CN1711991A

CN1711991A - Sustained release preparation of solution resistant medicine

Info

Publication number: CN1711991A
Application number: CN 200410048069
Authority: CN
Inventors: 李学广; 罗德球
Original assignee: Beijing Dezhong Wanquan Medicines Technological Development Co Ltd
Current assignee: Beijing D-Venturepharm Technology Development Co., Ltd.
Priority date: 2004-06-14
Filing date: 2004-06-14
Publication date: 2005-12-28
Anticipated expiration: 2024-06-14
Also published as: CN100413491C

Abstract

A release controlling agent for the medicine difficult to dissolve contains at least one cellulose polymer and at least one auxiliary easy to dissove in water. It features that the release of medicine is independent to the pH value of intestine.

Description

A kind of controlled release preparation of insoluble drug

Technical field

The present invention relates to a kind of controlled release preparation of insoluble drug, this preparation can make the release of medicine near zero level, and makes the dissolving release dynamics of medicine change insensitive to pH in the intestinal scope.

Technical background

Insoluble drug is generally very low at the gastronintestinal system dissolubility, as nifedipine (Nifedipine), felodipine (Felodipine) etc.; Other has some to be acid or alkaline, shows the dissolubility that influenced by pH at the different parts of gastronintestinal system, as gliclazide (Gliclazide), cisapride (Cisapride) etc.

The means that can realize the zero-order release system at present still are osmotic pump preparation, percutaneous drug administration preparation etc. more satisfactoryly.Osmotic pump preparation adopts the semipermeable membrane material coating, and interior branch is two-layer, and one deck is a medicine layer, contains the osmotic pressure active substance simultaneously, makes a call to a small delivery aperture on the clothing film surface of this layer; One deck is an expanding layer, produces motive force after the imbibition, and the medicine of medicine layer is released small delivery aperture.Yet there is technical difficulty in it, produce to realize and the problem of quality control, and the release insoluble lamellar body in back that finishes must excrete, and the serious problems that slice, thin piece is accumulated in intestinal might take place.The percutaneous drug administration preparation kind is more, structure differs, as membrane controlled release type, viscose glue decentralized, skeleton diffused, pair micro-reservoirs type etc., can realize zero-order release preferably, but also have problems, as be fit to make the medicament categories of said preparation limitation, the medicine transit dose is low, cost is high, commercial production realizes that difficulty is big etc.

The purpose of this invention is to provide the production technology that a kind of technology is easily gone, equipment cost is not high, the plan zero-order release system of preparation insoluble drug makes the release kinetics equation can reach zero level.Present technique need not high-tech difficulty, expensive technology.

Another object of the present invention is to make drug release change insensitive to the dissolve medium pH in the simulation intestinal scope.

Among the patent CN1342068 with cellulosic polymer (as hydroxypropyl emthylcellulose) and glucose syrup (as maltodextrin) applied in any combination in the Gliclazide delayed-release matrix tablet, can make release near zero level, and make that the dissolving release dynamics of gliclazide is insensitive to the change of pH.

Adopt the combination of cellulosic polymer and ease of solubility adjuvant among the present invention, with the inside and outside method that combines that adds cellulosic polymer is added in the preparation simultaneously, just can make release, and change insensitive the dissolve medium pH in the simulation intestinal scope near zero level.

Description of drawings

Fig. 1 is the stripping curve of embodiment 1 tablet in different pH buffer

Fig. 2 is the stripping curves of embodiment 2 tablets in different pH buffer

Fig. 3 is the stripping curves of embodiment 3 tablets in different pH buffer

Fig. 4 is the stripping curves of embodiment 4 tablets in different pH buffer

The technical measures that carry out an invention

Physiologically active ingredient among the present invention is insoluble drug such as gliclazide (Gliclazide), cisapride (Cisapride), nifedipine (Nifedipine), felodipine (Felodipine) etc.The percentage by weight of biological active substances is 1%-50%, and optimum percentage by weight is 10%-30%.

This product can be tabletting behind dry granulation or the wet granulation, and wherein cellulosic polymer is by Nei Jia with add the mode that combines and add.In add: during granulation adjuvant system is gone in the granule; Add: before the tabletting adjuvant is mixed adding with granule.The percentage by weight of the cellulosic polymer among the present invention is 10%-60%, and optimum percentage by weight is 15%-35%.

The percentage by weight of the ease of solubility adjuvant among the present invention is 5%-50%.

For realizing the present invention, in the mixture of cellulosic polymer, ease of solubility adjuvant and medicine, can further add other conventional adjuvant, as diluents microcrystalline cellulose, dicalcium phosphate dihydrate, lactose, sucrose or starch; Cosolvent polyvidone, Polyethylene Glycol, poloxamer, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether or their mixture; Magnesium stearate lubricant, Pulvis Talci etc.

The tablet that adopts the present invention to prepare, drug release behavior be near zero level, and change insensitive to the dissolve medium pH in the simulation intestinal scope.

Embodiment

The present invention is described in further detail below in conjunction with embodiment.

Specify the present invention in conjunction with the embodiments, but be not limited to following embodiment.Wherein " % " is meant " weight % ".

Embodiment 1

Gliclazide HPMC K4M HPMC K100LV, (in add) HPMC K100LV, (adding) dicalcium phosphate dihydrate mannitol magnesium stearate

18.1％ 12.0％ 9.0％ 9.0％ 31.3％ 20.0％ 0.6％

Preparation technology:

Gliclazide, HPMC K4M, HPMC K100LV (in add), dicalcium phosphate dihydrate, mannitol are by the equivalent method mixing that progressively increases, with 80% ethanol water system soft material, cross 20 mesh sieves, add HPMC K100LV (adding) and magnesium stearate, tabletting after 60 ℃ of oven dry.

Embodiment 2

Gliclazide HPMC K15M HPMC K100LV (in add) HPMC K100LV (adding) microcrystalline cellulose PEG 4000 PVP K30 dolomols

18.1％ 10.0％ 10.0％ 5.0％ 34.3％ 19.0％ 3.0％ 0.6％

Preparation technology:

Gliclazide, with PMC K15M, HPMC K100LV (in add), microcrystalline Cellulose, PEG 4000 by the equivalent method mixing that progressively increases, PVP K30 alcoholic solution system soft material with 12%, cross 20 mesh sieves, add HPMC K100LV (adding) and magnesium stearate, tabletting after 60 ℃ of oven dry.

Embodiment 3

Cisapride HPMC K100M HPMC K4M (in add) HPMC K4M (adding) microcrystalline cellulose PEG 4000 PVP K30 dolomols

40.0％ 15.0％ 10.0％ 5.0％ 21.4％ 5.0％ 3.0％ 0.6％

Preparation technology:

Cisapride, HPMC K100M, HPMC K4M (in add), microcrystalline Cellulose, PEG 4000 are by the equivalent method mixing that progressively increases, PVP K30 alcoholic solution system soft material with 12%, cross 20 mesh sieves, add HPMC K4M (adding) and magnesium stearate, tabletting after 60 ℃ of oven dry.

Embodiment 4

Felodipine HPMC K15M HPMC K100LV (in add) HPMC K100LV (adding) micro crystal cellulose milk sugar PVP K30 dolomol

2％ 12％ 10％ 8％ 34.2％ 30％ 3％ 0.8％

Preparation technology:

Felodipine, HPMC K15M, HPMC K100LV (in add), microcrystalline Cellulose, lactose are by the equivalent method mixing that progressively increases, PVP K30 alcoholic solution system soft material with 12%, cross 20 mesh sieves, add HPMC K100LV (adding) and magnesium stearate, tabletting after 60 ℃ of oven dry.

The release test:

With the tablet for preparing by drug release determination method (two appendix XC first methods of Chinese Pharmacopoeia version in 2000), respectively with three kinds of phosphate buffer (pH5.4 of 900ml, pH6.8, pH7.8) be release medium, rotating speed is 100 rev/mins, obtain the different release profiles of each embodiment tablet, see Fig. 1～Fig. 4.

As described above, can prepare the plan zero-order release system of insoluble drug according to the present invention, and change insensitive the dissolve medium pH in the simulation intestinal scope.This kind technical matters is simple simultaneously, equipment cost is not high, is suitable for industrialized great production.

Claims

1. the controlled release preparation of an insoluble drug is characterized in that it comprises ease of solubility adjuvant at least a cellulosic polymer and at least a water, and the release that can make medicine is near zero level, and makes the dissolving release dynamics of medicine change insensitive to intestinal pH.

2. the described preparation of claim 1 can be tabletting behind dry granulation or the wet granulation, and wherein cellulosic polymer is by Nei Jia with add the mode that combines and add.In add: during granulation adjuvant system is gone in the granule; Add: before the tabletting adjuvant is mixed adding with granule.

3. as claim 1,2 described preparations, biological active substances is an insoluble drug, can be gliclazide, cisapride, nifedipine, felodipine etc.Its percentage by weight in preparation is 1%-50%, and optimum percentage by weight is 10%-30%.

4. as any one described preparation in the claim 1,2, it is characterized in that cellulosic polymer comprises the hydroxypropyl emthylcellulose of two kinds of different viscosities.

5. as any one described preparation in the claim 1,4, it is characterized in that cellulosic polymer comprises the mixture of the hydroxypropyl emthylcellulose of the hydroxypropyl emthylcellulose of 4000cP viscosity and 100cP viscosity.

6. as any one described preparation in the claim 1,4,5, it is characterized in that cellulosic polymer percentage by weight in preparation is 10%-60%, preferred weight percent is 15%-35%.

7. preparation as claimed in claim 1, wherein ease of solubility adjuvant percentage by weight in preparation is preferably 5%-50%.

8. preparation as claimed in claim 1 can contain other conventional adjuvant, as diluents microcrystalline cellulose, dicalcium phosphate dihydrate, lactose, sucrose or starch; Cosolvent polyvidone, Polyethylene Glycol, poloxamer, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether or their mixture; Magnesium stearate lubricant, Pulvis Talci etc.