Benvimod external suspension spray as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a Benvimod external suspension spray as well as a preparation method and application thereof. The preparation method of the vitimod suspension spray comprises the steps of preparation of a suspending aid, preparation of a water phase, preparation of an organic phase, dissolution of raw material medicines and the like. All phase solutions are uniformly mixed and then canned, the particle size of the raw material medicines is controlled within 50 microns, and the raw material medicines are dispersed and emulsified by adding a suspending aid, an emulsifier and the like, so that complicated processes such as homogenization and shearing of insoluble raw material medicines can be avoided. The benvimod suspension spray is 10 g: 0.1 g (1%). And finally, the non-quantitative benvimod external suspension spray which is moderate in viscosity and particle size, good in dispersity and stability and capable of improving the medication compliance of a patient is obtained.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to a benvimod external suspension spray and a preparation method thereof. Background Art

[0002] Tapinarov is a novel, first-in-class small molecule AhR agonist that can be used for topical treatment of atopic dermatitis, plaque psoriasis, psoriasis vulgaris, etc. in adults. It was first discovered as a metabolite (3,5-dihydroxy-4-isopropylstilbene), a Gram-negative bacillus that coexists with the rhabdomyositis nematode. In 1959, it was noted that rhabdomyositis containing large amounts of 3,5-dihydroxy-4-isopropylstilbene did not decay once dead, thus indicating its potential anti-inflammatory activity. Tapinarov is a therapeutic aryl hydrocarbon receptor modulator (TAMA) that binds to and activates the aryl hydrocarbon receptor (AhR). The human plasma protein binding of tapinarov is about 99% in vitro and can be made into topical preparations, including lotions, creams, foams, solutions, sprays, gels, patches, etc., which are applied to the affected area. In 2022, the FDA has approved the topical cream (1% / 10mg) for marketing. Summary of the invention

[0003] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a new external suspension spray and a preparation method thereof.

[0004] The scheme of the present invention comprises: A suspension spray for external use, each 100ml spray includes the following ingredients: Benvimod 0.1g~1.0g, propylene glycol 30~40g, glycerin 6~10g, polysorbate 80 0.1g~1.0g, lactic acid 0.1g~1.0g, polyethylene glycol 1.0g~5.0g, hydroxypropyl cellulose 1.0g~3.0g and balance water; including at least two of methylparaben, ethylparaben, propylparaben, sodium benzoate and potassium sorbate; also including at least one of sodium acetate, glacial acetic acid, citric acid, sodium citrate, tartaric acid and malic acid.

[0005] Preferably, the dosage of methylparaben is 0.015 to 0.2.

[0006] Preferably, the dosage of ethylparaben is 0.01 to 0.02.

[0007] Preferably, the dosage of propylparaben is 0.01 to 0.02.

[0008] Preferably, the dosage of sodium benzoate is 0.02-0.5.

[0009] Preferably, the dosage of potassium sorbate is 0.1 to 0.2.

[0010] Preferably, the molecular weight of polyethylene glycol is between 400 and 4000.

[0011] Preferably, each 100 ml spray comprises the following ingredients: 0.1g-1.0g of bevimod, 30-40g of propylene glycol, 6-10g of glycerol, 0.1g-1.0g of polysorbate 80, 0.1g-1.0g of lactic acid, 1.0g-5.0g of polyethylene glycol, 1.0g-3.0g of hydroxypropyl cellulose, 0.1g of potassium sorbate, 0.015-0.2g of methylparaben, 0.01-0.02g of ethylparaben, 0.01-0.02g of propylparaben, 0.01-0.02g of sodium benzoate, 0.02-0.5g of potassium sorbate and the remainder of water; including citric acid and sodium citrate.

[0012] The particle size distribution D90 of the bevimod is within 50 microns.

[0013] The viscosity of the suspension is 15-25 mPa·s.

[0014] Experiments have shown that the topical suspension spray can be used in the preparation of products suitable for topical treatment of mild to moderately stable psoriasis vulgaris in adults.

[0015] The medicine is an external preparation.

[0016] The method for preparing the benvimod external suspension spray is characterized by comprising: a) uniformly dispersing the benvimod API in a concentrated solution containing a suspending agent, so that the concentration of the benvimod API is 0.1 w / w% to 1 w / w%; b) The final particle size distribution D90 of the prepared suspension measured by laser diffraction or dynamic light scattering should be between 50 and 100 microns; c) After the solution is prepared, filter it and fill the filtrate into the sprayer.

[0017] The present invention adopts a spray to replace other existing forms of ointments, emulsions, gels, creams, patches, etc., which is easy to carry, does not need to be smeared or applied, and only needs to be sprayed on the affected area when used. It has the advantages of simple use, safety and convenience. Implementation

[0018] The following examples further describe the beneficial effects of the present invention. The examples are only for illustrative purposes and do not limit the scope of the present invention.

[0019] Example Benvimod external suspension spray Prescription composition:

[0020]

[0021] Preparation process: (1) Preparation of suspending agent: Dissolve the prescribed amount of hydroxypropyl cellulose in an appropriate amount of purified water, stir evenly, add the prescribed amount of polyethylene glycol, mix evenly, and obtain solution A; (2) Preparation of aqueous phase: Dissolve the prescribed amount of citric acid and sodium citrate in an appropriate amount of purified water. After complete dissolution, add the prescribed amount of glycerol to obtain solution B. (3) Preparation of organic phase: Dissolve the prescribed amount of preservative in propylene glycol until it is completely dissolved to obtain solution C; (4) Dissolution of API: Disperse the API in solution A, stir evenly, add the prescribed amount of polysorbate 80 and disperse, then add the heated and melted prescribed amount of lactic acid to obtain solution D; (5) Mix solutions A, B, C, and D in sequence and stir until uniform, then add purified water to make up to 100 ml; (6) After the solution is prepared, filter it and fill the filtrate into a sprayer.

[0022] Physical and chemical properties investigation: Physical and chemical properties investigation results of Examples 1 to 4

[0023] (Comparative Examples 1 to 4) The bevimod external suspension sprays of each comparative example are basically the same as Example 1, except for the differences shown in the following table

[0024] The relevant substances of the bevimod external suspension spray prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were detected, and the total impurity results are shown in the following table

[0025] It can be seen from the results that the Benvimod external suspension spray of Examples 1 to 4 has good fluidity, moderate viscosity and particle size, high dispersibility, good spray effect, is more convenient for patients to use, has higher stability and is convenient for production and packaging, improves patients' medication compliance, and complies with patients' medication needs. Moreover, the preparation process is simple and suitable for large-scale production.

Claims

1. A Benvimod external suspension spray, characterized in that: Each 100ml spray contains the following ingredients: Benvimod 0.1g~1.0g, propylene glycol 30~40g, glycerin 6~10g, polysorbate 80 0.1g~1.0g, lactic acid 0.1g~1.0g, polyethylene glycol 1.0g~5.0g, hydroxypropyl cellulose 1.0g~3.0g and balance water; including at least two of methylparaben, ethylparaben, propylparaben, sodium benzoate and potassium sorbate; also including at least one of sodium acetate, glacial acetic acid, citric acid, sodium citrate, tartaric acid and malic acid.

2. The external suspension spray according to claim 1, characterized in that The dosage of methylparaben is 0.015~0.

2.

3. The external suspension spray according to claim 1, characterized in that The dosage of ethylparaben is 0.01-0.

02.

4. The external suspension spray according to claim 1, characterized in that The dosage of propylparaben is 0.01~0.

02.

5. The external suspension spray according to claim 1, characterized in that: The dosage of sodium benzoate is 0.02~0.

5.

6. The external suspension spray according to claim 1, characterized in that: The dosage of potassium sorbate is 0.1-0.

2.

7. The external suspension spray according to claim 1, characterized in that: The molecular weight of polyethylene glycol is between 400 and 4000.

8. Benvimod 0.1g~1.0g, propylene glycol 30~40g, glycerol 6~10g, polysorbate 80 0.1g~1.0g, lactic acid 0.1g~1.0g, polyethylene glycol 1.0g~5.0g, hydroxypropyl cellulose 1.0g~3.0g, potassium sorbate 0.1g, methylparaben 0.015~0.2g, ethylparaben 0.01~0.02, propylparaben 0.01~0.02, sodium benzoate 0.02~0.5, potassium sorbate 0.1~0.2 and balance water; also includes at least one of sodium acetate, glacial acetic acid, citric acid, sodium citrate, tartaric acid and malic acid.

9. The external suspension spray according to claim 1, characterized in that: The viscosity of the suspension is 15-25 mPa·s.

10. Use of the topical suspension spray according to claim 1 in the preparation of a product suitable for topical treatment of mild to moderate stable psoriasis vulgaris in adults.

11. The use according to claim 10, characterized in that The medicine is an external preparation.

12. A method for preparing the bevimod external suspension spray according to any one of claims 1 to 11, comprising: a) uniformly dispersing the benvimod API in a concentrated solution containing a suspending agent, so that the concentration of the benvimod API is 0.1 w / w% to 1 w / w%; b) The final particle size distribution D90 of the prepared suspension measured by laser diffraction or dynamic light scattering should be between 50 and 100 microns; c) After the solution is prepared, filter it and fill the filtrate into the sprayer.

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