CN102579396B - Calcium dobesilate capsule composition - Google Patents
Calcium dobesilate capsule composition Download PDFInfo
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- CN102579396B CN102579396B CN 201210093474 CN201210093474A CN102579396B CN 102579396 B CN102579396 B CN 102579396B CN 201210093474 CN201210093474 CN 201210093474 CN 201210093474 A CN201210093474 A CN 201210093474A CN 102579396 B CN102579396 B CN 102579396B
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- calcium dobesilate
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Abstract
The invention relates to a calcium dobesilate capsule composition, which comprises calcium dobesilate serving as an active ingredient, a filling agent and a lubricating agent, wherein the filling agent is microcrystalline cellulose preferably, the lubricating agent is a mixture of silicon dioxide and atoleine, and a weight ratio of the silicon dioxide to the atoleine is (1:1)-(1:3). According to the calcium dobesilate capsule composition, by optimizing a formula and a process, the problem of poor stability during long-term storage is solved well to ensure the quality of medicines.
Description
Technical field
The present invention relates to a kind of compositions of calcium hydrophenyl sulfonate capsule, the pharmaceutical preparation, the formula that are specifically related to calcium dobesilate form and preparation method.
Background technology
Calcium dobesilate (calcium dobesilate) chemistry CBD by name, be a kind of blood capillary protection medicine of chemosynthesis, by the Switzerland Supreme Being, draws Rand Corporation to develop.This medicine was written into " European Pharmacopoeia " in 1997, within 1998, be written into " British Pharmacopoeia ", and introduce to the market June calendar year 2001 at home.From the seventies in last century, calcium dobesilate just is used for the treatment of diabetes and causes due to microcirculation disturbance abroad varicosis, hemorrhoid, myocardial infarction and pruritic dermatitis.The higher area in living standard, aged people, for improving the microcirculation long-term taking, are acknowledged as unique matured product of prevention and treatment microcirculation dysfunction, particularly diabetic renal papillary necrosis.
Research shows that calcium dobesilate can reduce the wall of micrangium permeability, builds up one's resistance to disease; Improve lymph fluid and reflux, reduce edema; Reduce blood viscosity, correct albumins/globulins ratio, reduce hematoblastic high aggregation, thus the thrombosis of preventing, and improve the erythrocyte pliability.Also can suppress the high penetration effect that vaso-active substance causes blood capillary, reduce the tunica intima damage, improve the biosynthesis of basement membrane collagen.In addition, calcium dobesilate has obvious improvement effect to the microcirculation disturbance function.Can strengthen the activity of trunk and capillary endothelium nitric oxide synthetase, the capillary permeability of antagonistic activity oxygen clusters changes, thus the protection blood vessel; Can suppress macrophage activating factor, obviously reduce the macrophage adhesion thereby there is antiinflammatory action.
The current market orientation of calcium dobesilate mainly be take diabetic renal papillary necrosis as main, but it is as a kind of novel vascular protective agent, can also prevent and treat the various diseases that caused by blood capillary circulatory disturbance as the heart that (1) microcirculation disturbance causes, brain, kidney disease (myocardial infarction, angina pectoris, thrombus sequela, atherosclerosis of renal glomerulus etc.); (2) reduce blood viscosity; (3) prevention microthrombusis; (4) ice-cold, the pain of numb limbs and tense tendons, trick, the diseases such as skin pruritus; (5) varicosis syndrome etc.Along with to the deepening continuously of diabetes and chronic complicating diseases thereof and ischemic cardiac, cerebrovascular disease study on prevention, this medicine has broad application prospects.
Calcium dobesilate is widely used clinically at present, and a large amount of clinical practices show that calcium dobesilate is long-acting, safe and effective medicine, has special pharmacological action and therapeutic effect clinically.But in the existing calcium hydrophenyl sulfonate capsule preparation method of existing market, all use a certain amount of disintegrating agent to reach the complete stripping of calcium dobesilate, and the disintegrating agent majority has and draw moistly, be unfavorable for the long-term storage of calcium hydrophenyl sulfonate capsule.Owing to there being above problem, make the long-time stability of calcium hydrophenyl sulfonate capsule can not get larger improvement, be unfavorable for storage and the use of product.
Summary of the invention
The shortcoming of easy moisture absorption when overcoming calcium hydrophenyl sulfonate capsule long-time stability poor stability and long-term the storage, the invention provides a kind of formula and preparation method of calcium hydrophenyl sulfonate capsule.
Contain 2 phenolic hydroxyl groups in the molecular structure of calcium hydrophenyl sulfonate capsule, having determined that it has draws moist, photo-labile and the easy chemical property such as oxidation, the present invention is by the optimization to prescription and technique, well solve it in the long-term poor problem of stable upon storage, with this, guaranteed the quality of medicine.In the present invention, we substitute the disintegrating agent of generally applying in current calcium hydrophenyl sulfonate capsule with the microcrystalline Cellulose that is difficult for moisture absorption, reduce drawing of calcium hydrophenyl sulfonate capsule moist; In lubricant, by the screening to lubricant, we have selected with silicon dioxide and liquid paraffin, with a certain proportion of proportioning, can obviously improve the mobility of medicine, and because liquid paraffin itself possesses the effect of isolated medicine moisture absorption, therefore silicon dioxide and liquid paraffin are used in conjunction with the stability that can obviously improve medicine.
Calcium hydrophenyl sulfonate capsule provided by the invention, its technique is simple, easy to operate, reproducible, and sample quality is stable, is applicable to the large production of industrialization.
The invention provides a kind of calcium dobesilate capsule composition, said composition comprises: with composition weight meter, 60%～90% calcium dobesilate is as active component, 5%～40% filler, 0.2%～10% lubricant.
The invention provides a kind of compositions of calcium hydrophenyl sulfonate capsule, wherein with composition weight meter, described active component phenolsulfonic acid calcium content is 65%～85%.
The invention provides a kind of compositions of calcium hydrophenyl sulfonate capsule, described filler is a kind of, two or more the compositions in microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin or mannitol, preferably microcrystalline cellulose wherein, with composition weight meter, the content of described filler is 5%～30%.
The invention provides a kind of compositions of calcium hydrophenyl sulfonate capsule, described lubricant is a kind of, two or more the compositions in Pulvis Talci, silicon dioxide, magnesium stearate, liquid paraffin or hard alcohol fumaric acid sodium, wherein preferably silicon dioxide and liquid paraffin, the more preferably weight ratio 1: 1～1: 3 of silicon dioxide and liquid paraffin, with composition weight meter, the content of described lubricant is 0.2%～5%.
The invention provides a kind of preparation method of compositions of calcium hydrophenyl sulfonate capsule, comprise the steps:
1) calcium dobesilate was pulverized to 80 mesh sieves, microcrystalline Cellulose is crossed 80 mesh sieves;
2) take recipe quantity calcium dobesilate and filler, mix;
3) take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4) add the recipe quantity lubricant, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Calcium dobesilate capsule composition of the present invention, it is characterized in that being applicable to diabetic microangiopathy, non-diabetic microangiopathies, varicosis syndrome, with microcirculation disturbance occur together impaired function of vein, vein is peeled off and the treatment of venosclerosis and auxiliary treatment.
Inventing preferred technical scheme is:
A kind of calcium dobesilate capsule composition, said composition comprises: with composition weight meter, 60%～90% calcium dobesilate is as active component, 5%～40% microcrystalline Cellulose, 0.2%～10% silicon dioxide and liquid paraffin, the wherein weight ratio 1: 1～1: 3 of silicon dioxide and liquid paraffin.
A kind of calcium dobesilate capsule composition provided by the invention, it is characterized in that being applicable to diabetic microangiopathy, non-diabetic microangiopathies, varicosis syndrome, with microcirculation disturbance occur together impaired function of vein, vein is peeled off and the treatment of venosclerosis and auxiliary treatment.
The present composition, in prescription forms, by the screening to adjuvant in prescription, is selected suitable adjunct ingredient, makes medicine can not cause degraded because of moisture absorption.The multiplex disintegrating agent that arrived at present general calcium hydrophenyl sulfonate capsule prescription forms, in conjunction with the patent prescription, we have carried out the hygroscopicity experiment to disintegrating agent commonly used and filler, and experimental result is in Table 1.
Table 1 hygroscopicity comparing result
At granted patent " calcium hydrophenyl sulfonate capsule and preparation technology " (publication number: CN100377705C), do not use filler in optimizing prescriptions, and select to using carboxymethyl starch sodium as disintegrating agent, and in prescription, lubricant has been selected the wych-elm acid glyceride, mentioned the compressibility that the wych-elm acid glyceride is beneficial to capsule in granted patent, but the wych-elm acid glyceride to product moisture absorption aspect without remarkable improvement, to product stability without significantly improving.
At publication " a kind of calcium hydrophenyl sulfonate capsule and preparation method thereof " (publication number: CN102091055), disintegrating agent cross-linking sodium carboxymethyl cellulose and magnesium stearate lubricant have been used in optimizing prescriptions, cross-linking sodium carboxymethyl cellulose can cause the moisture absorption in the long-term storage process of product, magnesium stearate can cause Product mix inhomogeneous, dissolution that affects product etc. (refers to granted patent " calcium hydrophenyl sulfonate capsule and preparation technology " (publication number: CN100377705C)), optimizing prescriptions to the stability of calcium hydrophenyl sulfonate capsule without significantly improving, the production technology aspect has adopted fluidization, need just can obtain stable prod through preparation repeatedly, be unfavorable for industrialized great production, easily produce waste in production process, and, the disclosure patent is in order better to solve the dissolution of calcium hydrophenyl sulfonate capsule, but because calcium dobesilate is the easy soluble drug of water, select in a large number complexity on prescription and technique, expensive adjuvant and equipment, be unfavorable for the popularization on a large scale of product.
And the present invention finds when selecting specific filler and lubricant through great many of experiments and screening, can obviously improve the stability of medicine, and result of extraction is good.
The accompanying drawing explanation
Fig. 1 embodiment mono-and the stripping curve of Comparative Examples one sample in the 900ml0.1mol/L hydrochloric acid solution
Comparative Examples
Embodiment mono-
Below by embodiment, the present invention is further described.
Embodiment mono-
Prescription:
Technique:
1, calcium dobesilate was pulverized to 80 mesh sieves, microcrystalline Cellulose is crossed 80 mesh sieves;
2, take recipe quantity calcium dobesilate and microcrystalline Cellulose, mix;
3, take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4, add recipe quantity liquid paraffin and silicon dioxide, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Embodiment bis-
Technique:
1, calcium dobesilate was pulverized to 80 mesh sieves, microcrystalline Cellulose is crossed 80 mesh sieves;
2, take recipe quantity calcium dobesilate and microcrystalline Cellulose, mix;
3, take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4, add recipe quantity liquid paraffin and silicon dioxide, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Embodiment tri-
Preparation technology:
1) calcium dobesilate was pulverized to 80 mesh sieves, filler is crossed 80 mesh sieves;
2) take recipe quantity calcium dobesilate and microcrystalline Cellulose, lactose, mix;
3) take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4) add recipe quantity silicon dioxide and liquid paraffin, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Embodiment tetra-
Preparation technology:
1) calcium dobesilate was pulverized to 80 mesh sieves, filler is crossed 80 mesh sieves;
2) take recipe quantity calcium dobesilate and microcrystalline Cellulose, lactose mixes;
3) take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4) add recipe quantity silicon dioxide, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Embodiment five
A kind of calcium dobesilate capsule composition, said composition comprises: with composition weight meter,
Preparation technology:
1) calcium dobesilate was pulverized to 80 mesh sieves, filler is crossed 80 mesh sieves;
2) take recipe quantity calcium dobesilate and microcrystalline Cellulose, lactose mixes;
3) take 45% ethanol as wetting agent soft material processed, cross 28 mesh sieves and granulate, wet granular is dry under 80 ℃ of conditions, takes out dried particles;
4) add the recipe quantity magnesium stearate, mix homogeneously, cross 28 mesh sieve granulate, fills capsule No. 0.
Comparative Examples one (prior art publication number: the technical scheme of putting down in writing in CN100377705C)
Prescription:
Technique:
1, former, adjuvant were pulverized to 100 mesh sieves, standby;
2, the phenolsulfonic acid calcium raw material drug is dropped into to 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 recipe quantity carboxymethyl starch sodium, wych-elm acid glyceride, mix 50 and turn 15 minutes, sampling and measuring intermediate content and moisture.
5, capsule-filling.
Select embodiment mono-sample and Comparative Examples one sample to carry out stability test and dissolution investigation, can describe aspect stability product.Test method is as follows:
(1) get embodiment mono-sample and Comparative Examples one sample, place under 60 ℃ of high temperature, 40 ℃, RH75%, RH92.5% and intensity of illumination 4500Lx ± 500Lx condition, respectively at sampling in 5 days, 10 days, detect, and compared with 0 day, result of the test is in Table 2-table 7.
(2) get embodiment mono-sample and Comparative Examples one sample carries out the dissolution investigation according to the calcium hydrophenyl sulfonate capsule national drug standards, sample 5ml respectively at 5min, 10min, 20min, 30min, 45min, 60min, supplement the dissolution medium of synthermal same volume simultaneously, filter, get subsequent filtrate as need testing solution.Measured according to method under the dissolution determination item, and drawn stripping curve with time and dissolution, seen Fig. 1.
Table 2 embodiment mono-self-control calcium hydrophenyl sulfonate capsule influence factor result of the test
Table 3 embodiment bis-self-control calcium hydrophenyl sulfonate capsule influence factor result of the tests
Table 4 embodiment tri-self-control calcium hydrophenyl sulfonate capsule influence factor result of the tests
Table 5 embodiment four selfs calcium hydrophenyl sulfonate capsule influence factor processed result of the test
Table 6 embodiment five self-control calcium hydrophenyl sulfonate capsule influence factor result of the tests
Table 7 Comparative Examples one self-control calcium hydrophenyl sulfonate capsule influence factor result of the test
Result by embodiment 1-5 and Comparative Examples 1 relatively in 0.1mol/L hydrochloric acid dissolution without significant difference.
Study on the stability by above embodiment 1-5 and Comparative Examples 1 is known: 1, embodiment 1～5 sample is good at high temperature, high humidity, illumination condition stability inferior, with Comparative Examples 1, compares, and its related substance and moisture absorption weightening finish all are better than Comparative Examples; 2,, by the prescription proportioning in embodiment, when not adopting the higher disintegrating agent of hygroscopicity, can better solve the moisture absorption under the long-term storage requirement of product, and obviously improve stability; 3, in an embodiment, when using silicon dioxide and liquid paraffin mixture as lubricant, while using more separately silicon dioxide or other lubricants, stability is better.
Claims (1)
1. a calcium dobesilate capsule composition, said composition comprises: with composition weight meter, 60% ~ 90% calcium dobesilate is as active component, 5% ~ 40% microcrystalline Cellulose, 0.2% ~ 10% silicon dioxide and liquid paraffin, wherein the weight ratio of silicon dioxide and liquid paraffin is 1:1 ~ 1:3, and each included component percentage composition sum of said composition is 100%.
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| CN102579396B true CN102579396B (en) | 2013-12-25 |
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| CN103230383A (en) * | 2013-03-31 | 2013-08-07 | 北京万全阳光医学技术有限公司 | Calcium dobesilate capsule composition and preparation method thereof |
| CN106619564A (en) * | 2016-12-23 | 2017-05-10 | 北京满格医药科技有限公司 | Calcium dobesilate capsule and preparation method |
| CN110123776A (en) * | 2019-05-17 | 2019-08-16 | 贵州天安药业股份有限公司 | A kind of calcium hydrophenyl sulfonate capsule that efficient microcirculation improves |
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| CN100377705C (en) * | 2005-11-03 | 2008-04-02 | 上海朝晖药业有限公司 | Calcium hydrophenyl sulfonate capsule and its prepn process |
| CN1939291A (en) * | 2006-09-29 | 2007-04-04 | 何岩 | Hydroxyphenyl sulfonated calcium slow-releasing preparation |
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Address after: 750002 the Ningxia Hui Autonomous Region street, Jinfeng District, Yinchuan City Fu Ning Lane No. 57 Patentee after: Ningxia Kang Ya pharmaceutical Limited by Share Ltd Address before: 750002 No. 6 road, hi tech Industrial Development Zone, the Ningxia Hui Autonomous Region, Yinchuan Patentee before: Kangya Pharmaceutical Industry Co., Ltd., Ningxia |
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Granted publication date: 20131225 Termination date: 20190401 |