CN111297810A

CN111297810A - Sorafenib tosylate pharmaceutical composition and preparation method thereof

Info

Publication number: CN111297810A
Application number: CN201811512260.1A
Authority: CN
Inventors: 曾金; 沈金阳; 朱宏伟; 李杉杉; 孙运栋
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2018-12-11
Filing date: 2018-12-11
Publication date: 2020-06-19

Abstract

The invention relates to a sorafenib tosylate pharmaceutical composition and a preparation method thereof. The invention discloses a sorafenib tosylate pharmaceutical composition, which has larger granularity of raw material medicines and higher dissolution speed of the medicines. The invention relates to a preparation method of the tablet, which has simple process, no special requirement on the granularity of raw materials and good dissolution of the product.

Description

Sorafenib tosylate pharmaceutical composition and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a sorafenib tosylate tablet and a preparation method thereof.

Background

The chemical name of the sorafenib tosylate is 4- (4- {3- [ 4-chloro-3- (trifluoromethyl)Radical) phenyl]Ureido } phenoxy) -N2-methylpyridine-2-carboxamide-4-tosylate having the formula C₂₁H₁₆ClF₃N₄O₃·C₇H₈O₃S, molecular weight 637.03, having the following formula, in its pharmaceutical form, usually in the form of the tosylate salt.

Sorafenib tosylate is an oral multi-target anticancer drug developed by Bayer (Bayer) company, can inhibit a plurality of kinases existing in cells and on cell surfaces simultaneously, and comprises RAF kinase, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), platelet-derived growth factor receptor- β (PDGFR- β), KIT and FLT-3.2006 for 9 months, wherein 0.2g of Sorafenib tosylate produced by Bayer company is sold in China under the trade name of DuoJimet (Nexavar) and is used for treating inoperable late-stage renal cell carcinoma and inoperable or distant metastatic hepatocellular carcinoma.

Sorafenib tosylate is a poorly water-soluble drug, and in order to improve the dissolution of the drug after oral administration, the drug needs to be sufficiently micronized. Generally, the particle size D of sorafenib tosylate raw material is required₉₀Less than 20 μm.

In order to obtain sorafenib tosylate with sufficient fineness, the industry generally carries out jet milling, which can obviously increase the production cost of the medicament and increase the exposure probability of the medicament. Since sorafenib tosylate is an antitumor drug, the sorafenib tosylate has larger toxic and side effects, and can generate adverse effects on the health of production workers after the exposure is increased. The extremely fine drug particles also cause difficulties in industrial production, such as larger static electricity or more dust flying, and also cause adverse effects such as poor mixing efficiency.

Therefore, it is very necessary to find a prescription and a preparation method which have less strict requirements on the granularity of the medicine and can simplify the production process.

Disclosure of Invention

The invention aims to solve the technical problems and provides a prescription capable of effectively promoting the dissolution of sorafenib tosylate even if the granularity of the medicine is relatively large, such as the granularity D of raw materials₉₀The drug still has a faster dissolution speed between 20 and 60 mu m.

According to the sorafenib pharmaceutical composition, the diluent is selected from one or more of microcrystalline cellulose, lactose or mannitol, and preferably, the diluent is microcrystalline cellulose. The dosage of the diluent is 0.5-4%, preferably 1-2%.

According to the sorafenib pharmaceutical composition, the adhesive is selected from one or more of hypromellose, povidone or hypromellose, and preferably, the adhesive is hypromellose. The dosage of the adhesive is 0.5-2.5%, preferably 1% -2%. The addition method is to prepare a certain proportion of adhesive for addition or directly add the adhesive into the prescription.

According to the sorafenib pharmaceutical composition, the solubilizing agent is selected from sodium dodecyl sulfate, polyoxyethylene hydrogenated castor oil or tween 20, and preferably, the solubilizing agent is polyoxyethylene hydrogenated castor oil. The dosage of the solubilizer is 0-2%, preferably 0.5-1.5%. The addition method is to prepare a certain proportion of adhesive for addition or directly add the adhesive into the prescription.

According to the sorafenib pharmaceutical composition, the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium and crospovidone, and preferably, the disintegrant is croscarmellose sodium. More preferably, the disintegrating agent is added in an internal addition mode and an external addition mode, wherein the internal addition amount is 1-15%, the external addition amount is 1-15%, the further preferred internal addition amount is 5-10%, and the external addition amount is 5-10%. The weight ratio of the internal disintegrating agent to the external disintegrating agent is 1: 0.5 to 2, preferably 1: 1 to 1.5.

According to the sorafenib pharmaceutical composition, the lubricant is selected from one or more of sodium stearate fumarate, silicon dioxide or talcum powder, and preferably, the lubricant is talcum powder. The amount of the lubricant is 0-1.5%, preferably 0.5-1%.

The invention also provides a preparation method of the sorafenib tosylate pharmaceutical composition, which comprises the following steps:

1) screening and uniformly mixing sorafenib tosylate, a diluent, an adhesive and a disintegrating agent (added internally) according to the prescription amount, preparing a solubilizer into an aqueous solution, and wetting and granulating;

2) drying the granules prepared in the last step, adding a disintegrating agent (additionally added) and a lubricating agent, uniformly mixing, and pressing into tablets.

Detailed Description

Comparative example 1 and examples 1 to 5

TABLE 1

The preparation process comprises the following steps:

1. mixing sorafenib tosylate, microcrystalline cellulose, hydroxypropyl methylcellulose and croscarmellose sodium (added internally), preparing sodium dodecyl sulfate or polyoxyethylene hydrogenated castor oil into a water solution, and wetting and granulating;

2. wet granulating the above granules, and drying;

3. adding croscarmellose sodium (added) and talcum powder, and tabletting;

4. the tablets were coated with a coating powder having the trade name opadry.

The tablets prepared in examples 1 to 5 and comparative examples 1 to 2 and the commercially available preparations were subjected to dissolution curve detection by the following detection method: the dissolution medium is hydrochloric acid solution of pH1.0+ 1% SDS, the dissolution medium volume is 900mL, the dissolution medium temperature is 37 + -0.5 ℃, the rotation speed is 75rpm, and the paddle method is adopted. The dissolution profile results are shown in table 2.

TABLE 2

Through comparative examples 1 and 2, it can be found that the influence of the particle size on the dissolution of sorafenib is large, and the particle size D of the raw material₉₀Is controlled to5.5 μm can achieve rapid dissolution.

From examples 1 to 3, it was found that a large-particle-size starting material (particle size D) was used by adjusting the formulation composition₉₀20-60 μm), the medicine can be quickly dissolved out.

Examples 4 to 5 show that the rapid elution of the drug can be further promoted by replacing the surfactant.

Claims

1. A sorafenib tosylate pharmaceutical composition comprises sorafenib tosylate, a diluent, an adhesive, a solubilizer, a disintegrant and a lubricant, wherein the disintegrant is added in an internal addition and external addition mode, and the weight percentages of the components are as follows:

2. the sorafenib tosylate pharmaceutical composition according to claim 1, wherein the weight percentages of the components are as follows:

3. the sorafenib tosylate pharmaceutical composition of claim 2, wherein the weight ratio of the internal disintegrant to the external disintegrant is 1: 0.5 to 2, preferably 1: 1 to 1.5.

4. The sorafenib tosylate pharmaceutical composition of claim 1, wherein the diluent is selected from one or more of microcrystalline cellulose, lactose, or mannitol, preferably microcrystalline cellulose.

5. The sorafenib tosylate pharmaceutical composition according to claim 1, wherein the binder is selected from one or more of hypromellose, povidone, or hypromellose, preferably hypromellose.

6. Sorafenib tosylate pharmaceutical composition according to claim 1, characterized in that the solubilizer is selected from sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil or tween 20, preferably polyoxyethylene hydrogenated castor oil.

7. The sorafenib tosylate pharmaceutical composition according to claim 1, wherein the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, preferably croscarmellose sodium.

8. Sorafenib tosylate pharmaceutical composition according to claim 1, characterized in that the lubricant is selected from one or more of sodium fumarate stearate, silica or talc, preferably talc.

9. The sorafenib tosylate pharmaceutical composition of claim 1, wherein the particle size D of the sorafenib tosylate is the particle size D₉₀20 to 60 μm.

10. Process for the preparation of sorafenib tosylate pharmaceutical composition according to any of claims 1 to 8, comprising the following steps:

1) screening and uniformly mixing sorafenib tosylate, a diluent, an adhesive and an internal disintegrating agent according to the prescription amount, preparing a solubilizer into an aqueous solution, and wetting and granulating;

2) drying the granules prepared in the last step, adding an external disintegrating agent and a lubricant, uniformly mixing, and pressing into tablets.