Pharmaceutical compositions comprising ozanimod

Abstract

The present invention provides pharmaceutical compositions and dosage forms comprising ozanimod, or a pharmaceutically acceptable salt thereof, processes for the preparation thereof, and their use in the treatment of multiple sclerosis and / or ulcerative colitis.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING OZANIMODTECHNICAL FIELD

[0001] The present invention is directed to pharmaceutical compositions and dosage forms comprising ozanimod and pharmaceutically acceptable salts thereof, processes for the preparation thereof, and their use in the treatment of multiple sclerosis and / or ulcerative colitis.BACKGROUND

[0002] Ozanimod, or 5-(3-{(1 S)-1 -[(2-hydroxyethyl)amino]-2,3-dihydro-1 H-i nden-4-y I}- 1 ,2,4-oxadiazol-5-yl)-2[(propan-2-yl)oxy]benzonitrile, in the form of the hydrochloride salt, is the active pharmaceutical ingredient (API) in the branded pharmaceutical ZEPOSIA®, which is a prescription medication for use in the treatment of multiple sclerosis (MS) and ulcerative colitis (UC). ZEPOSIA® is provided as hard gelatin capsules for oral administration, containing 0.25, 0.5, and 1 mg ozanimod HCI, equivalent to 0.23, 0.46, and 0.92 mg of ozanimod, respectively. According to the product label, “ZEPOSIA capsules consist of the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The capsule shell, imprinted with black ink, contains the following inactive ingredients: black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.”

[0003] The chemical structure of ozanimod free base is shown below.

[0004] Pharmaceutical compositions, including capsule and tablet dosage forms of ozanimod and / or salts thereof, are reported in, for example, US 11 ,117,875 B2, US 2020 / 0031784 A1 , and US 11 ,117,876 B2.

[0005] One consideration in the provision of a formulated ozanimod hydrochloride drug product is associated with the high potency of the drug substance given that the dose of ozanimod hydrochloride in the marketed ZEPOSIA® capsules ranges from 0.25 mg to 1 mg. There are several challenges associated with manufacturing high potency drug substances that are related to, for example, safe handling practices to avoid inadvertent exposures, achieving content uniformity or homogeneity within the formulated product, accurate determination of the drug content in unit doses, drug substanceexcipient compatibility in formulated products, and effectively demonstrating cleanliness of equipment at very low detection levels.

[0006] There exists a need for improved pharmaceutical compositions and dosage forms comprising ozanimod and pharmaceutically acceptable salt thereof which address the unique challenges associated with a potent drug substance.SUMMARY

[0007] The present disclosure provides, inter alia, convenient minitablet dosage forms comprising ozanimod, or a pharmaceutically acceptable salt thereof, which allow for use of a principal pharmaceutical composition to be used for several dosage strengths, and dosage forms such as capsules comprising the minitablets. Further provided are methods of treating multiple sclerosis and / or ulcerative colitis using the dosage forms.

[0008] Accordingly, in a first aspect of the present invention, there is provided a minitablet comprising a pharmaceutical composition of ozanimod, or a pharmaceutically acceptable salt thereof, wherein the composition comprises from about 0.05 mg to about 0.2 mg ozanimod, expressed as free base equivalent. In a preferred embodiment of the first aspect, the ozanimod, or pharmaceutically acceptable salt thereof, is ozanimod hydrochloride. In another preferred embodiment of the first aspect, the composition comprises about 0.125 mg ozanimod hydrochloride. In a further preferred embodiment of the first aspect, the composition comprises from about 1 % w / w to about 1.5% w / w ozanimod, or a pharmaceutically acceptable salt thereof; from about 90% w / w to about 95% w / w of a diluent; from about 3% w / w to about 10% w / w of a disintegrant; and from about 0.5% w / w to about 1 .5% w / w of a lubricant. Preferably, the diluent is a cellulose-based excipient, more preferably it is microcrystalline cellulose. Within this embodiment of the first aspect, the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch and mixtures thereof. Preferably, the disintegrant is croscarmellose sodium. Further preferred within this embodiment of the first aspect, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and zinc stearate. Preferably, the lubricant is magnesium stearate. In a further preferred embodiment of the first aspect, the weight of the minitablet is from about 5 mg to about 15 mg. Preferably, the weight of the minitablet is about 10 mg. In another preferred embodiment of the first aspect, the minitablet has a diameter from about 1 mm to about 4 mm. Preferably, the diameter is from of about 2 mm to about 2.5 mm.

[0009] In a second aspect of the present invention, there is provided a capsule comprising one or more minitablets of the first aspect. Preferably, the minitablet comprises about 0.125 mg ozanimod hydrochloride and the capsule comprises 2, 4, or 8 minitablets. In a further embodiment of the second aspect, 80% of the ozanimod hydrochloride in the capsule dissolves within 15 minutes in 500 mL of 0.01 N hydrochloric acid at 37 °C using USP Apparatus 1 set to 100 rpm.

[0010] In a third aspect of the present invention, there is provided use of a pharmaceutical composition comprising at least about 1 % w / w ozanimod, or a pharmaceutically acceptable salt thereof, for the preparation of a capsule strength selected from the group consisting of about 0.23 mg, about 0.46 mg and about 0.92 mg ozanimod free base equivalent. In a preferred embodiment of the third aspect, the capsule strength is about 0.23 mg ozanimod free base equivalent. In a further preferred embodiment of the third aspect, the capsule strength is about 0.46 mg ozanimod free base equivalent. In another preferred embodiment of the third aspect, the composition comprises from about 1 % w / w to about 1.5% w / w ozanimod, or a pharmaceutically acceptable salt thereof. In a still further preferred embodiment of the third aspect, the ozanimod or pharmaceutically acceptable salt thereof is ozanimod hydrochloride.

[0011] In a fourth aspect of the present invention, there is provided a method for the treatment of multiple sclerosis or ulcerative colitis comprising the administration of the minitablet of the first aspect or the capsule of the second aspect, to a human subject.

[0012] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.DETAILED DESCRIPTION

[0013] The present disclosure provides, inter alia, convenient minitablet dosage forms comprising ozanimod, or a pharmaceutically acceptable salt thereof, which allow for use of a principal pharmaceutical composition to be used for several dosage strengths and use of the minitablets in the preparation of further dosage forms such as capsules. Further provided are methods of treating multiple sclerosis and / or ulcerative colitis using the dosage forms.

[0014] As used herein, ozanimod is used as a free base or a pharmaceutically acceptable salt thereof. When a salt of ozanimod is used, the amount can be expressed as free base equivalent, or the amount of salt that corresponds with the same amount of free base form. For example, the amount of 0.25 mg, 0.5 mg, and 1 mg ozanimod hydrochloride expressed as ozanimod free base equivalent is 0.23 mg, 0.46 mg, and 0.92 mg, respectively.

[0015] As used herein, an “immediate-release” (IR) dosage form refers to a dosage form which when taken orally substantially provides the API in a more immediate time period, such as within about one hour. The term also refers to a dosage form in which no deliberate effort has been made to modify the API release rate (wherein a disintegrant is not considered a modification in the context of capsules and tablets). For example, the pharmaceutical compositions of the present invention are preferably provided as immediate-release solid oral capsule dosage forms.

[0016] As used herein, the term “% w / w” (% weight / weight) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weightunit, expressed as a percentage. For example, with respect to a composition comprising a mixture of components, % w / w refers to the ratio of the weight of a component (in mg) to the weight of the composition (in mg), expressed as a percentage.

[0017] As used herein, the term “ppm” (parts per million) refers to the ratio of the weight of a subject component to the weight of another component, using the same weight unit, multiplied by one million. For example, with respect to the amount of / V- nitrosoozanimod (OZN-NO) in the pharmaceutical compositions of the present invention, ppm refers to: (weight OZN-NO in mg / weight ozanimod free base in mg) x 1 ,000,000. When the ozanimod is present as the hydrochloride salt, the weight of ozanimod free base equivalent to the amount of hydrochloride salt is used unless otherwise noted.

[0018] As used herein, the singular form "a", "an", and "the" include plural references. For example, "an" excipient includes one or more excipients. As used herein, the term “about” means “close to” and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, when the term “about” is used with respect to a numerical value, the value may vary within a reasonable range, such as within + / -2%, or + / -1 % of the stated value. It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0019] Any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “90 to 95” is intended to include any and all sub-ranges between and including the recited minimum value of 90 and the recited maximum value of 95, that is, all subranges beginning with a minimum value equal to or greater than 90 and ending with a maximum value equal to or less than 95, and all subranges in between, e.g., 90 to 94.3, or 92.5 to 95, or 91 to 94.

[0020] A pharmaceutical composition, as used herein, refers to a mixture of ozanimod or a pharmaceutically acceptable salt thereof, optionally a second active ingredient, and pharmaceutically acceptable excipient(s), such as diluent(s), disintegrant(s), lubricant(s), and / or mixtures thereof. The pharmaceutical composition facilitates administration of an active ingredient to a human subject. The pharmaceutical composition is preferablyadministered orally, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. For example, the pharmaceutical composition is preferably administered orally in a solid dosage form for oral administration, such as a tablet or a capsule.

[0021] As used herein, the phrase “therapeutically effective amount” means that amount of ozanimod, or a pharmaceutically acceptable salt thereof, that will elicit a biological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing, or halting of progression of the condition or disease, including but not limited to multiple sclerosis and / or ulcerative colitis.

[0022] In one embodiment of the present disclosure, there is provided a solid pharmaceutical composition comprising: a) from about 1 % w / w to about 1.5% w / w ozanimod, or a pharmaceutically acceptable salt thereof; b) from about 90% w / w to about 95% w / w of a diluent; c) from about 3% w / w to about 10% w / w of a disintegrant; and d) from about 0.5% w / w to about 1 .5% w / w of a lubricant.

[0023] The ozanimod may be provided as a free base or a pharmaceutically acceptable salt thereof. Preferably, the composition comprises ozanimod hydrochloride. The composition may comprise from about 1 % w / w to about 1.5% w / w ozanimod hydrochloride, preferably the composition comprises about 1.25% w / w ozanimod hydrochloride.

[0024] The solid pharmaceutical composition comprises from about 90% w / w to about 95% w / w of a diluent. For example, the composition may comprise 90% w / w, 90.5% w / w, 91 % w / w, 91 .5% w / w, 92% w / w, 92.5% w / w, 93% w / w, 93.5% w / w, 94% w / w, 94.5% w / w, or 95% w / w of a diluent. Preferably, the composition comprises about 92.75% w / w of adiluent. Suitable diluents include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, calcium sulphate, xylitol, lactitol and cellulose-based diluents. Preferably, the composition comprises a cellulose-based diluent. Suitable cellulose-based diluents include, for example, microcrystalline cellulose and cellulose derivatives such as esters and ethers thereof. Examples of cellulose-based excipients include, but are not limited to, microcrystalline cellulose (e.g. Pharmacel®), methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl ethyl cellulose, cellulose acetate phthalate, hydroxyethyl cellulose and mixtures thereof. Preferably, the cellulose-based excipient is microcrystalline cellulose.

[0025] The solid pharmaceutical composition comprises from about 3% w / w to about 10% w / w of a disintegrant. For example, the composition may comprise 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w, 7% w / w, 7.5% w / w, 8% w / w 8.5% w / w, 9% w / w, 9.5% w / w or 10% w / w of a disintegrant. Preferably, the composition comprises about 5% w / w of a disintegrant. Suitable disintegrants include, for example, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, com starch and mixtures thereof. As used herein, “low-substituted hydroxypropyl cellulose” means a low- substituted hydroxypropyl ether of cellulose, which when dried at 105°C for 1 hour, contains not less than 5.0 percent and not more than 16.0 percent of hydroxypropyl groups (-OCH2CHOHCH3). Preferably, the disintegrant is croscarmellose sodium.

[0026] The solid pharmaceutical composition comprises from about 0.5% w / w to about 1 .5% w / w of a lubricant. For example, the composition may comprise 0.5% w / w, 1 % w / w, or 1.5% w / w of a lubricant. Preferably, the composition comprises about 1 % w / w of a lubricant. Suitable lubricants include, for example, magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chaintriglycerides, poloxamer, polyethylene glycol and talc. Preferably, the lubricant is magnesium stearate.

[0027] Other excipients suitable for use in oral solid dosage forms, including preservative(s), stabiliser(s), silica based flow enhancer anti-adherent(s), and / or glidant(s) as described generally, for example, in Remington The Science and Practice of Pharmacy 21 st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45) may be added as required.

[0028] The pharmaceutical composition may be provided as a solid dosage form suitable for oral administration, such as a tablet, capsule, powder / particle, pellet, minitablet, and / or granule. In such form, the composition is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 0.001 mg / kg to about 1 mg / kg of body weight / day of ozanimod, or a pharmaceutically acceptable salt thereof. Preferably, the solid dosage form is a hard-gelatin capsule, comprising a composition of ozanimod hydrochloride and pharmaceutically acceptable excipients. Preferably, the amount of ozanimod, or salt thereof, present in the dosage form is equivalent to from about 0.1 mg to about 2 mg, or about 0.1 mg, or about 0.2 mg, or about 0.25 mg, or about 0.3 mg, or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about 0.8 mg, or about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3 mg, or about 1.4 mg, or about 1.5 mg, or about 1.6 mg, or about 1.7 mg, or about 1.8 mg, or about 1.9 mg, or about 2.0 mg of ozanimod hydrochloride. Preferably, a principal pharmaceutical composition is used to provide a solid dosage form comprising different strengths of ozanimod, or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition is used to provide a solid dosage form comprising 0.25 mg, 0.5 mg, or 1.0 mg of ozanimod hydrochloride that is considered bioequivalent to the respective branded 0.25 mg, 0.5 mg, or 1 .0 mg ZEPOSIA® drug products.

[0029] Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings andextended release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 46).

[0030] In a second embodiment of the present disclosure, there is provided a minitablet comprising ozanimod, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient(s).

[0031] The minitablet preferably comprises the solid pharmaceutical composition comprising ozanimod, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient(s) according to the first embodiment herein.

[0032] The minitablet dimensions may be expressed as the diameter along the longest axis. Preferably, the diameter of the minitablet may be from about 1 mm to about 4 mm, more preferably the diameter is from about 2 mm to about 2.5 mm.

[0033] The minitablet may have a weight from about 5 mg to about 15 mg, preferably the weight is about 10 mg, most preferably, the weight is 10 mg. The minitablet may comprise ozanimod, or a pharmaceutically acceptable salt thereof, that is equivalent to an amount of from about 0.05 mg to about 0.5 mg of ozanimod free base. Preferably, the minitablet comprises ozanimod, or a pharmaceutically acceptable salt thereof, that is equivalent to an amount of from about 0.05 mg to about 0.2 mg of ozanimod free base. More preferably, the minitablet comprises about 0.125 mg ozanimod hydrochloride (equivalent to 0.115 mg ozanimod free base).

[0034] In a third embodiment of the present disclosure, there is provided a capsule comprising one or more minitablets.

[0035] The capsule preferably comprises one or more of the minitablets according to the second embodiment herein. For example, a capsule may comprise one or more minitablets, each minitablet comprising a dose of ozanimod or a pharmaceutically acceptable salt thereof, equivalent to from about 0.115 mg to about 0.46 mg ozanimod free base, or equivalent to from about 0.115 mg to about 0.92 mg ozanimod free base.For example, a capsule may comprise 2 minitablets, each minitablet comprising about 0.125 mg ozanimod hydrochloride, providing a dose of about 0.25 mg ozanimod hydrochloride (equivalent to 0.23 mg ozanimod free base). Additionally, a capsule may comprise 4 minitablets, each minitablet comprising about 0.125 mg ozanimod hydrochloride, providing a dose of about 0.5 mg ozanimod hydrochloride (equivalent to 0.46 mg ozanimod free base). Further, a capsule may comprise 8 minitablets, each minitablet comprising about 0.125 mg ozanimod hydrochloride, providing a dose of about 1 mg ozanimod hydrochloride (equivalent to 0.92 mg ozanimod free base).

[0036] Preferably, a capsule comprising two or more minitablets, each minitablet comprising the equivalent of 0.115 mg ozanimod free base, provides a dose of 0.23 mg, 0.46 mg, or 0.92 mg of ozanimod that is considered bioequivalent to the respective branded 0.23 mg, 0.46 mg, or 0.92 mg of ozanimod in ZEPOSIA®.

[0037] Conveniently, the present invention allows use of a principal pharmaceutical composition having a fixed ratio of ozanimod, or a pharmaceutical salt thereof, with respect to excipient(s), to prepare a standard base unit minitablet such as a minitablet comprising 0.125 mg ozanimod hydrochloride. A suitable dose for administration can be provided by using one or more units of the minitablet in a capsule dosage form. Rather than maintain a conventional minimum capsule fill weight of, for example, 100 mg across all three dosage strengths, the minitablet format of the present invention allows for production of capsules having variable fill weights of 20 mg, 40 mg and 80 mg corresponding with the 0.25 mg, 0.5 mg and 1 mg respective dosage strengths of ozanimod hydrochloride. Compared to a capsule having a fill weight of 100 mg and an amount of ozanimod hydrochloride of 0.25 mg (0.25% w / w ozanimod hydrochloride), capsules comprising the minitablets of the present invention provide a dosage form having a five fold lower excipient-to-drug ratio of 1 .25% w / w ozanimod hydrochloride.

[0038] Maintaining a minimum fixed ratio of ozanimod, or a pharmaceutical salt thereof, with respect to excipient(s), such as for example 1.25% w / w ozanimod hydrochloride, may help to mitigate stability concerns arising from higher excipient-to- drug ratios. For example, as a secondary amine, ozanimod has the potential to undergo / V-nitrosation to generate (‘ / V-nitrosoozanimod’) of formula OZN-NO:

[0039] Impurities, such as / V-nitrosoozanimod, have been observed in conventional powder-filled capsule pharmaceutical drug products comprising ozanimod hydrochloride such as Zeposia® capsules.

[0040] Preferably, the pharmaceutical compositions and dosage forms of the present disclosure comprise no more than about 435 ppm, more preferably no more than about 200 ppm of / V-nitrosoozanimod with respect to ozanimod free base. Based on the FDA guidance document ‘Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities’ (August 2023) and further related ‘Table 1 : FDA Recommended Al Limits for Certain Hypothetical NDSRIs Based on Predicted Carcinogenic Potency Categorization’ (March 5, 2024), the recommended allowable intake (Al) for / V-nitrosoozanimod, is 400 ng / day. Since the maximum recommended human dose of ozanimod is 0.92 mg / day, a limit of 435 ppm of / V-nitrosoozanimod would limit exposure to within the recommended allowable intake as per the FDA guidance. Preferably, in the pharmaceutical compositions and dosage forms of the present disclosure, the levels of / V-nitrosoozanimod are no more than about 200 ppm, no more than about 100 ppm, no more than about 50 ppm or no more than about 25 ppm with respect to ozanimod free base after storage for 1 month at 25 °C, 60% relative humidity, for 2 months at 25 °C, 60% relative humidity, for 3 months at 25 °C, 60% relative humidity, for 4 months at 25 °C, 65% relative humidity, for 5 months at 25 °C, 60% relative humidity, for 6 months at 25 °C, 60% relative humidity and / or for 12 months at 25 °C, 60% relative humidity. Preferably, in the pharmaceutical compositions and dosage forms of the present disclosure, the levels of / V-nitrosoozanimod are no more than about 50 ppm with respect to ozanimod free base after storage for 12 months at 25 °C, 60% relative humidity.EXAMPLES

[0041] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein. The ozanimod hydrochloride used in the following examples was crystalline and had 0.65 ppm of OZN-NO impurity with respect to ozanimod free base. According to a white paper, the Pharmacel® 102 brand microcrystalline cellulose as used in the following examples contains <0.1 ppm nitrite and 0.8 ppm nitrate (Berardi, Alberto; Janssen, Pauline H.M; Dickhoff, Bastiaan, H.J., Sander van Gessel. “Nitrosamines Risk Mitigation.” DFE Pharma. Accessed 1 Feb. 2023).Analysis Method for Determining Impurity / V-nitrosoozanimod in Ozanimod Capsules

[0042] The method shown in Table 1 was used to quantify the amount of impurity / V- nitrosoozanimod (OZN-NO) in ozanimod capsules prepared in the examples that follow.* These parameters can be adjusted to achieve the adequate sensitivity to meet the criteria of system suitability.Example 1 : Preparation of Minitablets and Capsules

[0043] Immediate-release minitablets and capsules were prepared comprising ozanimod hydrochloride and the excipients shown in Table 2.$Mintablet*The quantity of ozanimod hydrochloride will be adjusted on ‘As-is’ assay value and compensated with Microcrystalline Cellulose Pharmacel 102 (Part 1 ).#Each minitablet contains 0.125 mg ozanimod hydrochloride equivalent to 0.115 mg ozanimod free base** 0.25 mg Ozanimod hydrochloride is equivalent to 0.23 mg ozanimod free base***0.50 mg Ozanimod hydrochloride is equivalent to 0.46 mg ozanimod free base****1.00 mg Ozanimod hydrochloride is equivalent to 0.92 mg ozanimod free baseAEach capsule of 0.23 mg strength contains 2 minitablets in a capsuleAAEach capsule of 0.46 mg strength contains 4 minitablets in a capsuleAAAEach capsule of 0.92 mg strength contains 8 minitablets in a capsule

[0044] The minitablets and capsules were manufactured using the components shown in Table 2 according to the following steps:1 ) About half of the microcrystalline cellulose (part 1 ), ozanimod hydrochloride and the remainder of the microcrystalline cellulose (part 1 ) were loaded into a bin and blended;2) Croscarmellose sodium and microcrystalline cellulose (part 2) was loaded into the bin from step 1 ) and the contents blended;3) The blended materials were then passed through a sizing screen using a Quadro Comil;4) The milled material from step 3) was loaded into a bin and blended;5) Steps 3) and 4) were repeated;6) The blended materials from step 5) were compacted and loaded into a bin;7) Hand-screened magnesium stearate was loaded into the bin from step 6) containing the compacted granules and the contents were blended;8) The blend from step 7) was compressed into minitabets;9) The minitablets were encapsulated into empty hard gelatin capsules.10)The filled capsules were packaged into either HDPE bottles with dessicant (0.92 mg capsule) or PVC / ACLAR clear blisters (0.23 mg and 0.46 mg capsules).

[0045] A dissolution study was conducted comparing 0.23 mg, 0.46 mg, and 0.92 mg ZEPOSIA® (‘RLD’) capsules with 0.23 mg, 0.46 mg, and 0.92 mg APO capsules containing 2, 4 and 8 minitablets, respectively and having the composition shown in Table 2. The dissolution testing was conducted in 500 mL of 0.01 N hydrochloric acid at 37 °C using USP Apparatus 1 set to 100 rpm. The results are provided in Table 2A.Example 2: Levels of / V-Nitrosoozanimod in Ozanimod Capsules

[0046] Packaged capsules prepared according to Example 1 were analysed for the presence of OZN-NO (ppm) with respect to ozanimod free base initially and following storage under ambient conditions (25 °C / 60% RH) for 12 months. The levels of OZN-NO in commercially obtained branded capsules ZEPOSIA® that were within shelf life were also analysed. The results are reported in Table 3.Table 3: Levels of OZN-NO in Packaged Capsules of Ozanimod HCI*Capsules were packaged as follows: 10 x 10 count, PVC / ACLAR Clear Blisters.**Capsules were packaged as follows: 30 count, 60CC heavy-weight HDPE bottles, dessicant: 2G Silica Gel StripPax.*** According to U.S. CDER Product Quality Review 2098990rig1s000, the shelf life of Zeposia 0.92 mg capsules is 36 months when stored at controlled room temperature.BQL: Below Quantitation Limit.Limit of Quantitation: 25 ppm.

Claims

What is claimed is:

1. A minitablet comprising a pharmaceutical composition of ozanimod, or a pharmaceutically acceptable salt thereof, wherein the composition comprises from about 0.05 mg to about 0.2 mg ozanimod, expressed as free base equivalent.

2. The minitablet of claim 1 , wherein the composition comprises from about 0.1 mg to about 0.15 mg ozanimod, or a pharmaceutically acceptable salt thereof, expressed as free base equivalent.

3. The minitablet of claim 1 , wherein the ozanimod, or pharmaceutically acceptable salt thereof, is ozanimod hydrochloride.

4. The minitablet of claim 3, wherein the composition comprises about 0.125 mg ozanimod hydrochloride.

5. The minitablet of any one of claims 1 to 4, wherein the composition comprises: a) from about 1 % w / w to about 1 .5% w / w ozanimod, or a pharmaceutically acceptable salt thereof; b) from about 90% w / w to about 95% w / w of a diluent; c) from about 3% w / w to about 10% w / w of a disintegrant; and d) from about 0.5% w / w to about 1 .5% w / w of a lubricant.

6. The minitablet of claim 5, wherein the diluent is a cellulose-based excipient.

7. The minitablet of claim 6, wherein the cellulose-based excipient is microcrystalline cellulose.

8. The minitablet of any one of claims 5 to 7, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, com starch and mixtures thereof.

9. The minitablet of any one of claims 5 to 8, wherein the disintegrant is croscarmellose sodium.

10. The minitablet of any one of claims 5 to 9, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and zinc stearate.

11. The minitablet of any one of claims 5 to 10, wherein the lubricant is magnesium stearate.

12. The minitablet of any one of claims 1 to 11 , wherein the weight of the minitablet is from about 5 mg to about 15 mg.

13. The minitablet of claim 12, wherein the weight of the minitablet is about 10 mg.

14. The minitablet of any one of claims 1 to 13, wherein the minitablet has a diameter from about 1 mm to about 4 mm.

15. The minitablet of claim 14, wherein the minitablet has a diameter from about 2 mm to about 2.5 mm.

16. A capsule comprising one or more minitablets of any one of claims 1 to 15.

17. The capsule of claim 16, wherein the minitablet comprises about 0.125 mg ozanimod hydrochloride and the capsule comprises 2, 4, or 8 minitablets.

18. The capsule of claim 17, wherein 80% of the ozanimod hydrochloride in the capsule dissolves within 15 minutes in 500 mL of 0.01 N hydrochloric acid at 37 °C using USP Apparatus 1 set to 100 rpm.

19. Use of a pharmaceutical composition comprising at least about 1 % w / w ozanimod, or a pharmaceutically acceptable salt thereof, for the preparation of a capsule strength selected from the group consisting of about 0.23 mg, about 0.46 mg and about 0.92 mg ozanimod free base equivalent.

20. The use of claim 19, wherein the capsule strength is about 0.23 mg ozanimod free base equivalent.21 . The use of claim 19, wherein the capsule strength is about 0.46 mg ozanimod free base equivalent.

22. The use of any one of claims 19 to 21 , wherein the composition comprises from about 1 % w / w to about 1.5% w / w ozanimod, or a pharmaceutically acceptable salt thereof.

23. The use of any one of claims 19 to 22, wherein the ozanimod or pharmaceutically acceptable salt thereof is ozanimod hydrochloride.

24. A method for the treatment of multiple sclerosis or ulcerative colitis comprising the administration of the minitablet of any one of claims 1 to 15, or the capsule of any one of claims 16 to 18, to a human subject in a therapeutically effective amount for the treatment of multiple sclerosis or ulcerative colitis.

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