CN102091055B - Calcium dobesilate capsule and preparation method thereof - Google Patents
Calcium dobesilate capsule and preparation method thereof Download PDFInfo
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- CN102091055B CN102091055B CN 201110030889 CN201110030889A CN102091055B CN 102091055 B CN102091055 B CN 102091055B CN 201110030889 CN201110030889 CN 201110030889 CN 201110030889 A CN201110030889 A CN 201110030889A CN 102091055 B CN102091055 B CN 102091055B
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Abstract
The invention discloses a calcium dobesilate capsule and a preparation method thereof. The calcium dobesilate capsule is prepared from calcium dobesilate, croscarmellose sodium, magnesium stearate and polyvinyl pyrrolidone, wherein every 1000 calcium dobesilate capsules contain 500g of calcium dobesilate, 20-50g of croscarmellose sodium and 2-6g of magnesium stearate. In addition, a traditional preparation method is improved in the invention, and the improved method comprises the following steps: on the basis of taking the croscarmellose sodium as a disintegrating agent and taking the magnesium stearate as a lubricating agent, adding a proper amount of the polyvinyl pyrrolidone to prepare a bonding agent; preparing the bonding agent and the calcium dobesilate as well as the croscarmellosesodium into granules by a multi-step granulation method; and spraying the ethanol solution of the magnesium stearate onto the surfaces of the granules to obtain calcium dobesilate capsules with stable quality, high dissolution rate and small content uniformity.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, more particularly the invention provides a kind of calcium hydrophenyl sulfonate capsule and preparation method thereof.
Background technology
Calcium hydrophenyl sulfonate capsule, English name: Calcium Dobesilate Capsules.This product Main Ingredients and Appearance is calcium dobesilate, and its chemical name is: CBD.Its structural formula is:
Molecular formula: C
12H
10CaO
10S
2H
2O, molecular weight: 436.42.
Improving constantly along with living standard in recent years.The diabetics that is called as affluenza has the trend that increases year by year.The many complication that caused by diabetes.Become one of big factors of harm people ' s health.Diabetic renal papillary necrosis (DR) is one of severe complication of diabetes.In European and American countries four large diseases causing blindnesses, occupy first.The incidence rate of China's diabetic retinopathy is about 45-58% according to statistics.According to the interrelated data statistics, diabetic duration is 35-39% in its DR incidence rate of person below 5 years; Course of disease 5-10 person is 50-56.7%.Increase to more than 10 years and be 69-90%.Being associated with hypertension, hyperlipidemia, Hemorheology such as the while whole body has obvious changer, and then the DR incidence rate is higher.20 years type ii diabetes persons of the course of disease, oral antidiabetic drug, its DR incidence rate is 60%, injection islets of langerhans rope person is 84%.As seen existing antidiabetic drug can not reduce generation and the development of DR.
Studies confirm that at present, the key that DR occurs is the retinal tissue anoxia.Early stage pathology is changed into pericapillary cells forfeiture, and microangioma forms, and capillary basement membrane thickens, and blood-retina barrier destroys, hemorrhage, oozing of blood and retinal edema.Late period, visible new vessels, abnormal vascular formed and fibroplasia, finally caused vitreous hemorrhage, even detachment of retina.At present the pathogenetic research of DR is focused mostly at the aspects such as effect of the accumulation of unusual, the protein non-enzyme glycosylation product of polyhydric alcohol metabolic pathway, protein kinase C activation, oxidative stress theory, cytokine.Tight glycemic control and laser therapy can reduce patient's the blindness and blinding clinically, but can not reverse the retina injury that has existed.And targetedly aldose reductase inhibitor and inhibitors of protein kinase C treatment can not be played good curative effect.Calcium dobesilate is the treatment for DR the earliest, also is to treat at present the comparatively ideal medicine of DR.
At present the preparation at the calcium dobesilate of China's list marketing has conventional tablet, dispersible tablet, granule and capsule, and wherein capsule is most widely used general clinically, and two kinds of specifications of 0.5g and 0.25g are arranged.
As disclosing the preparation method of following a kind of calcium hydrophenyl sulfonate capsule in the prior art:
One, prescription
The material name consumption
Calcium dobesilate-hydrate 521.5g
(being equivalent to calcium dobesilate 500g)
Carboxymethyl starch sodium 45.0g
Magnesium stearate 5.0g
Make 1000
Two, preparation technology
1, supplementary material was pulverized respectively 100 mesh sieves, lower dry 4 hours respectively at 60 ℃;
2, take by weighing calcium dobesilate-hydrate, carboxymethylstach sodium and the magnesium stearate of recipe quantity, evenly mixed by the equivalent incremental method;
3, get above-mentioned mixed powder art, measure content, the moisture (control moisture scope 4%-6%) of intermediate, qualified rear fill gets final product in No. 0 capsule.
But there are some problems in this technique:
1, adopt the granule that directly mixes, flowability is relevant with the character of raw material itself, often can that loading amount occurs be unstable because of the poor fluidity of raw material own in stowing operation, and the phenomenon that content uniformity is large.And easily cause the adhesions such as jumper bar, calculating dial of capsule filler, cause producing and normally to carry out.
2, magnesium stearate is a lubricant in this prescription, will reach mixing 50 and turn (15 minutes) fully mix homogeneously, the still non-compliant regulation of dissolution of product under these process conditions when always mixing.Be lower than this operation requirements such as incorporation time, can cause material to mix inhomogeneous, granule content there are differences, and sticking etc. can occur in stowing operation cause content uniformity.
Because the problems referred to above, this Process Planning model often causes certain difficulty when producing, thereby has limited application.The patent application of application number 200510110019.2 has proposed a kind of new hydroxyl sulfoacid calcium capsule and preparation technology.Per 1000 capsules are grouped into by the one-tenth of following weight: calcium dobesilate 500g, carboxymethyl starch sodium 20～40g, Rikemal B 200 2.5～5g, 95% ethanol 30g.Its preparation technology is: 1. supplementary material was pulverized respectively 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 turn 15 minutes, sampling and measuring intermediate content and moisture; 5. according to intermediate assay result, contain calcium dobesilate 0.5g by every capsules and calculate the capsule loading amount.Although the defectives such as the disintegration time, the dissolution that cause medicine because incorporation time is long that above-mentioned preparation method has avoided the employing magnesium stearate to cause to a certain extent are defective.But the capsule stability of its preparation and disintegrating property also have very large room for improvement.
In view of this, special proposition the present invention.
Summary of the invention
The invention provides calcium hydrophenyl sulfonate capsule that a kind of advantages of simple of writing out a prescription, feasible process are stable, the product quality controllability is good and preparation method thereof.
The first purpose of the present invention is to provide a kind of calcium hydrophenyl sulfonate capsule.Calcium hydrophenyl sulfonate capsule related substance provided by the present invention is low, good stability, and dissolution is good, and is quality controllable.The second purpose of the present invention is to provide the preparation method of above-mentioned calcium hydrophenyl sulfonate capsule.For achieving the above object, the present invention adopts following technical scheme:
A kind of calcium hydrophenyl sulfonate capsule, described capsule is prepared from by calcium dobesilate, cross-linking sodium carboxymethyl cellulose, magnesium stearate and polyvinylpyrrolidone, wherein per 1000 calcium hydrophenyl sulfonate capsules contain: calcium dobesilate 500g, cross-linking sodium carboxymethyl cellulose 20～50g, magnesium stearate 2～6g.
Per 1000 of described calcium hydrophenyl sulfonate capsule contains: calcium dobesilate 500g, cross-linking sodium carboxymethyl cellulose 30～40g, magnesium stearate 3～5g.
Per 1000 of described calcium hydrophenyl sulfonate capsule contains: calcium dobesilate 500g, cross-linking sodium carboxymethyl cellulose 35g, magnesium stearate 4g, polyvinylpyrrolidone 3g.
A kind of preparation method of as mentioned above calcium hydrophenyl sulfonate capsule, described preparation method comprises the preparation of calcium dobesilate granule, the preparation method of described granule is as follows:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, mix primary granule processed to the cross-linked carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 35-65% and recipe quantity 30-70%;
(4) with adding 5/13 binding agent and the calcium dobesilate of recipe quantity 35-65%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30-70% in the primary granule that makes, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying, fill.
The drying of described step 5 is carried out drying for the calcium dobesilate raw material powder of gained granule after will granulating and recipe quantity 0-35%, the cross-linked carboxymethyl cellulose raw material powder mixing of recipe quantity 0-40%.
The preparation method of described granule is as follows:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 45-60% and recipe quantity 40-70%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 40-55%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30-60%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying, fill;
The preparation method of preferred described granule is:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 55% and recipe quantity 60%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying, fill;
The preparation method of described granule is as follows:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 35-50% and recipe quantity 40-50%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 30-45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30-40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously carries out drying, fill with gained granule and the calcium dobesilate raw material powder of 5-35%, the cross-linked carboxymethyl cellulose raw material powder of 10-30% after the spraying;
The preparation method of preferred described granule is:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 40% and recipe quantity 40%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 25% calcium dobesilate raw material powder, 25% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, fill.
Pretreatment is in the described step 1: calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ± 5 ℃ of dryings 1 hour.
Alcoholic solution in the described step 5 is 40-80ml, preferred 60ml; Concentration of alcohol is 75-95%, preferred 85%.
Drying in the described step 5 is in fluid bed 55-85 ℃, dry 0.5-1.5 hour; Preferably with 70 ℃, dry 0.5-1.5 hour, be filled in the 0# Capsules after calculating loading amount according to the intermediate testing result, the present invention is carried out further introducing in detail below 800～1000/minute of the capsule-filling speed.
Calcium dobesilate is a kind of blood capillary circulation improving agent, clinical prevention and the treatment that is usually used in the various diseases that diabetic retinopathy, varicosis syndrome etc. cause by blood capillary circulatory disturbance.It is white or off-white color hygroscopic powder, powder fluidity is poor, therefore, when calcium hydrophenyl sulfonate capsule is carried out Formulation, therefore one side will fully take into account the poor fluidity of calcium dobesilate own needs the adding lubricant improve its flowability, will consider also that on the other hand adding lubricant still will keep the qualified dissolution of medicine afterwards.
The present invention has continued to use magnesium stearate in the calcium hydrophenyl sulfonate capsule tradition prescription as lubricant, and magnesium stearate is good lubricant, and it is used widely in the preparation process of medicine, and effect has also obtained abundant checking.Calcium hydrophenyl sulfonate capsule mostly adopts the supplementary material drying afterwards directly with the powder filled capsules in the prior art, since magnesium stearate with need regular hour and the rotating speed could abundant mixing mixing of calcium dobesilate and Carboxymethyl cellulose sodium, and often be easy under this condition cause the dissolution of capsule defective.Therefore, the two is difficult to take into account.
The invention provides a kind of preparation method of new calcium hydrophenyl sulfonate capsule, as disintegrating agent, magnesium stearate is as lubricant with crosslinked Carboxymethyl cellulose sodium for this calcium hydrophenyl sulfonate capsule.In order to overcome in the prior art supplementary material powder is directly mixed the problems such as the content uniformity that may occur in the encapsulated process and dissolution be defective, the present invention improves traditional preparation method, be specially with crosslinked Carboxymethyl cellulose sodium as disintegrating agent, on the basis of magnesium stearate as lubricant, add an amount of polyvinylpyrrolidone and prepare binding agent, by the multistep granulation with binding agent with calcium dobesilate and exchange Carboxymethyl cellulose sodium and be prepared into granule, alcoholic solution with magnesium stearate is sprayed to particle surface again, on the one hand, can be with the magnesium stearate even spraying on granule, play good lubrication, on the other hand, alcoholic solution with magnesium stearate wraps up granule the effect that also can play elimination static, is conducive to follow-up mixing, thereby further reaches the purpose that reduces content uniformity.Granule after the spraying is carried out dried, and intermediate is detected, directly the fill capsule gets final product.
Among the present invention, the alcoholic solution of magnesium stearate is that the 2-6g magnesium stearate is dissolved in 40-80ml ethanol because the dissolubility of magnesium stearate in alcohol be low, therefore, magnesium stearate added alcoholic solution after, can only form suspension under the room temperature.The concentration of alcoholic solution can be 75-95%, and those skilled in the art can select suitable concentration of alcohol and consumption according to prescription and practical operation condition.The present invention most preferably adds magnesium stearate in the alcoholic solution of 60ml85%.In addition, one skilled in the art will appreciate that heating can improve the dissolubility of magnesium stearate in ethanol, therefore, can heat to ethanol the hot alcoholic solution spraying granule of rear employing magnesium stearate, also can adopt the suspension of magnesium stearate and room temperature ethanol.After the spraying, the magnesium stearate in the suspension also can evenly be adsorbed on particle surface, plays the effect of lubricant.
In addition, as a preferred embodiment of the present invention, in pelletization, adopt calcium dobesilate and the crosslinked Carboxymethyl cellulose sodium of 70%-90% with binding agent and recipe quantity 65%-95% to be prepared into granule, the alcoholic solution with magnesium stearate is sprayed to particle surface again.The calcium dobesilate of remaining 5%-35% and the crosslinked Carboxymethyl cellulose sodium powder of 10-30% are mixed with granule after the spraying, dryly its intermediate is detected the fill capsule afterwards.In this technical scheme, utilize the percentage by weight of this prescription calcium dobesilate up to 95.3%, the consumption of adjuvant is low, causes the supplementary material part of partly granulating directly can ignore with the content uniformity that the powder filling capsule causes.In addition, magnesium stearate is sprayed to particle surface after, when mixing with remaining supplementary material powder, this granule itself also can play the effect of lubricant, improves the flowability of supplementary material powder, has further avoided content uniformity.And the mode one that adopts part to granulate is smaller volume after granulating, and is conducive to the fill of capsule, in addition because powder than the easier moisture absorption of granule, adopts the form fill of part granule also to help to improve the stability of medicine.
In two kinds of preparation methoies of the present invention, all relate to the preparation of calcium dobesilate granule, concrete, the present invention adopts the multistep granulation, comprises the steps:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
The present invention adopts polyvinylpyrrolidone to prepare binding agent, and PVP has good physiology inertia, does not participate in the human body metabolism, has again good biocompatibility, is a kind of ideal binding agent.In the early-stage Study, inventor's general knowledge multiple binding agent, the final discovery adopted polyvinylpyrrolidone to prepare binding agent and helped more to realize that multistep of the present invention granulates.Polyvinylpyrrolidone both can be water-soluble, can be dissolved in ethanol again, and those skilled in the art can be according to selecting any solvent, the alcoholic solution of preferably polyethylene ketopyrrolidine of the present invention in the actual production process.Wherein the consumption of polyvinylpyrrolidone is advisable with per 1000 capsules 2.5-5g, and most preferably in 1000 capsules, the consumption of polyvinylpyrrolidone is 3g.The ethanol of described ethanol preferred 95%.The visual concrete prescription of the consumption of the concentration of ethanol, consumption and polyvinylpyrrolidone and slightly inching, this technology is known to those skilled in the art already.
(3) get 8/13 binding agent, mix primary granule processed to the cross-linked carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 35-65% and recipe quantity 30-70%;
(4) with adding 5/13 binding agent and the calcium dobesilate of recipe quantity 35-65%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30-70% in the primary granule that makes, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying, fill.
As mentioned above, the present invention is by being divided into multistep with pelletization, first binding agent with 8/13 mixes most of calcium dobesilate and crosslinked Carboxymethyl cellulose sodium is made primary granule, mix with 5/13 binding agent mixing portion calcium dobesilate and crosslinked Carboxymethyl cellulose sodium again, further granulate, until without residual powder, granulate obtains intermediate grain, at last with the alcoholic solution of magnesium stearate to the processing of spraying of calcium dobesilate granule.
Granule by above-mentioned preparation method makes than the granule of available technology adopting with supplementary material powder and the direct mixing granulation preparation of binding agent, has better dissolution.After 5/13 binding agent adds in the step 4, the powder of the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate of recipe quantity 35-65%, recipe quantity 30-70% forms the new primary granule except a part and binding agent, another part can stick to the primary granule surface, form the granule of multiple structure, so just obtained the different sizes calcium dobesilate granule different from structure.May be that the multiple structure of formation provides better stripping passage to the stripping of calcium dobesilate when adopting multistep to granulate.It also may be the stripping that unique space of forming between the granule of different size more helps calcium dobesilate.The present invention reaches the purpose that improves dissolution by the composition of the consumption control granule of control binding agent.The present invention preferably carried out for two steps with 8/13,5/13 amount respectively with binding agent and granulates, but above-mentioned ratio is an optimal proportion, true if in the control step 3 in binding agent and the step 4 binder dosage be between the 1.2-2.5, can realize the raising of dissolution.
In addition, the concentration of alcohol of magnesium stearate also has a huge impact whole preparation method, excessive concentration causes spray amount few, be difficult to even spraying on the surface of calcium hydrophenyl sulfonate capsule, be difficult to play effect lubricated and elimination static, concentration is too low and easily cause spray amount excessive, causes the intermediate grain disintegrate, cause between the granule inter-adhesively, destroy the structure of multilayer particle.The inventor has done screening test according to prescription to the concentration of alcohol of magnesium stearate.The final discovery, when the concentration that is dissolved in the magnesium stearate of recipe quantity is that the 40-80ml alcoholic solution of 75-95% is, the time, can obtain satisfied spray effect, wherein, the consumption of preferred alcohol is 60ml; Concentration preferred 85%.
Drying in the step 5, the present invention adopts at 55-85 in fluid bed ℃, dry 0.5-1.5 hour; Preferably with 70 ℃, dry 0.5-1.5 hour.
The preparation method of two kinds of calcium hydrophenyl sulfonate capsules that the present invention is claimed includes the preparation process of above-mentioned calcium dobesilate granule, distinctive points is: scheme one adopts all supplementary materials all is prepared into the calcium dobesilate granule, during fill directly with granule filling; Scheme two adopts the part supplementary material to make the calcium dobesilate granule, and the part supplementary material directly mixes with granule with powder, and the mode with granule+powder during fill pours into capsule shells.
In scheme one, the inventor further defines the consumption of supplementary material in the primary granule preparation.The consumption that the consumption of strong this sodium sulfonate and crosslinked Carboxymethyl cellulose sodium is higher than in the intermediate grain process the two in the elementary granulation is as basic principle, specifically set and got 8/13 binding agent in the step 3, cross-linking sodium carboxymethyl cellulose to the calcium dobesilate that wherein adds recipe quantity 45-60% and recipe quantity 40-70%, mix primary granule processed; In the step 4 primary granule that makes is put into fluid bed, add the cross-linking sodium carboxymethyl cellulose of 5/13 binding agent and recipe quantity 40-55%, the calcium dobesilate of 30-60% recipe quantity, further granulate, until without residual powder, granulate gets intermediate grain; Then directly to the alcoholic solution of intermediate grain spraying magnesium stearate, mix drying, fill.
As preferably, scheme one can specifically adopt following technical scheme:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds 55% recipe quantity and recipe quantity 60%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying, fill;
In the design of scheme two, the inventor adopts reserve part supplementary material powder directly to be used as medicine, and concrete supplementary material use amount is: get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds the 35-50% recipe quantity and recipe quantity 40-50%, mix primary granule processed; The primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 30-45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30-40%, further granulate, until without residual powder, granulate gets intermediate grain; The alcoholic solution that adds magnesium stearate to the intermediate grain spraying, mix homogeneously carries out drying, fill with gained granule and the calcium dobesilate raw material powder of 5-35%, the cross-linked carboxymethyl cellulose raw material powder of 10-30% after the spraying.
As preferred embodiment, the preparation method of scheme two is:
(1) weighs each supplementary material, and carry out respectively pretreatment;
(2) prepare binding agent with pure water or anhydrous alcohol solution polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 40% and recipe quantity 40%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 25% calcium dobesilate raw material powder, 25% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, fill.
More particularly, contain as per 1000 take prescription: calcium dobesilate 500g, cross-linking sodium carboxymethyl cellulose 35g, magnesium stearate 4g, polyvinylpyrrolidone 3g, according to scheme two preferred preparation method preparations, the calcium hydrophenyl sulfonate capsule quality of gained is the most stable, dissolution and content uniformity all are in optimum range, are the most preferred embodiments of the present invention.
In addition, the claimed preparation method of the present invention is more reasonable in order to make, science, and the inventor has done special test to the pretreatment of crude drug and the filling of capsule, and is specific as follows:
The crude drug Study on pretreatment
Get this product crude drug, measure according to Chinese Pharmacopoeia version in 2005 two appendix IX E (granularity and particle size distribution method the second method), the result can not account for 23.8% by the granule of 60 mesh sieves, processes after sieve after therefore working out in preparation is produced raw material pulverizing.
Get this product crude drug, cross respectively 60,80,100 mesh sieves after the pulverizing, measure respectively the angle of repose of powder by fixing conical bottom method, the result is as follows:
Table 1 crude drug is measured angle of repose
Got by result of the test, the powder flowbility of crossing 100 mesh sieves is best, but does not satisfy the requirement of directly filling.
To the research discovery of this product crude drug, the crude drug powder surface is moistening, and certain viscosity is arranged, and affects flowing of granule.Carry out drying and processing therefore plan crude drug, to reduce or to eliminate this impact, improve powder flowbility.
Cross 100 mesh sieves after this product crude drug pulverized, carry out drying under 60 ± 5 ℃ of conditions, be 38.4 ° the angle of repose of measuring dried powder by fixing conical bottom method, and powder flowbility is better, can be directly used in capsule-filling.Work out this product crude drug pretreating process is in accordance with the law: cross 100 mesh sieves after pulverizing, and dry under 60 ± 5 ℃ of conditions.
Drying process
Equipment: CT-C-II type heated-air circulation oven
Get the calcium dobesilate that makes by the prescription of tentatively working out and preparation technology and the mixed powder of cross-linking sodium carboxymethyl cellulose, dry under 60 ℃ of conditions, respectively at sampling in the 0.5th, 1,2,3 hour, measure angle of repose, the result is as follows:
Table 2 is investigated drying time
Got by result of the test, after 1 hour, powder reaches minimum angle of repose in 60 ℃ of dryings, and powder has primary liquidity, satisfies the needs of subsequent technique.Work out drying process was in accordance with the law: in 60 ± 5 ℃ of dryings 1 hour.
Filling speed
Equipment: NJP1200D type fully-automatic capsule filling machine
The highest filling speed of capsule filling machine is 1200/minute, fill with 20 hertz (600/minute), 30 hertz (800/minute), 40 hertz (1000/minute), 50 hertz (1200 s'/minute) speed respectively, measure the content uniformity of capsule, the result is as follows:
Table 3 filling speed is investigated
According to the regulation of two appendix I of Chinese Pharmacopoeia version in 2005 E, the content uniformity limit of this product should be ± and 7.5%, be to guarantee product quality, the control content uniformity is in ± 5% scope in the preparation process.According to above-mentioned result of the test, consider production efficiency, working out capsule-filling speed is 800～1000/minute.
The calcium hydrophenyl sulfonate capsule related substance of the present invention's preparation is low, has effectively avoided content uniformity under the prerequisite that guarantees dissolution, and constant product quality is controlled.The prescription advantages of simple, preparation method is easy to operate, feasible process is stable.Its power consumption is few, can realize that suitability for industrialized production has considerable economic and social benefits, has very strong practicality.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
The preparation method of capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ± 5 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 2.5-5g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 55% and recipe quantity 60%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 800/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 2
The preparation method of capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 65 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 2.5-5g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 60% and recipe quantity 70%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 40%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 1000/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 3
The preparation method of capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 63 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 2.5-5g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 50% and recipe quantity 55%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 50%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 45%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 900/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 4
The preparation method of capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 2.5-5g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 65% and recipe quantity 70%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 800/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 5
The preparation method of capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 58 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 25-50g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 45% and recipe quantity 65%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 55%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 900/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 6
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 5-10g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 58% and recipe quantity 60%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 42%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution of magnesium stearate to intermediate grain spraying, mix homogeneously, drying detects intermediate, is filled in the 0# Capsules, 800/minute of capsule-filling speed after calculating loading amount according to the intermediate testing result.
Embodiment 7
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 5-10g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 48% and recipe quantity 44%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 32%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 36%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 20% calcium dobesilate raw material powder, 20% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 800/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
Embodiment 8
The preparation method of described granule is as follows:
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 15g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 50% and recipe quantity 50%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 30%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 20% calcium dobesilate raw material powder, 20% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 1000/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
Embodiment 9
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 10g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 45% and recipe quantity 45%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 20% calcium dobesilate raw material powder, 20% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 950/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
Embodiment 10
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 3.5-5g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 50% and recipe quantity 50%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 45%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 40%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 5% calcium dobesilate raw material powder, 10% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 800/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
Embodiment 11
The preparation method of described granule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 2.5-4g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 35% and recipe quantity 40%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 30%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 30%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 35% calcium dobesilate raw material powder, 30% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 800/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
Embodiment 12
The preparation method of described capsule is as follows:
(1) weighs each supplementary material, calcium dobesilate and Carboxymethyl cellulose sodium are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 3g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 40% and recipe quantity 40%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) to the alcoholic solution of intermediate grain spraying adding magnesium stearate, mix homogeneously is granulated; Gained granule and 25% calcium dobesilate raw material powder, 25% cross-linked carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules, 900/minute of capsule-filling speed after the intermediate testing result calculating loading amount.
In order further to verify the science of prescription of the present invention and preparation method, the inventor has done following test:
Test the detection of 1 experimental example sample
The present invention adopts detection method commonly used in the prior art that the product relevant parameter of embodiment 1-12 is tested, and the results are shown in Table 4,5:
The assay of table 4 embodiment sample
The assay of table 5 embodiment sample
The above results shows, the calcium dobesilate each side index that adopts the preparation of prescription of the present invention and preparation method is all qualified and significantly be better than prior art, steady quality.
Test example 2
This test example has been investigated and has been adopted prescription of the present invention and preparation method for the impact of the content uniformity of formulation products.The results are shown in Table 6.
Table 6 prescription of the present invention and preparation method are for the impact of the content uniformity of formulation products
Sequence number 1-5 is respectively embodiment 1,3,7,9,6 products of 12 in the upper table;
Sequence number 6-10 is respectively disclosed embodiment 1-5 in the application number 200510110019.2;
Sequence number 11 is commercially available calcium hydrophenyl sulfonate capsule (calcium dobesilate) 0.5g*10s*2 plate/box (the sharp monarch's pharmacy in Xi'an);
Sequence number 12 is disclosed calcium hydrophenyl sulfonate capsule in the prior art, and the prescription of this capsule is: calcium dobesilate-hydrate 521.5g (being equivalent to calcium dobesilate 500g), carboxymethyl starch sodium 45.0g, magnesium stearate 5.0g, make 1000.Employing is prepared from the method for the direct fill of supplementary material powder.
The above results shows, adopts prescription of the present invention and preparation method, and the content uniformity of gained calcium hydrophenyl sulfonate capsule is significantly less than prior art.
Test example 3
This test example has been investigated the stability of calcium hydrophenyl sulfonate capsule provided by the present invention, and result of the test sees Table 7,8.
Table 7, accelerated test
| 0 month | 1 month | 2 months | 3 months | 6 months | |
| 1 | 99.96 | 99.95 | 99.93 | 99.89 | 99.78 |
| 2 | 99.93 | 99.90 | 99.86 | 99.78 | 99.64 |
| 3 | 99.88 | 99.84 | 99.80 | 99.76 | 99.72 |
| 4 | 99.86 | 99.82 | 99.78 | 99.70 | 99.66 |
Table 8, long term test
| 0 month | 3 months | 6 months | 9 months | 12 months | 18 months | |
| 1 | 99.96 | 99.95 | 99.93 | 99.91 | 99.89 | 99.88 |
| 2 | 99.92 | 99.86 | 99.84 | 99.80 | 99.76 | 99.72 |
| 3 | 99.88 | 99.86 | 99.82 | 99.79 | 99.76 | 99.74 |
| 4 | 99.86 | 99.82 | 99.79 | 99.76 | 99.73 | 99.70 |
In this test, every group of sequence number 1-4 product got 50 at random, detects stability data according to 2005 editions appendix XIX of Chinese Pharmacopoeia C method, then gets each cell mean, inserts table.
Wherein: 1 is the product according to embodiment 12 preparations;
Sequence number 2 is disclosed embodiment 1 in the application number 200510110019.2;
Sequence number 3 is commercially available calcium hydrophenyl sulfonate capsule (calcium dobesilate) 0.5g*10s*2 plate/box (the sharp monarch's pharmacy in Xi'an);
Sequence number 4 is disclosed calcium hydrophenyl sulfonate capsule in the prior art, and the prescription of this capsule is: calcium dobesilate-hydrate 521.5g (being equivalent to calcium dobesilate 500g), carboxymethyl starch sodium 45.0g, magnesium stearate 5.0g, make 1000.Employing is prepared from the method for the direct fill of supplementary material powder.
The above results shows, adopts prescription of the present invention and preparation method, and the stability of gained calcium hydrophenyl sulfonate capsule has obtained the raising of significance.
The inventor has also done same test to other embodiment of the present invention, and the result has same trend, because length is limit, differs and one enumerates herein.
Claims (1)
1. calcium hydrophenyl sulfonate capsule is characterized in that:
The preparation method of described capsule is as follows:
(1) weighs each supplementary material, active component calcium dobesilate 500g and disintegrating agent cross-linking sodium carboxymethyl cellulose 35g are crossed respectively 100 mesh sieves, in 60 ℃ of dryings 1 hour;
(2) prepare binding agent with dissolve with ethanol 3g polyvinylpyrrolidone;
(3) get 8/13 binding agent, to the cross-linking sodium carboxymethyl cellulose of the calcium dobesilate that wherein adds recipe quantity 40% and recipe quantity 40%, mix primary granule processed;
(4) primary granule that makes is put into fluid bed, add the calcium dobesilate of 5/13 binding agent and recipe quantity 35%, the cross-linking sodium carboxymethyl cellulose of recipe quantity 35%, further granulate, until without residual powder, granulate gets intermediate grain;
(5) add the alcoholic solution that contains the 4g magnesium stearate lubricant to the intermediate grain spraying, mix homogeneously is granulated; Gained granule and 25% calcium dobesilate raw material powder, 25% cross-linking sodium carboxymethyl cellulose raw material powder after the spraying are carried out drying, intermediate is detected, according to being filled in the 0# Capsules after the intermediate testing result calculating loading amount, 900/minute of capsule-filling speed are made 1000.
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| CN102416006A (en) * | 2011-12-05 | 2012-04-18 | 上海朝晖药业有限公司 | Calcium dobesilate capsules and preparation method thereof |
| 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 |
| CN104622842B (en) * | 2014-12-23 | 2017-06-06 | 北京京丰制药集团有限公司 | A kind of calcium hydrophenyl sulfonate capsule and preparation method thereof |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771927A (en) * | 2005-11-03 | 2006-05-17 | 上海复星朝晖药业有限公司 | Calcium hydrophenyl sulfonate capsule and its prepn process |
| WO2006069806A1 (en) * | 2004-12-30 | 2006-07-06 | Laboratorios Del Dr. Esteve, S.A. | Pharmaceutical composition comprinsing a 2,5-dihydroxybenzenesulfonic compounds, a potassium ion channel modulator and a phosphodiesterase type 5 inhibitor |
| CN1939291A (en) * | 2006-09-29 | 2007-04-04 | 何岩 | Hydroxyphenyl sulfonated calcium slow-releasing preparation |
| CN101822648A (en) * | 2009-03-04 | 2010-09-08 | 姚春霞 | Preparation method and application of nano dobesilate calcium capsule or tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006069806A1 (en) * | 2004-12-30 | 2006-07-06 | Laboratorios Del Dr. Esteve, S.A. | Pharmaceutical composition comprinsing a 2,5-dihydroxybenzenesulfonic compounds, a potassium ion channel modulator and a phosphodiesterase type 5 inhibitor |
| CN1771927A (en) * | 2005-11-03 | 2006-05-17 | 上海复星朝晖药业有限公司 | Calcium hydrophenyl sulfonate capsule and its prepn process |
| CN1939291A (en) * | 2006-09-29 | 2007-04-04 | 何岩 | Hydroxyphenyl sulfonated calcium slow-releasing preparation |
| CN101822648A (en) * | 2009-03-04 | 2010-09-08 | 姚春霞 | Preparation method and application of nano dobesilate calcium capsule or tablet |
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