Relecotinib composition and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition of rucotinib and or pharmaceutically acceptable salts thereof and application of the composition.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a composition of ruxolitinib and / or a pharmaceutically acceptable salt thereof and uses thereof. Background Art

[0002] Ruxolitinib (also known as Ruxolitinib, Ruxolitinib), its chemical name is (R)-3-cyclopentyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile, and its phosphate structure is as follows:

[0003]

[0004] This product is a JAK1 and JAK2 tyrosinase inhibitor used for adult patients with intermediate-risk or high-risk primary myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis), myelofibrosis secondary to polycythemia vera (PPV-MF) or myelofibrosis secondary to primary thrombocytosis (PET-MF), and can treat splenomegaly or other symptoms associated with the above diseases.

[0005] Ruxolitinib phosphate cream was approved by the U.S. FDA in September 2021 for marketing under the trade name OPZELURA for short-term and discontinuous treatment of mild to moderate atopic dermatitis. It was approved for the treatment of vitiligo in July 2022.

[0006] CN103214483B discloses a patent for a compound of ruxolitinib and its phosphate; CN103002875B discloses a patent for a topical preparation of ruxolitinib and its phosphate, which comprises water, an oil component, an emulsifier component and a solvent component, and in Example 4, the solubility data of ruxolitinib and ruxolitinib phosphate are given:

[0007]

[0008] The above data show that the solubility of ruxolitinib and ruxolitinib phosphate in water, ethanol and isopropanol is very low, all less than 10 mg / ml (1%), so it is difficult to make a coating agent with the original reference of 1.5%.

[0009] WO2023 / 016583A discloses a patent for a gel of ruxolitinib, which uses diethylene glycol monoethyl ether as a penetration enhancer and claims to promote the absorption of ruxolitinib; CN114870016A discloses a microemulsion foam of a JAK inhibitor and its application. It is claimed that the microemulsion foam has no booster, is easy to produce and apply, has the functions of emollient and moisturizing, and has no irritation to the skin, and has no side effects such as itching, burning and tingling.

[0010] These preparations need to be used multiple times a day, which is inconvenient to use. For patients with vitiligo, all parts of the body may lose color and need medication. The use of the above dosage forms will cause the medicine to be smeared on the clothes, making it difficult for the affected parts to receive a sufficient effective dose and the efficacy to be guaranteed. At the same time, the clothes will be contaminated by the medicine.

[0011] In addition, for topical medications for vitiligo, what is needed is that the medication is applied locally to exert its efficacy, and the addition of a penetration enhancer will increase transdermal absorption, which will inevitably lead to an increase in blood drug concentration, which may lead to unpredictable systemic side effects.

[0012] In addition, according to current knowledge, ruxolitinib and ruxolitinib phosphate have low solubility in water and organic solvents, making it difficult to prepare external solutions, including film coatings, with the same concentration as the original marketed cream (1.5% in terms of alkali and 2.0% in terms of phosphate).

[0013] In summary, it is necessary to develop a more convenient and reasonable dosage form that is easy to use and can ensure that a sufficient dose of the drug is locally retained after use without entering the bloodstream and causing side effects, and at the same time will not be wiped off by clothing and will not contaminate clothing. Summary of the invention

[0014] On the one hand, the present invention aims to provide a high-concentration ruxolitinib film-coating agent. After the patient applies the drug locally, the solvent evaporates quickly, forming a strong, wear-resistant, transparent drug film on the surface of the diseased skin, which serves as a high-concentration drug reservoir, thereby achieving a sustained-release long-term effect without contaminating clothing.

[0015] Another aspect of the present invention is to provide a long-acting ruxolitinib preparation that only needs to be taken once a day or several days, or even once a few weeks, thereby increasing the patient's compliance with medication.

[0016] Another aspect of the present invention is to provide a drug that can cover the white spots of vitiligo, so that the white spots of vitiligo patients can be covered to their natural skin color after taking the drug, and at the same time produce drug effects. The pigment can refer to the chemical product, and according to different skin colors, the corresponding edible pigment can be added to prepare products with different skin color numbers.

[0017] Another aspect of the present invention is to provide a water-resistant and wear-resistant coating agent, which can be used for bathing after drying without causing the drug to dissolve and lose.

[0018] The present invention also provides a preparation that can produce the same therapeutic effect as the original research ruxolitinib phosphate emulsion, and the side effects are no greater than the original research reference, but the compliance of the medication is better, and inert skin color pigments can be added to directly cover white spots, greatly increasing the compliance of vitiligo patients.

[0019] Compared with the prior art, the ruxolitinib film-coating agent of the present invention has the following beneficial effects:

[0020] 1. The industrial production of the product is simple to operate, and it can be directly dissolved, mixed, filtered and canned.

[0021] 2. Quality control is simple and convenient, and the solution is uniform.

[0022] 3. It can cover white spots of vitiligo, has stable coloring, and is waterproof, sweat-proof, and friction-resistant.

[0023] 4. Does not stick to clothes, and does not affect bathing or washing.

[0024] 5. Good adhesion, can be easily used on face, neck, trunk and limbs.

[0025] 6. The effect lasts for a long time, and one dose can last for one to two weeks.

[0026] 7. The efficacy and safety are consistent with commercially available creams, and the compliance of use is greatly increased.

[0027] 8. Easy to remove, just wipe it clean with a wet wipe with 75% alcohol. DETAILED DESCRIPTION

[0028] The present invention is further described below by way of examples. It should be understood that the embodiments of the present invention are not limitations of the present invention, and simple improvements to the present invention under the premise of the concept of the present invention fall within the scope of protection claimed in the present invention.

[0029] Example 1 Solubility test of different film-forming materials on ruxolitinib phosphate

[0030] The solubility of different film-forming materials was investigated using ruxolitinib phosphate as the active ingredient and 95% ethanol as the solvent with or without plasticizer.

[0031] Weigh 0.9g of each film-forming material, add them to 10ml volumetric bottles, add 95% ethanol to make up the volume, sonicate at room temperature 20-30℃ until dissolved, add the active ingredient of ruxolitinib phosphate in batches until it is no longer dissolved by sonication, and determine the maximum amount of active ingredient ruxolitinib phosphate that can be dissolved at room temperature in different film-forming material prescriptions. The results are as follows:

[0032] ① Weigh about 900 mg of acrylic acid (ester) / octylacrylamide copolymer into a 10 ml volumetric flask, add 95% ethanol to make up the volume, sonicate at room temperature to dissolve, then add about 200 mg of ruxolitinib phosphate, sonicate at room temperature 20-30°C for 3 minutes, turbid, sonicate for another 3 minutes, still turbid and unclear. This indicates that the solubility of ruxolitinib phosphate in the 95% ethanol solution of acrylic acid (ester) / octylacrylamide copolymer film-forming material is not more than 2.0%. Apply it on a glass plate (100 mg / 1 cm 2 ), crystals precipitate after film formation, and the film-forming property is poor.

[0033] ② Weigh about 900 mg of hydroxypropyl cellulose (model HPC-L, batch number: NBL-2371) and add it to a 10 ml volumetric bottle. Add 95% ethanol to make up the volume, sonicate at room temperature to dissolve, then add about 200 mg of ruxolitinib phosphate, sonicate at room temperature at 20-30°C for 3 minutes, and it becomes turbid. Sonicate for another 3 minutes, and it is still turbid and not dissolve. This indicates that the solubility of ruxolitinib phosphate in the 95% ethanol solution of hydroxypropyl cellulose HPC-L film-forming material is not more than 2.0%. Apply it on a glass plate (100 mg / 1 cm 2 ), crystals precipitated after film formation, and the film-forming property was poor. ③ About 200 mg of ruxolitinib phosphate was weighed, added to a 10 ml volumetric flask, and 95% ethanol was added to make up the volume. Ultrasonication at room temperature 20-30 ° C for 6 minutes could not be dissolved, and a small amount of solid was not dissolved. 900 mg RL100 (quaternary ammonium methacrylate co-ester type A RI100) was added and ultrasonicated at room temperature to quickly dissolve. Then, ruxolitinib phosphate was added up to a maximum of 270 mg, which could be dissolved. Then 14.4 mg of ruxolitinib phosphate was added, which could not be dissolved. Then about 900 mg of RL100 was added, and the solution was dissolved. The film was dissolved by sonication, and then 28.8 mg of ruxolitinib phosphate was added at most. The film was basically dissolved by ultrasound. This shows that the film-forming material RL100 can greatly promote the dissolution of the active ingredient ruxolitinib phosphate. When 9% RL100 is added, the amount of ruxolitinib phosphate dissolved can be increased by more than 70 mg compared with no addition, and the solubility of ruxolitinib phosphate is increased by more than 35%; when 18% RL100 is added, the amount of ruxolitinib phosphate dissolved is increased by more than 113.2 mg (313.2 mg) compared with no addition, and the increase is more than 56.6%. Apply it on a glass plate (100 mg / 1 cm 2 ), no crystals are precipitated after film formation, it is a transparent film with excellent adhesion.

[0034] Conclusion: Unexpectedly, the quaternary ammonium methacrylate co-ester type A RL100 film-forming material can greatly increase the solubility of the active ingredient ruxolitinib phosphate in 95% ethanol, and can make the content of ruxolitinib phosphate in the prepared film-forming agent reach more than 3%, so that the drug efficacy of the reference preparation can be achieved and maintained for a long time after administration. Other film-forming materials do not have such solubilization effect, and the ruxolitinib phosphate in the prepared film-forming agent cannot reach 2%. In addition, the quaternary ammonium methacrylate co-ester type A RL100 film-forming material has good film-forming performance, high concentration of active ingredients does not crystallize, and the film-forming adhesiveness is good.

[0035] Example 2 Test on the content of quaternary ammonium (ammonium) methacrylate co-ester type A film-forming agent in the coating agent

[0036] 95% ethanol was used as the solvent and the reference preparation ruxolitinib (base) content of 1.5% (ruxolitinib phosphate 2.0%) was added to investigate the effect of the amount of film-forming material quaternary ammonium methacrylate co-ester Type A added on the quality of the coating agent, with a focus on the film-forming properties and whether ruxolitinib phosphate precipitated crystals.

[0037] Test process: About 200 mg of ruxolitinib phosphate was placed in a 10 ml volumetric bottle, and quaternary ammonium methacrylate co-ester A film-forming material (400 mg / 500 mg / 600 mg / 1000 mg) was added. 95% ethanol was added to the volume, and ultrasonically dissolved at room temperature to obtain a clear and uniform solution, which was the film-forming agent. The film-forming agent was adjusted to 100 mg / cm 2 Add the amount of dropwise onto the glass surface and leave it to evaporate and dry naturally. Observe the phenomenon the next day. The results are as follows:

[0038]

[0039] Conclusion: The test shows that the amount of film-forming agent RL100 added must be more than 4 times that of ruxolitinib phosphate, so that crystallization will not occur during film formation. Too little film-forming agent will cause crystallization, and too much film-forming agent will slow down the dissolution and increase the cost.

[0040] Example 3 Test on the content of plasticizer in coating agent

[0041] 95% ethanol was used as solvent; the reference preparation ruxolitinib (base) content was 1.5%; the film-forming material quaternary ammonium (ammonium) methacrylate co-ester type A was added at 4.5 times the amount of ruxolitinib phosphate; the effect of the amount of plasticizer medium-chain triglyceride added on the quality of the coating agent was investigated, with a focus on film-forming properties and whether ruxolitinib phosphate precipitated crystals.

[0042] Test process: About 200 mg of ruxolitinib phosphate was placed in a 10 ml volumetric bottle, and about 900 mg of quaternary ammonium methacrylate co-ester A film-forming material was added, and different amounts of plasticizer medium-chain triglycerides (added according to the proportion of different film-forming materials) were added, and then 95% ethanol was added to the volume, and ultrasonically dissolved at room temperature to obtain a clear and uniform solution, which was the coating agent. The coating agent was adjusted to 100 mg / cm 2 Add the amount of solution to the glass surface and leave it to evaporate and dry naturally. Observe the phenomenon on the next day. The results are as follows:

[0043]

[0044] Conclusion: The test shows that the amount of film-forming agent RL100 added is 4.5 times that of ruxolitinib phosphate, with 95% ethanol as solvent, and the amount of plasticizer medium-chain triglyceride added should not exceed 10% of the film-forming agent.

[0045] Example 4 Coating agent preparation 1

[0046] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 10.0g, stir to dissolve, add 2.0g of ruxolitinib phosphate, stir to dissolve, add 95% ethanol to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent (1.5%, based on ruxolitinib).

[0047] Example 5 Coating agent preparation 2

[0048] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, heat to 50-60°C, and add quaternary ammonium methacrylate co-ester type A ( RL100) 18.0g, stir to dissolve, add 3.0g of ruxolitinib phosphate, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent.

[0049] Example 6 Coating Preparation 3

[0050] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 9.0g, stir to dissolve, add 2.25g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent.

[0051] Example 7 Coating Preparation 4

[0052] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 10.0g, stir to dissolve, add 2.0g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent.

[0053] Example 8 Coating Preparation 5

[0054] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 15.0g, stir to dissolve, add 2.8g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent.

[0055] Example 9 Coating Preparation 6

[0056] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 15.0g, stir to dissolve, add 2.4g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to 100ml, filter to obtain a clear solution, add an appropriate amount of skin pigment, stir evenly, and the ruxolitinib phosphate coating agent is obtained.

[0057] Example 10 Preparation of coating agent 7

[0058] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 9.0g, stir to dissolve, add 2.25g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, add appropriate amount of natural edible sorghum red pigment to color, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib phosphate coating agent.

[0059] Example 10 Preparation of coating agent 7

[0060] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 9.0g, stir to dissolve, add 1.5g of ruxolitinib, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear solution, which is the ruxolitinib coating agent.

[0061] Example 11 Coating Preparation 8

[0062] Add 90 ml of 95% ethanol to a 500 ml three-necked flask, and add quaternary ammonium methacrylate co-ester type A ( RL100) 9.0g, add 1.0g of hydroxypropyl cellulose, stir to dissolve, add 2.25g of ruxolitinib phosphate, add 0.3g of medium-chain triglyceride, stir to dissolve, add 95% ethanol to make up to 100ml, filter to obtain a clear viscous solution, which is the ruxolitinib phosphate coating agent.

[0063] Example 12 Test on factors affecting typical film coating formulations

[0064] The ruxolitinib coating prepared in Example 6 was subjected to an accelerated test at 60° C. The results are as follows:

[0065]

[0066] Results: This indicates that the prescription has good stability (22.5 mg / ml is 100%).

[0067] Example 13 Ruxolitinib film-coated agent inhibits delayed-type hypersensitivity reaction in mice

[0068] The ruxolitinib film-coating agent in the embodiment 6 of this patent and the commercially available original cream are used. The efficacy of both was investigated in a T-cell driven murine delayed-type hypersensitivity test model. Balb / c mice were sensitized on days 0 and 1 by topical application of the antigen 2,4-dinitrofluorobenzene (DNFB) to the shaved abdomen of the mice. On day 5, the thickness of the ear was measured. This measurement was recorded and used as a baseline. The ears of the animals were then challenged by topical application of a total of 20 μl (10 μl applied to the inner auricle and 10 μl applied to the outer auricle) of 0.2% DNFB. The ears were measured again 24 to 72 hours after challenge. The test formulations were administered throughout the sensitization and challenge phases (days 1 to 7) to investigate the efficacy of both. Efficacy was indicated by a reduction in ear swelling compared to the untreated condition. Results: The results showed that both were effective, both were able to reduce ear swelling by more than 20%, and the effect of the homemade Example 6 film-coating once was comparable to the effect of the commercially available original cream used daily.

Claims

1. A ruxolitinib coating composition, characterized in that The composition comprises a film-forming material, quaternary ammonium methacrylate copolymer.

2. The coating composition according to claim 1, characterized in that The active ingredient of the composition is ruxolitinib phosphate.

3. The coating composition according to claim 1 or 2, characterized in that The film-forming material quaternary ammonium methacrylate copolymer is quaternary ammonium methacrylate copolymer A type.

4. The coating composition according to claim 1 to 3, characterized in that The solvent of the composition is 95% ethanol.

5. The coating composition according to claim 1 to 4, characterized in that The composition also includes a concealer pigment that matches your skin tone.

6. A ruxolitinib phosphate coating composition, characterized in that the composition comprises, based on the total weight of the composition: Ruxolitinib phosphate: 1.0% to 3.5%; Quaternary ammonium methacrylate copolymer type A ( RL100): 4% to 30% 95% Ethanol: 60% to 95%.

7. Use of the ruxolitinib film-coating according to claim 1 or 6 for treating diseases, wherein the diseases are one or more of dermatitis, psoriasis, vitiligo, hidradenitis, urticaria, and alopecia areata.

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