Anti-hepatitis b virus medicine dispersion combination at non-crystal state and medicine preparation thereof

A pharmaceutical preparation and composition technology, applied in the field of non-crystalline anti-hepatitis B virus drug dispersion composition and pharmaceutical preparations, can solve the problem of affecting the crystal form and chemical stability of adefovir dipivoxil, affecting chemical stability, etc. problem, achieve the effect of enhancing chemical stability and crystal form stability

Inactive Publication Date: 2009-07-29
MAI DE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high water content of the strong hydrophilic carrier used in this document, it is easy to induce recrystallization of adefovir dipivoxil and degradation through hydrolysis, thereby affecting the crystal form and chemical stability of adefovir dipivoxil
The document (CN1557327) discloses the method of heating and melting adefovir dipivoxil and polyethylene glycol (PEG) to prepare its co-melt. The resulting co-melt contains crystalline polyethylene glycol, which may induce adefovir dipivoxil. Adefovir dipivoxil recrystallizes, and the temperature is too high when heating and co-melting will lead to the degradation of adefovir dipivoxil and affect its chemical stability

Method used

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  • Anti-hepatitis b virus medicine dispersion combination at non-crystal state and medicine preparation thereof
  • Anti-hepatitis b virus medicine dispersion combination at non-crystal state and medicine preparation thereof
  • Anti-hepatitis b virus medicine dispersion combination at non-crystal state and medicine preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 Preparation of adefovir dipivoxil without crystalline form and entecavir without crystalline form and their stability

[0072] Method A: Dissolve 5.0 g of adefovir dipivoxil in crystalline form in 250 ml of ethanol solvent heated to 40-50 degrees (Celsius, the same below). After the resulting clear solution is cooled to room temperature (25-30 degrees), use a small spray dryer (Buchi Model-190 type) and nitrogen to spray dry all the solutions, and control the inlet temperature to 119-130 degrees and the outlet temperature to 50-65 degrees , The white oil thus obtained is adefovir dipivoxil (4.3 g) in the non-crystalline state. The adefovir dipivoxil of the obtained non-crystalline state is packed in 75 milliliters of plastic bottles (HDFE), and seals, and is placed in 40 degree / 75% relative humidity state and keeps three months, can observe with naked eyes 55-10% of the crystalline material is distributed in the oily form of adefovir dipivoxil. The results o...

Embodiment 2

[0074] Example 2 Preparation of the dispersion composition of adefovir dipivoxil without crystalline form and polyvinylpyrrolidone-ethylene acetate without crystalline form

[0075] Method C: Dissolve 5.0 g of adefovir dipivoxil in crystalline form and 10.0 g of polyvinylpyrrolidone-ethylene acetate (PVP-VA64, PlasdoneS-630, copovidone, the same below) without crystalline form in 250 ml, Heat the ethanol solvent to 50 degrees and keep stirring the solution. The hot solution thus obtained was further heated to boiling, and all solvent was evaporated by rotary distillation under reduced pressure (30-80 mmHg) to obtain a solid. The obtained solid was dried under vacuum at 40°C for 15 hours. Grinding the dried solid, further drying at a temperature between 35°C and 40°C for about 12 hours to remove the solvent, to obtain a dispersion composition of adefovir dipivoxil and polyvinylpyrrolidone-ethylene acetate without crystals (13.2g). X-ray powder diffraction pattern (attached fi...

Embodiment 3

[0078] Example 3 Preparation of the dispersion composition of entecavir without crystalline form and polyvinylpyrrolidone-ethylene acetate without crystalline form

[0079] Method F: Dissolve 5.0 g of crystalline entecavir and 10.0 g of non-crystalline polyvinylpyrrolidone-vinyl acetate in 200 ml of ethanol solvent heated to 50 degrees, and keep stirring the solution. The hot solution thus obtained was further heated to boiling, and all solvent was evaporated by rotary distillation under reduced pressure (30-80 mmHg) to obtain a solid. The obtained solid was dried under vacuum at 40°C for 15 hours. Grind the dried solid, and then further dry at a temperature between 35°C and 40°C for about 12 hours to remove the solvent to obtain a dispersion composition (13.0g) of entecavir and polyvinylpyrrolidone-ethylene acetate without crystals . X-ray powder diffraction pattern (see attached figure 2 -(1)) proves that the obtained product belongs to the non-crystalline form of enteca...

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Abstract

The invention relates to a disperse composition of a steady anti-hepatitis B virus drug with an amorphous form and amorphous polyvinylpyrrolidone-vinyl acetate (PVP-VA64) with the amorphous form and preparation methods thereof. The preparation methods comprise a spray drying method and a reduced pressure distillation method. The invention also relates to a pharmaceutical preparation containing the disperse composition and application thereof. The anti-hepatitis B virus drug in the disperse composition is adefovir dipivoxil, entikaweipian, or a compound of the two medicines. The anti-hepatitis B virus drug with the amorphous form, after forming the disperse composition, remarkably improves chemical stability and the polymorph stability, and can still maintain the amorphous form after three months under relative humidity state of 40 DEG C/75 percent.

Description

technical field [0001] The invention relates to a stable dispersion composition of an anti-hepatitis B virus drug without a crystal form and an auxiliary material without a crystal form and a preparation method thereof, including a spray drying method and a vacuum distillation method. The anti-hepatitis B virus drugs include entecavir, adefovir dipivoxil or the combination of these two drugs. The invention also relates to pharmaceutical preparations containing the dispersion composition and its use. Background technique [0002] Entecavir (entecavir or BMS-200475), chemical name: [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl]- 2-Methylenecyclopentyl]-6H-purin-6-one, the chemical structure is as follows: [0003] [0004] Entecavir is a deoxyguanosine analog that can effectively inhibit the replication of hepatitis B virus and is used for the treatment of hepatitis B disease. The drug was 100 to 1,000 times more potent than lamivudine in reducing the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513A61K47/30A61P1/16A61P31/12
Inventor 黄乐何慧敏
Owner MAI DE
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