CN100377705C

CN100377705C - Calcium hydrophenyl sulfonate capsule and its prepn process

Info

Publication number: CN100377705C
Application number: CNB2005101100192A
Authority: CN
Inventors: 熊洁; 包玉林; 蔡胜
Original assignee: Shanghai Fosun Pharmaceutical Group Co Ltd; Shanghai Zhaohui Pharmaceutical Co Ltd
Current assignee: Shanghai Fosun Pharmaceutical Group Co Ltd; Shanghai Zhaohui Pharmaceutical Co Ltd
Priority date: 2005-11-03
Filing date: 2005-11-03
Publication date: 2008-04-02
Anticipated expiration: 2025-11-03
Also published as: CN1771927A

Abstract

The present invention provides phenolsulfonic acid calcium capsules and a preparation technology thereof. A novel capsule formula and a novel technology are adopted by the present invention to overcome the disadvantages of the prior art. The technology of the present invention is favorable to industrialized production in a certain scale; moreover, the product quality is improved, and the dissolution is good.

Description

Calcium hydrophenyl sulfonate capsule and preparation technology

Technical field:

The invention belongs to technical field of medicine.Be specifically related to calcium hydrophenyl sulfonate capsule and preparation technology.

Background technology:

Diabetes are a kind of commonly encountered diseases, frequently-occurring disease, and its sickness rate is ascendant trend year by year.Diabetes have become after cardiovascular and cerebrovascular disease, tumor, hypertension the chronic disease of another threat people ' s health at present.Diabetic retinopathy (DR) is the common blood capillary complications of diabetes.Calcium hydrophenyl sulfonate capsule safe and effective prevention of energy and treatment of diabetic retinopathy become, and significantly reduce the diabetes patient who causes because of DR and lose one's sight, be the desirable medication of control DR.

The preparation method of existing calcium hydrophenyl sulfonate capsule is as follows:

One, prescription

The material name consumption

Calcium dobesilate monohydrate 521.5g

(being equivalent to calcium dobesilate 500g)

Carboxymethyl starch sodium 45.0g

Magnesium stearate 5.0g

Make 1000

Two, preparation technology

1, the supplementary material pulverize separately is crossed 100 mesh sieves, respectively at dry 4 hours of 60 ℃ of afternoons;

2, take by weighing calcium dobesilate monohydrate, carboxymethylstach sodium and the magnesium stearate of recipe quantity, evenly mixed by the equivalent incremental method;

3, get above-mentioned mixed-powder, measure content, the moisture (control moisture scope 4%-6%) of intermediate, qualified back fill gets final product in No. 0 capsule.

But there are some problems in this technology:

1, adopt direct blended granule, mobile relevant with the character of raw material itself, loading amount instability, the phenomenon that content uniformity is big take place because of the mobile difference of raw material itself in regular meeting in the time of in stowing operation.And cause the adhesions such as jumper bar, calculating dial of capsule filler easily, cause producing and normally to carry out.

2, magnesium stearate is a lubricant in this prescription, when total mixing, to reach to mix 50 and change (15 minutes) fully mix homogeneously, but under these process conditions the non-compliant regulation of dissolution of product.Be lower than this operation requirement as incorporation time, it is inhomogeneous to cause material to mix, and granule content there are differences, and sticking etc. can take place in stowing operation cause content uniformity.

Because the problems referred to above, this process scale type often causes certain difficulty when producing, thereby has limited application.

Summary of the invention:

Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research design is suitable for the calcium hydrophenyl sulfonate capsule production technology of suitability for industrialized production.

Technology of the present invention is based on following test:

The prescription screening

1, specification is determined

In the calcium hydrophenyl sulfonate capsule every to contain calcium dobesilate be 0.5g (being equivalent to calcium dobesilate monohydrate 521.5mg).

2, prescription screening

The calcium dobesilate monohydrate is a very soluble medicine in water, places more stablely in exsiccant air, therefore mainly investigates the characteristic of the disintegrate and the stripping of preparation when screening formula, to determine optimum formula.

The invention provides a kind of calcium hydrophenyl sulfonate capsule preparation, said preparation is made up of the composition of following weight, and per 1000 capsules contain:

Calcium dobesilate monohydrate 521.5g is equivalent to calcium dobesilate 500g

Carboxymethyl starch sodium 20g-40g

Rikemal B 200 2.5g-5g

95% ethanol 35g

Another purpose of the present invention is to put forward the preparation technology of having encircleed a kind of calcium hydrophenyl sulfonate capsule preparation, and this technology comprises the following steps:

One, per 1000 of prescription contains following weight composition:

Calcium dobesilate monohydrate 521.5g is equivalent to calcium dobesilate 500g

Carboxymethyl starch sodium 20g-40g

Rikemal B 200 2.5g-5g

95% ethanol 35g

Two, preparation technology

1, the supplementary material pulverize separately is crossed 100 mesh sieves;

2, the calcium dobesilate monohydrate is dropped into the high speed wet granulator and open stirring at low speed 1min, 120 rev/mins, add 95% alcohol granulation, stirring at low speed 3min, 120 rev/mins;

3,60～65 ℃ of aeration-dryings, 16 mesh sieve granulate;

4, add carboxymethyl starch sodium, Rikemal B 200, mix 50 and changeed the content of sampling and measuring intermediate and moisture 15 minutes;

5,, contain calcium dobesilate 0.5g by every capsules and calculate the capsule loading amount according to intermediate assay result.

6, capsule charge is measured dissolution.

Because the new prescription of process choice of the present invention, without magnesium stearate, select Rikemal B 200 for use, it is tasteless, inert substance, and is good with the various kinds of drug compatibility such as acidity; Have adhesion characteristic, can improve the compressibility in the capsule manufacture; Responsive to the long nothing of incorporation time; Disintegration time, dissolution to medicine do not have influence.Be acknowledged as and use safely.After the present invention uses this product, in actual production process, can overcome magnesium stearate and cause the disintegration time of medicine, dissolution defective because of incorporation time is long.It is short to overcome incorporation time again, the little actual poor operability of opereating specification; Magnesium stearate is disperseed the inhomogeneous phenomenons such as sticking, loading amount instability that occur in the capsule pouring process.Also improved processing step in addition, not only produced and can normally carry out continuously, and product quality is easy to control, the dissolution of product is guaranteed.

Technology of the present invention and existing technology have been carried out the comparison of dissolution, see the following form, and the result shows the dissolution height and the data stabilization of technology of the present invention.

The comparison of the dissolution data of the old and new's technology under different mixing condition

Mixing condition	Old technology dissolution (%)						New technology dissolution (%)
	Old technology dissolution (%)						New technology dissolution (%)						Sample 1	2	3	4	5	6	Sample 1	2	3	4	5	6
	10 change	101.05	99.42	99.58	98.27	100.40	97.62	98.11	98.76	97.78	97.46	95.66	Sample 1	2	3	4	5	6	Sample 1	2	3	4	5	6	99.25
20 change	10 change	101.05	99.42	99.58	98.27	100.40	97.62	98.11	98.76	97.78	97.46	95.66	81.95	79.34	80.81	84.07	76.40	79.99	99.25	98.60	97.29	100.07	98.44	99.57	99.25
20 change	30 change	75.91	69.22	71.83	74.44	71.34	70.36	99.09	97.62	100.27	98.11	98.93	81.95	79.34	80.81	84.07	76.40	79.99	99.25	98.60	97.29	100.07	98.44	99.57	99.74
40 change	30 change	75.91	69.22	71.83	74.44	71.34	70.36	99.09	97.62	100.27	98.11	98.93	73.46	69.22	68.40	62.85	71.01	66.28	97.95	101.21	99.74	98.44	99.91	98.76	99.74
40 change	50 change	56.81	71.66	61.38	68.73	65.79	62.36	100.56	99.58	101.38	98.76	97.95	73.46	69.22	68.40	62.85	71.01	66.28	97.95	101.21	99.74	98.44	99.91	98.76	100.56
60 change	50 change	56.81	71.66	61.38	68.73	65.79	62.36	100.56	99.58	101.38	98.76	97.95	52.56	50.93	52.23	48.48	50.44	51.91	100.40	99.42	102.03	100.89	99.09	100.72	100.56

The specific embodiment:

Example 1-30:

The calcium hydrophenyl sulfonate capsule example

Operational approach:

1, the supplementary material pulverize separately is crossed 100 mesh sieves.

2, the calcium dobesilate monohydrate, carboxymethyl starch sodium, the Rikemal B 200 that claim recipe quantity.

3, the calcium dobesilate monohydrate input high speed wet granulator of recipe quantity is opened stirring at low speed 1min, add 95% alcohol granulation, stirring at low speed (120 rev/mins) 3min.

4,60～65 ℃ of aeration-dryings, 16 mesh sieve granulate.

5, add recipe quantity carboxymethyl starch sodium, Rikemal B 200, mix 50 and change (15 minutes), the content of sampling and measuring intermediate and moisture.

6,, contain calcium dobesilate 0.5g by every capsules and calculate the capsule loading amount according to intermediate assay result.

7, capsule charge is measured dissolution.

Above-mentioned example product dissolution determination method:

Getting this product, is solvent according to dissolution method (two appendix XC first methods of Chinese Pharmacopoeia version in 2005) with water 900ml.Rotating speed is that per minute 100 changes, operation in accordance with the law, and in the time of 30 minutes, it is an amount of to get solution, filters, and precision is measured subsequent filtrate 3ml and is put in the 50ml measuring bottle, is diluted with water to scale, shakes up, and goes out to measure trap according to spectrophotography at the 301nm wavelength; The in addition accurate calcium dobesilate reference substance that is dried to constant weight of becoming to learn from else's experience 130 ℃ is an amount of, and thin up is made the solution that contains anhydrous calcium dobesilate 30ug among the 1ml approximately, measures with method, calculates the dissolution of every capsules, and limiting the quantity of is 80% of labelled amount, should be up to specification.

The dissolution testing result

Instance number	Dissolution result (%)
	Dissolution result (%)							1	2	3	4	5	6	On average
	Example 1	99.72	98.65	99.14	99.58	98.36	98.90	1	2	3	4	5	6	On average	99.06
Example 2	Example 1	99.72	98.65	99.14	99.58	98.36	98.90	99.46	99.97	98.76	99.03	99.25	99.14	99.27	99.06
Example 2	Example 3	99.66	100.03	99.18	98.89	99.57	99.46	99.46	99.97	98.76	99.03	99.25	99.14	99.27	99.46
Example 4	Example 3	99.66	100.03	99.18	98.89	99.57	99.46	99.25	99.57	98.78	99.86	99.03	99.36	99.31	99.46
Example 4	Example 5	99.50	98.67	99.72	100.16	99.25	100.03	99.25	99.57	98.78	99.86	99.03	99.36	99.31	99.55
Example 6	Example 5	99.50	98.67	99.72	100.16	99.25	100.03	99.75	100.46	99.36	98.28	100.23	99.89	99.66	99.55
Example 6	Example 7	100.16	99.89	99.57	99.25	100.54	98.89	99.75	100.46	99.36	98.28	100.23	99.89	99.66	99.72
Example 8	Example 7	100.16	99.89	99.57	99.25	100.54	98.89	99.50	100.32	98.72	99.03	99.36	98.55	99.25	99.72
Example 8	Example 9	99.72	99.55	100.39	99.14	99.50	98.95	99.50	100.32	98.72	99.03	99.36	98.55	99.25	99.54
Example 10	Example 9	99.72	99.55	100.39	99.14	99.50	98.95	99.89	100.03	100.37	99.36	99.47	99.03	99.69	99.54
Example 10	Example 11	100.32	99.89	100.59	99.50	99.14	99.44	99.89	100.03	100.37	99.36	99.47	99.03	99.69	99.81
Example 12	Example 11	100.32	99.89	100.59	99.50	99.14	99.44	99.72	99.95	100.41	99.03	99.65	100.14	99.82	99.81
Example 12	Example 13	99.89	98.80	100.23	99.14	98.67	99.50	99.72	99.95	100.41	99.03	99.65	100.14	99.82	99.37
Example 14	Example 13	99.89	98.80	100.23	99.14	98.67	99.50	99.75	99.97	99.25	100.03	100.23	100.32	99.92	99.37
Example 14	Example 15	99.89	99.50	98.75	100.28	99.27	99.03	99.75	99.97	99.25	100.03	100.23	100.32	99.92	99.45
Example 16	Example 15	99.89	99.50	98.75	100.28	99.27	99.03	100.26	99.33	99.59	98.72	98.95	99.50	99.39	99.45
Example 16	Example 17	98.79	99.39	98.25	98.69	98.70	99.62	100.26	99.33	99.59	98.72	98.95	99.50	99.39	98.91
Example 18	Example 17	98.79	99.39	98.25	98.69	98.70	99.62	100.32	99.70	99.89	99.03	99.50	99.66	99.68	98.91
Example 18	Example 19	99.25	100.46	99.70	99.62	98.95	100.23	100.32	99.70	99.89	99.03	99.50	99.66	99.68	99.70
Example 20	Example 19	99.25	100.46	99.70	99.62	98.95	100.23	100.32	100.03	99.89	100.14	99.95	100.40	100.12	99.70
Example 20	Example 21	99.25	100.23	99.50	98.89	99.95	99.70	100.32	100.03	99.89	100.14	99.95	100.40	100.12	99.59
Example 22	Example 21	99.25	100.23	99.50	98.89	99.95	99.70	100.46	98.79	99.25	99.46	100.08	99.25	99.55	99.59
Example 22	Example 23	99.70	99.89	100.23	98.79	99.50	100.14	100.46	98.79	99.25	99.46	100.08	99.25	99.55	99.71
Example 24	Example 23	99.70	99.89	100.23	98.79	99.50	100.14	100.46	100.32	99.70	99.89	100.23	100.03	100.10	99.71
Example 24	Example 25	98.70	99.50	100.23	99.89	99.79	99.25	100.46	100.32	99.70	99.89	100.23	100.03	100.10	99.56
Example 26	Example 25	98.70	99.50	100.23	99.89	99.79	99.25	99.39	99.70	100.37	99.47	100.03	98.85	99.64	99.56
Example 26	Example 27	99.42	99.58	98.76	99.25	100.40	99.58	99.39	99.70	100.37	99.47	100.03	98.85	99.64	99.50
Example 28	Example 27	99.42	99.58	98.76	99.25	100.40	99.58	100.89	100.07	99.89	100.40	99.74	99.58	100.10	99.50
Example 28	Example 29	99.95	99.70	100.40	99.25	99.42	100.03	100.89	100.07	99.89	100.40	99.74	99.58	100.10	99.79
Example 30	Example 29	99.95	99.70	100.40	99.25	99.42	100.03	100.07	99.68	99.09	100.72	98.89	99.62	99.68	99.79

Claims

1. calcium hydrophenyl sulfonate capsule agent is characterized in that per 1000 capsules said preparations are grouped into by the one-tenth of following weight:

Calcium dobesilate monohydrate 521.5g is equivalent to calcium dobesilate 500g

Carboxymethyl starch sodium 20g-40g

Rikemal B 200 2.5g-5g

95% ethanol 35g.

2. the preparation technology of a calcium hydrophenyl sulfonate capsule agent as claimed in claim 1 is characterized in that this technology comprises the following steps:

(1) per 1000 capsules of prescription are grouped into by the one-tenth of following weight

Calcium dobesilate monohydrate 521.5g is equivalent to calcium dobesilate 500g

Carboxymethyl starch sodium 20g-40g

Rikemal B 200 2.5g-5g

95% ethanol 30g

(2) preparation technology

1. the supplementary material pulverize separately is crossed 100 mesh sieves;

2. the calcium dobesilate monohydrate is dropped into the high speed wet granulator and open stirring at low speed 1min, 120 rev/mins, add 95% alcohol granulation, stirring at low speed 3min, 120 rev/mins;

3. 60～65 ℃ of aeration-dryings, 16 mesh sieve granulate;

4. add carboxymethyl starch sodium, Rikemal B 200, mix 50 and changeed the content of sampling and measuring intermediate and moisture 15 minutes;

5. according to intermediate assay result, contain calcium dobesilate 0.5g by every capsules and calculate the capsule loading amount.