CN101502491B - Dirithromycin enteric-coated formulation - Google Patents

Abstract

The invention relates to a dirithromycin (DRM) enteric preparation with hydroxypropyl methylcellulose phthalate (HPMCP) being the framework material of drug-containing core and the coating material of an enteric coating layer. The enteric preparation has the advantages that the drug content is higher, the drug dissolution rate is less affected by the coating material, the preparation cost is low and the preparation process is simple.

Description

A kind of dirithromycin enteric coated preparation

Technical field

The present invention relates to a kind of enteric coated preparation of macrolide antibiotics dirithromycin.

Background technology

Dirithromycin is the derivant of erythromycin, belongs to macrolide antibiotics, is applicable to the age more than 12 years old, the patient of responsive microbial various infection, and curative effect is outstanding and safe and reliable.Dirithromycin goes on the market with the dosage form of conventional tablet at first, but because it is very responsive to acid medium, promptly destroyed in very short time in gastric juice, side by side erythromycin and catabolite thereof easily cause gastrointestinal reaction, and in the intestinal juice alkaline environment, the comparatively stable and easily absorption of dirithromycin, for addressing this problem, domestic manufacturer has developed kinds such as dirithromycin enteric coatel tablets, enteric coated capsule in succession.

Patent 200510136661.8 discloses a kind of dirithromycin enteric coated micropill and preparation method thereof, wherein disclosed enteric layer coating material is a crylic acid resin, when being to use this coating material, wants the major defect of this technical scheme the special concern consumption, be easy to cause the medicine dissolution rate to descend in case coating is excessive, and for making the coating amount be fit to not only rely on merely experience, also to carry out acid resisting test and determine suitable coating amount, and then increase the difficulty of technology, also destroy the seriality of technology.

Patent 200810069467.6 discloses enteric coated capsule of a kind of erythromycin and preparation method thereof, has still adopted crylic acid resin in the wherein disclosed coating solution, and also there be the problem same with patent 200510136661.8 in this technical scheme.

For addressing the above problem, the invention provides a kind of technical scheme, in this technical scheme, the coating material of enteric layer is selected from for example plasticizer etc. of Hydroxypropyl methyl cellulose phtalate and some pharmaceutical excipients.In line with better adapting to the principle that industry is produced greatly and reduced cost, contain and also adopt Hydroxypropyl methyl cellulose phtalate in the pill core as framework material and binding agent, the wonderful discovery of result, when adopting the Hydroxypropyl methyl cellulose phtalate conduct to contain pill core crab material and enteric layer coating material, the result of extraction of medicine is similar with the listing product, in addition, unexpectedly be, increase the coating amount of Hydroxypropyl methyl cellulose phtalate, do not reduce the dissolution rate of dirithromycin.Because the enforcement of the technical program makes production technology further simplify, and, the seriality of production technology and the dissolution rate of medicine when having reduced cost, have been guaranteed because of the few medicament contg height of the technical program supplementary product kind.

Summary of the invention

The present invention aims to provide a kind of absorption and does not receive the gastric emptying influence, and release is even, the bioavailability height, and zest is little, the dirithromycin enteric coated preparation of favorable reproducibility.

The present invention aims to provide a kind of drug dissolution, and influenced by coating material little, and supplementary product kind is few, and cost is low, the simple dirithromycin enteric coated preparation of production technology.

The present invention aims to provide a kind of dirithromycin enteric coated preparation to address the above problem.

Enteric coated preparation of the present invention, include enteric coated micropill, described micropill is by containing pill core, sealing coat, enteric layer three parts are formed, wherein contain pill core and be made up of the alcoholic solution of dirithromycin and Hydroxypropyl methyl cellulose phtalate, this contains pill core by extruding the spheronization preparation, and enteric layer is made up of Hydroxypropyl methyl cellulose phtalate and one or more pharmaceutically useful excipient.

Described the composed as follows of pill core that contain:

Dirithromycin

Hydroxypropyl methyl cellulose phtalate (HPMCP)

Alcoholic solution

Hydroxypropyl methyl cellulose phtalate preferably is dissolved in 80% the alcoholic solution, and the concentration that HPMCP accounts for 80% alcoholic solution is about 5-10%, is 3-8% and HPMCP accounts for the percentage by weight that contains pill core.Hydroxypropyl methyl cellulose phtalate plays framework material and binding agent in containing pill core.Contain pill core by extruding the spheronization preparation.

Described sealing coat composed as follows:

HPMC

Plasticizer

Filmogen is selected from HPMC, plasticizer and is selected from PEG, propylene glycol, diethyl phthalate, the triethyl citrate etc. one or more in sealing coat.Behind the sealing coat coating, pastille micropill weightening finish 1-3%.Antiplastering aid (Pulvis Talci) is looked concrete condition and can be added and can not add.

Described enteric layer composed as follows:

Hydroxypropyl methyl cellulose phtalate

Plasticizer

Alcoholic solution

Perhaps

Hydroxypropyl methyl cellulose phtalate is mixed coating powder (interior plasticizer-containing, antiplastering aid etc.)

Alcoholic solution

Enteric coating layer comprises that (the market Hydroxypropyl methyl cellulose phtalate on sale that has perhaps contained plasticizer is mixed coating powder, preferred 80% alcoholic solution for Hydroxypropyl methyl cellulose phtalate (HPMCP) and plasticizer.Plasticizer is selected from PEG, propylene glycol, diethyl phthalate, the triethyl citrate etc. one or more.With HPMCP mixing coating powder is example, and it is dissolved in 80% the ethanol, and solid content generally accounts for the 6-10% of enteric coating layer gross weight.Hydroxypropyl methyl cellulose phtalate has plasticity as enteric-coating material, and the characteristics of good film-forming property can use no or little plasticizer during coating, not only can improve the micropill outward appearance but also can strengthen resistance to gastric juice.Dissolution medium pH value low (pH5.0-5.5), the medicine stripping is fast, the bioavailability height.Simultaneously, HPMCP has stability for storage, and 3-4 never degenerates under the storage condition, and is littler than acrylic resin to the influence of the release of medicine, absorption.

The specific embodiment

Following preferred embodiment only is used to illustrate implementation process of the present invention rather than is used for limiting protection domain, and is as follows:

Embodiment 1

Dirithromycin ball core prescription:

Supplementary material title consumption

Dirithromycin 125g

HPMCP 5g

80% ethanol 100ml

The contagion gown prescription:

HPMC(3cap) 2.5g

Triethyl citrate 0.25g

80% ethanol 100ml

The enteric coating prescription:

HPMCP 7.5g

Diethyl phthalate 0.75g

80% ethanol 125ml

The preparation method of dirithromycin enteric piller is as follows:

Contain the pill core preparation:

Get HPMCP and slowly join in 100ml 80% ethanol that has agitating device, constantly stir until being dissolved into settled solution, as adhesive.

With 125g dirithromycin crushing screening, be that adhesive is made suitable soft material with solution.Start and to extrude rolling circle equipment, the selection hole diameter of sieve (perforated) plate is 0.8mm, 4000 rev/mins of rotating speeds, extrude round as a ball, with the piller drying of gained.The gained piller is crossed the 20-30 mesh sieve.

The contagion gown preparation:

Get HPMC (3cap) 2.5g and be dissolved in the 125ml80% ethanol,, add triethyl citrate 0.25g to settled solution, standby.

The preparation of HPMCP enteric coating liquid:

Get HPMC and mix powder 7.5g and add 80% ethanol 125ml and add the 0.75g diethyl phthalate and be stirred to uniform suspendible body, standby.Setting the peristaltic pump rotating speed is 20 ± 5 rev/mins, stream pressure 0.5～0.65Mpa, 25～30 ℃ of material bed tempertaures, spouting velocity 5ml/ minute, use atomizing lance earlier contagion gown to be wrapped in the dirithromycin piller, make piller weightening finish about 1-3%, the HPMCP enteric coating liquid is contained evenly be ejected on the ball core intermittently operated then, after having sprayed coating solution, in coating pan dry 10 minutes earlier, in 40 ℃ of dryings 2 hours, promptly get enteric dirithromycin piller then.Calculate the capsule of packing into No. 3 after the loading amount, promptly get the dirithromycin slow releasing capsule.

According to present embodiment gained dirithromycin slow releasing capsule content is 99.6%, and 30 minutes releases are 96.1% in simulated gastric fluid release＜5%, the pH6.8 phosphate buffer.

Embodiment 2

Dirithromycin ball core prescription:

The title consumption

Dirithromycin 250g

HPMCP 8g

80% ethanol 160ml

The contagion gown prescription:

HPMC(5cap) 2.5g

PEG400 2.5g

Pulvis Talci 7.5g

80% ethanol 250ml

The enteric coating prescription:

HPMCP 20g

Triethyl citrate 2g

80% ethanol 330ml

The preparation method of dirithromycin enteric piller is as follows:

Contain the pill core preparation:

Get HPMCP8g and slowly join in 160ml 80% ethanol that has agitating device, constantly stir until being dissolved into settled solution, as adhesive.

With 250g dirithromycin crushing screening, be that adhesive is made suitable soft material with solution.Start and to extrude rolling circle equipment, the selection hole diameter of sieve (perforated) plate is 1mm, 4000 rev/mins of rotating speeds, extrude round as a ball, with the piller drying of gained.The gained piller is crossed the 18-22 mesh sieve.

The contagion gown preparation:

Get HPMC (5cap) 2.5g and be dissolved in the 250ml80% ethanol,, add 2.5gPEG400 to settled solution, standby.

The preparation of HPMCP enteric coating liquid:

Get HPMC and mix powder 20g and add 80% ethanol 330ml and add the 2g triethyl citrate and be stirred to uniform suspendible body, standby.Setting the peristaltic pump rotating speed is 20 ± 5 rev/mins, stream pressure 0.5～0.65Mpa, 25～30 ℃ of material bed tempertaures, spouting velocity 5ml/ minute, use atomizing lance earlier contagion gown to be wrapped in the dirithromycin piller, make piller weightening finish about 1-3%, the HPMCP enteric coating liquid is contained evenly be ejected on the ball core intermittently operated then, after having sprayed coating solution, in coating pan dry 10 minutes earlier, in 40 ℃ of dryings 2 hours, promptly get enteric dirithromycin piller then.Calculate the capsule of packing into No. 3 after the loading amount, promptly get the dirithromycin slow releasing capsule.According to present embodiment gained dirithromycin slow releasing capsule content is 100.2%, and 30 minutes releases are 99.8% in simulated gastric fluid release＜5%, the pH6.8 phosphate buffer.

Embodiment 3

Dirithromycin ball core prescription:

Supplementary material title consumption

Dirithromycin 250g

HPMCP 8g

80% ethanol 150ml

The contagion gown prescription:

HPMC(3cap) 2.5g

Propylene glycol 2.5g

80% ethanol 100ml

The enteric coating prescription:

HPMCP 25g

Diethyl phthalate 2.5g

80% ethanol 416ml

The preparation method of dirithromycin enteric piller is as follows:

Contain the pill core preparation:

Get 8gHPMCP and slowly join in 150ml 80% ethanol that has agitating device, constantly stir until being dissolved into settled solution, as adhesive.

With 250g dirithromycin crushing screening, be that adhesive is made suitable soft material with solution.Start and to extrude rolling circle equipment, the selection hole diameter of sieve (perforated) plate is 0.8mm, 4000 rev/mins of rotating speeds, extrude round as a ball, with the piller drying of gained.The gained piller is crossed the 20-30 mesh sieve

The contagion gown preparation:

Get HPMC (3cap) 2.5g and be dissolved in the 125ml80% ethanol,, add propylene glycol 2.5g to settled solution, standby.

The preparation of HPMCP enteric coating liquid:

Get HPMCP and mix powder 25g and add 80% ethanol 416ml and add the 2.5g diethyl phthalate and be stirred to uniform suspendible body, standby.Setting the peristaltic pump rotating speed is 20 ± 5 rev/mins, stream pressure 0.5～0.65Mpa, 25～33 ℃ of material bed tempertaures, spouting velocity 3ml/ minute, use atomizing lance earlier contagion gown to be wrapped in the dirithromycin piller, make piller weightening finish about 1-2%, the HPMCP enteric coating liquid is contained evenly be ejected on the ball core intermittently operated then, after having sprayed coating solution, in coating pan dry 10 minutes earlier, in 40 ℃ of dryings 2 hours, promptly get enteric dirithromycin piller then.Calculate the capsule of packing into No. 2 after the loading amount, promptly get the dirithromycin slow releasing capsule.According to present embodiment gained dirithromycin slow releasing capsule content is 101.5%, and 30 minutes releases are 101% in simulated gastric fluid release＜1%, the pH6.8 phosphate buffer.

With the foregoing description with carry out the dissolution contrast test according to the homemade dirithromycin enteric coated capsule of the preferred embodiment in the patent 200510136661.8, the result is as follows:

As can be seen from the above table, prepared dirithromycin enteric coated preparation medicament contg height is (more than 50% according to the present invention, be higher than far away the contrast reference preparation 20%), according to the measurement result of 30 minutes releases in the pH6.8 phosphate buffer as can be seen, HPMCP has kept the high stripping quantity of dirithromycin in rational amount ranges, along with the HPMCP consumption strengthens, it is less to the influence of principal agent rate of release, and acid resistance improves.

Claims (3)

1. dirithromycin enteric coated micropill, form by containing pill core, sealing coat, enteric layer, it is characterized in that containing in the described micropill pill core is made up of the alcoholic solution of dirithromycin and Hydroxypropyl methyl cellulose phtalate, this contains pill core by extruding the spheronization preparation, wherein, to account for the percentage by weight that contains pill core be 3-8% to Hydroxypropyl methyl cellulose phtalate; Enteric layer is made up of Hydroxypropyl methyl cellulose phtalate and one or more pharmaceutically useful excipient, and wherein, the weight of Hydroxypropyl methyl cellulose phtalate mixing coating powder accounts for the 6-10% of enteric layer gross weight.

2. dirithromycin enteric coated micropill according to claim 1 is characterized in that it contains:

Contain pill core:

125mg-250mg dirithromycin, 5-10mg Hydroxypropyl methyl cellulose phtalate, an amount of 80% ethanol;

Sealing coat:

1.25-7.5mg hypromellose, 1-8mg PEG400 or propylene glycol, 0.125-0.75mg triethyl citrate or diethyl phthalate, an amount of 80% ethanol;

Enteric layer:

7.5-25mg Hydroxypropyl methyl cellulose phtalate, 0.75-2.5mg triethyl citrate or diethyl phthalate, an amount of 80% ethanol.

3. capsule preparations that contains any described dirithromycin enteric coated micropill among the claim 1-2.