Pharmaceutical formulations of indoleamine 2,3-dioxygenase inhibitors

Abstract

The present application relates to pharmaceutical compositions containing (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate, which is not susceptible to salt disproportionation. TIFF2022547307000013.tif200164

Description

[Technical field]

[0001] The present application relates to a pharmaceutical composition comprising (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate, which has less heterogeneous salts and can provide a stable solid formulation. [Background technology]

[0002] Indoleamine 2,3-dioxygenase ("IDO" or "IDO1") is an IFN-γ target gene that plays an important role in immune regulation and expression of its immunosuppressive functions in several ways. There is a pathophysiological link between IDO and cancer. Disruption of immune homeostasis is closely related to tumor growth and progression, and the production of IDO within the tumor microenvironment is thought to promote tumor growth and metastasis. Furthermore, increased levels of IDO activity have been associated with a variety of different tumors (Brandacher, G. et al., Clin. Cancer Res., 12(4):1144-1151 (Feb. 15, 2006)). In addition to cancer, IDO has also been implicated in other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (e.g., rheumatoid arthritis).

[0003] (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide ("Compound I"), also commonly referred to as "linrodostat", is disclosed as a potent IDO inhibitor (see, for example, International Publication WO2016 / 073770). The methanesulfonate salt of Compound I ("Compound I-MSA") has been shown to be a salt with excellent properties. [ka]

[0004] In the development of pharmaceutical formulations, the determination and combination of excipients and how they interact with the active pharmaceutical ingredient ("API") is one of the most important aspects. Many APIs are manufactured and formulated as salts because the solids have a higher dissolution rate and bioavailability compared to the free form of the API crystals. The free form of the API has a basic site and a very small pKa (e.g., pKa 4.6), which may pose risks such as long-term storage stability issues, proton transfer, and / or further disproportionation.

[0005] In developing solid oral dosage formulations containing ionic drug salts, some excipients are known to convert the API to the free base. The formulation design must take into account factors that affect the disproportionation of the salt during formulation or storage and how it affects the quality and efficacy of the product. Therefore, there is a demand for stable pharmaceutical compositions. Summary of the Invention

[0006] Described herein are pharmaceutical compositions of compound I-MSA suitable for oral administration.

[0007] In a first aspect, the present invention provides a pharmaceutical composition suitable for oral administration, (i) a structure: [ka] a therapeutically effective amount of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate having the formula: (ii) crospovidone as a disintegrant in an amount of 2.0% to 7.0% w / w of the composition; and (iii) magnesium stearate as a lubricant in an amount of 0.25% to 1.75% w / w of the composition; wherein the weight ratio of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to the total amount of magnesium stearate is 8.0 to 40.0; and The present invention provides a pharmaceutical composition, comprising (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid, with less than 25% disproportionation by weight of the salt to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

[0008] In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose as a first diluent, and anhydrous lactose as a second diluent, collectively in an amount of 50%-80% w / w of the composition.

[0009] In some embodiments, the pharmaceutical composition further comprises silicon dioxide as a glidant in an amount between 1.0% and 3.0% w / w of the composition.

[0010] In one embodiment, the pharmaceutical composition comprises less than 5% by weight of the salt disproportionated from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide. In another embodiment, the pharmaceutical composition comprises less than 3% by weight of the salt disproportionated from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

[0011] In one embodiment, the pharmaceutical composition contains (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in a weight ratio of 23.0 to 40.0 relative to the total amount of magnesium stearate.

[0012] In certain embodiments, the pharmaceutical composition comprises (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in an amount between 15% and 20% w / w of the composition.

[0013] In certain embodiments, the pharmaceutical composition comprises a first diluent and a second diluent in a weight ratio of 2:1 to 1:2.

[0014] In another embodiment, the pharmaceutical composition comprises a first diluent in an amount of 25% to 40% w / w of the composition. In a further embodiment, the pharmaceutical composition comprises a second diluent in an amount of 25% to 40% w / w of the composition.

[0015] In certain embodiments, the pharmaceutical composition comprises silicon dioxide in an amount of 2.0% w / w of the composition.

[0016] In certain embodiments, the pharmaceutical composition has an intragranular phase and an extragranular phase. In further embodiments, the pharmaceutical composition has the following intragranular and extragranular phases: (a) Internal granular phase: (i) (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in an amount of 12% to 18% w / w of the composition; (ii) containing crospovidone as a disintegrant in an amount of 2% to 3% w / w of the composition; (iii) Magnesium stearate as a lubricant in an amount of 0.25% to 0.75% w / w of the composition. (b) External granular phase: (i) crospovidone as a disintegrant in an amount of 2% to 3% w / w of the composition; and (ii) Magnesium stearate as a lubricant in an amount of 0.50% to 1.00% w / w of the composition.

[0017] In one embodiment, the pharmaceutical composition further comprises in the inner granular phase microcrystalline cellulose as a first diluent, and anhydrous lactose as a second diluent in a total amount of 75% to 80% w / w of the composition, and silicon dioxide as a flow agent in an amount of 1.5% to 2.5% w / w of the composition.

[0018] In one embodiment, the pharmaceutical composition contains less than 10% disproportionated salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide after 12 weeks in an open environment at 40° C. and 75% relative humidity, and has a particle size distribution as determined by D90 ranging from about 7 μm to about 165 μm.

[0019] In certain embodiments, the pharmaceutical composition contains less than 3% by weight of disproportionated salt from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide after storage for 24 weeks at 25° C. and 60% relative humidity in a 200 cc high density polyethylene bottle.

[0020] In some embodiments, the pharmaceutical composition has a particle size distribution, as determined by D90, ranging from about 10 μm to about 165 μm.

[0021] In certain embodiments, the pharmaceutical composition contains less than 3% by weight of disproportionated salt from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide after 6 months in a blister pack at 25° C. and 60% relative humidity.

[0022] In certain embodiments, the pharmaceutical composition contains less than 3% by weight of disproportionated salt from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide methanesulfonate to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide after 4 weeks at 25° C. and 60% relative humidity.

[0023] In certain embodiments, the pharmaceutical composition contains less than 3% by weight of disproportionated salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate after 4 weeks at 40° C. and 75% relative humidity.

[0024] In certain embodiments, the pharmaceutical composition contains less than 3% by weight of salts and mixtures disproportionated from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide after 24 weeks at 25° C. and 60% relative humidity.

[0025] In some embodiments, the pharmaceutical composition comprises a composition selected from the group consisting of a tablet, a crushed tablet, a capsule or capsule powder, minitablets, and beads.

[0026] In another embodiment, the pharmaceutical composition further comprises citric acid. [Brief description of the drawings]

[0027] The following detailed description provides examples, but is not intended to limit the invention to the specific embodiments described, and may best be understood in conjunction with the accompanying drawings.

[0028] [Figure 1] FIG. 1 illustrates the percent free base of tablets containing croscarmellose sodium or crospovidone as disintegrants in open high density polyethylene ("HDPE") bottles at 40° C. / 75% relative humidity ("RH").

[0029] [Diagram 2] FIG. 2 illustrates the percent free base in tablets with various drug to magnesium stearate ratios in open high density polyethylene bottles at 40° C. / 75%.

[0030] [Diagram 3] FIG. 3 illustrates an embodiment of a process for producing film-coated tablets of 100 mg, 50 mg, and 25 mg of Compound I-MSA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention will be more readily understood upon reading the following detailed description, taken together with the figures and examples which form a part of the present invention. It is to be understood that the present invention is not limited to the specific apparatus, methods, applications, conditions or parameters described and / or presented herein, and further that the terminology used herein is for illustrative purposes only and is not intended to limit the claimed invention. Also, as used in the specification, including the appended claims, the singular forms "a," "an," and "the" include the plural, and unless expressly stated otherwise, a reference to a particular numerical value includes at least that particular value.

[0032] As used herein, the terms "comprising," "having," "including," and the like are intended to be open-ended, variable phrases, terms, or words that require the presence of the specified components / steps, and allow for the presence of other components / steps. However, these descriptions should also be construed as describing a composition or method as "consisting of" and "consisting essentially of" the recited compounds, in which case only the specified compounds may be present along with any pharmaceutical carriers, and other compounds are excluded.

[0033] All ranges in the disclosure are inclusive of the recited endpoints and are independently combinable (e.g., the range "100 mg to 200 mg" includes the endpoints of 100 mg and 200 mg, and all intermediate values). The endpoints of the ranges and any values ​​in the disclosure are not limited to that precise range or value, but are broad enough to include approximations of those ranges and / or values.

[0034] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds where the parent compound is modified by making acid or base salts thereof.

[0035] The term "API" refers to active pharmaceutical ingredient. As used herein, API refers to compound I-MSA or (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate.

[0036] Pharmaceutically Acceptable Compositions and Formulations In an embodiment of the present application, the pharmaceutical composition of the present invention comprises 10%-40% w / w of API, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition of the present invention comprises 15%-20% w / w of API, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition of the present invention comprises 17%-18% w / w of API, based on the weight of the pharmaceutical composition.

[0037] The pharmaceutical composition of the present invention includes a diluent. The diluent of the present invention may include, for example, a first diluent and optionally a second diluent. Diluents generally known to those skilled in the art include, for example, sugar alcohols, sugars, cellulose, starch-derived diluents, and combinations thereof. More specific diluents known to those skilled in the art include dextrin, sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, aspartame, mannitol, starch, corn starch, PVP (polyvinylpyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose ("MCC"), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose, calcium hydrogen phosphate, silicified microcrystalline cellulose, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, magnesium aluminum silicate, and polymethacrylate. An embodiment of the diluent of the present application is lactose (e.g., anhydrous lactose, high-speed lactose, or a combination thereof). Another embodiment is microcrystalline cellulose, such as microcrystalline cellulose PH 302. The application contemplates the use of combined diluents, such as microcrystalline cellulose and lactose.

[0038] In embodiments of the invention that include two diluents, a first diluent and a second diluent, the ratio of the first diluent to the second diluent is 2:1 to 1:2. In some embodiments, the ratio of the first diluent to the second diluent is 1:1. In some embodiments, the first diluent is microcrystalline cellulose and the second diluent is lactose.

[0039] The composition of the present invention comprises 50%-80% w / w of a diluent based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 75%-80% w / w of a diluent based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 35%-40% w / w of a first diluent and 35%-40% w / w of a second diluent based on the weight of the pharmaceutical composition.

[0040] The pharmaceutical composition of the present invention may include a flow agent. Flow agents known to those skilled in the art include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc, magnesium carbonate, micronized silicon dioxide, starch, and combinations thereof. The present application contemplates the use of silicon dioxide as a flow agent. The composition of the present invention includes 1.0% to 3.0% w / w of a flow agent based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes 1.75% to 2.25% w / w of a flow agent based on the weight of the pharmaceutical composition.

[0041] In some embodiments of the present invention, the pharmaceutical composition comprises granules. In some embodiments, the granules of the composition may have an internal granular phase and an external granular phase. In some embodiments, the internal granular phase comprises a glidant and the external granular phase does not comprise a glidant.

[0042] The pharmaceutical composition of the present invention includes a disintegrant. Disintegrants known to those skilled in the art include, for example, starch-based disintegrants, cellulose-based disintegrants, povidone-based disintegrants, etc. Specific examples of disintegrants include, but are not limited to, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, sodium carbonate, crospovidone (crosslinked polyvinylpyrrolidone ("PVP")), sodium carboxymethyl starch (sodium starch glycolate), crosslinked sodium carboxymethylcellulose (croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, sodium alginate, calcium carboxymethylcellulose, and magnesium aluminum silicate (Veegum). The present application contemplates the use of crospovidone (crosslinked povidone) as a disintegrant.

[0043] The pharmaceutical composition of the present invention contains 2.0% to 7.0% w / w of a disintegrant based on the weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition of the present invention contains 2.5% w / w of a disintegrant in the internal granular phase and 2.5% w / w of a disintegrant in the external granular phase based on the weight of the pharmaceutical composition.

[0044] The pharmaceutical composition of the present invention may include a lubricant. Lubricants are well known to those skilled in the art, and include, for example, stearic acid, stearates, and combinations thereof. Examples of stearates include calcium stearate, magnesium stearate, sodium stearyl fumarate, and combinations thereof. The lubricant of the present invention may include one lubricant or a combination of lubricants (i.e., one or more). The present application contemplates the use of magnesium stearate as a lubricant.

[0045] The pharmaceutical composition of the present invention comprises about 0.25% to about 1.75% w / w of a lubricant. In some embodiments, the lubricant forms part of the internal granular phase and part of the external granular phase. In some embodiments, the pharmaceutical composition of the present invention comprises 0.25% to 0.75% w / w of a lubricant in the internal granular phase, based on the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention comprises 0.50% to 1.00% w / w of a lubricant in the external granular phase, based on the weight of the pharmaceutical composition.

[0046] The provided composition can be formulated into a single formulation. The formulation method is well known to those skilled in the art. In some embodiments, the present invention provides a formulation that includes a solid formulation as a tablet, crushed tablet, capsule or capsule powder, mini-tablet, or bead.

[0047] The pharmaceutical compositions of the invention may include an organic acid. The present application contemplates the use of citric acid as the organic acid.

[0048] (Tablet manufacturing) Tablets can be manufactured according to methods well known to those skilled in the art, such as dry granulation (e.g., roller compactor), wet granulation (e.g., fluidized bed granulation and high shear granulation), and direct compression, depending on the type of excipients used. This application relates to a method of manufacturing tablets by dry granulation (see, e.g., FIG. 3).

[0049] For example, tablets were prepared according to the following general steps, which are also illustrated in FIG. (1) Pre-blending: API and pharma- ceutically acceptable excipients are blended during manufacturing. For example, but not limited to, first, API and intragranular excipients (first diluent, optional second diluent, glidant, disintegrant (other than intragranular lubricant)) are sieved and added to a blender and blended for the first time to obtain a first blend. Separately, intragranular lubricant is sieved and blended with the first blend and added to a blender and blended for the second time. (2) Dry Granulation: (a) Roller Compactor: The API and pharma- ceutically acceptable excipients were passed through a roller compactor to obtain a compact. The compact was then milled to obtain granules. (b) Milling (Preparation of Milled and Sieved Granules): The API and pharma-ceutically acceptable excipients were milled and / or sieved. (3) External granule blend: The milled and / or sieved granules containing API and internal granule excipients were blended with the external granule excipients in the final blend. (4) Compression: The final blend was compressed into tablets using a tablet press. (5) If necessary, the tablets were film-coated with a film-coating agent.

[0050] (Example) The following examples are offered for illustrative purposes and are not intended to limit the scope of the claims appended hereto. All references cited in these examples and throughout this specification are incorporated herein for all legal purposes to be served by reference.

[0051] The present application provides a pharmaceutical composition comprising the methanesulfonate salt of Compound I. The chemical formula of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, also referred to as "Compound I," "linrodostat" or the "free base," is: 25 H 28 ClFN 2 O 4 S, has a molecular weight of 410.92 g / mol and the molecular weight of the methanesulfonate salt is 507.02 g / mol. To achieve a drug loading of 12.5% ​​as the free base, 15.43% of the drug substance as the methanesulfonate salt must be added to the formulation.

[0052] (Preliminary testing of tablet formulations) In excipient compatibility tests, compound I-MSA exhibited favorable chemical stability in commonly used pharmaceutical excipients, indicating that compound I-MSA is suitable for formulation with excipients.

[0053] Example 1: Types of disintegrants Raman imaging detected the free base in tablets placed under stressed conditions (open bottle at 40°C / 75% relative humidity ("RH")), suggesting that salt disproportionation had occurred for compound I-MSA. Following this observation, several factors in the disproportionation of the methanesulfonate salt to the free base were evaluated. Surprisingly, one factor that had an impact was the type of disintegrant.

[0054] Cation (e.g. Na + , Ca 2+ , or Mg 2+ ) was found to promote and induce the disproportionation of methanesulfonate. During formulation development, the sodium ion source suspected to cause methanesulfonate disproportionation was croscarmellose sodium. Therefore, crospovidone was evaluated instead as a tablet disintegrant. Tables 1 and 2 show tablets containing crospovidone. [Table 1]

[0055] Table 1 shows the ingredients of the pharmaceutical compositions, including the function of the ingredients as well as the % w / w of the composition. The pharmaceutical compositions were formulated into 100 mg, 50 mg, and 25 mg tablets as shown in the table. [Table 2]

[0056] Table 2 illustrates different tablet compositions (or formulations) containing crospovidone and either magnesium stearate or stearic acid as a lubricant in a 100 mg tablet. [Table 3]

[0057] Comparative compositions containing croscarmellose sodium are shown in Table 3. The compositions containing croscarmellose sodium in Table 3 were compared to compositions containing crospovidone such as those in Table 1. Long-term stability studies were performed on the compositions as shown in Figure 1, which shows the amount of free base in two tablet compositions containing croscarmellose sodium or crospovidone. Surprisingly, the amount of free base was found to be much lower in the compositions containing crospovidone (12.1%) compared to the compositions containing croscarmellose sodium (45.7% when stored in an open system at 40°C / 75% RH for 24 weeks).

[0058] Table 4 summarizes the free base content observed after storage for up to 6 months under different conditions. As shown in Table 4, the data confirmed that the addition of croscarmellose sodium to the composition made it more susceptible to salt disproportionation during storage. Therefore, crospovidone was used instead of croscarmellose sodium as a disintegrant in the final tablet composition. The results also showed that the tablet blend was less susceptible to salt disproportionation than the coated tablets. 5 g of the final blend stored for 24 weeks in HDPE bottles (200 mL) at 25°C / 60% RH had less than 3% conversion to free base. [Table 4]

[0059] Example 2: API / Magnesium Stearate Ratio With reference to Table 5, data shows that the API / magnesium stearate ratio in the composition influences the amount of disproportionation of methanesulfonate. Figure 2 shows the percentage of free base of tablet compositions (or formulations) with various drug loading / magnesium stearate ratios after 4 weeks of storage in open HDPE bottles at 40°C / 75%RH. Compositions containing croscarmellose sodium or crospovidone as disintegrants showed a decrease in the amount of free base as the drug loading / magnesium stearate ratio increased (see Table 5). However, it was also observed that too high a drug loading / magnesium stearate ratio increases processing parameters (e.g. powder flow and stickiness during roller compaction or tableting). Therefore, although a higher drug loading / magnesium stearate ratio increases stability, a minimum amount of magnesium stearate is essential. [Table 5]

[0060] Example 4: Lubricant Evaluation In Table 6, compositions containing both magnesium stearate and stearic acid were evaluated for their effect on salt disproportionation. Comparing the compositions in Table 6 for 4 weeks at 40° C. / 75% RH in open conditions, there was less salt disproportionation when stearic acid was used as the lubricant (free base amount of .about.9% for magnesium stearate vs. less than 3% for stearic acid). However, it was found that higher amounts of stearic acid required the same amount of lubricant as magnesium stearate. When the magnesium stearate containing compositions were protected from moisture and elevated temperatures, the compositions had similar amounts of salt disproportionation as the stearic acid compositions. [Table 6]

[0061] Example 5: Effect of surface area on stability Two selected coated tablets were subjected to stress conditions to determine the differences between the blend and the compact. The data in Table 7 (see also Table 4) indicate that the final blend is less prone to salt disproportionation, suggesting that the mechanical stress during compression results in an accelerated increase in the amount of free base detected in the tablet.

[0062] The data for both free base percentages are summarized in Table 7. [Table 7]

[0063] Example 6: Effect of particle size on stability In a study of the effect of particle size on stability of Compound I-MSA, the particle size and surface area ratio of Compound I-MSA had no effect on stability. Applicants measured the amount of free base in an inventive composition containing unmilled API (larger particles with D90 of 165 μm exhibited approximately 9.4% free base) and a composition containing milled API (smaller particles with D90 of <20 μm exhibited approximately 10.4% free base) after 12 weeks of storage at 40° C. / 75% RH in an open system. The results show a comparison of the amount of disproportionation of salt.

[0064] Those skilled in the art appreciate that micro-substances (drugs with small particle sizes) are more susceptible to the effects of oxygen in the air, temperature, light, humidity, and excipients with which they interact, and are relatively more unstable than those with large or coarse particle sizes. In other words, it is known that pharmaceutical active ingredients with small particle sizes are more susceptible to disproportionation than those with large particle sizes. In the present application, it was shown that the particle size has no effect at all in the range of about 7 μm to 165 μm. This result was surprising because it is known that the larger the surface area, the more the particle size and surface area ratio affect stability.

[0065] Example 7: Differences in stability due to packaging [Table 8] As shown in Table 8, tablets stored in high density polyethylene (HDPE) bottles with desiccant and sealed in alu / alu (aluminum-aluminum foil blisters) had salt disproportionation below the detection limit after six months at 25° C. / 60% relative humidity (RH), 30° C. / 75% RH, and 40° C. / 75% RH. The free base after six months in polyvinyl chloride / polychlorotrifluoroethylene (PVC / ACLAR®) blisters was 4.2%.

[0066] The examples and embodiments described herein are presented for illustrative purposes only, and various modifications or variations in some of the embodiments are within the scope of the present invention and the appended claims.

Claims

1. (i) a structure: 【Chemistry 1】 in a therapeutically effective amount, between 15% and 20% w / w of the composition, of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate having the formula: (ii) crospovidone as a disintegrant in an amount of 2.0% to 7.0% w / w of the composition; (iii) magnesium stearate as a lubricant in an amount of 0.25% to 1.75% w / w of the composition; and (iv) microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent, in an amount, combined, of 50% to 80% w / w of the composition; wherein the weight ratio of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to total magnesium stearate is 8.0 to 40.0; and 1. A pharmaceutical composition suitable for oral administration, wherein disproportionation of the salt (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight.

2. 10. The pharmaceutical composition of claim 1, further comprising silicon dioxide as a glidant in an amount of 1.0% to 3.0% w / w of the composition.

3. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate to total magnesium stearate is 23.0 to 40.

0.

4. 2. The pharmaceutical composition of claim 1, comprising the first diluent and the second diluent in a weight ratio of 2:1 to 1:

2.

5. 2. The pharmaceutical composition of claim 1, wherein the first diluent comprises 25% to 40% w / w of the composition.

6. 2. The pharmaceutical composition of claim 1, wherein the second diluent comprises 25% to 40% w / w of the composition.

7. 3. The pharmaceutical composition of claim 2, comprising silicon dioxide in an amount of 2.0% w / w of the composition.

8. 2. The pharmaceutical composition of claim 1, wherein the composition has an inner granular phase and an outer granular phase.

9. (a): (i) (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate in an amount of 12% to 18% w / w of the composition; (ii) crospovidone as a disintegrant in an amount of 2% to 3% w / w of the composition; (iii) magnesium stearate as a lubricant in an amount of 0.25% to 0.75% w / w of the composition; (iv) microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent in a combined amount of 50% to 80% w / w of the composition; (b): having an outer granular phase comprising: (i) crospovidone as a disintegrant in an amount of 2% to 3% w / w of the composition; and (ii) magnesium stearate as a lubricant in an amount of 0.50% to 1.00% w / w of the composition.

9. The pharmaceutical composition of claim 8.

10. 10. The pharmaceutical composition of claim 9, wherein the intragranular phase further comprises silicon dioxide as a glidant in an amount of 1.5% to 2.5% w / w of the composition.

11. 2. The pharmaceutical composition of claim 1, wherein after storage for 24 weeks in a high density polyethylene bottle (200 cc) at 25° C. and 60% relative humidity, less than 3% by weight of the salt (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid has disproportionated to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide has been disproportionated.

12. 2. The pharmaceutical composition of claim 1, wherein after 6 months in a blister pack at 25° C. and 60% relative humidity, less than 3% by weight of the salt (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid has disproportionated to (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

13. 2. The pharmaceutical composition of claim 1, wherein after 4 weeks at 25° C. and 60% relative humidity, less than 3% by weight of the salt (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid has disproportionated to (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

14. 2. The pharmaceutical composition of claim 1, wherein after 4 weeks at 40° C. and 75% relative humidity, less than 3% by weight of the salt (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid has disproportionated to (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

15. 2. The pharmaceutical composition of claim 1, wherein the composition is a mixture and, after 24 weeks in a closed system at 25° C. and 60% relative humidity, the salt disproportionated from (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight.

16. 2. The pharmaceutical composition of claim 1, wherein the composition is selected from the group consisting of a tablet, a crushed tablet, a capsule or capsule powder, minitablets, and beads.

17. 10. The pharmaceutical composition of claim 1, further comprising citric acid.

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