CN108272763A - A kind of Calcium Dobsilate and preparation method thereof - Google Patents
A kind of Calcium Dobsilate and preparation method thereof Download PDFInfo
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- CN108272763A CN108272763A CN201810271800.5A CN201810271800A CN108272763A CN 108272763 A CN108272763 A CN 108272763A CN 201810271800 A CN201810271800 A CN 201810271800A CN 108272763 A CN108272763 A CN 108272763A
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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Abstract
The present invention provides a kind of Calcium Dobsilate and preparation method thereof, the raw material of the Calcium Dobsilate includes:Calcium Dobesilate, filler, disintegrant, adhesive and lubricant;Wherein, the parts by weight of the Calcium Dobesilate, disintegrant, adhesive and lubricant account for 29~50%, 35~55%, 3~13%, 0.2~1% and the 0.4~2% of the Calcium Dobsilate total weight parts respectively.This programme can improve the bioavilability of Calcium Dobesilate.
Description
Technical field
The present invention relates to technical field of medicine, more particularly to a kind of Calcium Dobsilate and preparation method thereof.
Background technology
Calcium Dobesilate is suitable for prevention and treatment microcirculation as a kind of microcirculation improver or Vasoprotectant
A variety of diseases caused by obstacle, especially suitable for the heart, brain and kidney diaseases, example caused by diabetic retinopathy microcirculation disorder
Such as myocardial infarction, angina pectoris and microthrombus are clinically largely used from after the listing of last century the seventies.
Before, the Calcium Dobesilate clinically used is generally capsule or tablet, use phenolsulfonic acid calcium powder with
The pharmaceutic adjuvants such as starch, a small amount of sugar and dextrin are made through encapsulated or tabletting.The Calcium Dobesilate of capsule or tablet collapses
Solution property is relatively slow, i.e. drug-eluting speed is more slow, this makes it be difficult to be fully absorbed by body, so as to cause phenolsulfonic acid
The bioavilability of calcium is relatively low.
Invention content
An embodiment of the present invention provides a kind of Calcium Dobsilates and preparation method thereof, can improve Calcium Dobesilate
Bioavilability.
In a first aspect, an embodiment of the present invention provides a kind of Calcium Dobsilates, including:Calcium Dobesilate, filling
Agent, disintegrant, adhesive and lubricant;Wherein,
The Calcium Dobesilate, filler, disintegrant, adhesive and lubricant parts by weight account for the phenolsulfonic acid respectively
29~50%, 35~55%, 3~13%, 0.2~1% and the 0.4~2% of calcium dispersible tablet total weight parts.
The characteristics of dispersible tablet is to be dispersed into very little particle simultaneously within the time as short as possible (generally in 3min) after meeting water
Uniform suspension is formed, therefore, compared with conventional tablet, dispersible tablet is with state is good, jitter time is short, drug-eluting is rapid
The advantages of.Oxybenzene sulphur provided in this embodiment containing Calcium Dobesilate and appropriate filler, disintegrant, adhesive and lubricant
Sour calcium dispersible tablet so that when patient takes the Calcium Dobsilate, drug energy Fast Stripping in patient's body, to make
Obtaining body can quickly absorb the drug, and thus improve the bioavilability of Calcium Dobesilate.
In addition, since the disintegration of capsule or tablet Calcium Dobesilate is relatively slow, prevent it from fully being inhaled by body
It receives, therefore when needing quick acting, it has to escalated dose for the first time, and when once taking medicine more, it is easy to old man, children
Difficulty is brought with the patient of dysphagia.And Calcium Dobsilate provided in an embodiment of the present invention improves Calcium Dobesilate
Bioavilability, on the one hand can reduce the dosage of patient, on the other hand since its is rapidly dissolvable in water, Huan Zheye
It is taken again after being dissolved in water, therefore, Calcium Dobsilate is suitable for the patient of old man, children and dysphagia, energy
Reduce the medication degree of difficulty of these patients.
Optionally, the disintegrant can be microcrystalline cellulose M101.Microcrystalline cellulose M101 has good mobility
And disintegration, make microcrystalline cellulose M101 other than with good filling effect, also there is certain rush to be disintegrated effect, i.e.,
Microcrystalline cellulose is both used as filler, while being also used as disintegrant, so that the dispersible tablet after tabletted is with good
Hardness, and its dispersion rate is improved to a certain extent.In addition, containing phenolic hydroxyl group in the molecular structure of Calcium Dobesilate, determine
It, which has, draws moist, this causes the long-time stability of Calcium Dobesilate poor, and uses microcrystalline cellulose not easy to moisture absorption
M101 is as filler and disintegrant, and it is moist to be effectively improved drawing for Calcium Dobsilate, to improve Calcium Dobesilate
The long-time stability of dispersible tablet.
Preferably, the parts by weight of the microcrystalline cellulose M101 account for the Calcium Dobsilate total weight parts 35~
45%.
Optionally, the disintegrant includes:Any one or two kinds of carboxyrnethyl starch sodium and crospovidone.
Carboxyrnethyl starch sodium has good mobility and compressibility, moreover it is possible to improve the disintegration of drug.Therefore selection carboxylic first
Disintegrant of the sodium starch as Calcium Dobsilate, can be effectively improved the mouldability of dispersible tablet, to increase dispersible tablet
Hardness and improve to a certain extent its dispersibility.
Crospovidone is a kind of water-insoluble disintegrant, several with high capillary activity and excellent hydration capability
Tendency without gel can effectively improve the dispersion performance of Calcium Dobsilate as disintegrant.
Preferably, when the disintegrant includes carboxyrnethyl starch sodium and crospovidone, the carboxyrnethyl starch sodium and crosslinking
The parts by weight of povidone account for the 1~8% and 2~5% of the Calcium Dobsilate total weight parts respectively.Selection is suitably matched
Than being conducive to the dispersion performance for further improving Calcium Dobesilate, to be conducive to improve the bioavilability of Calcium Dobesilate.
Preferably, the parts by weight of the carboxyrnethyl starch sodium account for the 5~7% of the Calcium Dobsilate total weight parts;
The parts by weight of the crospovidone account for the 3~5% of the Calcium Dobsilate total weight parts.
Optionally, described adhesive includes:PVP K30.
Optionally, the lubricant includes:Any one in magnesium stearate and silica or two kinds.
Magnesium stearate is white, the easily fine powder without grittiness, has soapy feeling with skin contact, has good adhesion,
Therefore magnesium stearate can be used as lubricant use.When preparing Calcium Dobsilate as lubricant, can effectively it solve
Due to Calcium Dobesilate draw it is moist caused by sticking phenomenon, be convenient for Calcium Dobsilate preparation, and make made of
Calcium Dobsilate surface is smooth, and has good finish.
Silica has larger specific surface area, therefore it is with good suction-operated, as lubricant
Calcium Dobsilate is prepared, the mobility of powder or particle in preparation process can be obviously improved.Actually preparing
Cheng Zhong, silica are usually used in the form of superfine silica gel powder as lubricant, the adsorbable medicine of silanol group on superfine silica gel powder surface
Object, and disintegration and the dissolution rate of drug are significantly improved, to be conducive to improve the bioavilability of Calcium Dobesilate.
Preferably, when the lubricant includes magnesium stearate and silica, the magnesium stearate and silica
Parts by weight account for the 0.2~1% and 0.2~1% of the Calcium Dobsilate total weight parts respectively.
Preferably, the parts by weight of the Calcium Dobesilate account for the Calcium Dobsilate total weight parts 40~
50%.
Preferably, the grain size of the Calcium Dobesilate is not less than 200 mesh.
Second aspect, an embodiment of the present invention provides a kind of Calcium Dobsilates that any of the above-described embodiment provides
Preparation method, including:
The component of following weight percent is weighed respectively:Calcium Dobesilate 29~50%, filler 35~55%, disintegrant
3~13%, adhesive 0.2~1% and lubricant 0.4~2%;
The component weighed is mixed, and tabletting is carried out to mixed component, obtains the Calcium Dobesilate dispersion
Piece.
Tabletting will be carried out after the Calcium Dobesilate of corresponding parts by weight and disintegrant, filler, adhesive and mix lubricant
Calcium Dobsilate is can be made into, it is simple for process, easy to operate, and sample quality is stablized, and the big production of industrialization is suitable for.
Optionally,
The component for weighing following weight percent respectively:The component of following weight percent is weighed respectively:Oxybenzene sulphur
Sour calcium 29~50%, filler 35~55%, disintegrant 3~13%, adhesive 0.2~1% and lubricant 0.4~2%, packet
It includes:
The component of following weight percent is weighed respectively:Calcium Dobesilate 40~50%, microcrystalline cellulose M10135~
45%, carboxyrnethyl starch sodium 5~7%, crospovidone 3~5%, magnesium stearate 0.2~1% and silica 0.2~1%.
Optionally,
It is described to mix the component weighed, including:
0.2~1% PVP K30 is added in 15~20% 80% ethyl alcohol, obtains adhesive after mixing;
By 40~50% Calcium Dobesilate and 35~45% microcrystalline cellulose M101,2~3% carboxyrnethyl starch sodium, 1
~2% crospovidone mixes 3~8min in wet granulator;
Described adhesive is added in the wet granulator, is pelletized using the wet granulator, obtains centre
Shot-like particle;
The intermediate shot-like particle is dried;
By after drying the intermediate shot-like particle and 3~4% carboxyrnethyl starch sodium, 2~3% crospovidone, 0.2~
1% magnesium stearate and 0.2~1% silica mix 5~15min in total mixed machine, obtain the mixed component.
When generally preparing dispersible tablet by a granulation, the dispersion effect of manufactured dispersible tablet is not easy control, this may
It is to have wrapped up disintegrant since major ingredient particle is thinner so that disintegrant fully cannot absorb water and expand, it is difficult to play disintegrant
Due calving disaggregation.In order to improve the dispersion effect of Calcium Dobsilate, to improve the biological utilisation of Calcium Dobesilate
Degree, the embodiment of the present invention prepare Calcium Dobsilate using the method for tabletting again of first pelletizing.Specifically, first by phenolsulfonic acid
Intermediate shot-like particle is made in calcium and suitable amount of adhesive and disintegrant mixing, after intermediate shot-like particle is dried, then by its with it is appropriate
Disintegrant and lubricant are mixed, then carry out tabletting to mixed component, obtain Calcium Dobsilate.Thus a side
Face improves the mobility of phenolsulfonic acid calcium powder, has on the other hand also disperseed point of the main ingredient (Calcium Dobesilate) with disintegrant
Cloth makes the contact surface of disintegrant and water increase, the rush disintegrating property of disintegrant is improved, to improve the dispersibility of Calcium Dobesilate
Can, thus improve the bioavilability of Calcium Dobesilate.
Meanwhile disintegrant is mixed with Calcium Dobesilate at twice, is added before preparing intermediate shot-like particle for the first time, second
Secondary addition after preparing intermediate shot-like particle.Since the grain size of intermediate shot-like particle is more than the grain size of Calcium Dobesilate so that second
The disintegrant of secondary addition more disperses, so that the disintegrant being added for second has very high capillary activity and hydration
Ability can rapidly suck water in Calcium Dobsilate, so that Calcium Dobsilate expansion and disintegration is at small
Grain.Then, the disintegrant being added for the first time absorbs water so that little particle disintegration is more tiny powder particle, to improve main ingredient
The dissolution rate and bioavilability of (Calcium Dobesilate).
Optionally,
It is described that the intermediate shot-like particle is dried, including:
The intermediate shot-like particle is placed in the baking oven that temperature is 48 DEG C~52 DEG C, so that the intermediate shot-like particle is described
It is dried in baking oven;
It often dries 0.5h and stirs the intermediate shot-like particle;
The intermediate shot-like particle is taken out from the baking oven after dry 4~5h, the centre after being dried is granular
Object.
Optionally,
It is described to be pelletized using the wet granulator, including:
The rotating speed for controlling the mixing paddle of the wet granulator is 10~20r/s, the granulating cutter of the wet granulator
Rotating speed is 20~30r/s.
It is pelletized at the appropriate speed by controlling wet granulator so that the particle fine uniform made, hardness are moderate.
Optionally,
It is described obtain intermediate shot-like particle after, it is described the intermediate shot-like particle is dried before, further wrap
It includes:
The intermediate shot-like particle is crossed into 20~40 mesh sieve.
Optionally,
It is described the intermediate shot-like particle is dried after, in the intermediate shot-like particle and 3 by after drying
~4% carboxyrnethyl starch sodium, 2~3% crospovidone, 0.2~1% magnesium stearate and 0.2~1% silica into
Before row mixing, further comprise:
The intermediate shot-like particle after drying is crossed into 20~40 mesh sieve.
Before it is dried and net is sieved after dry in manufactured intermediate shot-like particle, is sieved to intermediate shot-like particle according to grain size with this
Choosing so that the grain size of intermediate shot-like particle is less than the particle of general wet granulation, thus substantially increases dissolution rate and the life of drug
Object availability.
Optionally,
In the component for weighing following weight percent respectively:Calcium Dobesilate 29~50%, filler 35~55%, disintegration
Before agent 3~13%, adhesive 0.2~1% and lubricant 0.4~2%, further comprise:
The Calcium Dobesilate is crushed, and the Calcium Dobesilate after crushing is crossed into 170~250 mesh sieve.
The grain size of the general phenolsulfonic acid calcium product directly bought is in 60 mesh or so, in order to ensure manufactured Calcium Dobesilate
The dispersion performance of dispersible tablet usually first crushes phenolsulfonic acid calcium product, and superfine communication technique can be used in when crushing, such as
Micronization processes are carried out to Calcium Dobesilate using micronizer, and the Calcium Dobesilate after crushing is sieved, to ensure hydroxyl
The grain size of benzene sulfonic acid calcium is sufficiently small, so that manufactured phenolsulfonic acid dispersible tablet forms uniform dispersion after water disintegration, adds
The dissolution of fast drug.
Optionally,
It is described that tabletting is carried out to mixed component, including:
Tabletting is carried out to the mixed component using double pressed-disc techniques of main pressure after first precompressed.
The air between intermediate shot-like particle is discharged by precompressed, main pressure is worked as a buffer so that pressure is more balanced, to
So that being not easy to dust in tableting processes, and the tablet weight variation between molding dispersible tablet is reduced as far as possible so that piece weight is more stable, protects
Demonstrate,prove the highly consistent of Calcium Dobsilate product quality.
An embodiment of the present invention provides a kind of Calcium Dobsilate and preparation method thereof, by by Calcium Dobesilate with
Calcium Dobsilate is made in appropriate filler, disintegrant, adhesive and lubricant so that patient takes the Calcium Dobesilate
When dispersible tablet, thus drug energy Fast Stripping in patient's body improves oxybenzene sulphur so that body can quickly absorb the drug
The bioavilability of sour calcium.
Specific implementation mode
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in the embodiment of the present invention
Technical solution is clearly and completely described, it is clear that described embodiments are some of the embodiments of the present invention, rather than complete
The embodiment in portion, based on the embodiments of the present invention, those of ordinary skill in the art are in the premise for not making creative work
Lower obtained every other embodiment, shall fall within the protection scope of the present invention.
Embodiment 1
Raw material prescription:
Preparation process:
Step A1:Calcium Dobesilate is crushed using micronizer, and the Calcium Dobesilate after crushing is crossed 200
Mesh sieves;
Step B1:PVP K30 is weighed by recipe quantity, the PVP K30 weighed is added in 80% ethyl alcohol, until solution
Gross weight reaches 60kg, and adhesive is made;
Step C1:The microcrystalline cellulose of Calcium Dobesilate and recipe quantity that sieve is crossed in step A1 is weighed by recipe quantity
M101, and weigh 8kg carboxyrnethyl starch sodiums and 6kg cross filament ketone;
Step D1:Each component that step C1 is weighed is mixed into 5min in wet granulator, step is added in mixed process
Adhesive made of rapid B1, then starts to pelletize using wet granulator, and the mixing paddle of wet granulator is controlled in pelletization
Rotating speed is 15r/s, and the rotating speed of granulating cutter is 25r/s, obtains intermediate shot-like particle;
Step E1:Intermediate shot-like particle made from step D1 is crossed into 30 mesh screens;
Step F1:The intermediate shot-like particle for crossing net in step E1 is placed in heated-air circulation oven, heated-air circulation oven is set
Temperature be 50 DEG C ± 2 DEG C, stir intermediate shot-like particle after often drying 30min, discharge after dry 4h.
Step G1:Intermediate shot-like particle after drying is crossed into 30 mesh screens and carries out whole grain;
Step H1:Magnesium stearate and silica are weighed by recipe quantity, and weighs 11.2kg carboxyrnethyl starch sodiums and 7.8kg friendships
Join povidone, then by the component weighed in such a way that equivalent is progressively increased with the centre after whole grain it is granular it is total mix machine in mix 10min,
Discharging;
Step I1:Tabletting is carried out to mixed material using double pressed-disc techniques of rear main pressure after first precompressed, obtains oxybenzene
Sulfonic acid calcium dispersible tablet, then Calcium Dobsilate is carried out aluminum-plastic packaged.
Dispersing uniformity detection experiment:
By the hanging basket for being loaded with Calcium Dobsilate (the sieve pore internal diameter of the stainless steel cloth of hanging basket is 710 μm) by upper
The stainless steel shaft at end is hung on metallic support, is immersed in the beaker for filling 1000ml (15~25 DEG C of water temperature), and adjust hanging basket
Sieve is away from beaker bottom 25mm when position makes its decline, and sieve is at the 15mm of underwater when regulating liquid surface height makes to hang blue rise.
General standard provides that each grain dispersible tablet should be all disintegrated in 3min and by sieve, test result shows embodiment
1 Calcium Dobsilate provided is all disintegrated in 60s and (most of dispersible tablet is disintegrated simultaneously in 30s or so by sieve
Pass through sieve), comply with standard regulation.
Dissolution rate contrast test:
It is measured according to Chinese Pharmacopoeia dissolution rate and drug release determination method (0,931 second method of general rule), with 900ml hydrochloric acid solutions
(9ml is diluted to the dilute solution of 1000ml) is dissolution medium, and rotating speed 50r/min is operated in accordance with the law, is taken after 15min appropriate molten
Liquid, it is accurate after filtering to measure subsequent filtrate 5ml, it is placed in 50ml measuring bottles, is diluted to scale with hydrochloric acid solution, shakes up, as examination
Product solution.Separately take Calcium Dobesilate reference substance, it is accurately weighed, add hydrochloric acid solution to dissolve and quantify dilution the molten of 25ug/ml is made
Liquid (takes Calcium Dobesilate reference substance 12.5mg, is placed in 100ml measuring bottles, add hydrochloric acid solution to dissolve and be diluted to scale, separately take
In 5ml to 25ml measuring bottles, add hydrochloric acid solution to dissolve and be diluted to scale to obtain the final product), according to Chinese Pharmacopoeia " spectrophotometry
Method " (general rule 0401) measures, and absorbance is measured at the wavelength of 301nm.
Standard provides the dissolution rate of dispersible tablet 80% or so, the dissolution for the Calcium Dobsilate that embodiment 1 provides
For degree up to 95~100%, result of extraction is good.
Embodiment 2
Raw material prescription:
It is identical as the raw material prescription that embodiment 1 provides;
Preparation process:
The preparation process provided with embodiment 1 is essentially identical, the difference is that:
The crystallite of 12.8g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 10.8g crospovidone and recipe quantity, recipe quantity is fine
It ties up element M101 and adhesive to mix, to prepare intermediate shot-like particle, then by 6g carboxyrnethyl starch sodiums and 3g crospovidone and drying
Tabletting after intermediate shot-like particle mixing afterwards.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 2 comply with standard regulation.
Embodiment 3
Raw material prescription:
It is identical as the raw material prescription that embodiment 1 provides;
Preparation process:
The preparation process provided with embodiment 1 is essentially identical, the difference is that:
By the microcrystalline cellulose of 10g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 8g crospovidone and recipe quantity, recipe quantity
M101 and adhesive mixing, to prepare intermediate shot-like particle, then by 8.8g carboxyrnethyl starch sodiums and 5.8g crospovidone and drying
Tabletting after intermediate shot-like particle mixing afterwards.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 3 comply with standard regulation.
Embodiment 4
Raw material prescription:
Preparation process:
Step A4:Calcium Dobesilate is crushed using micronizer, and the Calcium Dobesilate after crushing is crossed 200
Mesh sieves;
Step B4:PVP K30 is weighed by recipe quantity, the PVP K30 weighed is added in 80% ethyl alcohol, until solution
Gross weight reaches 100g, and adhesive is made;
Step C4:The microcrystalline cellulose M101 of Calcium Dobesilate and recipe quantity that net is crossed in step A4 is weighed by recipe quantity,
And weigh 10g carboxyrnethyl starch sodiums and 4g cross filament ketone;
Step D4:Each component that step C4 is weighed is mixed into 3min in wet granulator, step is added in mixed process
Adhesive made of rapid B4, then starts to pelletize using wet granulator, and the mixing paddle of wet granulator is controlled in pelletization
Rotating speed is 10r/s, and the rotating speed of granulating cutter is 20r/s, obtains intermediate shot-like particle;
Step E4:Intermediate shot-like particle made from step D4 is crossed into 20 mesh screens;
Step F4:The intermediate shot-like particle for crossing net in step E4 is placed in heated-air circulation oven, heated-air circulation oven is set
Temperature be 50 DEG C ± 2 DEG C, stir intermediate shot-like particle after often drying 30min, discharge after dry 4.5h.
Step G4:Intermediate shot-like particle after drying is crossed into 20 mesh screens and carries out whole grain;
Step H4:Magnesium stearate and silica are weighed by recipe quantity, and weighs 15g carboxyrnethyl starch sodiums and the poly- dimension of 6g crosslinkings
Ketone, then by the component weighed in such a way that equivalent is progressively increased with the centre after whole grain is granular mixes 8min in total mixed machine, discharge;
Step I4:Tabletting is carried out to mixed material using double pressed-disc techniques of rear main pressure after first precompressed, obtains oxybenzene
Sulfonic acid calcium dispersible tablet, then Calcium Dobsilate is carried out aluminum-plastic packaged.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 4 comply with standard regulation.
Embodiment 5:
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 4 is essentially identical, the difference is that:
By the microcrystalline cellulose of 4g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 14g crospovidone and recipe quantity, recipe quantity
Then M101 and adhesive mixing 8min prepares intermediate shot-like particle, and controls in pelletization, the mixing of wet granulator
Paddle rotating speed is 20r/s, and the rotating speed of granulating cutter is 30r/s, then by 6g carboxyrnethyl starch sodiums and 11g crospovidone with it is dry after in
Between shot-like particle mixing after tabletting.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 5 comply with standard regulation.
Embodiment 6
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 5 is essentially identical, the difference is that:
By the microcrystalline cellulose of 2g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 5.6g crospovidone and recipe quantity, recipe quantity
Then M101 and adhesive mixing 4min prepares intermediate shot-like particle, and controls in pelletization, the mixing of wet granulator
Paddle rotating speed is 14r/s, and the rotating speed of granulating cutter is 26r/s, and obtained intermediate shot-like particle crosses 40 mesh sieve, discharges after dry 4.5h, then
40 mesh sieve is crossed, tabletting after then mixing 3g carboxyrnethyl starch sodiums and 4.4g crospovidone with the intermediate shot-like particle after drying.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 6 comply with standard regulation.
Embodiment 7
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 6 is essentially identical, the difference is that:
By the microcrystalline cellulose of 16g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 18g crospovidone and recipe quantity, recipe quantity
Then M101 and adhesive mixing 7min prepares intermediate shot-like particle, and controls in pelletization, the mixing of wet granulator
Paddle rotating speed is 18r/s, and the rotating speed of granulating cutter is 27r/s, and obtained intermediate shot-like particle crosses 25 mesh sieve, discharges after dry 4h, after
25 mesh sieve, tabletting after then mixing 24g carboxyrnethyl starch sodiums and 7g crospovidone with the intermediate shot-like particle after drying.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 7 comply with standard regulation.
Embodiment 8
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 7 is essentially identical, the difference is that:
By the microcrystalline cellulose of 14g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 20g crospovidone and recipe quantity, recipe quantity
Then M101 and adhesive mixing 4min prepares intermediate shot-like particle, and controls in pelletization, the mixing of wet granulator
Paddle rotating speed is 15r/s, and the rotating speed of granulating cutter is 25r/s, and obtained intermediate shot-like particle crosses 35 mesh sieve, discharges after dry 4h, after
35 mesh sieve, tabletting after then mixing 11g carboxyrnethyl starch sodiums and 5g crospovidone with the intermediate shot-like particle after drying.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 8 comply with standard regulation.
Embodiment 9
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 8 is essentially identical, the difference is that:
By the microcrystalline cellulose of 2g carboxyrnethyl starch sodiums and the Calcium Dobesilate of 7g crospovidone and recipe quantity, recipe quantity
Then M101 and adhesive mixing 6min prepares intermediate shot-like particle, and controls in pelletization, the mixing of wet granulator
Paddle rotating speed is 14r/s, and the rotating speed of granulating cutter is 26r/s, and obtained intermediate shot-like particle crosses 30 mesh sieve, discharges after dry 4h, after
30 mesh sieve, tabletting after then mixing 3g carboxyrnethyl starch sodiums and 7g crospovidone with the intermediate shot-like particle after drying.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 9 comply with standard regulation.
Embodiment 10
Raw material prescription:
Preparation process:
Step A10:Calcium Dobesilate is crushed using micronizer, and by the Calcium Dobesilate mistake after crushing
200 mesh sieve;
Step B10:PVP K30 is weighed by recipe quantity, the PVP K30 weighed is added in 80% ethyl alcohol, until molten
Liquid gross weight reaches 100g, and adhesive is made;
Step C10:The microcrystalline cellulose of Calcium Dobesilate and recipe quantity that net is crossed in step A10 is weighed by recipe quantity
M101 is added into wet granulator, and adhesive made of step B10 is added, and then starts to pelletize using wet granulator,
The mixing paddle rotating speed that wet granulator is controlled in pelletization is 10r/s, and the rotating speed of granulating cutter is 20r/s, is obtained intermediate granular
Object;
Step D10:Intermediate shot-like particle made from step C10 is crossed into 30 mesh screens;
Step E10:The intermediate shot-like particle that net is crossed in step D10 is placed in heated-air circulation oven, setting hot air circulation is dried
The temperature of case is 50 DEG C ± 2 DEG C, stirs intermediate shot-like particle after often drying 30min, discharges after dry 4h.
Step F10:Intermediate shot-like particle after drying is crossed into 30 mesh screens and carries out whole grain;
Step G10:Magnesium stearate is weighed by recipe quantity, it is then that it is granular with the centre after whole grain in such a way that equivalent is progressively increased
Object mixes 5min in total mixed machine, discharges;
Step H10:Tabletting is carried out to mixed material using double pressed-disc techniques of rear main pressure after first precompressed, obtains oxybenzene
Sulfonic acid calcium dispersible tablet, then Calcium Dobsilate is carried out aluminum-plastic packaged.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 10 comply with standard regulation.
Embodiment 11
Raw material prescription:
Preparation process:
The preparation process provided with embodiment 10 is essentially identical, the difference is that:
By the Calcium Dobesilate of 14g carboxyrnethyl starch sodiums and recipe quantity, the microcrystalline cellulose M101 and adhesive of recipe quantity
5min is mixed, intermediate shot-like particle is then prepared, after obtained intermediate shot-like particle, in after 11g carboxyrnethyl starch sodiums and drying
Between shot-like particle mixing after tabletting.
Dispersing uniformity detection experiment and dissolution rate contrast test are carried out using the method that embodiment 1 provides, testing result
The dispersibility of Calcium Dobsilate and dissolution rate made of display embodiment 11 comply with standard regulation.
According to said program, various embodiments of the present invention at least have the advantages that:
1, in embodiments of the present invention, by by Calcium Dobesilate and appropriate filler, disintegrant, adhesive and lubricant
Calcium Dobsilate is made so that when patient takes the Calcium Dobsilate, drug can be quickly in patient's body
Thus dissolution improves the bioavilability of Calcium Dobesilate so that body can quickly absorb the drug, and can reduce patient's
Dosage is suitable for the patient of old man, children and dysphagia, can reduce the medication degree of difficulty of these patients.
2, in embodiments of the present invention, it is used as and is filled out using the microcrystalline cellulose M101 with filling effect and rush disintegration effect
Agent and disintegrant are filled, can be effectively improved that drawing for Calcium Dobsilate is moist, to improve the length of Calcium Dobsilate
Phase stability, while its dispersion rate is improved to a certain extent.
3, in embodiments of the present invention, the mouldability of dispersible tablet can be effectively improved as disintegrant using carboxyrnethyl starch sodium,
To increase the hardness of dispersible tablet and improve its dispersibility to a certain extent.
4, in embodiments of the present invention, Calcium Dobesilate dispersion is effectively increased as disintegrant using crospovidone
The dispersion performance of piece.
5, in embodiments of the present invention, it selects magnesium stearate as lubricant, can effectively solve due to Calcium Dobesilate
Draw moist caused sticking phenomenon, be convenient for the preparation of Calcium Dobsilate, and makes manufactured Calcium Dobsilate
Surface is smooth, and has good finish.
6, in embodiments of the present invention, select silica as lubricant, the adsorbable drug of silanol group on surface is shown
The disintegration for improving drug and dissolution rate are write, to be conducive to improve the bioavilability of Calcium Dobesilate.
7, in embodiments of the present invention, intermediate grain first is made in Calcium Dobesilate and suitable amount of adhesive and disintegrant mixing
Shape object after intermediate shot-like particle is dried, then it is mixed with appropriate disintegrant and lubricant, then to mixed group
Part carries out tabletting, obtains Calcium Dobsilate.Prepare Calcium Dobsilate by way of tabletting again of first pelletizing, one
Aspect improves the mobility of phenolsulfonic acid calcium powder, has on the other hand also disperseed point of the main ingredient (Calcium Dobesilate) with disintegrant
Cloth makes the contact surface of disintegrant and water increase, the rush disintegrating property of disintegrant is improved, to improve the dispersibility of Calcium Dobesilate
Can, thus improve the bioavilability of Calcium Dobesilate.
8, in embodiments of the present invention, mixed component is pressed using double pressed-disc techniques of main pressure after first precompressed
Piece is discharged the air between intermediate shot-like particle by precompressed, is worked as a buffer to main pressure so that and pressure is more balanced, so that
It is not easy to dust in tableting processes, and reduces the tablet weight variation between molding dispersible tablet as far as possible so that piece weight is more stable, ensures hydroxyl
Benzene sulfonic acid calcium dispersible tablet product quality it is highly consistent.
It should be noted that herein, such as first and second etc relational terms are used merely to an entity
Or operation is distinguished with another entity or operation, is existed without necessarily requiring or implying between these entities or operation
Any actual relationship or order.Moreover, the terms "include", "comprise" or its any other variant be intended to it is non-
It is exclusive to include, so that the process, method, article or equipment including a series of elements includes not only those elements,
But also include other elements that are not explicitly listed, or further include solid by this process, method, article or equipment
Some elements.In the absence of more restrictions, the element limited by sentence " including one ", is not arranged
Except there is also other identical factors in the process, method, article or apparatus that includes the element.
Finally, it should be noted that:The foregoing is merely presently preferred embodiments of the present invention, is merely to illustrate the skill of the present invention
Art scheme, is not intended to limit the scope of the present invention.Any modification for being made all within the spirits and principles of the present invention,
Equivalent replacement, improvement etc., are included within the scope of protection of the present invention.
Claims (10)
1. a kind of Calcium Dobsilate, which is characterized in that its raw material includes:Calcium Dobesilate, disintegrant, glues filler
Mixture and lubricant;Wherein,
The Calcium Dobesilate, filler, disintegrant, adhesive and lubricant parts by weight account for the Calcium Dobesilate point respectively
29~50%, 35~55%, 3~13%, 0.2~1% and the 0.4~2% of discrete piece total weight parts.
2. Calcium Dobsilate according to claim 1, which is characterized in that
The filler includes:Microcrystalline cellulose M101;
And/or
The disintegrant includes:Any one or two kinds of carboxyrnethyl starch sodium and crospovidone;
And/or
Described adhesive includes:PVP K30;
And/or
The lubricant includes:Any one in magnesium stearate and silica or two kinds.
3. Calcium Dobsilate according to claim 2, which is characterized in that
The parts by weight of the Calcium Dobesilate account for the 40~50% of the Calcium Dobsilate total weight parts;
And/or
When the disintegrant includes carboxyrnethyl starch sodium and crospovidone, the weight of the carboxyrnethyl starch sodium and crospovidone
Part accounts for the 1~8% and 2~5% of the Calcium Dobsilate total weight parts respectively;
And/or
When the lubricant includes magnesium stearate and silica, the parts by weight of the magnesium stearate and silica account for respectively
The 0.2~1% and 0.2~1% of the Calcium Dobsilate total weight parts.
4. Calcium Dobsilate according to claim 3, which is characterized in that
The parts by weight of the microcrystalline cellulose M101 account for the 35~45% of the Calcium Dobsilate total weight parts;
And/or
The parts by weight of the carboxyrnethyl starch sodium account for the 5~7% of the Calcium Dobsilate total weight parts;
And/or
The parts by weight of the crospovidone account for the 3~5% of the Calcium Dobsilate total weight parts.
5. Calcium Dobsilate according to claim 1, which is characterized in that
The grain size of the Calcium Dobesilate is not less than 200 mesh.
6. a kind of preparation method of any Calcium Dobsilate of claim 1 to 5, which is characterized in that including:
The component of following weight percent is weighed respectively:Calcium Dobesilate 29~50%, filler 35~55%, disintegrant 3~
13%, adhesive 0.2~1% and lubricant 0.4~2%;
The component weighed is mixed, and tabletting is carried out to mixed component, obtains the Calcium Dobsilate.
7. preparation method according to claim 6, which is characterized in that
The component for weighing following weight percent respectively:Calcium Dobesilate 29~50%, filler 35~55%, disintegrant
3~13%, adhesive 0.2~1% and lubricant 0.4~2%, including:
The component of following weight percent is weighed respectively:Calcium Dobesilate 40~50%, microcrystalline cellulose M10135~45%, carboxylic
First sodium starch 5~7%, crospovidone 3~5%, magnesium stearate 0.2~1% and silica 0.2~1%.
8. preparation method according to claim 7, which is characterized in that
It is described to mix the component weighed, including:
0.2~1% PVP K30 is added in 15~20% 80% ethyl alcohol, obtains adhesive after mixing;
By 40~50% Calcium Dobesilate and 35~45% microcrystalline cellulose M101,2~3% carboxyrnethyl starch sodium, 1~
2% crospovidone mixes 3~8min in wet granulator;
Described adhesive is added in the wet granulator, is pelletized using the wet granulator, is obtained intermediate granular
Object;
The intermediate shot-like particle is dried;
By after drying the intermediate shot-like particle and 3~4% carboxyrnethyl starch sodium, 2~3% crospovidone, 0.2~1%
Magnesium stearate and 0.2~1% silica mix 5~15min in total mixed machine, obtain the mixed component.
9. preparation method according to claim 8, which is characterized in that
It is described that the intermediate shot-like particle is dried, including:
The intermediate shot-like particle is placed in the baking oven that temperature is 48 DEG C~52 DEG C, so that the intermediate shot-like particle is in the baking oven
In be dried;
It often dries 0.5h and stirs the intermediate shot-like particle;
The intermediate shot-like particle is taken out from the baking oven after dry 4~5h, the intermediate shot-like particle after being dried;
And/or
It is described to be pelletized using the wet granulator, including:
The rotating speed for controlling the mixing paddle of the wet granulator is 10~20r/s, the rotating speed of the granulating cutter of the wet granulator
For 20~30r/s;
And/or
It is described obtain intermediate shot-like particle after, it is described the intermediate shot-like particle is dried before, further comprise:
The intermediate shot-like particle is crossed into 20~40 mesh sieve;
And/or
It is described the intermediate shot-like particle is dried after, in the intermediate shot-like particle and 3~4% by after drying
Carboxyrnethyl starch sodium, 2~3% crospovidone, 0.2~1% magnesium stearate and 0.2~1% silica mixed
Before conjunction, further comprise:
The intermediate shot-like particle after drying is crossed into 20~40 mesh sieve.
10. preparation method according to claim 6, which is characterized in that
In the component for weighing following weight percent respectively:The component of following weight percent is weighed respectively:Phenolsulfonic acid
Before calcium 29~50%, filler 35~55%, disintegrant 3~13%, adhesive 0.2~1% and lubricant 0.4~2%, into
One step includes:
The Calcium Dobesilate is crushed, and the Calcium Dobesilate after crushing is crossed into 170~250 mesh sieve;
And/or
It is described that tabletting is carried out to mixed component, including:
Tabletting is carried out to the mixed component using double pressed-disc techniques of main pressure after first precompressed.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110179763A (en) * | 2019-04-01 | 2019-08-30 | 海南林恒制药股份有限公司 | A kind of Calcium Dobsilate and preparation method thereof |
CN112618503A (en) * | 2021-01-20 | 2021-04-09 | 天津市中央药业有限公司 | Cefdinir dispersible tablet |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1582910A (en) * | 2004-05-28 | 2005-02-23 | 徐新盛 | Calcium phenol sulfonate dispersive tablets and their preparation |
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 |
CN103284962A (en) * | 2012-02-23 | 2013-09-11 | 重庆圣华曦药业股份有限公司 | Moxifloxacin dispersible tablet and preparation method thereof |
CN103877038A (en) * | 2012-12-24 | 2014-06-25 | 江苏万邦生化医药股份有限公司 | Calcium dobesilate dispersible tablet and preparation method thereof |
-
2018
- 2018-03-29 CN CN201810271800.5A patent/CN108272763A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1582910A (en) * | 2004-05-28 | 2005-02-23 | 徐新盛 | Calcium phenol sulfonate dispersive tablets and their preparation |
CN1259042C (en) * | 2004-05-28 | 2006-06-14 | 徐新盛 | Calcium phenol sulfonate dispersive tablets and their preparation |
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 |
CN103284962A (en) * | 2012-02-23 | 2013-09-11 | 重庆圣华曦药业股份有限公司 | Moxifloxacin dispersible tablet and preparation method thereof |
CN103877038A (en) * | 2012-12-24 | 2014-06-25 | 江苏万邦生化医药股份有限公司 | Calcium dobesilate dispersible tablet and preparation method thereof |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110179763A (en) * | 2019-04-01 | 2019-08-30 | 海南林恒制药股份有限公司 | A kind of Calcium Dobsilate and preparation method thereof |
CN110179763B (en) * | 2019-04-01 | 2020-07-17 | 海南林恒制药股份有限公司 | Calcium dobesilate dispersible tablets and preparation method thereof |
CN112618503A (en) * | 2021-01-20 | 2021-04-09 | 天津市中央药业有限公司 | Cefdinir dispersible tablet |
CN112618503B (en) * | 2021-01-20 | 2022-04-15 | 天津市中央药业有限公司 | Cefdinir dispersible tablet |
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