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Entecavir microspheres and pharmaceutical composition for parenteral administration containing same

A technology of entecavir and its composition, which is applied in the field of entecavir microspheres and injection compositions containing them, can solve the problems of low solubility of organic solvents, difficulty in thinking, and difficulty in preparing microspheres, and achieve the effect of improving medication compliance

Inactive Publication Date: 2016-06-29
DONG KOOK PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

That is, it is not necessary to develop an oral preparation into an injection preparation unless it is a special case like a neuropsychiatric drug, and entecavir has been developed as an oral solvent that is easy to administer, so it does not necessarily need to be developed into an injection, and, It is not easy to think of using microspheres to develop sustained-release drugs, so until now, entecavir has been administered in the form of oral preparations
[0016] In addition, the existing microsphere preparation method usually uses dichloromethane, benzyl alcohol, ethyl acetate, etc. as the organic phase to dissolve the main component and the copolymer, and put it into the continuous phase of the water phase to prepare microspheres. , but when entecavir is used, it is difficult to prepare microspheres due to the low solubility of these organic solvents

Method used

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  • Entecavir microspheres and pharmaceutical composition for parenteral administration containing same
  • Entecavir microspheres and pharmaceutical composition for parenteral administration containing same
  • Entecavir microspheres and pharmaceutical composition for parenteral administration containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～3

[0048] Embodiment 1~3: the preparation of microsphere

[0049] 2.5 g of Entecavir (manufacturer: Astech Pharmaceutical Co., Ltd.) was dissolved in 40.0 g of dimethyl sulfoxide (the first organic phase), and 7.5 g of the entecavir shown in Table 1 below was biodegraded. Polymer (manufacturer: Boehringer Ingelheim) was dissolved in 27.0 g of dichloromethane (manufacturer: Merck) (second organic phase). After mixing the completely dissolved first organic phase and the second organic phase and fully mixing to make a dispersion liquid, the dispersion liquid was slowly added to 0.5% polyvinyl alcohol (Mn=30,000~70,000 at 20°C, Sigma Co., Ltd. ) in the aqueous phase, microspheres were prepared using an L4RT mixer (Silverson, UK) at 3,000 rpm. Afterwards, the temperature was raised to 47°C to volatilize the organic solvent, and then cooled to 20°C again to filter the microspheres, and after washing the filtered microspheres with water for injection several times, the microspheres w...

Embodiment 4

[0054] Embodiment 4: the preparation of microsphere

[0055] Weigh 2.5g of Entecavir (manufacturer: Astech Pharmaceutical Co., Ltd.) and 7.5g of biodegradable polymer (manufacturer: Boehringer Ingelheim) RG756S, and add 40.0g of dimethyl sulfoxide and 27.0 g of dichloromethane was dissolved (the first organic solvent phase). After fully mixing the organic solvent phases, the dissolved organic solvent phase was slowly added to 0.5% polyvinyl alcohol (Mn=30,000~70,000, Sigma) aqueous solution phase at 20° C., using a 3,000rpm L4RT mixer ( West Watson (Silverson, UK) to prepare microspheres. Afterwards, the temperature was raised to 47°C to volatilize the organic solvent, and then cooled to 20°C again to filter the microspheres, and after washing the filtered microspheres with water for injection several times, the microspheres were prepared by freeze-drying.

Embodiment 5

[0056] Embodiment 5: the preparation of microsphere

[0057] Weigh 2.5g of Entecavir (manufacturer: Astech Pharmaceutical Co., Ltd.) and 7.5g of biodegradable polymers (manufacturer: Boehringer Ingelheim) (RG756S:RG504H=8:2), and add 30.0 g of acetic acid and 37.0 g of dichloromethane to dissolve it (the first organic solvent phase). After fully mixing the organic solvent phases, the dissolved organic solvent phase was slowly added to 0.5% polyvinyl alcohol (Mn=30,000~70,000, Sigma) aqueous solution phase at 20° C., using a 3,000rpm L4RT mixer ( West Watson (Silverson, UK) to prepare microspheres. Afterwards, the temperature was raised to 47°C to volatilize the organic solvent, and then cooled to 20°C again to filter the microspheres, and after washing the filtered microspheres with water for injection several times, the microspheres were prepared by freeze-drying.

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Abstract

The present invention relates to entecavir microspheres and a pharmaceutical composition for parenteral administration containing the same. The entecavir microspheres are manufactured by a method comprising the steps of: dissolving entecavir and a biodegradable biocompatible polymer in at least one solvent; putting the solution of the entecavir and biodegradable biocompatible polymer in a hydrophilic polymer solution, followed by stirring, to form microspheres; and removing the solvent. The entecavir is sufficiently sealed in the entecavir microsphere at approximately 80% or more based on the input amount, and the elution of the entecavir is maintained for 30 days or more, and thus the entecavir microspheres can continuously exhibit efficacy, thereby improving medication compliance of patients.

Description

technical field [0001] The invention relates to an entecavir microsphere and an injection composition comprising the same. The purpose of the present invention is to prepare entecavir, which has been only used orally, into biodegradable biocompatible polymer microspheres, thereby providing a slow-release pharmaceutical composition for non-oral administration. Background technique [0002] Entecavir is a guanosine nucleoside analog of the following structural formula, which is used as a therapeutic agent for chronic hepatitis B virus infection. [0003] [0004] Entecavir as a therapeutic agent for chronic hepatitis B virus infection is a drug that needs to be taken every day and for a lifetime. The bioavailability at the time of oral administration is close to 100%, but since the absorption rate decreases with meals, oral administration is required 2 hours before meals, which is inconvenient. [0005] As far as the prescription mode of the currently marketed oral formul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K47/48A61K47/30A61K31/52
CPCA61K9/0019A61K9/1647A61K31/522A61P31/20
Inventor 严信李德根车庚会
Owner DONG KOOK PHARMA CO LTD