CN103040828B

CN103040828B - R-1132 and preparation method thereof

Info

Publication number: CN103040828B
Application number: CN201310003871.4A
Authority: CN
Inventors: 王苏南; 汤金春
Original assignee: CHANGZHOU KANGPU PHARMACEUTICAL Co Ltd
Current assignee: CHANGZHOU KANGPU PHARMACEUTICAL Co Ltd
Priority date: 2013-01-07
Filing date: 2013-01-07
Publication date: 2015-12-02
Anticipated expiration: 2033-01-07
Also published as: CN103040828A

Abstract

The present invention relates to a kind of R-1132 preparation prescription, technique, preparation prescription every ten thousand Central Plains supplementary product kinds and consumption: diphenoxylate hydrochloride 25g, atropine sulfate 0.25g, starch 152-168g, lactose 522.5-577.5g, calcium hydrogen phosphate 47.5-52.5g, 40%(ml/ml) ethanol 76-84g, magnesium stearate 6.65-7.35g.R-1132 of the present invention has good dissolution and content uniformity.

Description

R-1132 and preparation method thereof

Technical field

The present invention relates to R-1132 and preparation method thereof.

Background technology

The hydrochloric diphenoxylate 2.5mg of the every sheet of R-1132, atropine sulfate 25 μ g, for acute and chronic functional diarrhea and chronic enteritis.Diphenoxylate can directly act on intestinal smooth muscle, by suppressing intestinal mucosa sensor, eliminate the wriggling reflection of local mucosa and weaken enterokinesia, the segmental that simultaneously can increase intestinal is shunk, intestinal contents is made to pass through to postpone, being conducive to the absorption of enteral moisture, showing stronger anti-diarrhea effect, is functional diarrhea specific drug.But existing R-1132 dissolution difference difference is large, it is also often comparatively large that ordinary tablet is less than 80%, A+1.8S, and because principal agent atropine content is low, uniformity of dosage units is undesirable.

Summary of the invention

The present invention will solve the technical problem that existing R-1132 dissolution is little, uniformity of dosage units is undesirable.

R-1132 prescription provided by the invention every ten thousand Central Plains supplementary product kinds and consumption: diphenoxylate hydrochloride 25g, atropine sulfate 0.25g, starch 152-168g, lactose 522.5-577.5g, calcium hydrogen phosphate 47.5-52.5g, 40%(ml/ml) ethanol 76-84g, magnesium stearate 6.65-7.35g.

As preferred R-1132 prescription of the present invention every ten thousand Central Plains supplementary product kinds and consumption: diphenoxylate hydrochloride 25g, atropine sulfate 0.25g, starch 160g, lactose 550g, calcium hydrogen phosphate 50g, 40%(ml/ml) ethanol 80g, magnesium stearate 7g.

The present invention also provides a kind of preparation method of R-1132, comprises the following steps:

1, supplementary material is pulverized, is sieved;

2, supplementary material weighs, mixes:

Because former medicine (diphenoxylate hydrochloride) is measured few (5% of≤total amount) in prescription, the equivalent dilution method that progressively increases is adopted to carry out in operation.Operate as follows: first take and the starch of diphenoxylate hydrochloride equal weight and former medicine mixed diluting, sieve, then the starch taking mixture equal weight mixes with it, sieves, obtain the principal agent material mixture of mix homogeneously; Take lactose, calcium hydrogen phosphate and remaining starch;

Take atropine sulfate, be dissolved in 40% ethanol (ml/ml);

3, granulate: load weighted diphenoxylate hydrochloride, lactose, calcium hydrogen phosphate and remaining starch have been mixed in principal agent material by material, in input mixer-granulator, first be dry mixed 10 ~ 15 minutes, property adds 40% ethanol (ml/ml) being dissolved with atropine sulfate prepared again, wet mixing 5 ~ 10 minutes, start and granulate at a high speed, it is that 10 ~ 12Hz makes wet granular that cutter rotating speed controls;

4, dry; Add in the feed hopper of HighefficientFluidbeddrier by the wet granular made by material, inlet temperature controls at about 80 DEG C, and leaving air temp controls about 45 DEG C.Drying time, control was 5 ~ 10 minutes, and granule to be dried confirms dried (moisture control 3% ~ 5%).Stop heating, cooling.Discharging when drop temperature about 37 DEG C.

5, granulate: by the granule Fast granulate machine granulate after oven dry, selects cylinder screen cloth, 16 ~ 18 orders.

6, always mix: the granule after each material granulate is contained in elevator and is fed in three-dimensional motion mixer, and drop into load weighted lubricant magnesium stearate mixing mixing in 10 ~ 15 minutes;

7, tabletting;

8, pack.

The technique effect of R-1132 of the present invention is: have good dissolution and content uniformity.

Detailed description of the invention

Embodiment 1 R-1132 prescription

Table 1

The preparation of embodiment 2 R-1132

1, supplementary material is pulverized, is sieved: the pulverizing of supplementary material has come by omnipotent high speed disintegrator; Sieve and use shaking screen.Sieved 80 mesh sieves of requirement vortex oscillation such as crude drug diphenoxylate hydrochloride and supplementary product starch, magnesium stearate, calcium hydrogen phosphate; Lactose adjuvant requires to pulverize sieved 80 mesh sieves of rear vortex oscillation with omnipotent high speed disintegrator;

2, weigh: first take and be fed into mixed diluting in container with the supplementary product starch of diphenoxylate hydrochloride equal weight together with former medicine, cross 80 mesh sieves, then the starch taking mixture equal weight mixes with it, cross 80 mesh sieves, obtain the mixture of mix homogeneously;

Take the adjuvant of other ormal weight again: lactose, calcium hydrogen phosphate and remaining starch;

Because atropine sulfate amount is minimum, be dissolved in 40% ethanol for subsequent use;

3, granulate: often expect that supplementary material drops in efficient wet granulator by material by load weighted; build cover; start anchor type stirring paddle; first be dry mixed 10 ~ 15 minutes; property adds 40% ethanol having dissolved atropine sulfate prepared again, wet mixing 5 ~ 10 minutes, starts and granulates at a high speed; it is 10 ~ 12Hz that cutter rotating speed controls, and makes suitable wet granular;

4, dry: add in the feed hopper of HighefficientFluidbeddrier by the wet granular made by material, inlet temperature controls at about 80 DEG C, and leaving air temp controls about 45 DEG C.Drying time, control was 5 ~ 10 minutes, and granule to be dried confirms dried (moisture control is 3% ~ 5%).Stop heating, cooling.Discharging when drop temperature about 37 DEG C;

5, granulate: by the granule Fast granulate machine granulate after oven dry, selects cylinder (16 ~ 18 order);

6, always mix: the granule after each material granulate is contained in elevator and is fed in three-dimensional motion mixer, and drop into load weighted lubricant magnesium stearate mixing 10 ~ 15 minutes;

7, tabletting;

8, pack.

The item inspection of the R-1132 that embodiment 3 is prepared according to prescription and embodiment 2 method of embodiment 1

Dissolution: dissolution medium: containing the aqueous acetic acid of 0.2mol/L; Operative installations 1, rotating speed 150rpm, 45 minutes time, detection method: mobile phase: acetonitrile: potassium dihydrogen phosphate (65:35), standard solution: compound concentration is the solution of the diphenoxylate hydrochloride standard substance of 250ug/ml, is settled to 500ml with dissolution medium, filter, chromatographic system; 210nm wavelength detecting, L11 packed column (3.9mm*30mm), flow velocity: 1.0ml/ minute, standard solution sample introduction, record chromatogram, tailing factor must not more than 1.5, relative standard deviation must not cross 2.0%, by standard solution and product to be tested sample introduction respectively, and sample size 50ul, record chromatogram, in 45 minutes, dissolution must not lower than the 75%(of labelled amount with reference to USP Method 34 editions).

Outward appearance, uniformity of dosage units: by Chinese Pharmacopoeia 2010 editions inspection

Table 2

Table 2 result shows that the present invention selects the adjuvant of specific proportioning that gained tablet can be made to obtain desirable outward appearance, dissolution and uniformity of dosage units.

Comparative example 1 changes R-1132 prescription by table 3, prepares R-1132 according to embodiment 2 method, carries out item inspection according to embodiment 3 method

Table 3

Table 3 result shows: contrast prescription 1, compared with the prescription 2 in table 1, adopts 42%(ml/ml) ethanol, the tablet hardness of extrusion is bad (being about 15N), easy loose pieces, friability 1.8%.

Contrast 2, compared with the prescription 2 in table 1, adopts 38%(ml/ml) ethanol, gained tablet hardness is excessive, bright and clean not, and dissolution declines, and average dissolution is 82%.

Contrast prescription 3 is compared with prescription 1, and change lactose into sucrose, gained tablet not only outer light is bright and clean not, and disintegrate is difficult, and dissolution is only 76%.

It can thus be appreciated that, the present invention is directed to every ten thousand diphenoxylate hydrochloride 25g, atropine sulfate 0.25g selects the ethanol of certain concentration as binding agent and select starch, lactose, calcium hydrogen phosphate can obtain desirable slice, thin piece outward appearance, desirable dissolution and uniformity of dosage units as filler gained tablet.

Comparative example 2 presses the R-1132 prescription of table 1, prepares R-1132 by the following method, carries out item inspection according to embodiment 3 method

1, supplementary material is pulverized, is sieved; (with embodiment 2)

2, weigh: first take and be fed into mixed diluting in container with the supplementary product starch of diphenoxylate hydrochloride, atropine sulfate gross weight equal weight together with diphenoxylate hydrochloride, atropine sulfate; cross 80 mesh sieves; the starch taking mixture equal weight again mixes with it; cross 80 mesh sieves, obtain the mixture of mix homogeneously; Take the adjuvant of other ormal weight again: lactose, calcium hydrogen phosphate and remaining starch;

3, granulate: often expect that supplementary material drops in efficient wet granulator by material by load weighted; build cover; start anchor type stirring paddle; first be dry mixed 10 ~ 15 minutes; property adds 40% ethanol again, wet mixing 5 ~ 10 minutes, starts and granulates at a high speed; it is 10 ~ 12Hz that cutter rotating speed controls, and makes suitable wet granular; 4 ~ 8(is with embodiment 2)

The i.e. same diphenoxylate hydrochloride of feed postition of this preparation technology atropine sulfate compared with embodiment 2, but not add after being dissolved in 40% ethanol.Obtained sheet agent content homogeneity A+1.8S, as table 4, data show, because atropine content in this prescription is low, every sheet content, at 0.03mg, adopts and directly adds hybrid mode, is difficult to mix homogeneously.

Table 4

With above-mentioned according to desirable embodiment of the present invention for enlightenment, by above-mentioned description, associated production personnel in the scope not departing from this invention technological thought, can carry out various change and amendment completely.The technical scope of this invention is not limited to the content in description, must determine its technical scope according to right.

Claims

1. a R-1132, every ten thousand Central Plains supplementary product kinds and consumption: diphenoxylate hydrochloride 25g, atropine sulfate 0.25g, starch 160g, lactose 550g, calcium hydrogen phosphate 50g, 40%ml/ml ethanol 80g, magnesium stearate 7g,

The preparation method of described R-1132 is,

(1) supplementary material is pulverized, is sieved

After supplementary material is pulverized by omnipotent high speed disintegrator, with sieved 80 mesh sieves of vortex oscillation;

(2) supplementary material weighs, mixes

First take and be fed into mixed diluting in container with the supplementary product starch of diphenoxylate hydrochloride equal weight together with former medicine, cross 80 mesh sieves, then the starch taking mixture equal weight mixes with it, cross 80 mesh sieves, obtain the principal agent material mixture of mix homogeneously,

Take lactose, calcium hydrogen phosphate and remaining starch,

Take atropine sulfate, be dissolved in 40%ml/ml ethanol;

(3) granulate, load weighted lactose, calcium hydrogen phosphate and remaining starch being added mixes in principal agent material mixture, in input mixer-granulator, first be dry mixed 10 ~ 15 minutes, property adds the 40%ml/ml ethanol being dissolved with atropine sulfate prepared again, wet mixing 5 ~ 10 minutes, starts and granulates at a high speed, it is 10 ~ 12Hz that cutter rotating speed controls, and makes wet granular;

(4) dry, the wet granular made is added in the feed hopper of HighefficientFluidbeddrier by material, inlet temperature controls at 80 DEG C, leaving air temp controls 45 DEG C, and drying time, control was 5 ~ 10 minutes, and granule to be dried confirms dried, namely moisture control is 3% ~ 5%, stop heating, cooling, discharging when drop temperature 37 DEG C;

(5) granulate, by the granule Fast granulate machine granulate after oven dry, selects cylinder screen cloth, sieve number 16 ~ 18 order;

(6) always mix, the granule after each material granulate is contained in elevator and drops in three-dimensional motion mixer, and drop into load weighted lubricant magnesium stearate mixing mixing in 10 ~ 15 minutes;

(7) tabletting;

(8) pack.