PHARMACEUTICAL FORMULATIONS OF INDOLAMINE 2,3-DIOXYGENASE INHIBITORS

Abstract

The present invention relates to a pharmaceutical composition comprising methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide that is resistant to salt disproportionation: (see Formula).

Description

PHARMACEUTICAL FORMULATIONS OF INDOLAMINE 2,3-DIOXYGENASE INHIBITORS Field of Invention The present application is directed to a pharmaceutical composition comprising methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide having a low salt disproportion resulting in a stable solid dosage form. Background of the Invention Indolamine 2,3-dioxygenase (IDO or IDO1) is an IFN-γ target gene that plays a role in immunomodulation, and its immunosuppressive function manifests 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 IDO production in the tumor microenvironment appears to aid in tumor growth and metastasis. Furthermore, elevated levels of IDO activity are associated with a variety of different tumors (Brandacher, G. et al., Clin. Cancer Res., 12(4):1144-1151 (February 15, 2006)). In addition to cancer, IDO has been implicated in immunosuppression, chronic infections, and various diseases and disorders, among other conditions. Azoznn / zznz / E / YiAi Ref. 332237 autoimmune (e.g., rheumatoid arthritis). (R)-N-(4-chlorophenyl)-2-((13,43)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (Compound I), also generally referred to as linrodostat, was described as a potent IDO inhibitor (see, for example, International Publication No. WO2016 / 073770). The methanesulfonic acid salt of Compound I (Compound I-MSA) is described as the salt form with superior properties. Rzoznn / zznz / E / viAi TO I-MSA Compound One of the most important aspects in the development of pharmaceutical formulations is the identity and combination of excipients and how they interact with the active pharmaceutical ingredient (API). Many APIs are manufactured and formulated as salts due to their improved solid-state properties, which lead to faster dissolution rates and greater bioavailability compared to free-form crystalline APIs. These free-form APIs may have a basic site where the pKa is too low (e.g., pKa 4.6) and are at risk of experiencing long-term storage stability issues, proton transfer, and / or increased disproportionation. In the development of solid oral dosage forms containing the ionizable drug salt, some excipients are known to cause the conversion of the active pharmaceutical ingredient (API) to the free base. Formulation design must consider the factors that affect salt disproportionation during processing or storage and how this impacts product quality and performance. Therefore, there is a need for stable pharmaceutical compositions. Brief Description of the Invention This document describes pharmaceutical compositions of Compound I-MSA suitable for oral administration. In a first aspect, the invention provides a pharmaceutical composition suitable for oral administration comprising: (i) a therapeutically effective amount of methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide present in an amount of between 5% and 40% w / w of the composition having the Rzoznn / zznz / E / viAi structure: Rzoznn / zznz / E / YiA (ii) crospovidone as a disintegrant present in an amount between 2.0% and 7.0% w / w of the composition; and, (iii) magnesium stearate as a lubricant present in an amount between 0.25% and 1.75% w / w of the composition; wherein the ratio of methanesulfonic acid salt of (A)-N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to total magnesium stearate is 8.0 to 40.0 by weight; and wherein the disproportion of methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)~N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 25% by weight. In one embodiment, the pharmaceutical composition further comprises microcrystalline cellulose as the first diluent and anhydrous lactose as the second diluent present in a total amount between 50% and 80% w / w of the composition. In one embodiment, the pharmaceutical composition further comprises silicon dioxide as a glide present in an amount of 1.0% to 3.0% w / w of the composition. In one embodiment, the pharmaceutical composition comprises a disproportionate methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((13,43)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount of less than 5% by weight. In another embodiment, the pharmaceutical composition comprises a disproportionate methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount less than 3% by weight. In one embodiment, the pharmaceutical composition comprises the methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((13,-43)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to total magnesium stearate in a ratio of 23.0 to 40.0 by weight. In one embodiment, the pharmaceutical composition comprises methanesulfonic acid salt of (A)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide present in an amount between 15% Rzoznn / zznz / E / viAi at 20% w / w of the composition. In one embodiment, the pharmaceutical composition comprises a first diluent and a second diluent in a ratio that varies between 2:1 and 1:2 by weight. In another embodiment, the pharmaceutical composition comprises a first diluent in an amount ranging from 25% to 40% w / w of the composition. In a further embodiment, the pharmaceutical composition comprises a second diluent present in an amount ranging from 25% to 40% w / w of the composition. In one embodiment, the pharmaceutical composition comprises silicon dioxide present in an amount of 2.0% w / w of the composition. In one embodiment, the pharmaceutical composition comprises an intragranular phase and an extragranular phase. In another embodiment, the pharmaceutical composition comprises: (a) an intragranular phase comprising: (i) methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide present in an amount of between 12% and 18% w / w of the composition; (ii) crospovidone as a disintegrant present in an amount of 2% to 3% w / w of the composition; (iii) magnesium stearate as a lubricant present in an amount of 0.25% to 0.75% w / w of the composition; (b) an extragranular phase comprising: (i) crospovidone as a disintegrant present in an amount of 2% to 3% w / w of the composition; and, (ii) magnesium stearate as a lubricant present in an amount of 0.50% to 1.00% w / w of the composition. In one embodiment, the pharmaceutical composition comprises an intragranular phase further comprising microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent present in a total amount of between 75% to 80% w / w of the composition; and silicon dioxide as a glide present in an amount of 1.5% to 2.5% w / w of the composition. In one embodiment, the pharmaceutical composition comprises the methanesulfonic acid salt disproportionation of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide to (R?)-A7'-(4-chlorophenyl)-2-((1S,4S?)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount of less than 10% after 12 weeks at 40°C and 75% relative humidity in an open environment and has a particle size distribution characterized by a D90 having a value of approximately 7 microns to approximately 165 microns. In one embodiment, the pharmaceutical composition comprises a disproportionate salt of methanesulfonic acid salt Rzoznn / zznz / E / YiAi of (A)-N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (H)-N-(4-chlorophenyl)-2-((15,45)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount less than 3% by weight after 24 weeks stored in a 200 cc high-density polyethylene bottle at 25 °C and 60% relative humidity. In one embodiment, the pharmaceutical composition comprises a particle range distribution characterized by a D90 having a value of approximately 10 microns to approximately 165 microns. In one embodiment, the pharmaceutical composition comprises the methanesulfonic acid salt disproportionation of (R)-N-(4-chlorophenyl)-2-((25,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide to (A)-N-(4-chlorophenyl)-2-((15,45)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount of less than 3% by weight after 6 months at 25 °C and 60% relative humidity in blister pack. In one embodiment, the pharmaceutical composition comprises the methanesulfonic acid salt disproportionation of (R)-N-(4-chlorophenyl)-2-((15,43)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide to (H)-N-(4-chlorophenyl)-2-((15,45)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount of less than 3% by weight after 4 weeks at 25 °C and 60% relative humidity. In one embodiment, the pharmaceutical composition comprises the methanesulfonic acid salt disproportionation of (R)-N-(4-chlorophenyl)-2-((1 Sz4 S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide to (R)-N-(4-chlorophenyl)-2-((15,4S)4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide in an amount of less than 3% by weight after 4 weeks at 40 °C and 75% relative humidity. In one embodiment, the pharmaceutical composition comprises a mixture and the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)~N-(4-chlorophenyl)-2 —((1S,4 5)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 24 weeks at 25 °C and 60% relative humidity. In one embodiment, the pharmaceutical composition comprises a composition selected from the group consisting of tablet, crushed tablet, capsule or powdered contents of a capsule, mini tablets and pearls. In another form, the pharmaceutical composition also includes citric acid. Brief Description of the Figures The following detailed description, provided by way of example but not intended to limit the invention solely to the specific embodiments described, can be better understood in conjunction with the accompanying figures. Figure 1 illustrates the percentage of free base in tablet formulations containing croscarmellose sodium or crospovidone as a disintegrant at 40 °C / 75% relative humidity (RH), open high-density polyethylene (HDPE) bottle. Figure 2 illustrates the percentage of free base in tablet formulations of different drug loading ratios to magnesium stearate at 40 °C / 75%, open high-density polyethylene bottle. Figure 3 illustrates one embodiment of the method for producing a film-coated tablet of 100 mg, 50 mg, and 25 mg of Compound I-MSA. Detailed Description of the Invention The present invention can be more easily understood with reference to the following detailed description taken in conjunction with the accompanying figures and examples, which form part of this invention. It should be understood that this invention is not limited to the specific devices, methods, applications, conditions, or parameters described and / or shown herein, and that the terminology used herein is intended to describe particular embodiments by way of example only and is not intended to be limiting to the claimed invention. Furthermore, as used in the description including the appended claims, the singular forms a, one, and the include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The terms "comprises," "includes," "having," "has," "may," "contains," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the listed ingredients / steps and permit the presence of other ingredients / steps. However, such descriptions should also be interpreted as describing compositions or processes as consisting of and consisting essentially of the listed compounds, permitting the presence of only the listed compounds, along with any pharmaceutical carriers, and excluding other compounds. All intervals described herein include the aforementioned endpoint and can be combined independently (e.g., the 100 mg to 200 mg interval includes the endpoints, 100 mg and 200 mg, and all intermediate values). The endpoints of the intervals and any values ​​described herein are not limited to the precise interval or value; they are sufficiently imprecise to include values ​​that approximate these intervals and / or values. As used herein, pharmaceutically acceptable salts refers to derivatives of the compounds described where the original compound is modified by making acidic or basic salts of it. The term API refers to the active pharmaceutical ingredient. As used herein, API refers to Compound I-MSA or the methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-11)cyclohexyl)propanamide. Pharmaceutically Acceptable Compositions and Formulations In some aspects of the application, the pharmaceutical compositions of the invention include 10% to 40% w / w of API, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical compositions of the invention include 15% to 20% w / w of API, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical compositions of the invention include 17% to 18% w / w of API, based on the weight of the pharmaceutical composition. The pharmaceutical compositions of the invention include a diluent. The diluent of the invention may include, for example, a first diluent and, optionally, a second diluent. Diluents generally known in the art include, for example, sugar alcohols, sugars, celluloses, starch-derived diluents, and combinations thereof. More specific diluents Rzoznn / zznz / E / viAi known in the art include dextrin, sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, aspartame, mannitol, starch, corn starch, PVP (polyvinylpyrrolidone), low molecular weight HPC (hydroxypropylcellulose), microcrystalline cellulose (MCC), low molecular weight HPMC (hydroxypropylmethylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose, dicalcium phosphate, silicified microcrystalline cellulose, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, magnesium aluminum silicate, and polymethacrylates. One embodiment of a diluent of the present application is lactose, for example, lactose (anhydrous), high-speed lactose, or a combination thereof. Another option is microcrystalline cellulose, for example, microcrystalline cellulose PH 302. This application contemplates the use of a combination of diluents, such as microcrystalline cellulose and lactose. In those aspects of the invention that include two diluents, i.e., a first diluent and a second diluent, the ratio of the first diluent to the second diluent is between 2:1 and 1:2. In one embodiment, the ratio of the first diluent to the second diluent is 1:1. In one embodiment, the first diluent is microcrystalline cellulose and the second diluent is lactose. The compositions of the invention include among 50% y 80% en p / p de diluyente, en base al peso de la composición farmacéutica. En una modalidad, la composición farmacéutica comprende entre 75% y 80% en p / p de diluyente, basado en el peso de la composición farmacéutica. En una modalidad, la composición farmacéutica comprende entre 35% y 40% en p / p de un primer diluyente y entre 35% y 40% en p / p de un segundo diluyente, en base al peso de la composición farmacéutica. The pharmaceutical compositions of the invention may include a slider. Sliders known in the art may include, among others, silicon dioxide, colloidal silicon dioxide, talc, magnesium carbonate, calcium silicate, fumed silicon dioxide, starch, and combinations thereof. This application contemplates the use of silicon dioxide as a slider. The compositions of the invention include between 1.0% and 3.0% w / w of a slider, based on the weight of the pharmaceutical composition. In one embodiment, the pharmaceutical compositions comprise between 1.75% and 2.25% w / w of a slider, based on the weight of the pharmaceutical composition. In one embodiment of the invention, the pharmaceutical composition comprises granules. In one embodiment, the granules of the composition may have an intragranular phase and an extragranular phase. In one embodiment, the intragranular phase comprises a gluent, while the extragranular phase does not contain a gluent. The pharmaceutical compositions of the invention include a disintegrant. Disintegrants known in the art include, for example, starch-based disintegrants, cellulose-based disintegrants, povidone-based disintegrants, and the like. Specific examples of disintegrants include, but are not limited to, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, crospovidone (crosslinked polyvinylpyrrolidone (PVP)), sodium starch glycolate (sodium starch glycolate), crosslinked sodium starch glycolate (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 (a crosslinked povidone) as a disintegrant. The pharmaceutical compositions of the invention include between 2.0% and 7.0% w / w of a disintegrant, based on the weight of the pharmaceutical composition. In one embodiment, the pharmaceutical compositions of the invention include 2.5% w / w of an intragranular phase disintegrant and 2.5% w / w of an extragranular phase disintegrant, based on the weight of the pharmaceutical composition. The pharmaceutical compositions of the invention Rzoznn / zznz / E / viAi may include a lubricant. Lubricants are known in the art and include, for example, stearic acid, stearic acid salts, and combinations thereof, and the like. Examples of stearic acid salts are calcium stearate, magnesium stearate, sodium stearyl fumarate, and combinations thereof. The lubricant of the invention may include one lubricant or a combination of (i.e., more than one) lubricants. This application contemplates the use of magnesium stearate as a lubricant. The pharmaceutical compositions of the invention include between approximately 0.25% and approximately 1.75% w / w of a lubricant. In one embodiment, a lubricant is part of both the intragranular and extragranular phases. In one embodiment, the pharmaceutical compositions of the invention include between 0.25% and 0.75% w / w of a lubricant in an intragranular phase, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical compositions of the invention include between 0.50% and 1.00% w / w of a lubricant in an extragranular phase, based on the weight of the pharmaceutical composition. The provided compositions can be formulated in a unit-dose form. Such formulations are well known to those skilled in the art. In certain embodiments, the present invention provides a Rzoznn / zznz / E / YiAi formulation comprising a solid dosage form such as a tablet, crushed tablet, capsule or powdered contents of a capsule, mini tablets or pearls. The pharmaceutical compositions of the invention may include an organic acid. This application contemplates the use of citric acid as the organic acid. Tablet Preparation Tablets can be prepared according to methods known in the art, including dry granulation (e.g., roller compaction), wet granulation (e.g., fluidized bed granulation and high-shear granulation), and direct compression, and the type of excipients used will vary accordingly. This application is for a method of preparing tablets by dry granulation (see, for example, Figure 3). For example, the tablets were prepared in accordance with the following general steps, which are also illustrated in Figure 3: (1) Premixing: The API and pharmaceutically acceptable excipients were mixed during the manufacturing process. In a non-limiting example, first, the API and intragranular excipients (first diluent, optional second diluent, glidant, disintegrant; except for the intragranular lubricant) were sieved through a sieve, Rzoznn / zznz / E / viAi were added to a mixer and mixed for a first mixing period to produce an initial mix. Separately, an intragranular lubricant was passed through a sieve, mixed with a portion of the initial mix, added to the mixer, and mixed for a second mixing period. (2) Dry granulation: (a) Roller compaction: The API and pharmaceutically acceptable excipients were passed through a roller compactor to produce compacts. The compacts were then ground to obtain granules. (b) Milling (preparation of crushed / sieved granules): The API and pharmaceutically acceptable excipients were crushed and / or sieved. (3) Extragranular mixture: the granules comprising the API and intragranular excipients that had been crushed / sieved were mixed with extragranular excipients into a final mixture. (4) Compression: The final mixture was compressed into tablets using a tablet press. (5) Optionally, the tablets were coated with a film containing a film coating agent. EXAMPLES The following examples are provided for illustrative purposes and are not intended to limit the scope of the Rzoznn / zznz / E / viAi claims provided in this document. All bibliographic citations in these examples and throughout this description are incorporated herein by references for all legal purposes. This application provides a pharmaceutical composition comprising the methanesulfonic acid 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 C25H28CIFN2O4S, which has a molecular weight of 410.92 g / mol, and the molecular weight of the methanesulfonic acid 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 methanesulfonic acid salt must be added to the formulation. Preliminary Tablet Formulation Development In an excipient compatibility study, Compound I-MSA exhibited acceptable chemical stability with commonly used pharmaceutical excipients, indicating that Compound I-MSA was suitable for formulation with the excipients. Example 1: Type of Disintegrant Raman images detected free base in Rzoznn / zznz / E / viAi tablets subjected to stressful storage conditions at 40 °C / 75% relative humidity (RH) in an open bottle, suggesting that salt disproportionation had occurred in Compound I-MSA. Following this observation, several factors were evaluated to overcome the occurrence of salt disproportionation of the methanesulfonic acid salt with respect to the free base. One factor with a surprising impact was the type of disintegrant. Cations such as Na+, Ca2+, or Mg2+ facilitate or induce the disproportionation of the methanesulfonic acid salt. During formulation development, croscarmellose sodium was suspected as a contributing factor to the disproportionation of the methanesulfonic acid salt. Consequently, crospovidone was evaluated as an alternative disintegrant in the tablet formulation. Tables 1 and 2 show the tablet formulations prepared with crospovidone. Table 1: Compositions with Crospovidone Rzoznn / zznz / E / viAi Composeute ea P? Amount per Tablet mg in 10 mg (free base) of tablets mg in 50 mg (free base) of tablets mg in 25 mg (free base) of tablets Extra-granular Compound I-MSA 15.42 123.36 61.68 30.54 Anhydrous Lactose 38.165 305.32 152.66 76.33 Cellulose 152.66 76 77 Microconstalysate 38.165 305.32 Silicon Dioxide 2.00 16.0 8.0 4.0 Crospovidone 2.50 20.0 10.0 5.0 Magnesium Esterate 0.50 4.0 2.0 1.0 Extra-granular Crospovidone 2.50 20.0 10.0 5.0 Magnesium Stearate 0.75 6.0 3.0 1.5 Total 100.0 800.0 400.0 200.0 Pe&úla Rfwfemmiphyte 3.0 24.0 CJ z 0? 13 •4· 1 2 CJ 3.8 15.2 of PdiEtüa 4.6 24.0 9.20 Total 824.0 415.2 209.20 Table 1 illustrates the components of the pharmaceutical composition, including the function of each component and its w / w percentage. The pharmaceutical composition was formulated in 100 mg, 50 mg, and 25 mg tablets, as shown in the table. Table 2: Composition Containing Crospovidone with either Magnesium Stearate or Stearic Acid as a Lubricant Rzoznn / zznz / E / YiAi Component Amount per Tablet mg in 190 mg of tablets % w / w mg in 100 mg of tablets % w / w Intra-granular Compound I-MSA 15.42a 123.36 15.42a 123.36 Anhydrous Lactose 38.165 305.32 38.04 304.32 Microcellulose 38.165 305.32 38.04 304.32 Silicon Dioxide 2.00 16.00 2.00 16.00 Crospovidone 2.50 200 2.50 20.00 Magnesium Stearate 0.50 4.00 NA NA Stearic Acid NA NA 1.50 12.00 Extra-granular Crospovidone 2.50 20.0 2 50 20.00 Magnesium Stearate 0.75 6.00 NA NA Stearic Acid 1.00 8.00 Total 100.00 800.06 100.00 800.00 aIntensity come base bbre. Table 2 illustrates different tablet compositions (or formulations) containing crospovidone with magnesium stearate or stearic acid as a lubricant in 100 mg tablets. Table 3: Composition of Croscarmellose Tablet Sodium Rzoznn / zznz / E / viAi (Comparative) ConiponeHte % ea w / w mg in 100 mg tablets mg in 25 mg tablet Iníra-granular Cost i- MSA 15.42s 123.36 30.84 Anhydrous Lactose 38.165 305.32 76.33 CeMosa Mkrocdsta&ta 38.165 305.32 76.33 Silicon Dioxide 2.00 16.0 4.00 CroscamK:Side Iose· 2.50 20.0 5.00 Magnesium Stearate 0.50 4.0 1.00 Estra-granular Sodium Croscansefesa 2.50 20.0 5.00 Magnesium Stearate 0.75 6.0 1.50 Total 100.0 800.0 200.00 Film Coating 3.00 24.00 6.00 Total 824.00 206.00 The indicated intensity is like the free base. Table 3 shows comparative compositions containing croscarmellose sodium. The croscarmellose sodium compositions in Table 3 were then compared with crospovidone-containing compositions, such as those in Table 1. The compositions underwent long-term stability testing, as illustrated in Figure 1, which shows the free base levels in the two tablet compositions containing croscarmellose sodium and crospovidone. Surprisingly, the crospovidone-containing composition was found to have a much lower free base level (12.1% when stored at 40°C / 75% RH after opening for 24 weeks) compared to the croscarmellose sodium-containing composition (45.7%). Table 4 summarizes the free base level observed during storage under different conditions for up to 6 months. As shown in Table 4, the data confirmed that the addition of croscarmellose sodium to the composition can lead to greater salt disproportionation during storage. Consequently, crospovidone was used as a disintegrant instead of croscarmellose sodium for the final tablet composition. The results also confirmed that tablet blends exhibited less salt disproportionation than coated tablets. At 24 weeks, 5 grams of the final blend stored in 200 ml HDPE bottles at 25 °C / 60% RH provided Azoznn / zznz / E / YiAi less than 3% conversion to the free base. Table 4: Percentage of Free Base Level for Tablet formulations containing croscarmellose sodium Rzoznn / zznz / E / YiAi Packaging Conditions of Aíaiarenamienío 0 Panto de Tiempo (Weeks) 4 12 24 % of Free Base 25 C / 60% RH closed <3 NA <3 5 grams of final mixture if 200cc HDPE Bottle 40 / 75% RH closed NA 5.2 NA 9 40 75% RH open 18.5 NA 21.0 2 tablets at 25 °C / 60% RH closed c 7 5.6 7 7 200 cc HDPE Bottle 40 °C / 75% RH closed 22.4 28.4 38.8 40 °C 75% RH open NA 34.1 36.0 45.7 12 tablets at 40 °C / 75% RH closed 13.4 14.0 29.3 200 ce HDPE bottle with desiccant Example 2: API / magnesium stearate ratio With reference to Table 5, the data demonstrate that the API / magnesium stearate ratio in the composition impacted the level of disproportionation of the methanesulfonic acid salt. Figure 2 shows the % free base level in tablet compositions (or formulations) with different drug / magnesium stearate loading ratios after 4 weeks of storage at 40 °C / 75% RH in opened HDPE bottles. For compositions containing croscarmellose sodium or crospovidone as a disintegrant, the free base level decreased as the drug / magnesium stearate loading ratio increased (see Table 5). However, it was also observed that an excessively high drug / magnesium stearate loading ratio increased processability parameters such as powder flow and adherence during roller compaction or tablet forming.Therefore, while a high ratio provided better stability, a minimal amount of magnesium stearate was required. Table 5: Formulation Details of Tablets Containing Croscarmellose Sodium or Crospovidone and Drug / Magnesium Stearate, Acid Modifier or Different Lubricant Loading Ratio Rzoznn / zznz / E / viAi F&nn'sfaewB. ABCBEFGH Iscra-Gra&ular Compuesto l-MSA 19.29 15.42 15.42 15.42 30.001 40.00 15.42 15.62 Sio>íd&de si&:io 2.06 2.00 2.00 2.30 2..O0 2.00 2.66 2.02 Celulosa mk í-otti st ahm 36.48 56.33 38.165 3E.165 30. S75 25..S75 37.165 38.65 Lactosa anhidra 36.45 20.M 38.165 38.165 30.875 25.875 37.165 38.65 OfG'Scaiíneksa de soát© 2.50 2.50 2.50 ... ... ... .... ¿•.5 j Crt'spoyKfom ... ... ... 2.50 2.50 2.50 2.50 — Esteararo de magnesium 0 50 0.75 0.75 0.75 075 075 075 — Crystalline acid ... ... ... ... ._. 2.60 Extra-Granular en w / w} Cí oseármelo sa de sodium 2.50 2.56 2.30 ... 2.53 Cfcspovidona .._ 2.50 2.50 2.50 2.56 .... SstearatG de magnesium 0.25 0.56 0.56 0.50 0.50 0.50 0.50 — Esteáric acid ... ... 0.50 0.56 — — Cubierta de — ___ 3.00 3.Q0 — ... — latal recub.) JGO.GÜ 100.00 100.00 1Θ0.00: 100.00 ΙΰΟ.ΟΘ 1001® 100.00 Table type Nudeo Núdec Recutoerta P.eoubieíta Núcko Núcleo Núcleo Núcleo Relación de AFi-Esteaiarc de magnesium 12.3 12.3 12.3 24.0 32.0 12.3 _.% of free base e- after 20.50 32.10 34.60 SO. 00 5.00 5.06 6.06 <3.06. 3 weeks • 5% RH under conditions of aíjEacenaiBiento· abienc Example 4: Lubricant Study Table 6 evaluates compositions containing both magnesium stearate and stearic acid for their effect on salt disproportion. A comparison of the compositions in Table 6 after 4 weeks at 40 °C / 75% RH under open conditions showed lower salt disproportion (~9% freebase for magnesium stearate versus less than 3% for stearic acid) when stearic acid was used as the lubricant. However, higher levels of stearic acid were found to be required to provide lubricity levels similar to those of magnesium stearate. When the magnesium stearate compositions were protected from moisture and elevated temperatures, they provided similar levels of salt disproportion to the stearic acid compositions. Table 6: Compositions with Magnesium Stearate or Stearic Acid as a Lubricant Rzoznn / zznz / E / viAi 5 Component % is ρφ Amount per Tablet in 100 mg of tablets mg ea lt>0 mg of tablets % in ρ φ Intra-granular Compound I-MSA 15.42a 123.36 15.420a 123.36 Anhydrous Lactose 38.165 305.32 35.04 304.32 Microcrystalline Cellulose 38.165 305.32 38.04 304.32 Silicon Dioxide 2.00 16.00 2.00 16.00 10 Crosscopeptide 2.50 20.0 2.50 20.00 Magnesium Stearate 0.50 4.00 NA NA Stearic Acid NA NA 1.50 12.00 Extra-granular Crospovidae 2.50 20.0 2.50 20.00 Magnesium Stearate 0.75 6.00 NA NA Stearic Acid 1.00 8.00 15 Total 100.00 800.00 100.00 800.00 aIntensity as a free base. Example 5: Effect of Surface Area on Stability Two selected coated tablet formulations were subjected to stress storage conditions to study the difference between blends and compacts. The data in Table 7 (see also Table 4) illustrate that the final blend was less prone to salt disproportionation, indicating that mechanical stress during compression contributed to the observed free base level in the tablets at an accelerated rate. The percentage of free database data for both batches is summarized in Table 7. Table 7: Results Showing the Mixture That Has Better Stability than the Compacts Rzoznn / zznz / E / viAi Packaging Storage Conditions 0 Time (Weeks) % of Free Base 24 4 12 5 g of final urine 25 °C / 60% RH closed < 3 NA < 3 in 2 cc HDPE bottle 40 °C / 75% RH closed NA 5.2 NA 9.0 40 75% RH open 18.5 NA 21.0 2 tablets in bottle 25 °C / 60% RH closed 5 2 5.6 2 cc HDPE 40 °C / 75% RH closed NA 22.4 28.4 38.8 40 °C / 75% RH open 34.1 36.0 45.7 : 2 tablets in bottle 40 °C 75% RH closed with desiccant 13.4 14.0 29.3 Example 6: Effect of Particle Size on Stability In a study of the effect of particle size on the stability of Compound I-MSA, the particle size-to-surface area ratio of Compound I-MSA surprisingly had no effect on stability. The applicant measured the amount of free base at 40°C / 75% RH under open conditions after 12 weeks between the inventive composition containing uncrushed API (the largest particle size with a D90 of 165 microns showed approximately 9.4% free base) versus crushed API (the smallest particle size with a D90 of <20 microns showed approximately 10.4% free base). These results showed comparable amounts of salt disproportionation. A person skilled in the art will appreciate that fine materials (small drug particle size) are relatively more susceptible to stability problems caused by atmospheric oxygen, heat, light, humidity, and interacting excipients than larger or coarser particle sizes. In other words, active pharmaceutical ingredients with smaller particle sizes are known to exhibit greater disproportion compared to those with larger particle sizes. In the present application, no impact of particle size was observed in the range of approximately 7 microns to 165 microns. Consequently, these results were surprising, as the relationship between particle size and surface area is known to impact stability due to the larger surface area. Rzoznn / zznz / E / viAi Example 7; Stability. Provided by Different Packaged TABLE 8: DESPROPORTION OF SAL IN VARIOUS CONDITIONS Rzoznn / zznz / E / viAi OF STORAGE Pastos de Tiempo (Months) Packaged Conditions of Álmaceaamieuto % of Free Base 0 1 3 6 Paqueteen 25 60%RH Corada <3 <3 <3 Ampoule 30 / 75% RH Carada. NA <3 <3 <3 PVC / Aclar 40 °C / 753% RH cenada <3 3.0 4.2 7 5 °C / 60% RH corada <3 <3 Paquete en ampolla 30 °C / 75% RH corada NA <3 <3 Alu / Alu 40 °C / 75% RH carada <3 <3 <3 25 °C7 60% RH cerrada <3 <3 <3 con desecante 30 tabletas en 30 °CZ 75% caTada NA <3 <3 <3 botella HDPE CO!1 dssecsnte de 200 cc 40 75% rh abierta 5.6 6.8 6.6 40 ®C / 75% RH corada <3 <3 con desecante As shown in Table 8, tablets packaged in sealed high-density polyethylene (HDPE) bottles with desiccant and alu / alu (aluminum-aluminum foil blister pack) stored at 25°C / 60% RH, 30°C / 75% RH, and 40°C / 75% RH for 6 months resulted in salt disproportionation levels below the detection limit. The free base level at 6 months in polyvinyl chloride / polychlorotrifluoroethylene (PVC / ACLAR®) blisters was 4.2%. The examples and embodiments described herein are for illustrative purposes only and, in some embodiments, several modifications or changes must be included within the scope of the invention and the scope of the appended claims. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A pharmaceutical composition suitable for oral administration, characterized in that it comprises: (i) a therapeutically effective amount of methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide present in an amount of between 5% and 40% w / w of the composition having the structure: (ii) crospovidone as a disintegrant present in an amount of between 2.0% and 7.0% w / w of the composition; and, (iii) magnesium stearate as a lubricant present in an amount of between 0.25% and 1.75% w / w of the composition; where the ratio of methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4 11)cyclohexyl)propanamide to total magnesium stearate is 8.0 to 40.0 by weight; and, wherein the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 25% by weight.

2. The pharmaceutical composition according to claim 1, characterized in that it further comprises microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent present in a total amount of between 50% and 80% w / w of the composition.

3. The pharmaceutical composition according to claim 1, characterized in that it further comprises silicon dioxide as a slip present in an amount of 1.0% to 3.0% w / w of the composition.

4. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2((1S,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 5% by weight.

5. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2-Rzoznn / zznz / E / YiAi ( (1S,4 SJ —4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((13,43)-4-(6-fluoroquinolin-411)cyclohexyl)propanamide is less than 3% by weight.

6. The pharmaceutical composition according to claim 1, characterized in that the ratio of methanesulfonic acid salt of (Λ)-N-(4-chlorophenyl)-2-((1S,4S)-4(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to total magnesium stearate is 23.0 to 40.0 by weight.

7. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt of (A)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is present in an amount between 15% and 20% w / w of the composition.

8. The pharmaceutical composition according to claim 2, characterized in that the first diluent and the second diluent are present in a ratio ranging from 2:1 to 1:2 by weight.

9. The pharmaceutical composition according to claim 2, characterized in that the first diluent is present in an amount that varies between 25% and 40% w / w of the composition.

10. The pharmaceutical composition according to claim 2, characterized in that the second diluent is present in an amount ranging from 25% to 40% w / w of the composition. Rzoznn / zznz / E / viAi 11. The pharmaceutical composition according to claim 3, characterized in that silicon dioxide is present in an amount of 2.0% w / w of the composition.

12. The pharmaceutical composition according to claim 1, characterized in that it comprises an intragranular phase and an extragranular phase.

13. The pharmaceutical composition according to claim 12, characterized in that it comprises: (a) an intragranular phase comprising: (i) methanesulfonic acid salt of (R)-N-(4-chlorophenyl)-2-((1S,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide present in an amount of between 12% and 18% w / w of the composition; (ii) crospovidone as a disintegrant present in an amount of 2% to 3% w / w of the composition; (iii) magnesium stearate as a lubricant present in an amount of 0.25% to 0.75% w / w of the composition; (b) an extragranular phase comprising: (i) crospovidone as a disintegrant present in an amount of 2% to 3% w / w of the composition; and, (ii) magnesium stearate as a lubricant present in an amount of 0.50% to 1.00% w / w of the composition.

14. The pharmaceutical composition according to Rzoznn / zznz / E / YiAi claim 13, characterized in that the intragranular phase further comprises microcrystalline cellulose as a first diluent and anhydrous lactose as a second diluent present in a total amount of between 75% to 80% w / w of the composition; and silicon dioxide as a glide present in an amount of 1.5% to 2.5% w / w of the composition.

15. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2-({15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to {R)-N-(4-chlorophenyl)-2-((15,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 10% by weight after 12 weeks at 40°C and 75% relative humidity and has a particle size distribution distinguished by a D90 having a value of approximately 7 microns to approximately 165 microns.

16. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2-((1S,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to {R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 24 weeks stored in a 200 cc high-density polyethylene bottle at 25°C and 60% relative humidity.

17. The pharmaceutical composition according to Azoznn / zznz / E / YiAi 38 claim 1, characterized in that the particle size distribution distinguished by a D90 has a value of approximately 10 microns to approximately 165 microns.

18. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((13,45)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 6 months at 25°C and 60% relative humidity in blister pack.

19. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportion of (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 4 weeks at 25 °C and 60% relative humidity.

20. The pharmaceutical composition according to claim 1, characterized in that the methanesulfonic acid salt disproportionation of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 4 weeks at 40°C and 75% relative humidity. Rzoznn / zznz / E / viAi 21. The pharmaceutical composition according to claim 1, characterized in that it is a mixture and the methanesulfonic acid salt disproportionation of (R)-N-(Achlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide to (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is less than 3% by weight after 24 weeks at 25°C and 60% relative humidity in a closed container.

22. The pharmaceutical composition according to claim 1, characterized in that it is selected from the group consisting of tablet, crushed tablet, capsule or powdered contents of a capsule, mini-tablet and pearls.

23. The pharmaceutical composition according to claim 1, characterized in that it further comprises Rzoznn / zznz / E / viAi citric acid.