CN106619564A - Calcium dobesilate capsule and preparation method - Google Patents
Calcium dobesilate capsule and preparation method Download PDFInfo
- Publication number
- CN106619564A CN106619564A CN201611272181.9A CN201611272181A CN106619564A CN 106619564 A CN106619564 A CN 106619564A CN 201611272181 A CN201611272181 A CN 201611272181A CN 106619564 A CN106619564 A CN 106619564A
- Authority
- CN
- China
- Prior art keywords
- calcium
- filler
- lubricant
- calcium dobesilate
- granulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Abstract
The invention relates to a calcium dobesilate capsule and a preparation method, and belongs to the technical field of pharmaceutical preparations. According to the technical scheme, the calcium dobesilate capsule is prepared from a therapeutically effective dose of calcium dobesilate, filler and a lubricant. The capsule is characterized by being produced with a wet granulation and dry granulation combined process. The materials are subjected to wet granulation before the dry granulation process, the problem of poor mobility due to too large proportion of calcium dobesilate in a prescription is solved, and the problem of high variability of each sample in the early stage of the dissolution process is also solved.
Description
Technical field：
The present invention relates to a kind of calcium hydrophenyl sulfonate capsule and preparation method, belong to technical field of medicine.
Background technology：
Diabetes are that a kind of glucose in blood easily piles up excessive disease.With the improvement of people's living standards, people
Mouthful aging and obesity rates increase, and the incidence of disease of China's diabetes has the trend of rising.Onset diabetes are slow, and symptom is hidden
Hide, the state of an illness is complicated, often merges various complication.Retinopathy, ephrosis and neurological disorder are referred to as three big complication of diabetes.
When diabetes are treated, it is necessarily required to be treated for these complication.Calcium Dobesilate is regarded in treatment diabetic keratopathy
Nethike embrane disease has its unique curative effect.
Calcium hydrophenyl sulfonate capsule puts goods on the market the seventies in last century in Europe, is clinically mainly used in the micro- blood of diabetic keratopathy
(capillary fragility and permeability increase, capillary for pipe pathology (retinopathy and glomerulosclerosis) and microvascular lesions
Disease, acrocyanosis).Calcium Dobesilate is by suppressing vaso-active substance (histamine, serotonin, bradykinin, hyaluronic acid
Enzyme, prostaglandin) cause high penetration effect, so as to improve the biosynthesis of basilar memebrane collagen.It is high that it can reduce capillary
Permeability, reduces blood-high-viscosity, reduces blood platelet high activity, oozes out so as to mitigate retina, bleeding, reduces microaneurysm
Deng.The permeability that simultaneously Calcium Dobesilate passes through reduction capillary, stable blood-retina barrier, can reduce retinal blood
Liquid exosmoses, and keeps the normal dilution of blood.By reducing macromolecular plasma protein and reducing Rigidity of red cells and coherency, can
Improve blood circulation, by reducing hematoblastic high coherency, can prevent ischemic from occurring.
The country introduces to the market the medicine in June calendar year 2001.There are Calcium Dobesilate granule, capsule on domestic market
Agent, conventional tablet and dispersible tablet.In the capsule preparations of domestic market sales, import drugs listing is relatively early, and release behavior more delays
Slowly, but because Calcium Dobesilate is highly soluble in water, carry out taking many commercially available capsules and carrying out parallel examination when In Vitro Dissolution curve is investigated
Test, it is found that variability is larger between same batch sample；The preparation of domestic manufacturer's listing, release behavior is very fast, with import system
Agent difference is obvious.These all cause clinical effectiveness to have differences, and to disease treatment hidden danger is brought.
The content of the invention
Goal of the invention：The present invention is intended to provide a kind of good quality, discharging stable calcium hydrophenyl sulfonate capsule and its preparation
Method.
Because soluble in water, import listing preparation dissolution is slow release characteristic to Calcium Dobesilate, in In Vitro Dissolution test
It was found that needing just to can reach complete dissolution in 2～3 hours.When finding that carrying out In Vitro Dissolution detects simultaneously, import lists preparation molten
Go out early stage each sample stripping quantity to differ greatly.In order to reach the purpose for slowing down release, inventor herein enters to prescription and technique
Row research, has been surprisingly found that if carried out after wet granulation to sample, then carry out dry granulation in research, and obtained particle is carried out
Filling capsule.Obtained sample is carried out after In Vitro Dissolution detection, finds consistent same of In Vitro Dissolution feature and import listing preparation
When, difference is significantly reduced between dissolution early stage same batch sample, and sample quality lists preparation better than import.
Wet granulation and dry granulation are the two kinds of granulation modes commonly used in preparation process, and normal conditions choose one of which
As the means for improving powder flowbility or mouldability in tablet technique tableting processes.Wet granulation is added in drug powder
Adhesive, by the method that the bridge formation or adhesive effect of adhesive coalesce together powder and prepare particle.Wet granulation includes
Extruding granulation, rotation granulation, fluidized granulation and stirring granulation etc..Particle made by wet method through moistened surface, with particle matter
Measure, good looking appearance, the wearability advantage good compared with strong, compact property is most widely used in medical industry.Dry granulation
Technology is to be pressed into thin slice, then the granulation mode for being ground into particle by dry-pressing granulator.Powder is passed through in the space for limiting
Apply external force and compress as dense state.Producing the stable power reunited has bridging power, low-viscosity (mobile) liquid cohesive force, the table of floc sedimentation
Face power and interpolymerized power.The obtained particles benefit of dry-pressing granulation is in the stability, disintegrative and the dissolution that improve particle.
Inventor herein uses pregelatinized starch according to Calcium Dobesilate property soluble in water, in auxiliary material, utilizes
Pregelatinized starch meets the characteristic that water forms gel, delays the dissolution of Calcium Dobesilate；The obtained pellet hardness of the granulation of dry-pressing simultaneously
Higher, disintegration slows down in water, is also beneficial to delay the dissolution of Calcium Dobesilate.It is made under the collective effect of two factors
The In Vitro Dissolution feature for obtaining capsule is consistent with commercially available import preparation, but while finds between the same each sample of dissolution early stage self-control sample
Stripping quantity variability is big.Inventor is creative to combine wet granulation technology, and wet granulation is carried out to material before dry granulation,
I.e. Calcium Dobesilate and other auxiliary materials and mixings, add a small amount of water as wetting agent, are pelletized.Using the water for adding so that hydroxyl
The pre-paying Starch Fraction aquation wrapped up around benzene sulfonic acid calcium, Calcium Dobesilate is wrapped up wherein, is avoided in dissolution test
The a large amount of Calcium Dobesilate directly contact moisture of early stage, cause each sample stripping quantity variability too big.
The technical scheme is that：A kind of calcium hydrophenyl sulfonate capsule, by the Calcium Dobesilate for the treatment of effective dose, filling
Agent and lubricant are constituted, it is characterised in that the technique combined using wet granulation and dry granulation is produced.
Currently preferred technical scheme is, a kind of calcium hydrophenyl sulfonate capsule, it is characterised in that filler is in prescription
Consumption is 5mg-100mg, preferred 10mg-50mg；Consumption of the lubricant in prescription is 1mg-20mg, preferred 5mg-10mg.
Filler of the present invention, one or more in starch, microcrystalline cellulose, lactose, pregelatinized starch.
Lubricant of the present invention, one or more in magnesium stearate, talcum powder and silica.
The preparation method of calcium hydrophenyl sulfonate capsule of the present invention, it is characterised in that
The first step：Calcium Dobesilate raw material is sieved for subsequent use with filler, lubricant；
Second：Calcium Dobesilate is well mixed with filler using the mixing apparatus commonly used in preparation process；
3rd step：By Calcium Dobesilate and filler with the aqueous solution of ethanol as wetting agent, using wet granulation technology, enter
Row wet granulation, sieves, and is dried；
4th step：By dried particle and mix lubricant；
5th step：Mixed material is carried out into dry granulation；
6th step：Filling capsule.
Beneficial effect：The present invention solves prescription by before dry granulation process, first material being carried out into wet granulation
The bad problem of mobility caused by middle phenolsulfonic acid ca proportion is excessive, while reducing process in leaching early stage each sample variability
Big problem.
Specific embodiment
Embodiment 1
Prescription：
Preparation technology：Calcium Dobesilate, lactose, magnesium stearate are crossed into 80 mesh sieves, it is standby；Weigh recipe quantity Calcium Dobesilate
And lactose, be well mixed, with 10% ethanol solution on high speed wet granulator wet granulation, wet granular is dried, sieve whole
Grain, adds the mixing of recipe quantity magnesium stearate, filling in dry granulating machine dry granulation.
Embodiment 2：
Prescription：
Preparation technology：With embodiment 1
Embodiment 3
Prescription：
Preparation technology：Calcium Dobesilate, pregelatinized starch, magnesium stearate are crossed into 80 mesh sieves, it is standby；Weigh recipe quantity oxybenzene
Sulfoacid calcium and pregelatinized starch, in fluidised bed granulator, with 10% ethanol solution in granulation, wet granular are dried, whole grain of sieving,
The mixing of recipe quantity magnesium stearate is added, it is filling in dry granulating machine dry granulation.
Comparative example 1：
Prescription：
Preparation technology：Calcium Dobesilate, lactose, magnesium stearate are crossed into 80 mesh sieves, it is standby；Weigh recipe quantity Calcium Dobesilate
And lactose, it is well mixed, it is filling in dry granulating machine dry granulation.
Comparative example 2：
Prescription：
Preparation technology：Calcium Dobesilate, microcrystalline cellulose, magnesium stearate are crossed into 80 mesh sieves, it is standby；Weigh recipe quantity oxybenzene
Sulfoacid calcium and microcrystalline cellulose, are well mixed, filling in dry granulating machine dry granulation.
Above example is carried out into stripping curve detection, dissolving-out method is：According to dissolution method (Chinese Pharmacopoeia 2015 editions
4th 0,931 first method), with 0.1M hydrochloric acid 900ml as dissolution medium, operate in accordance with the law, respectively at each point in time sampling, filter,
Subsequent filtrate is taken as need testing solution, while supplementing the synthermal dissolution medium of same volume.Separately take Calcium Dobesilate reference substance
In right amount, it is configured to be suitable for the solution of concentration, as reference substance solution, by external standard method with the dissolution of each time point of calculated by peak area
Degree.The results are shown in Table 1：
The each embodiment dissolution rate testing result of table 1
As a result understand, all samples dissolved corrosion is slow release, using the comparative example 1 of direct dry granulation,
Comparative example 2 and commercially available import preparation are in dissolution early stage, and stripping quantity variability is larger, and adopt the combination of dry method after first wet method
Embodiment 1, embodiment 2 and the product of embodiment 3 obtained by technique, the dissolution early stage coefficient of variation is less.
Claims (5)
1. a kind of calcium hydrophenyl sulfonate capsule, is made up of, filler the Calcium Dobesilate for the treatment of effective dose, filler and lubricant
Consumption in prescription is 5mg-100mg, and consumption of the lubricant in prescription is 1mg-20mg, it is characterised in that adopt wet method
It is prepared by the technique that granulation and dry granulation are combined.
2. calcium hydrophenyl sulfonate capsule described in claim 1, it is characterised in that consumption of the filler in prescription is 10mg-50mg；
Consumption of the lubricant in prescription is 5mg-10mg.
3. calcium hydrophenyl sulfonate capsule described in claim 1, it is characterised in that the filler, selected from starch, microcrystalline cellulose,
One or more in lactose, pregelatinized starch.
4. calcium hydrophenyl sulfonate capsule described in claim 1, it is characterised in that the lubricant, selected from magnesium stearate, talcum powder and
One or more in silica.
5. the preparation method of calcium hydrophenyl sulfonate capsule described in claim 1, it is characterised in that
The first step：Calcium Dobesilate raw material is sieved for subsequent use with filler, lubricant；
Second：Calcium Dobesilate is well mixed with filler using the mixing apparatus commonly used in preparation process；
3rd step：By Calcium Dobesilate and filler with the aqueous solution of ethanol as wetting agent, using wet granulation technology, carry out wet
Method is pelletized, and is sieved, and is dried；
4th step：By dried particle and mix lubricant；
5th step：Mixed material is carried out into dry granulation；
6th step：Filling capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611272181.9A CN106619564A (en) | 2016-12-23 | 2016-12-23 | Calcium dobesilate capsule and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611272181.9A CN106619564A (en) | 2016-12-23 | 2016-12-23 | Calcium dobesilate capsule and preparation method |
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| Publication Number | Publication Date |
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| CN106619564A true CN106619564A (en) | 2017-05-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611272181.9A Pending CN106619564A (en) | 2016-12-23 | 2016-12-23 | Calcium dobesilate capsule and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114601816A (en) * | 2021-10-09 | 2022-06-10 | 北京惠之衡生物科技有限公司 | Calcium dobesilate capsule composition and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579396A (en) * | 2012-04-01 | 2012-07-18 | 宁夏康亚药业有限公司 | Calcium dobesilate capsule composition |
-
2016
- 2016-12-23 CN CN201611272181.9A patent/CN106619564A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579396A (en) * | 2012-04-01 | 2012-07-18 | 宁夏康亚药业有限公司 | Calcium dobesilate capsule composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114601816A (en) * | 2021-10-09 | 2022-06-10 | 北京惠之衡生物科技有限公司 | Calcium dobesilate capsule composition and preparation method thereof |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170510 |
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| RJ01 | Rejection of invention patent application after publication |