Ozanimod hydrochloride capsule and preparation method thereof

Abstract

The invention provides an ozanimod hydrochloride capsule and a preparation method thereof. The ozanimod hydrochloride capsule provided by the invention is prepared from ozanimod hydrochloride, colloidal silicon dioxide, microcrystalline cellulose (PH-105), microcrystalline cellulose (PH-112) and other auxiliary materials, the colloidal silicon dioxide and the microcrystalline cellulose (PH-105) are added in the first-step mixing process, and the addition amount of the colloidal silicon dioxide and the microcrystalline cellulose (PH-105) is controlled, so that the problems of mixing uniformity and content uniformity of a small-dose drug, especially a small-dose drug with the drug content of less than 1%, are solved, the quality control is improved, and the dosage of the drug is reduced. The ozanimod hydrochloride capsule prepared by the preparation method disclosed by the invention has the advantages that the dissolution rate and the in-batch dissolution uniformity of the ozanimod hydrochloride capsule in water and a medium with the pH value of 6.8 are improved, the bioavailability of the preparation is improved, the individual difference is reduced, and the medication safety is improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations and relates to an ozanimod hydrochloride preparation, and in particular to an ozanimod hydrochloride capsule and a preparation method thereof. Background Art

[0002] Ozanimod hydrochloride is chemically named 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile hydrochloride, with a molecular formula of C 23 H 24 N4O3·HCl, molecular weight is 440.92, chemical structure is

[0003]

[0004] Ozanimod hydrochloride is an orally effective sphingosine-1-phosphate (S1P) receptor modulator that selectively binds to S1P receptor subtype 1 (S1P1) and subtype 5 (S1P5) with high affinity. On March 25, 2020, the FDA approved the marketing of Ozanimod hydrochloride capsules from Bristol-Myers Squibb (BMS) in the United States, with the trade name: ZEPOSIA, specifications: 0.23mg, 0.46mg, 0.92mg (calculated as Ozanimod), for the treatment of relapsing multiple sclerosis. In May 2021, the FDA again approved Ozanimod hydrochloride capsules for the treatment of ulcerative colitis in adults. On January 31, 2023, Ozanimod hydrochloride capsules were approved for marketing in China, with the trade name of Therposia.

[0005] Ozamod hydrochloride is a small-scale, highly active drug that is extensively metabolized in the human body to form many circulating active metabolites, including two major active metabolites CC112273 and CC1084037. The activity of these two metabolites and their selectivity for S1P1 and S1P5 are similar to those of the parent drug. After multiple doses, about 94% of the total circulating active substances are ozanimod (6%), CC112273 (73%) and CC1084037 (15%). In patients with relapsing multiple sclerosis (RMS), the model-based average effective half-life of the metabolite CC112273 is about 11 days, and the accumulation ratio is about 16. RMS patients require long-term drug maintenance treatment, and metabolites with high accumulation ratios are prone to accumulation in the body, increasing adverse drug reactions, and may even cause poisoning. Therefore, drugs such as Ozamod hydrochloride that are small in size, highly active, and have a high metabolite accumulation ratio have very high requirements for product content uniformity and dissolution uniformity. Differences in content and dissolution of preparations have a great impact on the efficacy and safety of the drug.

[0006] Existing Ozamod hydrochloride capsules have the defects of high process difficulty and poor quality controllability. The specifications of Ozamod hydrochloride capsules are very small, and it is very easy to have uneven material mixing and unqualified content uniformity of the preparation during the preparation process. In addition, the commercially available Ozamod hydrochloride capsules (Therposcia) dissolve slowly in water and pH 6.8 medium, and the intra-batch uniformity is poor, which affects the bioavailability, efficacy and drug safety of the preparation.

[0007] Therefore, it is necessary to provide a preparation process for Ozamod hydrochloride capsules with a simple and controllable process, uniform preparation content, rapid dissolution and high dissolution uniformity. Summary of the invention

[0008] The purpose of the present invention is to solve the technical problems in the prior art regarding uneven content of Ozamod hydrochloride preparations, slow dissolution in some media, and poor batch uniformity, and to provide an Ozamod hydrochloride capsule with uniform content, rapid dissolution, simple and easy-to-control process, suitable for industrial and fully enclosed production and a preparation method thereof. The present invention provides an Ozamod hydrochloride capsule, comprising: Ozamod hydrochloride, colloidal silicon dioxide, microcrystalline cellulose (PH-105), microcrystalline cellulose (PH-112), a disintegrant and a lubricant; the Ozamod hydrochloride capsule, with 0.25 mg as 1 mass portion, has the following contents of each component:

[0009]

[0010] The preparation method of the Ozamod hydrochloride capsules is as follows:

[0011] First, ozanimod hydrochloride is premixed with colloidal silicon dioxide and microcrystalline cellulose (PH-105), sieved and mixed (first step of mixing), then microcrystalline cellulose (PH-112) and disintegrant are added, mixed again (second step of mixing), and finally lubricant is added and mixed (total mixing), and then capsules are filled.

[0012] As a preferred technical solution, the particle size of Ozamod hydrochloride is D90≤90μm and D50≤20μm.

[0013] As a preferred technical solution, the amount of colloidal silicon dioxide is 2-3 parts by mass, i.e. 0.5 mg to 0.75 mg.

[0014] As a preferred technical solution, the amount of colloidal silicon dioxide is 2 parts by mass, i.e. 0.5 mg.

[0015] As a preferred technical solution, the amount of microcrystalline cellulose (PH-105) is 30-40 parts by weight, that is, 7.5 mg to 10 mg.

[0016] As a preferred technical solution, the amount of microcrystalline cellulose (PH-105) is 40 parts by mass, i.e. 10 mg.

[0017] As a preferred technical solution, the mesh aperture is 0.4 mm-0.5 mm.

[0018] As a preferred technical solution, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate.

[0019] The mixing uniformity RSD value of the total mixed material of the Ozamod hydrochloride capsules prepared by the present invention is less than or equal to 3.0%.

[0020] The content uniformity A+2.2S value of Ozamod hydrochloride in the Ozamod hydrochloride capsules prepared by the present invention is less than or equal to 6.4, which is better than the content uniformity of the commercially available Ozamod hydrochloride capsules.

[0021] The Ozamod hydrochloride capsules prepared by the present invention are rapidly dissolved in various media and have good intra-batch uniformity, especially in water and pH 6.8 media, and the dissolution is better than that of the commercially available Ozamod hydrochloride capsules.

[0022] The present invention also provides a method for preparing any one of the aforementioned Ozamod hydrochloride capsules, comprising the following steps:

[0023] (1) Premix ozanimod hydrochloride with 0.5 mg to 1 mg of colloidal silicon dioxide and 5 mg to 10 mg of microcrystalline cellulose (PH-105), pass through a sieve with a pore size of 0.4 to 0.5 mm, and mix for 15 to 20 minutes;

[0024] (2) Add microcrystalline cellulose (PH-112) and disintegrant and mix for 15-20 minutes;

[0025] (3) Add lubricant and mix for 3-5 minutes;

[0026] (4) Filling capsules.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The present invention controls the addition steps and addition amounts of colloidal silicon dioxide and microcrystalline cellulose (PH-105), so that the prepared ozanimod hydrochloride total mixed material has high mixing uniformity and uniform content of active ingredients in the preparation, thereby improving the safety of patient medication and quality controllability.

[0029] 2. The solubility of the Ozamod hydrochloride capsules prepared by the technical solution of the present invention in water and pH 6.8 medium is greatly improved, and the dissolution batch uniformity is also significantly improved, which can improve the bioavailability of the Ozamod hydrochloride capsules, reduce individual differences, and improve the safety of medication.

[0030] 3. The technical solution of the present invention has simple process, is easy to control, and is suitable for industrial and fully enclosed production. DETAILED DESCRIPTION

[0031] The colloidal silica used in the present invention is purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd., and the specific model is AEROSIL 200. The remaining raw materials and auxiliary materials are all common commercially available products. The particle size of Ozamod hydrochloride is D 90 ≤90μm, D 50 ≤20μm.

[0032] There are three specifications of Ozamod hydrochloride capsules available on the market: 0.23 mg, 0.46 mg and 0.92 mg, and the weight of the capsule contents is 100 mg. Obviously, compared with the other two specifications, the 0.23 mg specification is the most difficult to mix and is most likely to have content uniformity problems. Therefore, the present invention selects an embodiment of the 0.23 mg specification to illustrate the advantages of the invention, and controls the weight of the capsule contents to be 100 mg by fine-tuning the prescription amount of microcrystalline cellulose (PH-112).

[0033] The specific formulas of Examples 1-3 are shown in Table 1.

[0034] Table 1 Prescription of Examples 1-3

[0035]

[0036] Example 1-3 Preparation method:

[0037] Ozamod hydrochloride, colloidal silicon dioxide (AEROSIL 200) and microcrystalline cellulose (PH-105) are placed in a mixing barrel, premixed at a speed of 20 rpm for 2 minutes, and discharged. Sieve with a crushing and granulating machine, use a sieve with an aperture of 0.4 mm, and set the speed to 300 rpm. The sieved material is placed in a mixing barrel again and mixed at a speed of 20 rpm for 15 minutes. Microcrystalline cellulose (PH-112) and cross-linked sodium carboxymethyl cellulose are added and mixed at a speed of 20 rpm for 15 minutes. Magnesium stearate is added and mixed at a speed of 20 rpm for 3 minutes. For capsule filling, use No. 4 gelatin hollow capsules.

[0038] The specific formulas of Examples 4-7 are shown in Table 2.

[0039] Table 2 Prescriptions for Examples 4-7

[0040]

[0041]

[0042] The preparation methods of Examples 4-7 are the same as those of Example 1.

[0043] In order to better illustrate the advantages of the present invention, 10 groups of comparative examples were set up with reference to the Ozamod hydrochloride capsules and preparation method thereof of Example 1.

[0044] The specific formulas of Comparative Examples 1-7 are shown in Table 3.

[0045] Table 3 Comparative Examples 1-7 Prescription

[0046]

[0047] Comparative Examples 1-7 Preparation Method:

[0048] Comparative Example 1: The preparation method is the same as that of Example 1.

[0049] Comparative Example 2: Ozamod hydrochloride and microcrystalline cellulose (PH-105) are placed in a mixing barrel, premixed at a speed of 20rpm for 2min, and discharged. Screened with a crushing granulator, using a sieve with an aperture of 0.4mm, and setting a speed of 300rpm. The sieved material is placed in a mixing barrel again and mixed at a speed of 20rpm for 15min. Microcrystalline cellulose (PH-112), colloidal silicon dioxide (AEROSIL 200) and cross-linked sodium carboxymethyl cellulose are placed in a mixing barrel, premixed at a speed of 20rpm for 2min, discharged, and sieved with a crushing granulator, using a sieve with an aperture of 0.8mm, and setting a speed of 300rpm. The sieved material is placed in a mixing barrel again and mixed at a speed of 20rpm for 15min. Magnesium stearate is added and mixed at a speed of 20rpm for 3min. Capsules are filled using No. 4 gelatin hollow capsules.

[0050] Comparative Example 3: Ozamod hydrochloride and microcrystalline cellulose (PH-105) are placed in a mixing barrel, premixed at a speed of 20rpm for 2min, and discharged. Screened with a crushing granulator, using a sieve with an aperture of 0.4mm, and setting a speed of 300rpm. The sieved material is placed in a mixing barrel again and mixed at a speed of 20rpm for 15min. Microcrystalline cellulose (PH-112) and cross-linked sodium carboxymethyl cellulose are added and mixed at a speed of 20rpm for 15min. Colloidal silicon dioxide (AEROSIL 200) is added, premixed at a speed of 20rpm for 2min, discharged, sieved with a crushing granulator, using a sieve with an aperture of 0.8mm, and setting a speed of 300rpm. The sieved material is placed in a mixing barrel again, magnesium stearate is added, and mixed at a speed of 20rpm for 3min. Capsules are filled with No. 4 gelatin hollow capsules.

[0051] Comparative Example 4: The preparation method is the same as that of Example 1.

[0052] Comparative Example 5: Ozamod hydrochloride, talc and microcrystalline cellulose (PH-105) are placed in a mixing barrel, premixed at a speed of 20rpm for 2min, and discharged. Sieve with a crushing and granulating machine, use a sieve with an aperture of 0.4mm, and set the speed to 300rpm. The sieved material is placed in a mixing barrel again and mixed at a speed of 20rpm for 15min. Microcrystalline cellulose (PH-112) and cross-linked sodium carboxymethyl cellulose are added and mixed at a speed of 20rpm for 15min. Magnesium stearate is added and mixed at a speed of 20rpm for 3min. Capsules are filled using No. 4 gelatin hollow capsules.

[0053] Comparative Example 6: The preparation method is the same as that of Example 1.

[0054] Comparative Example 7: The preparation method is the same as that of Example 1.

[0055] Comparative Example 8 is a commercially available Ozamod hydrochloride capsule, manufacturer: Celgene International Sarl; trade name: Batch number: K2044AA, specification: 0.23mg.

[0056] Comparative Example 9 is a commercially available Ozamod hydrochloride capsule, manufacturer: Celgene International Sarl; trade name: Batch number: K2044AA, specification: 0.46mg.

[0057] Comparative Example 10 is a commercially available Ozamod hydrochloride capsule, manufacturer: Celgene International Sarl; trade name: Batch number: J2118BA, specification: 0.92mg.

[0058] Test Example 1: Mixing uniformity and content uniformity

[0059] After the total mixing process of Examples 1-7 and Comparative Examples 1-7 was completed, samples were taken from 11 different positions of the mixing barrel for the investigation of mixing uniformity. The specific sampling method refers to the "Technical Guiding Principles for the Study of Mixing Uniformity and Central Control Dosage Unit Uniformity of Chemical Oral Solid Preparations".

[0060] Take an appropriate amount of the above-mentioned total mixed material, and test it according to the method under the content determination item of the registration standard for imported drugs of Ozamod Hydrochloride Capsules (JX20230003), and calculate the RSD value of the mixing uniformity of each total mixed material, with a limit of 5.0% (Technical Guidelines for Research on Mixing Uniformity and Central Control Dose Unit Uniformity of Chemical Oral Solid Preparations).

[0061] The Ozamod hydrochloride capsules prepared in Examples 1-7 and Comparative Examples 1-7, as well as the commercially available Ozamod hydrochloride capsules of Comparative Examples 8-10, were tested according to the method under the content uniformity item of the registration standard for imported drugs for Ozamod hydrochloride capsules (JX20230003), and the content uniformity A+2.2S value of each capsule was calculated, with a limit of 15.0 (General Rules of Part Four of the 2020 Edition of the Chinese Pharmacopoeia 0941).

[0062] The RSD values ​​of the mixing uniformity of the total mixed materials of each embodiment and comparative example and the content uniformity A+2.2S value of the capsules are shown in Table 4.

[0063] Table 4 Results of mixing uniformity (RSD value) and content uniformity (A+2.2S value)

[0064] sample RSD(%) A+2.2S Example 1 1.8 4.1 Example 2 2.4 5.4 Example 3 2.2 5.0 Example 4 2.9 6.4 Example 5 2.6 5.8 Example 6 1.6 3.5 Example 7 1.3 2.8 Comparative Example 1 5.5 13.5 Comparative Example 2 6.6 15.6 Comparative Example 3 6.5 15.3 Comparative Example 4 3.9 9.6 Comparative Example 5 4.5 11.4 Comparative Example 6 6.8 16.0 Comparative Example 7 6.4 15.1 Comparative Example 8 / 8.0 Comparative Example 9 / 7.2 Comparative Example 10 / 6.8

[0065] It can be seen from the results in the above table that the mixing uniformity of the total mixed materials prepared in Examples 1-7 and the content uniformity of the capsules both achieve the expected technical effects well, and the content uniformity is better than that of the commercially available capsules in Comparative Examples 8-10.

[0066] Compared with Example 1, the amount of colloidal silicon dioxide added in Comparative Example 1 is less, the flow-aiding effect is poor, and the improvement of the mixing uniformity of the total mixed material and the uniformity of the capsule content is not ideal.

[0067] Compared with Example 1, the amount of colloidal silicon dioxide added in Comparative Examples 2-3 is the same, but it is added in the second mixing process and the total mixing process respectively. Since the particle sizes of Ozamod hydrochloride and microcrystalline cellulose (PH-105) are very fine in the first mixing process, the material fluidity is poor, and the mixing effect is general without adding a glidant. Even if colloidal silicon dioxide is added in the second mixing process or the total mixing process, it also affects the mixing uniformity of the total mixed material and the content uniformity of the capsule.

[0068] Compared with Example 1, the amount of colloidal silicon dioxide added in Comparative Example 4 is greater. The results show that the more times the colloidal silicon dioxide is added, the better.

[0069] Compared with Example 1, in Comparative Example 5, talcum powder was selected as the glidant, but the effect was obviously inferior to that of colloidal silicon dioxide.

[0070] In Comparative Example 6, compared with Example 1, the amount of microcrystalline cellulose (PH-105) added is less, and the dilution effect on Ozamod hydrochloride is poor, which affects the mixing uniformity of the first step mixing process, thereby affecting the mixing uniformity of the total mix and the content uniformity of the capsules.

[0071] In Comparative Example 7, compared with Example 1, the amount of microcrystalline cellulose (PH-105) added is higher, and Ozamod hydrochloride cannot be evenly mixed in the excess microcrystalline cellulose (PH-105), resulting in poor mixing uniformity of the total blend and poor content uniformity of the capsules.

[0072] Test Example 2: Dissolution curve

[0073] The Ozamod hydrochloride capsules prepared in Examples 1, 6, and 7 and the commercially available capsules of Comparative Examples 8-10 were tested according to the method under the dissolution item of the registration standard for imported drugs for Ozamod hydrochloride capsules (JX20230003), with 0.01N hydrochloric acid solution, pH 4.5 acetic acid-sodium acetate buffer, pH 6.8 phosphate buffer and water as dissolution media, respectively. The cumulative dissolution percentage and the intra-batch dissolution uniformity (RSD / %, n=12) were calculated, and the results are shown in Tables 5-8 below.

[0074] Table 5 Dissolution data in 0.01N hydrochloric acid solution

[0075]

[0076]

[0077] Table 6 Dissolution data in pH 4.5 acetic acid-sodium acetate buffer

[0078]

[0079] Table 7 Dissolution data in pH 6.8 phosphate buffer

[0080]

[0081] Table 8 Dissolution data in water

[0082]

[0083]

[0084] The above experimental results show that:

[0085] The Ozamod hydrochloride capsules prepared in Examples 1, 6, and 7 are rapidly dissolved in the four dissolution media, and the dissolution batch uniformity is good. In particular, in aqueous media and pH 6.8 phosphate buffer, the dissolution rate is significantly faster than that of the commercially available capsules of Comparative Examples 8-10, and the dissolution batch uniformity is significantly better than that of the commercially available capsules. This shows that the present invention can significantly improve the dissolution rate and dissolution batch uniformity of Ozamod hydrochloride in these two media, which is beneficial to the improvement of bioavailability and the quality control of the preparation.

Claims

1. An Ozamod hydrochloride capsule, comprising: Ozamod hydrochloride, colloidal silicon dioxide, microcrystalline cellulose PH-105, microcrystalline cellulose PH-112, disintegrant and lubricant; The Ozamod hydrochloride capsules, with 0.25 mg as 1 mass portion, have the following contents of each component: The preparation method of the Ozamod hydrochloride capsules is as follows: First, ozanimod hydrochloride, colloidal silicon dioxide and microcrystalline cellulose PH-105 are premixed, sieved and mixed in the first step; then microcrystalline cellulose PH-112 and disintegrant are added and mixed in the second step; finally, lubricant is added and mixed, and capsules are filled.

2. The Ozamod hydrochloride capsule according to claim 1, characterized in that The particle size of Ozamod hydrochloride is D 90 ≤90μm, D 50 ≤20μm.

3. The Ozamod hydrochloride capsule according to claim 1, characterized in that The colloidal silicon dioxide is used in an amount of 2-3 parts by mass.

4. The Ozamod hydrochloride capsule according to claim 3, characterized in that The colloidal silicon dioxide is used in an amount of 2 parts by mass.

5. The Ozamod hydrochloride capsule according to claim 1, characterized in that The amount of microcrystalline cellulose PH-105 is 30-40 parts by weight.

6. The Ozamod hydrochloride capsule according to claim 5, characterized in that The amount of microcrystalline cellulose PH-105 used is 40 parts by weight.

7. The Ozamod hydrochloride capsule according to claim 1, characterized in that The sieve mesh aperture is 0.4 mm to 0.5 mm.

8. The Ozamod hydrochloride capsule according to claim 1, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium.

9. The Ozamod hydrochloride capsule according to claim 1, characterized in that The lubricant is magnesium stearate.

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