard enteric-coated delayed-release tablets can have an average plasma Tmax (hr) at least about 6 to about 10 times higher than that of the reference product IR dosage form.

[0223] In some embodiments, the sustained-release composition of the present disclosure (e.g., sustained-release tablets or capsules) is released in the plasma or serum of a subject who has been orally administered the sustained-release composition for at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, and at least about 2 This may produce an average Tmax of the compound (e.g., PRX-3140 acid) of 2 hours, at least about 23 hours, at least about 24 hours, at least about 26 hours, at least about 28 hours, at least about 30 hours, at least about 32 hours, at least about 34 hours, at least about 36 hours, at least about 38 hours, at least about 40 hours, at least about 42 hours, at least about 44 hours, at least about 46 hours, at least about 48 hours, at least about 50 hours, at least about 55 hours, at least about 60 hours, at least about 65 hours, at least about 70 hours, at least about 75 hours, or at least about 80 hours.In some embodiments, the sustained-release composition is released in the plasma or serum of subjects who have been orally administered the sustained-release composition for 4 to 80 hours, 5 to 80 hours, 6 to 80 hours, 7 to 80 hours, 8 to 80 hours, 9 to 80 hours, 10 to 80 hours, 15 to 80 hours, 24 to 80 hours, 36 to 80 hours, 48 ​​to 80 hours, 4 to 70 hours, 5 to 70 hours, 6 to 70 hours, 7 to 70 hours, 8 to 70 hours, 9 to 70 hours, 10 to 70 hours, 15 to 70 hours, 24 to 70 hours, 36 hours and This can produce average Tmax values ​​for compounds of 70 hours, 48-70 hours, 4-60 hours, 5-60 hours, 6-60 hours, 7-60 hours, 8-60 hours, 9-60 hours, 10-60 hours, 15-60 hours, 24-60 hours, 36-60 hours, 48-60 hours, 4-55 hours, 5-55 hours, 6-55 hours, 7-55 hours, 8-55 hours, 9-55 hours, 10-55 hours, 15-55 hours, 24-55 hours, 36-55 hours, or 48-55 hours.

[0224] Furthermore, the higher Tmax and drug release profile of sustained-release compositions compared to IR dosage forms suggest that the release rate and absorption rate or uptake rate (as used interchangeably in this disclosure) of the compound (PRX-3140 or its polymorphs or salts) into the subject's blood from orally administered sustained-release compositions are also slower compared to the release rate and absorption rate of the compound from IR dosage forms. In certain embodiments, this disclosure provides that sustained-release compositions in the form of sustained-release tablets or capsules, such as enteric-coated delayed-release capsules, can achieve one or more of the pharmacokinetic parameters and mean plasma concentrations disclosed in Table 13 after oral administration of single and multiple doses of the sustained-release composition to a subject. In some embodiments, the mean Tmax of the sustained-release compositions of this disclosure after a single dose is approximately 5–8 hours.

[0225] Exemplary pharmacokinetic parameters for multiple doses (e.g., once-daily doses) of sustained-release tablets or capsules in the form of enteric-coated delayed-release tablets or capsules as disclosed herein are provided herein.

[0226] Similarly, in certain embodiments, the sustained-release compositions of the present disclosure can provide or achieve at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the mean plasma Cmax (ng / mL) of the IR dosage form when the sustained-release compositions and IR dosage forms are orally administered to a subject in multiple equivalent doses (for example, 1 mg once daily for 14 days). In certain embodiments, the sustained-release compositions of the Disclosure, for example, in the form of enteric-coated delayed-release tablets of the Disclosure, can provide or achieve an average plasma Cmax (ng / mL) of at least about 45% of the Cmax of the IR dosage form when the sustained-release compositions and IR dosage forms are orally administered to a fasted subject in multiple equivalent doses (as a non-limiting example, 4 mg once daily for 14 days).

[0227] The average time to reach steady-state levels of PRX-3140 acid in the blood, serum, or plasma of a subject after multiple administrations of the sustained-release composition of this disclosure is approximately 14 days. At steady state, the sustained-release composition of this disclosure exhibits less variation over the administration interval compared to the reference product IR dosage form.

[0228] The compositions of this disclosure (e.g., compositions comprising PRX-3140) can produce steady-state mean concentrations (Cavg) of PRX-3140 acid in a subject. In some embodiments, the compositions produce concentrations in the subject of 1 ng / mL to 10 ng / mL, 5 ng / mL to 15 ng / mL, 10 ng / mL to 20 ng / mL, 15 ng / mL to 25 ng / mL, 20 ng / mL to 30 ng / mL, 25 ng / mL to 35 ng / mL, 30 ng / mL to 40 ng / mL, 35 ng / mL to 45 ng / mL, 40 ng / mL to 50 ng / mL, and 45 ng / mL to 60 ng / mL. It is possible to produce mean steady-state concentrations (Cavg) of 50 ng / mL to 70 ng / mL, 60 ng / mL to 80 ng / mL, 70 ng / mL to 90 ng / mL, 80 ng / mL to 100 ng / mL, 90 ng / mL to 110 ng / mL, 100 ng / mL to 120 ng / mL, 110 ng / mL to 130 ng / mL, 120 ng / mL to 140 ng / mL, or 130 ng / mL to 150 ng / mL. In some embodiments, the composition can induce in the subject an average steady state (Cavg) of 1 ng / mL to 10 ng / mL, 5 ng / mL to 15 ng / mL, 10 ng / mL to 20 ng / mL, 15 ng / mL to 25 ng / mL, 20 ng / mL to 30 ng / mL, 25 ng / mL to 35 ng / mL, or 30 ng / mL to 40 ng / mL per milligram of PRX-3140 administered to the subject.

[0229] In certain embodiments, the Disclosure provides that a sustained-release composition, for example in the form of a sustained-release capsule, can achieve one or more of the pharmacokinetic parameters shown in Table 13 after multiple oral doses to a subject or at steady state. In other embodiments, the median Tmax of the sustained-release composition of the Disclosure after multiple doses or at steady state is in the range of 3 to 24 hours. In at least one embodiment, the median Tmax of the sustained-release composition of the Disclosure after multiple doses or at steady state is 8.7 hours.

[0230] This disclosure provides that, in some embodiments, the relative bioavailability of compounds from sustained-release compositions of this disclosure, such as enteric-coated delayed-release tablets, when administered orally in single and / or multiple doses, is in the range of at least about 50% to at least about 150% compared to the equivalent single or multiple doses of the IR dosage form administered orally to the subject. Sustained-release compositions in the form of sustained-release tablets or capsules (see Example 15) having improved pharmacokinetic parameters (such as longer plasma and serum Tmax) and lower % variability of compounds (PRX-3140 acid) may be desirable for longer-term use for the treatment of Alzheimer's disease, as well as for continued use and adherence by the subject.

[0231] Accordingly, this disclosure provides that the compound (PRX-3140 or its polymorphs or salts) is absorbed in a controlled and sustained manner after 2 hours and is available systemically. This disclosure also provides that the sustained-release composition exhibits dose proportionality in peak drug concentrations in plasma and serum, as well as in AUC curves such as AUC24, over a dose range of 0.1 mg to about 500 mg.

[0232] In another embodiment, a method for treating a subject having or at risk of having Alzheimer's disease is provided herein, the method comprising (a) orally administering a sustained-release composition of the Disclosure to the subject; (b) obtaining or having obtained a biological sample such as whole blood, plasma, and / or serum from the subject; (c) measuring or having measured PRX-3140 acid in the subject's whole blood, plasma, and / or serum over a period of time, for example, at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 120 hours, at least 7 days, or at least 14 days; and (d) orally administering a different sustained-release composition of the Disclosure to the subject, the sustained-release composition being able to achieve one or more parameters of either or both of Tables 12 and 13.

[0233] Accordingly, a method is provided herein for maintaining plasma PRX-3140 acid levels above 1 nM in subjects requiring such maintenance by orally administering a sustained-release composition containing PRX-3140 or a polymorph or salt thereof to the subject. In some embodiments, the subject's plasma PRX-3140 acid level is maintained at a steady-state level above 10 nM. In some embodiments, the subject's plasma PRX-3140 acid level is maintained at a steady-state level in the range of 1 nM to 1000 nM (e.g., 1 nM to 500 nM, 1 nM to 300 nM, 1 nM to 200 nM, 1 nM to 100 nM, or 1 nM to 50 nM). In some embodiments, the subject's plasma PRX-3140 acid level is maintained at a steady-state level above 1 nM.

[0234] In one embodiment, the present invention relates to a sustained-release dosage form in which, when administered once daily to a healthy subject or patient under steady state, the percentage variation in total and / or free PRX-3140 acid blood concentration, measured as (Cmax-Cmin) / C mean, is smaller than the variation observed when the IR dosage form is administered in a once-daily regimen and is administered at a daily dose of a similar molecule of crystalline PRX-3140. The reduction is preferably at least 10%, for example at least 20%, preferably at least 30%, for example at least 40%, and more preferably at least 50%.

[0235] In one embodiment, the present invention relates to a sustained-release dosage form in which, when administered to at least six healthy subjects in a fasted state, the average residence time of PRX-3140 acid measured in the blood is at least 50% longer than the average residence time measured under similar conditions to that of the IR dosage form.

[0236] In further embodiments, the present invention provides a method for providing immunosuppressive treatment to a patient requiring immunosuppressive treatment in a once-daily regimen by administration of a sustained-release formulation as described herein, wherein, once a steady state is achieved, one or more of the following are provided: a decrease in Cmax, a decrease in % variability, an increase in AUC, an extension of the time to Tmax, and an increase in Cmin. Furthermore, the method provides Cmin that correlates with bioavailability with a correlation coefficient of 0.75 to 1, such as at least 0.80, preferably 0.85, more preferably 0.90, even more preferably at least 0.95, and even more preferably at least 0.97.

[0237] In preferred embodiments, differences in bioavailability are substantially independent of the time of day the dosage is administered. This offers the possibility of a once-daily dosing regimen at bedtime or in the evening, in addition to the usual morning dose. More importantly, however, if a patient actually takes the dosage form at a time different from that prescribed and expected (patient non-compliance), the patient's risk is reduced in terms of decreased exposure and the resulting increased risk of side effects.

[0238] The present invention will be further described with reference to the following embodiments. However, it should be noted that these embodiments, like the embodiments described above, are illustrative and should not be construed as limiting the possible scope of the present invention. VII. Method for producing pharmaceutical compositions

[0239] In further embodiments, the disclosure provides a method for producing a pharmaceutical composition, further comprising formulating particles.

[0240] In certain embodiments, the particles are formulated into unit doses such as tablets or capsules.

[0241] In some embodiments in which the pharmaceutical composition further comprises at least one additive, the disclosure also provides a method for producing the pharmaceutical composition, further comprising mixing particles with at least one additive to form a second mixture, and formulating the second mixture.

[0242] In certain embodiments, the particles are formulated into unit doses such as tablets or capsules.

[0243] III. Treatment Methods This disclosure relates to compositions and methods for reducing weight, maintaining weight, reducing weight gain, altering body composition, treating diabetes, lowering fasting blood glucose, lowering HbA1c, lowering mean daily blood glucose, or lowering postprandial blood glucose in subjects who require or desire weight loss, weight maintenance, weight gain reduction, body composition alteration, diabetes treatment, fasting blood glucose, HbA1c, lowering mean daily blood glucose, or lowering postprandial blood glucose by chronic administration of crystalline PRX-3140 potassium salt in an orally sustained-release composition. The methods intend to administer an effective amount of crystalline PRX-3140 potassium salt orally to a subject for a long period or continuous period to influence the desired results described herein. When used herein in connection with the treatment of diabetes, reduction of HbA1c, control of postprandial blood glucose, reduction of fasting blood glucose and reduction of total daily blood glucose concentration, subjects requiring it may include subjects with diabetes, impaired glucose tolerance, insulin resistance, or those unable to autoregulate their blood glucose. In further embodiments, the subject requires or desires weight loss.

[0244] The methods disclosed herein are intended to be useful in maintaining levels of PRX-3140 that control fasting blood glucose with limited effects on inducing weight loss, decreased appetite, slowed gastric emptying, or the exertion of postprandial blood glucose control, or without any detectable effects on inducing weight loss, decreased appetite, slowed gastric emptying, or the exertion of postprandial blood glucose control, or without inducing weight loss, decreased appetite, slowed gastric emptying, or the exertion of postprandial blood glucose control. In particular, the methods disclosed herein are useful for controlling fasting blood glucose without inducing weight loss. Patient populations that would benefit from fasting blood glucose control without weight loss include, but are not limited to, elderly patients, patients with human immunodeficiency virus (HIV) infection, or other patients for whom weight loss is contraindicated. Furthermore, methods are provided for reducing the rise in postprandial blood glucose concentration compared to preprandial blood glucose concentration, thereby reducing the difference in blood glucose concentration before and after meals. This results in a reduction in diurnal fluctuations in blood glucose levels, as determined, for example, by the seven-point self-monitoring of blood glucose as described herein. Any method for determining the circulating blood glucose concentration in a patient may be used in conjunction with the claimed method.

[0245] Similarly, in the field of blood glucose control, the crystalline PRX-3140 potassium salt sustained-release formulation can be administered orally according to the methods disclosed herein for a period sufficient to achieve target HbA1c, target fasting blood glucose level, target total daily blood glucose concentration, etc., thereafter the plasma concentration of PRX-3140 acid may be reduced to a maintenance level or discontinued. If discontinued, administration may be resumed later as needed. In one embodiment, the crystalline PRX-3140 potassium salt sustained-release formulation is administered according to the methods disclosed herein for a period sufficient to lower or stabilize fasting blood glucose levels, and to lower or eliminate fasting blood glucose levels that are higher or higher than the desired fasting blood glucose level.

[0246] In some embodiments, the methods disclosed herein further provide for the crystalline PRX-3140 potassium salt to be co-administered with one or more oral antidiabetic agents. Such agents include, but are not limited to, metformin, sulfonylurea (SU), thiazolidinedione (TZD), or any combination thereof. Exemplary agents include pioglitazone, rosiglitazone, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, chlorpropamide, and tolbutamide. The crystalline PRX-3140 potassium salt sustained-release formulation can also be co-administered with insulin. Co-administration can be achieved by any suitable means or dosing regimen.

Example

[0247] Example Example 1 - Small scale preparation of 50 grams of crystalline PRX-3140 potassium salt. U.S. Patent Nos. 7,488,736 and 7,982,040 described the preparation of PRX-3140 in a six-step process. The supply of 3-piperidin-1-yl-propylamine enables the synthesis of crystalline microparticle form I of the PRX-3140 potassium salt in a four-step process on a 50 gram scale, as shown in Figure 2.

[0248] Procedure 1. Reduction amination - methyl 2 - isopropylaminothiophene - 3 - carboxylate (3). In a 3 L three - necked round - bottom flask equipped with a mechanical stirrer, methyl 2 - aminothiophene - 3 - carboxylate (90.52 g, 0.5758 mol) and sodium triacetoxyborohydride (207.48 g, 0.979 mol) were added. Anhydrous dichloromethane (640 mL) was added and the mixture was stirred for 2 minutes. Then a solution of formic acid (53.01 g, 1.1517 mol) and 2,2 - dimethoxypropane (299.88 g, 2.8793 mol) was added and the mixture was stirred under argon at 15 - 32 °C (internal temperature) for 30 minutes (cooled with cold water if necessary). The dropping funnel was rinsed with anhydrous dichloromethane (92 mL) and charged into the reaction mixture. After the addition was complete, the resulting mixture was stirred at 25 - 30 °C for 2 hours. The reaction mixture was added to an aqueous potassium hydroxide (304.1 g, 4.607 mol) solution (905 mL) at 5 °C, the temperature was maintained below 40 °C, the reaction flask was rinsed with dichloromethane (100 mL) and added to the mixture. The resulting mixture was stirred at room temperature for 0.5 hour, then filtered and the residue was washed with dichloromethane (300 mL). The filtrate was diluted with water (0.5 L) and the phases were separated. The aqueous phase was extracted with dichloromethane (0.5 L). The combined organic phases were mixed with water (0.5 L) and stirred for 0.5 hour. The phases were separated again and the organic phase was dried over Na2SO4. By filtration and concentration, 114.7 g of the crude product was obtained as a red oil, which was dissolved in heptane (0.50 L), stirred with neutral alumina (90 g) for 0.5 hour, then filtered and the filtrate was evaporated. The title compound (105.8 g, 92%) was obtained as a yellowish oil. HPLC purity: 98.2%. 1H NMR (300 MHz, CDCl3) δ 7.35 (br s, 1 H), 7.00 (d, J = 5.7 Hz, 1H), 6.14 (dd, J = 5.7, 1.2 Hz, 1H), 3.78 (s, 3H), 3.56 - 3.44 (m, 1H), 1.32 (s, 3H), 1.29 (s, 3H).

[0249] Step 2. Acylation and Cyclization - Methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (5). A solution of starting amine 3 (89.7 g, 0.450 mol) and pyridine (71.2 g, 0.900 mol) in butyronitrile (0.9 L) was heated to 70-75 degrees Celsius with stirring under argon. A solution of methyl malonyl chloride (116.7 g, 0.855 mol) in butyronitrile (0.45 L) was added dropwise to the reaction mixture, and the temperature was maintained at 70-75 degrees Celsius (internal temperature) with vigorous stirring (especially at the beginning, the heating was turned off occasionally). At the end of the addition, after maintaining the temperature for 8-10 minutes, sodium methoxide solution (25%, 390.0 g, 415 mL, 1.80 mol) was added over 10 minutes at the same temperature. The resulting mixture was stirred at the same temperature for 10 minutes and then cooled to room temperature. Water (0.45 L) was added and stirred at room temperature for 20 minutes. The phases were separated, and the organic phase was extracted with water (0.45 L). The combined aqueous phase was washed with RINKAN (2 × 0.45 L). The aqueous phase was then acidified to pH 4.0-4.5 with 1:5 v / v HCl / water at room temperature. The resulting solid was filtered and washed with water (2 × 180 mL). The filtered cake was dried overnight in a vacuum oven at 45-50 degrees Celsius. The title compound was obtained as a yellow solid (68.48 g, 57%). HPLC purity: 98.1%. The filtrate remained cloudy overnight, and a second filtration yielded a second harvest (9.68 g, 8%, HPLC purity: 87.4%), which was not used in the next step. ¹H NMR (300 MHz, CDCl3) δ 7.32 (d, J=5.7 Hz, ¹H), 6.90 (d, J=6.0 Hz, ¹H), 4.00 (s, ³H), 1.70-1.60 (m, ¹H), 1.64 (s, ³H), 1.61 (s, ³H).

[0250] Step 3. Amidation and Salt Formation 4-Hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide hydrochloride (8). A mixture of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (5, 2 g, 7.48 mmol) and 3-piperidine-1-yl-propylamine (6, 1.12 g, 7.85 mmol, 1.05 equivalents) was heated at 90-95 degrees Celsius for 2 hours. TLC analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and 1 M HCl (7.4 mL) was added. The organic layer was separated and washed with water (4 mL). The organic layer was treated with concentrated hydrochloric acid (1.4 g). The organic phase was concentrated to approximately 11 mL (9.9 g). n-butanol (10 mL) was added to the residue. The mixture was re-concentrated to a volume of approximately 11 mL (9.9 g). The residue was heated to 50 degrees Celsius and diluted with MTBE (20 mL). The mixture was stirred at 50 degrees Celsius for 40 minutes, cooled to room temperature, and then kept overnight at -10 degrees Celsius. The slurry was filtered at 0-5 degrees Celsius. The filtered cake was washed with n-butanol / MTBE (1:3, 2 × 4 mL) and dried in a rotary evaporator to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide hydrochloride (8, 2.35 g, yield: 75%, HPLC: 99.65%) as a white solid. The batch was started with 66.35 g of ester 5, yielding 84.5 g of the title compound 8 (yield: 82%). 1 H NMR(300MHz,DMSO-d6)δ10.24(br t,J=5.4Hz,1H),9.91(br s,1H),7.38(d,J=5.7Hz,1H),7.32(d,J=5.7Hz,1H),3.47-3.30(m,4H),3.08-2.98(m,2H),2.90- 2.76(m,2H),2.05-1.93(m,2H),1.82-1.62(m,6H),1.57(s,3H),1.55(s,3H),1.44-1.26(m,1H).

[0251] Step 4: Preparation of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt). A mixture of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide hydrochloride (8, 2.35 g, 5.68 mmol), MTBE (23.5 mL), water (11.75 mL), and 1 M KOH solution (5.6 mL) was stirred at room temperature for 20 minutes. The mixture still contained an insoluble hydrochloride. NaHCO3 (0.49 g) was added to the above mixture and stirring was continued for 0.5 hours. The mixture became a clear solution. The organic layer was separated. The aqueous layer was extracted with an additional MTBE (20 mL). The combined organic layers were concentrated to dryness to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide (2.17 g) as the free base.

[0252] The above free base (2.17 g, 5.68 mmol) was dissolved in acetonitrile (23.5 mL) at 45-50 degrees Celsius. To the above solution, a solution of KOH (0.43 g, 6.53 mmol) in water (1.8 mL) was added. The resulting mixture was stirred at 50 degrees Celsius for 0.5 hours, cooled to room temperature, and then cooled at 0-5 degrees Celsius for 3 hours. The solid was filtered to obtain 3 g of wet product, which was dissolved in a mixture of acetonitrile (42 mL) and water (3 mL) at 50 degrees Celsius. The solution was filtered to remove the insoluble solid. The filtrate was concentrated to a volume of 21 mL. Acetonitrile (21 mL) was added and concentrated to a volume of 21 mL. This process was repeated twice. The residue was placed in an ice bath for 3 hours, filtered, and the filtered cake was washed with acetonitrile (0°C, 2 × 6 mL) and dried in a rotary evaporator to obtain crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt (1.75 g, yield: 74.2%, HPLC: 99.9%, KF: 1.19%) as a white solid. A batch starting with 84.5 g of hydrochloride 8 was converted to 76.3 g of crystalline fine particulate form I of PRX-3140 potassium salt (yield: 90%, HPLC: 99.6%, KF: 0.66%). 1H NMR(300MHz,DMSO-d6)δ10.79(t,J=5.3Hz,1H),7.13(d,J=5.4Hz,1H),6.80 (d,J=5.4Hz,1H),3.19-3.11(m,2H),2.70-2.40(m,6H),1.62-1.30(m,15H).

[0253] Example 2 - X-ray diffraction of crystalline PRX-3140 potassium salt prepared in two scales. Using the crystalline fine particle morphology I of the PRX-3140 potassium salt samples from Example 1 and the scale-up batch, differences in the crystal structure of the two samples were identified by standard X-ray diffraction (XRD) measurements. In both examples, the same peaks were obtained, as shown in Figures 3A and 3B and Tables 1 and 2, respectively. [Table 1] [Table 2]

[0254] Example 3 - Photostability experiment of PRX-3140 potassium salt. Two samples of PRX-3140 potassium salt in crystalline fine particle form I were prepared for the photostability test: (1) 1.5 g spread uniformly across a glass petri dish and covered with a clear quartz cover, and (2) 1.5 g spread uniformly across a glass petri dish and covered with aluminum foil. The samples were exposed to low-temperature white fluorescence and 200 watt-hours / m2 of UVA light at 40°C / 75%RH, according to ICH photostability guidelines Q1B = 1.2 million lux hours. The samples were exposed for 2 days and tested using HPLC.

[0255] The control photostability sample of PRX-3140 potassium salt met the specifications and showed HPLC results comparable to those obtained for the t=0 sample, although an increase in water content from 0.9% w / w to 3.1% w / w was observed. Exposure was performed in a cabinet set to 25 degrees Celsius / 60% RH. The sample was significantly lumpy and required grinding to obtain accurate assay results. [Table 3]

[0256] Figure 4 shows the HPLC chromatograms of the PRX-3140 potassium salt photostability experiment (A) unexposed control sample and (B) PRX-3140 potassium salt photostability exposed sample. Changes in the crystalline fine particle morphology I of PRX-3140 potassium salt were evident after exposure to UVA and white light. The samples changed color, particularly on the upper exposed surface of the material, and showed clear changes in the HPLC data. The irradiated photostability sample of PRX-3140 potassium salt met the USP stability specifications of (1) total impurities less than 2.0% area and (2) no single impurities exceeding 0.5% area, and the reported assay value of 94.2% w / w was below the specification limit. While the single impurity profile met the specification (<0.2%), significant changes were observed. In particular, the number of trace impurities increased in the chromatogram region between RRT1.5 and 2.1. Total impurities increased from 0.20% in the control sample to 0.77% in the exposed sample. In the exposed samples, 0.16% of the RRT1.83 impurity, which was not present before exposure, was formed. Other changes included a change in the material's appearance to a sticky solid and an increase in water content to 4.3% w / w.

[0257] Example 4 - Forced decomposition experiment of crystalline PRX-3140 potassium salt. Crystalline fine particulate form I of PRX-3140 potassium salt was subjected to forced decomposition experiments using 24-hour exposure to acid, base, or hydrogen peroxide. The samples were neutralized and analyzed using LC-UV-MS. The LC-UV-MS conditions are listed in Table 4. [Table 4]

[0258] Control Sample: Figure 6A is the standard (control) HPLC UV chromatogram of crystalline fine particle form I of potassium salt PRX-3140 at 250 nm. The UV spectrum of the parent molecule is shown in Figure 6B. Maximals are observed at 220, 250, and 320 nm. Chromatograms of all samples were collected at all three wavelengths, with 250 nm being the dominant wavelength based on lambda max. The starting material was 98.6% pure based on the peak area at 250 nm. The mass spectrum of the parent molecule PRX-3140 at 12.2 min is shown in Figure 6C. The protonated PRX-3140 molecular ion [M+H]+ is observed at 378.2 m / z.

[0259] Sample preparation: 50 mg of crystalline fine particle form I of potassium salt PRX-3140 was weighed into a 25 mL volumetric flask and diluted to volume with water (2 mg / mL stock). 1 mL of stock was added to four 4 mL vials. 1 mL of either 1N HCl, 1N NaOH, 3% H2O2, or DI water (control) was added to the appropriate vial, mixed, and stored at room temperature for 24 hours. After storage, acidic and baseic samples were neutralized by adding 1 mL of their respective solutions. 1 mL of water was added to the peroxide samples and control so that all samples had a final concentration of 0.67 mg / mL. Samples were analyzed using LC-UV-MS.

[0260] Table 5 lists comparisons of control, acid, base, and peroxide samples showing percentage peak area versus relative retention time (RRT) at 250 nm. While some small changes can be observed between the control and the acid and base samples, the overall purity (peak area) of the parent molecule is only slightly higher for the acid and base samples. Some trace impurities appear to react with the acid or base to reshape the parent molecule. The greatest change in purity was observed in the peroxide sample, where two major impurities were formed, with purity at 250 nm ranging from 98.6% to 80.6%. [Table 5]

[0261] Acid-decomposed sample: Based on the purity peak area at 250 nm, the control was 98.6% and the acid sample was 98.9%. 1N HCl over 24 hours had a very small effect on the PRX-3140 potassium salt.

[0262] Base-decomposed sample: Based on the purity peak area at 250 nm, the control was 98.6% and the base sample was 98.7%. 1N NaOH over 24 hours had a very small effect on the PRX-3140 potassium salt.

[0263] Peroxide-decomposed sample: The UV chromatogram of the peroxide-decomposed sample at 250 nm is shown at full scale in Figure 7A. Two major impurity peaks are observed at 9.6 minutes and 13.3 minutes (RRT 0.78 and 1.05 respectively). Based on the purity peak area at 250 nm, the control was 98.6% and the peroxide sample was 80.6%. 3% hydrogen peroxide was reacted with PRX-3140 for 24 hours to form two major decomposition products.

[0264] Figure 7B is the mass spectrum of PRX-3140a at 9.6 minutes (RRT 0.78). [M+H]+ was observed at 258.0 m / z, the ammonium adduct [M+H+NH3]+ was observed at 275.1, the sodium adduct [M+Na]+ was observed at 280.1, and the sodium dimer [2M+Na]+ was observed at 537.1 m / z. It should be noted that this is a labile molecule and it is necessary to lower the fragmentor voltage from 150 to 70 V to see the protonated molecular ion. At higher voltages, molecular fragments were observed at 216.0, 198.0, and 152.0. The proposed structure of PRX-3140a is Formula II: ##STR00002##. 5-hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, which has the chemical formula C10H11NO5S and is shown in Figure 5.

[0265] Figure 7C shows the mass spectrum of PRX-3140b at 13.3 min (RRT 1.05). [M+H]+ is observed at 394.2 m / z, and [2M+H]+ is observed at 787.4 m / z. This compound is present in the control, acid, and base samples, but at very low levels (<0.03%). In the peroxide sample, this peak is present at 9.1%. The proposed structure of PRX-3140b is formula III:##STR00003##.[7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridine-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidine-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, having the chemical formula C19H27N3O4S, as shown in Figure 5.

[0266] Example 5 - Decomposition experiment of PRX-3140 with 30% peroxide. Crystalline fine particulate form I of PRX-3140 potassium salt was subjected to a second forced decomposition experiment using 24-hour exposure to 30% hydrogen peroxide. The sample was evaporated to dryness and analyzed using LC / UV / MS and NMR analysis. Two major decomposition products were observed by LC / UV / MS.

[0267] Sample preparation: 60 mg (55 μL) of 30% hydrogen peroxide (0.5 mmol) was added dropwise at 0°C to a suspension of PRX-3140 potassium salt (208 mg, 0.5 mmol) suspended in 5 mL of dry acetone. The resulting suspension was stirred under argon and allowed to spontaneously rise to room temperature overnight (18 hours). The solvent was removed under vacuum at room temperature, and then acetonitrile (5 mL) was added to the residue, which was evaporated to dryness at 40°C. The weight of the residue of the PRX-3140 30% peroxide sample was 300 mg.

[0268] The 1H NMR spectrum of the crude 30% peroxide sample is shown in Figure 8A. For comparison, the 1H NMR spectrum of the potassium salt PRX-3140 is shown in Figure 8B.

[0269] The solid portion of the PRX-3140 30% peroxide sample was subjected to LC / UV / MS analysis. 2 milligrams of sample were weighed into a 4 mL vial. 2 mL of 20 / 80 methanol / water was added to the vial and vortexed vigorously. Figure 9A is the HPLC chromatogram of the H2O2 sample at 250 nm. Three major peaks, including the parent molecule, are observed at 12.5 min. After 18 hours of exposure to 30% hydrogen peroxide, a purity of 29.6% was observed for the parent molecule PRX-3140. Figure 9B shows the UV spectrum of the parent molecule at 12.5 min. Maximum values ​​are observed at 220, 250, and 320 nm. Chromatograms of all samples were collected at all three wavelengths, with 250 nm as the dominant wavelength based on lambda max. Figure 10A is the UV spectrum of the peak at 8.9 min. Compared to the parent molecule, no high-end absorption is present (320 nm). Figure 10B shows the UV spectrum of the peak at 12.9 min. The spectrum is identical to that of the parent molecule shown in Figure 9B. Figure 11A shows the mass spectrum of the parent molecule PRX-3140 at 12.5 min. The protonated molecular ion [M+H]+ is detected at 378.2 m / z. Figure 11B shows the mass spectrum of PRX-3140a at 8.9 min (RRT 0.73 compared to 0.78 in Example 4). [M+H]+ is detected at 258.0 m / z, [M+H+NH3]+ at 275.1 m / z, [M+Na]+ at 280.1 m / z, and [2M+Na]+ at 537.1 m / z. Note that this is a fragile molecule and the fragmenter voltage needs to be reduced from 150V to 70V to observe the protonated molecular ions. At higher voltages, molecular fragments were observed at 216.0, 198.0, and 152.0. The proposed structure of PRX-3140a is shown in Figure 5. Figure 11C is the mass spectrum of the maximum decomposition product of PRX-3140b at a relative retention time (RRT) of 12.9 min, 1.04 (compared to 1.05 in Example 4). The [M+H]+ at 394.2 m / z may be the parent molecule + oxygen (+O). The proposed structure of PRX-3140B is shown in Figure 5.

[0270] Example 6 - PRX-3140 Additive Compatibility Experiment. Additive testing and compatibility experiments were performed on crystalline fine particle form I of PRX-3140 potassium salt. The inventors conducted additive compatibility experiments on a binary blend (50:50 w / w) of crystalline fine particle form I of PRX-3140 potassium salt samples mixed with (1) pregelatinized starch, NF (Colorcon), (2) microcrystalline cellulose (Avicel PH-105, DuPont), (3) magnesium stearate NF (Avantor), (4) stearic acid, NF (Letco), (5) granular food grade lecithin (Spectrum), (6) polyethylene glycol 3,350, USP (Dow), (7) HPB-cyclodextrin (CTD), (8) silicon dioxide, FCC (Spectrum), and (9) mannitol USP (Spectrum). The samples were analyzed by the HPLC assay described in Example 4. The samples were stored at 40°C / 75%RH and tested by LC-UV-MS at days 0, 30, 60, and 90. The assays and purities are shown in Table 6. At each time point, the powder samples were weighed and diluted with 50:50 methanol:DI water. The samples for HPLC analysis were filtered through a 0.45 micron PTFE filter for injection. [Table 6]

[0271] The PRX-3140:lecithin (50:50) sample degraded over a 90-day experiment, and the degradation product of PRX-3140a (RRT 1.06) increased to over 1%. Figure 12A shows the PRX-3140:lecithin (50:50) sample at time 0, and Figure 12B shows the sample at day 90 demonstrating the increase in PRX-3140B (RRT 1.05) at 40 degrees Celsius.

[0272] Example 7 - Preparation of PRX-3140 potassium salt PDS. 10 g of crystalline fine particle form I of PRX-3140 potassium salt (Alchem ​​Laboratories Corp.) and 10 g of microcrystalline cellulose (Avicel PH-105, DuPont) were mixed in a 50 mL tube. The powder was then ground into a fine powder using a Retsch mill. Particles smaller than 600 microns were separated by sieving (30 mesh). The resulting white powder was obtained in a yield of over 90% of crystalline PRX-3140 potassium salt PDS powder containing particles with a diameter of less than 500 microns.

[0273] Example 8 - Preparation of immediate-release oral PRX-3140 potassium salt capsules. An immediate-release oral dosage form (gelatin capsule) containing crystalline fine particle form I of PRX-3140 potassium salt particles prepared in Example 7 was dry-mixed with additional microcrystalline cellulose (Avicel PH-105, DuPont) to achieve the correct capsule filling weight (400-500 mg) to achieve the desired dose. Then, the clear gelatin #1 capsules were filled with the mixture using a Torpac Profill 3700 machine to obtain capsules containing 320 mg of PRX-3140 potassium salt PDS, including 50 mg of PRX-3140. Samples were taken to verify load uniformity, content uniformity, and dissolution time.

[0274] Example 9 - Dissolution of immediate-release oral PRX-3140 potassium salt. Capsules from Example 8 were exposed to acidic buffer for 60 minutes to mimic the stomach environment. To demonstrate dissolution, the release of over 75% of PRX-3140 in solution over 15–30 minutes in acidic buffer was tested using a USP dissolution apparatus and HPLC.

[0275] Example 10 - Preparation of sustained-release oral PRX-3140 potassium salt PDS. PRX-3140 potassium salt (Alchem ​​Laboratories Corp.) in crystalline particulate form I, microcrystalline cellulose (MCC), and different sustained-release polymers were weighed (1) Methocel E4M (Mn 86,000, 2% viscosity in water approx. 4,000 mPa·s), (2) Methocel K100M (Mn=220,000, 2% viscosity, approx. 100,000 mPa·s), (3) Kollidon SR (80% polyvinyl acetate, weight-average molecular weight approx. 450,000 daltons / polyvinylpyrrolidone, weight-average molecular weight approx. 55,000 daltons), and (4) xanthan gum (100 g total each), and mixed and ground in a glass mortar and pestle. Particles smaller than 500 microns were separated by sieving (35 mesh). A ratio of 3.3% was used to fill size 1 capsules to a filling weight of 300 mg, yielding 10 mg of PRX-3140 per capsule. The weight percentages of each component are shown in Table 7 below. [Table 7]

[0276] Example 11 - X-ray diffraction of sustained-release oral PRX-3140 potassium salt. Using sustained-release PRX-3140 potassium salt particles from formulations 7 and 9 of Example 10, differences in the crystalline structure of the two sustained-release PRX-3140 powder samples were identified by standard X-ray diffraction (XRD) measurements. In both examples, the same peaks were obtained, as shown in Figures 13A and 13B and Tables 8 and 9, respectively. [Table 8] [Table 9]

[0277] The XRD baselines of formulations 7 and 9 generally showed characteristic profiles of microcrystalline cellulose and cellulose samples.

[0278] Example 12 - Additive suitability study for sustained-release oral PRX-3140 potassium salt. Additive testing and suitability studies were performed on PRX-3140 potassium salt in crystalline particulate form I, mixed with the sustained-release polymer from Example 10. Samples were stored at 40°C / 75%RH and assayed and tested for purity by LC-UV-MS on day 30. At each time point, powder samples were weighed and diluted with 20:80 methanol:DI water. Samples for HPLC analysis were filtered through a 0.45 micron injection PTFE filter. Table 10 shows the assays and purity of samples stored at 40°C / 75%RH and tested by LC-UV-MS on day 30. [Table 10]

[0279] The xanthan gum sample of formulation 9 degraded slightly over the 30-day study (2.55% impurities), but the PRX-3140b degradation product (RRT 1.08) did not increase. The impurity peak is most likely attributable to xanthan gum impurities.

[0280] Example 13 - Preparation of sustained-release oral PRX-3140 potassium salt capsules. The sustained-release oral dosage form containing PRX-3140 potassium salt particles in crystalline microparticle form I, prepared in Example 10, was dry-mixed with further microcrystalline cellulose (Avicel PH-105, DuPont) to achieve the correct capsule filling weight to obtain the desired dose. White gelatin #1 capsules were then filled with the mixture in a Torpac Profill 3700 machine to obtain capsules containing 200-250 mg of PRX-3140 potassium salt PDS, each containing 10 mg of PRX-3140. Samples were taken to verify the uniformity of the load, the uniformity of the content, and the dissolution time.

[0281] Example 14 - Dissolution of sustained-release oral PRX-3140 potassium salt. Capsule formulations from Example 13 (n=10 each) were placed in a USP dissolution type 1 basket and sampled in deionized water at 37 degrees Celsius for 24 hours. At each time point, samples for HPLC analysis were filtered through a 0.45 micron injection PTFE filter. The release percentages for each formulation are shown in Table 11 and Figure 14 below. [Table 11]

[0282] Example 15 - Pharmacokinetics of immediate-release and sustained-release capsules. A Phase I single-dose dose-escalation study was conducted in male volunteers under fasting conditions using PRX-3140 potassium salt, and pharmacokinetic data (PRX-3140 acid) were obtained at 5 and 50 mg dose levels. Healthy volunteers were initially enrolled, and six subjects completed all procedures. A second Phase I open-label multi-dose dose-escalation study was conducted using PRX-3140 potassium salt, and pharmacokinetic data were obtained for up to 14 days with once-daily dose levels of 10, 30, 100, and 200 mg. Serum concentrations of PRX-3140 acid were determined using validated liquid chromatography combined with tandem mass spectrometry (LC / MS / MS). The calculated mean serum concentrations and PK parameters of PRX-3140 immediate-release "drug-containing capsules" at each time point are summarized in Table 12 below, and a graph of the fitted mean PRX-3140 acid serum concentration against time at each dose level is shown in Figure 15. Parameters such as Cmax, Tmax, AUC24, and T1 / 2 were estimated. [Table 12]

[0283] PK data suggested that the immediate-release (IR) drug capsule PRX-3140 was absorbed at a relatively rapid rate (Tmax 1–2 hours), and exposure showed moderate to high inter-subject variability. Cmax values ​​at doses of 30–200 mg showed less variability than Cmax values ​​at the relatively lower doses studied (5 and 10 mg). After multiple oral administrations of 10, 30, 100, or 200 mg of immediate-release drug capsule PRX-3140 over 14 days, the mean exposure to PRX-3140 (Cmax and AUC24) appeared to increase proportionally to the dose. Absorption was moderately rapid, with Tmax ranging from 1 to 2 hours. The dose-related increase in mean trough serum concentration was evident throughout the treatment period, with steady state appearing to be reached by approximately day 7 in the 10, 30, and 100 mg cohorts, and by day 14 in the 200 mg immediate-release "drug-containing capsule" PRX-3140 cohort.

[0284] The calculated mean serum concentrations and PK parameters of formulation 7's sustained-release (SR) capsules at each time point are summarized in Table 13 below, and a logarithmic graph of the fitted mean PRX-3140 acid serum concentration against time is shown in Figure 15. Parameters such as Cmax, Tmax, AUC24, and T1 / 2 were estimated. [Table 13]

[0285] The calculated PK data suggested that the PRX-3140 dosage form of sustained-release formulation 7 was absorbed more slowly (Tmax 8.7 hours). The Cmax value of the PRX-3140 dosage form of sustained-release formulation 7 was lower compared to similar doses of the immediate-release "drug-containing capsules" PRX-3140 shown in Table 13 above. After multiple oral administrations of sustained-release PRX-3140 formulation 7 at 10, 30, 100, or 200 mg for 14 days, the mean exposure to PRX-3140 acid (AUC24) appeared to increase dose-proportionally. The dose-related increase in steady-state serum concentration was proportional to the dose level, and the percentage change from peak to trough decreased due to the relatively slower absorption of the PRX-3140 dosage form of sustained-release formulation 7 after once-daily administration. The results from this study show that, compared to the IR dosage form, the SR dosage form exhibits a relatively high AUC24 (systemic exposure) and a relatively low variability % of PRX-3140 acid at steady state. According to the present invention, the SR dosage form achieves a steady-state calculated mean concentration (Cavg) of at least 1 ng / ml of PRX-3140 free acid at a dose of 1 mg of PRX-3140 at that time.

[0286] Example 16 - Enteric-coated sustained-release oral PRX-3140 potassium salt capsules. An enteric-coated sustained-release oral dosage form (gelatin capsule) containing the PRX-3140 dosage form of Formulation 7 prepared in Example 13 was prepared as follows. Alternatively, Enprotect® (Capsugel) capsules may be used. The enteric coating of the capsules or tablets of this example was performed in a rotary pan coater equipped with a sprayer. Dry nitrogen gas and a peristaltic pump-driven liquid supply were provided to the spray head. The coating consisted of Eudragit L100 dissolved in 97% / 3% isopropanol / aqueous solution. Samples were taken to verify uniformity of load, uniformity of coating, uniformity of content, and dissolution time.

[0287] Example 17 - Preparation of sustained-release tablets of PRX-3140 potassium salt. Tableting of the blended mixture can be performed by direct compression, dry granulation, or wet granulation. Tablets were prepared using the direct compression method, in particular to reduce the possibility of degradation of PRX-3140 in the solution phase. The blended mixture was collected and directly dry-compressed using a tablet press (Lumac single-punch model TDP-30) to form matrix tablets containing the sustained-release agent. The enteric coating of sustained-release tablets of crystalline PRX-3140 potassium salt tablets under conditions similar to Example 16 was used to demonstrate the dissolution delay time under acidic dissolution conditions.

[0288] Example 18 - Blood glucose levels of control versus sustained-release oral PRX-3140 potassium salt capsules. A Phase I single-dose escalation study under feeding conditions was conducted in male volunteers using PRX-3140 potassium salt at a 15 mg dose level. After oral administration of 15 mg of PRX-3140 potassium salt, a mean blood glucose reduction (-19.5%) was observed compared to the control. To further evaluate the effect of the oral crystalline PRX-3140 potassium salt sustained-release formulation, blood glucose levels in patients were collected and plotted against the time shown in Figure 16 (control blood glucose levels) and Figure 17 (blood glucose levels after administration of sustained-release oral PRX-3140 potassium salt capsules of formulation 7, 10 mg / day). The calculated mean glucose concentrations, as well as the standard deviation, minimum and maximum blood glucose levels for the control and PRX-3140 sustained-release capsules of formulation 7, 10 mg, 30 mg, or 100 mg / day, are summarized in Table 14 below. [Table 14]

[0289] This study was also conducted to investigate the effects of PRX-3140 sustained-release capsules on fasting and postprandial blood glucose levels in subjects. Subjects were monitored daily for vital signs (including blood pressure, heart rate, respiratory rate, and body temperature) and adverse events. In addition, blood samples were taken to assess glucose levels. Glucose was tested within 60 minutes before breakfast and at different time points throughout the day. All three formulations of PRX-3140 sustained-release capsules (10 mg, 30 mg, and 100 mg) had similar self-monitored blood glucose profiles and similar mean 24-hour blood glucose levels at baseline (115.5 mg / dL, n=27). Mean blood glucose levels decreased in all three formulations of PRX-3140 sustained-release capsules (93.1–100.3 mg / dL, n=15–40).

Claims

1. A sustained-release oral dosage form in the form of a tablet or capsule, wherein the sustained-release oral dosage form is (a) Compounds of formula I: 【Chemistry 9】 ##STR00001##, (b) Microcrystalline cellulose, and (c) i. Hydroxypropyl methylcellulose having a number-average molecular weight of approximately 86,000 to approximately 220,000 Daltons. ii. A polymer mixture comprising polyvinyl acetate and polyvinylpyrrolidone, wherein the polyvinyl acetate has a weight-average molecular weight of about 450,000 daltons, the polyvinylpyrrolidone has a weight-average molecular weight of about 55,000 daltons, and the concentration of the polyvinyl acetate in the polymer mixture is about 80% by weight, and iii. Xanthan gum, It comprises at least one sustained-release polymer selected from, More than 90% by weight of the compound of formula I is in a crystalline form of form I, characterized by an X-ray powder diffraction pattern with major peaks at 22.3 ± 0.3 degrees, 25.3 ± 0.3 degrees, and 5.4 ± 0.3 degrees (2-theta). The release of the compound of formula I from the oral dosage form, as defined by in vitro dissolution, is up to 50% as measured by reversed-phase high-performance liquid chromatography (HPLC) at 2 hours and at least 50% as measured by HPLC at 12 hours, and the dissolution of the oral dosage form is performed at 50 revolutions per minute, from 0 to 2 hours in water or simulated gastric fluid at pH 1.2, and after 2 hours in simulated intestinal fluid at pH 6.8, according to the general procedure of the United States Pharmacopeia (USP) II dissolution test (paddle method) or USP I (basket method). A sustained-release oral dosage form in the form of tablets or capsules.

2. The sustained-release oral dosage form according to claim 1, wherein the at least one sustained-release polymer is the hydroxypropyl methylcellulose.

3. The sustained-release oral dosage form according to any one of claims 1 to 2, wherein the at least one sustained-release polymer is the hydroxypropyl methylcellulose having a number-average molecular weight of about 86,000 daltons.

4. The sustained-release oral dosage form according to any one of claims 1 to 2, wherein the at least one sustained-release polymer is the hydroxypropyl methylcellulose having a number-average molecular weight of about 220,000 daltons.

5. The sustained-release oral dosage form according to claim 1, wherein the at least one sustained-release polymer is a polymer mixture comprising polyvinyl acetate and polyvinylpyrrolidone.

6. The sustained-release oral dosage form according to claim 1, wherein the at least one sustained-release polymer is xanthan gum.

7. The sustained-release oral dosage form according to any one of claims 1 to 6, wherein the oral dosage form is in the form of a capsule.

8. The sustained-release oral dosage form according to any one of claims 1 to 6, wherein the oral dosage form is in the form of a tablet.

9. The sustained-release oral dosage form according to claim 8, further comprising a tablet coating.

10. The sustained-release oral dosage form according to any one of claims 1 to 9, wherein the weight ratio of microcrystalline cellulose to at least one sustained-release polymer is about 1:3 to about 3:

1.

11. The sustained-release oral dosage form according to claim 10, wherein the weight ratio of microcrystalline cellulose to at least one sustained-release polymer is about 1:1 to about 3:

1.

12. The sustained-release oral dosage form according to any one of claims 1 to 11, wherein the oral dosage form contains about 2% to about 10% by weight of the compound of formula I.

13. The sustained-release oral dosage form according to claim 12, wherein the oral dosage form contains about 2% to about 5% by weight of the compound of formula I.

14. The sustained-release oral dosage form according to claim 13, wherein the oral dosage form contains about 3.3% by weight of the compound of formula I.

15. The aforementioned oral dosage form is (a) Compounds of formula II: 【Chemistry 10】 ##STR00002## and / or (b) Compounds of formula III: 【Chemistry 11】 ##STR00003## A sustained-release oral dosage form according to any one of claims 1 to 14, further comprising:

16. The sustained-release oral dosage form according to claim 15, wherein the oral dosage form comprises, if present, less than 0.5% by weight of the compound of formula II and, if present, less than 0.5% by weight of the compound of formula III.

17. The sustained-release oral dosage form according to any one of claims 1 to 16, wherein the oral dosage form contains 0.1 mg to about 250 mg of the compound of formula I.

18. A method for treating a disease in a person requiring treatment of the disease, comprising administering to the person at least once per day a therapeutically effective amount of a sustained-release oral dosage form according to any one of claims 1 to 17 in order to achieve a steady-state mean concentration (Cavg) of at least 1 ng / ml of PRX-3140 free acid in the blood.

19. The method according to claim 18, wherein the disease is type 2 diabetes.

20. The method according to claim 18, wherein the disease is type 1 diabetes.

21. The method according to claim 18, further comprising administering glucocorticoid therapy to the human.

22. The method according to claim 18, wherein the disease is obesity.

Images