CN101032476A - Medical combination including rhein or diacetylrhein and the preparing method thereof - Google Patents
Medical combination including rhein or diacetylrhein and the preparing method thereof Download PDFInfo
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Abstract
The present invention relates to one kind of medicine composition containing rheinic acid or diacetyl rheinic acid and its pharmaceutically acceptable salt, dispersant carrier material and other supplementary material. The medicine composition is prepared through a melting process, a solvent process, a melting-solvent process or a fine grinding process to prepare effective component dispersoid; and further dropping the dispersoid into condensing agent to prepare dripping pill, or other steps to prepare different other preparations. The medicine composition of the present invention has raised bioavailability, and may be applied widely in treating osteoarthritis, rheumatoid arthritis, hyperlipemia and other diseases.
Description
Technical field
The present invention relates to a kind of Pharmaceutical composition.Specifically, the present invention relates to chrysophanic acid or diacetyl rhein and pharmaceutically acceptable salt thereof is active component, solid dispersion pharmaceutical composition of forming with dispersible carrier and preparation method thereof, be used for the treatment of arthritis, comprise osteoarthritis, rheumatism and rheumatoid arthritis, also can be used for cardiovascular disease etc.
Background technology
Osteoarthritis, rheumatic arthritis and rheumatoid arthritis are the higher joint diseases of sickness rate, with the former is example, sickness rate is about 10% of total population, to the patient more than 60 years old, have the patient more than 50% to be affected, to the women below 45 years old, the sickness rate of 45 years old to 60 years old and over-65s is respectively 2%, 30% and 68%; Then be respectively 3%, 24.5% and 58% for the male.Along with aged tendency of population, the ratio that morbidity population accounts for total population will get more and more.
The medicine of treatment osteoarthritis mainly contains steroidal class and non-steroidal anti-inflammatory drug at present.The untoward reaction of steroidal anti-inflammatory drugs is known by people.Also there are a lot of untoward reaction in cyclooxygenase-2 inhibitors in the nonsteroidal antiinflammatory drug (COX), can cause digestive tract hemorrhage as oral and injection, and especially the old people more is easy to generate untoward reaction, and this is very disadvantageous for the old disease occurred frequently of this class of osteoarthritis.
Chrysophanic acid is a kind of dissociated anthraquinone chemical compound that extracts from comprise plants such as Chinese herb rhubarb, and its structural formula is:
Diacetyl rhein is its acetylate, and its structural formula is as follows:
(diacetyl rhein)
The chemical name of chrysophanic acid is 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracene carboxylic acid.Chrysophanic acid also can obtain by synthetic method, and this chemical compound is water-soluble hardly.
Patent IT1098332 has announced that chrysophanic acid and diacetyl rhein have the activity of treatment of arthritis as a kind of interleukin (IL)-1 inhibitor.But studies show that the main adverse reaction of oral diacetyl rhein still is diarrhoea, incidence rate is 7%-29.7%.Mainly by unabsorbed drug-induced.So the necessary new preparation that can avoid such untoward reaction of producing, to improve bioavailability.
In order to reduce the diarrhoea untoward reaction, patent US6124358 discloses a kind of method that improves oral chrysophanic acid and diacetyl rhein bioavailability by the raw material micronization; EP0809995 discloses a kind of gel preparation of chrysophanic acid to reduce the method that the diarrheal order of severity takes place and lowers diarrheal.But above patent all is difficult to avoid fully this untoward reaction of suffering from diarrhoea.
Patent CN 1197338A discloses a kind of pharmaceutical composition, and with vegetable oil, mineral oil and animal oil thing carrier are equipped with dispersant and make new preparation to improve bioavailability.
Solid dispersion technology be with solid dispersion in solid, normally a kind of poorly water soluble drugs is with molecule, colloidal state, crystallite or amorphous state, be dispersed in the another kind of water-soluble material or slightly solubility, in the enteric solubility material, the solid dispersion system of formation (solid dispersesystem) is to reach the purpose of rapid release or slow release.
For being the solid dispersions technique of purpose to improve dissolution, the dissolution rate of solid dispersion depends on the character of used active substance to a great extent, the characteristic of carrier material and formulation method.Whether active constituents of medicine is suitable for this preparation technology, adopts which kind of preparation technology, selects which kind of carrier for use, will depend on the character of medicine and carrier, must explore by test and just can finish, and has Unpredictability.
Goal of the invention:
One object of the present invention is to replenish the deficiency of existing preparation, the solid dispersion of a kind of chrysophanic acid and diacetyl rhein or its pharmaceutically acceptable salt is provided, it can improve the bioavailability height, reduce adverse reaction rate, drop pill for one of invention, granule can also significantly reduce the medicine cost.
Another object of the present invention is to provide the preparation method of the solid dispersion of a kind of chrysophanic acid and diacetyl rhein or its pharmaceutically acceptable salt.
A further object of the present invention is to provide the compositions of the solid dispersion that contains a kind of chrysophanic acid and diacetyl rhein or its pharmaceutically acceptable salt.With the preparation of said composition preparation particularly drop pill and dispersible tablet, preparations such as granule can be oral, but also buccal, preparation is simple, and production cost is low.
Summary of the invention:
The present invention relates to a kind of Pharmaceutical composition.Specifically, the present invention relates to chrysophanic acid or diacetyl rhein and pharmaceutically acceptable salt thereof is active component, with solid dispersion pharmaceutical composition of forming as pharmaceutically suitable carrier (being dispersible carrier) of the disperse matrix of solid dispersion and preparation method thereof, be used for the treatment of arthritis, comprise osteoarthritis, rheumatism and rheumatoid arthritis, also can be used for cardiovascular disease etc.Compositions of the present invention comprises active constituents of medicine chrysophanic acid (purity is more than 50%), diacetyl rhein and at pharmaceutically acceptable salt, carrier material and other adjuvant, carrier is selected from polyethylene glycols, the polyvinylpyrrolidone class, cyclodextrin, surfactant-based, ureas, at least a or several mixture in organic acid and the saccharide; The weight ratio of chrysophanic acid or diacetyl rhein and carrier is 3: 1～1: 30, adopts fusion method, solvent method, and solvent-fusion method or abrasive micropowderization prepare the effective ingredient dispersion, splash into then and make drop pill in the condensing agent.Also this dispersion cooling can be made dispersible tablet, disintegrating tablet, hard capsule, granule, and soft capsule after the pulverizing.This invention can improve bioavailability of medicament, reduces the adverse reaction rate of medicine, and wherein drop pill can significantly reduce the medication preparation cost.This invention can be widely used in treating aspects such as osteoarthritis, rheumatoid arthritis, blood fat reducing and atherosclerosis.
The technical solution adopted for the present invention to solve the technical problems is, the solid dispersion of a kind of chrysophanic acid and diacetyl rhein or its pharmaceutically acceptable salt, comprise above-mentioned active component and dispersible carrier, the weight ratio of active constituents of medicine and carrier is 3: 1～1: 30, more preferably 1: 3～1: 10, solid dispersion that is obtained and preparation single dose stripping quantity half an hour thereof were not less than 95% of labelled amount.Proportioning: calculate active constituents of medicine: carrier=3: 1～1: 30 with gram or kilogram.Be preferably 1: 3～1: 10.
Wherein chrysophanic acid and diacetyl rhein or its pharmaceutically acceptable salt can extract from plant and be semi-synthetic and obtain, and also can be complete synthesis acquisitions.
Physical property according to chrysophanic acid and diacetyl rhein and salt thereof is chosen suitable carrier, and preferred carrier is selected from: polyvinylpyrrolidone (PVP) class, polyethylene glycols (PEG) class, cyclodextrin, surfactant-based, ureas, one or more in organic acid and the saccharide.More preferably PEG4000 or PEG6000 in the polyethylene glycols material, saccharide is dextran more preferably, lactose, mannitol or sucrose, a kind of in the sucrose ester or their mixture.
When carrier is selected the mixture of above-mentioned carrier for use, mixed carrier is formed: Polyethylene Glycol and beta-schardinger dextrin-, Polyethylene Glycol and poloxamer, the mixture of Polyethylene Glycol and polyoxyethylene stearate 40 esters or Polyethylene Glycol and carboxymethyl starch sodium or Polyethylene Glycol and sucrose ester, the ratio of the former with the latter is 12: 1～1: 1.Preferred 10: 1～1: 1.
Pharmaceutical composition of the present invention is characterized in that described active constituents of medicine high degree of dispersion is in carrier.For this reason, the formulation method of pharmaceutical composition of the present invention is:
A. fusion method comprises the steps:
A. active constituents of medicine is ground into fine particle;
B. carrier is heated to fusion, adds the active constituents of medicine granule, or drug solution, fully mixing;
C. fused mass is placed the rustless steel pallet of ice bath, make its rapid cooling curing, place exsiccator dry, pulverize, promptly obtain the solid dispersion compositions.Also can directly make dropping pill formulation.
B. solvent-fusion method comprises the steps:
A. with active constituents of medicine dissolving or be suspended in the organic solvent of heating, described organic solvent is selected from glacial acetic acid, ethanol, acetone, ethyl acetate etc.;
B. carrier is heated to fusion, adds medicine-active ingredient solution, fully mixing;
C. evaporate organic solvent, cooling, drying is solidified, and is carried out, and pulverizes, and promptly obtains the solid dispersion compositions; After also solvent evaporation can being treated, directly make dropping pill formulation.
C. solvent-solvent method comprises the steps:
A. active constituents of medicine is dissolved or is suspended in the organic solvent described in the organic solvent and be selected from glacial acetic acid, ethanol, acetoneand ethyl acetate etc.;
B. carrier is dissolved in the solvent, adds medicine-active ingredient solution, fully mixing;
C. evaporate organic solvent, cooling, drying is solidified, and is pulverized, and promptly obtains the solid dispersion compositions.After also solvent evaporation can being treated, directly make dropping pill formulation.
D. spray drying method comprises the steps:
A. with the dissolving of active constituents of medicine and carrier or be suspended in ethanol or the glacial acetic acid;
B. with this mixed solution supersound process 15-30min, carry out spray drying again, promptly obtain described active component and get solid dispersion.
E. polishing comprises the steps:
A. active constituents of medicine and carrier (preferred nonionic surfactants such as PEG, saccharide etc.) are mixed in proportion;
B. this mixture is ground to form 20～100 microns granule, preferably do not need heated air stream to spray in the micropowder pulverizer and finish.Promptly obtain described active component and get solid dispersion.
The preparation method of the solid dispersion of chrysophanic acid and diacetyl rhein and salt thereof can also be selected conventional polishing, spray drying method, fusion method and solvent method etc. for use.
1. polishing
Carrier (preferred Polyethylene Glycol and PVP or its mixture) and medicament mixed is even, place grinder (the preferably grinder that need not heat), grind the 3-30 branch, make about 20～40 microns of its particle diameters.
2. spray drying method
Active component or its salt are dissolved in ethanol, in the solution such as ethyl acetate, this solution were mixed ultrasonic 20 minutes, carry out spray drying again, promptly get the solid dispersion of chrysophanic acid and diacetyl rhein and salt thereof.
3. fusion method
Chrysophanic acid and diacetyl rhein and salt thereof are dissolved in the solvent, the solvent preferred alcohol, water, ethyl acetate makes fusion with the carrier heating, adds above-mentioned solution, also can directly drug powder be added in the melting carrier.Fully stir to remove and desolvate, pulverizing was ground 120 mesh sieves and was got final product.
4 solvent methods
Chrysophanic acid and diacetyl rhein and salt thereof and carrier are dissolved in the solvent, stir dissolving, mix homogeneously; Rotary evaporation boils off solvent, and drying in the vacuum drier is put in cooling, pulverizes, and grinds, and crosses 120 mesh sieves.Solvent preferred alcohol and ethyl acetate.
Above fusion method, the solid dispersion of solvent method gained can be made dropping pill formulation with the drop pill machine, dispersible tablet etc. after solvent eliminates.The dispersions obtained preparation that is mainly used in granule of nebulization.
Aforesaid common micronized mixture can be made into capsule, hard gelatin capsule, and emulsifiable paste, ointment, suppository and Tabules also comprise the pharmaceutical preparation of conventional excipients in addition.Dosage form for Orally-administrable, can use for example diluent such as lactose, cellulose and sugar, lubricant such as magnesium stearate and stearic acid, disintegrating agent such as starch glycolate and carboxymethyl cellulose, anti-caking agent such as silicon dioxide, adhesive, thin film forms chemical compound such as hydroxypropyl emthylcellulose and acrylic paint, and speedup is moulded agent such as decanedioic acid dibutyl ester and Polyethylene Glycol, sweetener such as Radix Asparagi glucide and saccharin sodium, hide wide agent such as Pulvis Talci and titanium dioxide, coloring agent such as ferrum oxide, flavoring agent, antiseptic such as methyl parahydroxybenzoate.For the percutaneous dosage form, can use band fat and the excipient that contains water (vaseline and water), surfactant and emulsifying agent such as Isosorbide Dinitrate and glyceryl monostearate, viscosifier such as ketone group octadecanol, gel and sodium carboxymethyl cellulose, and antiseptic such as p-Hydroxybenzoate.For the concrete condition of transdermal dosage form, can use plasticizer and glycerol triacetate and polymer such as methacrylate.But the dosage form of rectally comprises lipophilic and hydrophilic excipient such as glyceride, polyoxyethylene glycol.The total amount of the excipient in the compositions changes according to used pharmaceutical dosage form usually, and can be about 50%-90% of composition total weight.
The preparation drop pill can adopt general drop pill, and adjusts the temperature control system of drop pill, makes the water dropper temperature heating of drop pill machine and is controlled at (50～90) ℃, and preferred 60～70 ℃, the temperature cooling of condensing agent also remains on (40～-5) ℃; When treating that the temperature of condensing agent in drop pill water dropper and the condensation column is stable respectively and reaching desired state of temperature, to contain the fused solution of drug extract and substrate and/or emulsion and/or suspension places in the water dropper jar of water dropper machine, splash in the condensing agent, condensing agent can be a liquid paraffin, methyl-silicone oil, any one in the vegetable oil; The drop pill that will be shunk molding by the drop pill outlet takes out, and removes the surface condensation agent, is drying to obtain, and also can form film clothing drop pill to increase the stability of this medicine by coating.
Because the bioavailability of this medicine depends primarily on the degree of this active component in digestive tract dispersion and stripping, so the present invention is with the test method of dissolution method as absorbing state in the analogue body, the preparation that the solid dispersion that is obtained is prepared carries out dissolution test, uses the facilitation of technology of the present invention to active component stripping and bioavailability to judge.
The invention will be further described below by the detailed description of embodiment, but do not limit the present invention.
The preparation of embodiment 1 chrysophanic acid sodium dispersion and dispersible tablet
Restrain chrysophanic acid sodium or diacetyl rhein sodium or diacetyl rhein potassium to 25 and be dissolved in earlier in 4.5 gram sodium bicarbonate (4.5% aqueous solution) aqueous solutions, add 7.5 gram hydroxyethyl-celluloses (simultaneously as disintegrating agent), the abundant stirring forms solution A; 2.5 gram gels, 0.5 gram spice, 25 gram sucrose and 60 gram mannitol mixed dissolutions are made solution B, solution A and solution B are mixed, add the suitable quantity of water dilution, and abundant mixing, put into the mould sharp freezing, evacuation in freeze dryer sublimes up into the material bone dry, press seal, packing.The gross weight of six kinds of adjuvants is 100 grams, makes 1000,100 milligrams of every adjuvants, and 25 milligrams of chrysophanic acid sodium of principal agent, promptly oral cavity disintegration tablet heavily is 125 milligrams.Through check, all compound pharmacopeia of every index is about the requirement of dispersible tablet.
The preparation of embodiment 2 fusion method solid dispersion and drop pill
(PEG-6000: sodium carboxymethyl cellulose=10: 1) heating makes fusion with 1000 gram composite interstitial substances, reducing temperature makes between 60～70 ℃, then chrysophanic acid or diacetyl rhein powder 200 grams are joined in the PEG-6000 fused solution, stir rapidly, behind fused solution to be formed and/or suspension and/or the emulsion, splash into according to a conventional method and make drop pill in the condensing agent.After also can treating the dispersion cooling, pulverize, make other dosage form.
Embodiment 3 chrysophanic acids or chrysophanic acid sodium or diacetyl rhein or diacetyl rhein potassium 100 grams, add in ethanol or the aqueous solution, heating for dissolving, put into fused PEG-4000, after fully mixing, vacuum drying is made drop pill after waiting to eliminate solvent according to a conventional method, or cooling to pulverize the back encapsulated or make other dosage form.
Embodiment 4 is incorporated into 10 kilograms of chrysophanic acids or 10 kilograms of diacetyl rheins and 50 kilograms of PEG-6000 in the blender continuously, and is mixed to the formation uniform powder.
The mixture of powders that so obtains is carried out common micronization in the air-flow jet mill.Obtain about 20 microns of powder mean diameter thus.
Can add other excipient and make capsule, preparations such as tablet.
Embodiment 5 with tristerin 100 gram with 60 ℃ of heating in water bath to fusion, 20 gram diacetyl rhein powder are joined in the above-mentioned molten mass, after fully stirring, make drop pill according to the method described above, also can cool off, encapsulated after pulverizing, tabletting etc.
Embodiment 6 is with diacetyl rhein potassium or chrysophanic acid sodium or chrysophanic acid or diacetyl rhein 100 grams and 30 gram glucoses, and 20 gram sucrose fully mix, and common micronization, then with 10 gram compressibility sorbitol, 20 gram mannitol, 10 gram sodium bicarbonate, 9.9 the gram citric acid, the saccharin sodium of the Aspartame of 0.05 gram and 0.05 gram fully mixes, and adds wetting agent and makes soft material, sieve oven dry, granulate, tabletting behind the adding lubricant, make 2000, every heavy 100 milligrams, and wherein principal agent contains 50 milligrams.The new drug requirements of customs declaration of compound this dosage form of each index after testing.
Embodiment 7 is with chrysophanic acid sodium or diacetyl rhein potassium 100 grams and 20 gram sucrose, 30 gram glucoses, a little Aspartame and saccharin sodium and antioxidant, 5 gram sodium bicarbonate, 10 gram PEG-4000, after fully mixing, ultrasonic making is dissolved in water or ethanol water, granule is made in lyophilization or be spray dried to granule.
Following table is various carriers, the external stripping situation of the drop pill that the preparation of compositions of various ratios becomes:
The test of drug extract and single-matrix and mixed-matrix
(medicine: substrate=1: 3)
| The substrate title | The solid dispersion preparation | Effective ingredient | Dissolve scattered time limit (minute) |
| Macrogol 4000 | Solvent method | 25％ | ＜30 |
| Polyethylene glycol 6000 | Solvent method | 25％ | ＜30 |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | Fusion method | 25％ | ＜30 |
| Poloxamer: Polyethylene Glycol=1: 10 | Solvent-solvent method | 25％ | ＜30 |
| Sodium carboxymethyl cellulose: Polyethylene Glycol=1: 12 | Solvent method | 25％ | ＜30 |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | Fusion method | 25％ | ＜30 |
| Tristerin | Fusion method | 16％ | ＜20 |
Claims (10)
1. solid dispersion compositions that can improve bioavailability contains as the chrysophanic acid of active component or diacetyl rhein and pharmaceutically acceptable salt thereof with as pharmaceutically suitable carrier of the disperse matrix of solid dispersion.
2. pharmaceutical composition according to claim 1 is characterized in that the weight ratio of active component and carrier is: 3: 1～1: 30.
3. pharmaceutical composition according to claim 1, it is characterized in that described carrier is selected from the polyvinylpyrrolidone class, polyethylene glycols, cyclodextrin, poloxamer, polyethyleneglycol glyceride, ureas, at least a or several mixture in organic acid and ester thereof and the saccharide (comprising sucrose ester).
4. the described pharmaceutical composition of claim 3, its mixed carrier composition characteristic is: Polyethylene Glycol and beta-schardinger dextrin-, Polyethylene Glycol and poloxamer, the mixture of Polyethylene Glycol and polyoxyethylene stearate 40 esters or Polyethylene Glycol and carboxymethyl starch sodium or Polyethylene Glycol and sucrose ester, the ratio of the former with the latter is 12: 1～1: 1.
5. the described pharmaceutical composition of claim 1, wherein active component chrysophanic acid or diacetyl rhein and pharmaceutically acceptable salt thereof can be synthetic, also can be plant extract.
6. the described pharmaceutical composition of claim 1 is characterized in that described active constituents of medicine high degree of dispersion in carrier, and formulation method is:
A. fusion method comprises the steps:
A. active constituents of medicine is ground into fine particle;
B. carrier is heated to fusion, adds the active constituents of medicine granule, or drug solution, fully mixing;
C. fused mass is placed the rustless steel pallet of ice bath, make its rapid cooling curing, place exsiccator dry, pulverize, promptly obtain the solid dispersion compositions.Also can directly make dropping pill formulation.
B. solvent-fusion method comprises the steps:
A. with active constituents of medicine dissolving or be suspended in the organic solvent of heating, described organic solvent is selected from glacial acetic acid, ethanol, acetone, ethyl acetate etc.;
B. carrier is heated to fusion, adds medicine-active ingredient solution, fully mixing;
C. evaporate organic solvent, cooling, drying is solidified, and is carried out, and pulverizes, and promptly obtains the solid dispersion compositions; After also solvent evaporation can being treated, directly make dropping pill formulation.
C. solvent-solvent method comprises the steps:
A. active constituents of medicine is dissolved or is suspended in the organic solvent described in the organic solvent and be selected from glacial acetic acid, ethanol, acetoneand ethyl acetate etc.;
B. carrier is dissolved in the solvent, adds medicine-active ingredient solution, fully mixing;
C. evaporate organic solvent, cooling, drying is solidified, and is pulverized, and promptly obtains the solid dispersion compositions.After also solvent evaporation can being treated, directly make dropping pill formulation.
D. spray drying method comprises the steps:
A. with the dissolving of active constituents of medicine and carrier or be suspended in ethanol or the glacial acetic acid;
B. with this mixed solution supersound process 15-30min, carry out spray drying again, promptly obtain described active component and get solid dispersion.
E. polishing comprises the steps:
A. active constituents of medicine and carrier (preferred nonionic surfactants such as PEG, saccharide etc.) are mixed in proportion;
B. this mixture is ground to form 20～100 microns granule, preferably do not need heated air stream to spray in the micropowder pulverizer and finish.Promptly obtain described active component and get solid dispersion.
7. a pharmaceutical composition contains the described solid dispersion of claim 1 and other acceptable accessories.
8. compositions as claimed in claim 7, said composition can be made oral, the preparation of rectum or skin (percutaneous or transdermal).
9. the compositions as claim 1 or 7 is preparing treatment of arthritis, the application in the medicine of diseases such as cardiovascular.
10. purposes as claimed in claim 9, described preparation can be for oral, the preparation of rectum or skin (percutaneous or transdermal).
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610057255 CN101032476A (en) | 2006-03-10 | 2006-03-10 | Medical combination including rhein or diacetylrhein and the preparing method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610057255 CN101032476A (en) | 2006-03-10 | 2006-03-10 | Medical combination including rhein or diacetylrhein and the preparing method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009040702A2 (en) * | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| EP2471515A2 (en) * | 2007-09-14 | 2012-07-04 | Wockhardt Limited | Rhein or diacerein compositions |
| CN104188951A (en) * | 2014-09-18 | 2014-12-10 | 上海慈瑞医药科技有限公司 | Diacerein composition and preparing method thereof |
| CN114796149A (en) * | 2022-04-27 | 2022-07-29 | 苏州中化药品工业有限公司 | Diacerein capsule with high bioavailability and preparation method thereof |
-
2006
- 2006-03-10 CN CN 200610057255 patent/CN101032476A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2471515A2 (en) * | 2007-09-14 | 2012-07-04 | Wockhardt Limited | Rhein or diacerein compositions |
| EP2471516A2 (en) * | 2007-09-14 | 2012-07-04 | Wockhardt Limited | Rhein or diacerein compositions |
| EP2471516A3 (en) * | 2007-09-14 | 2012-12-26 | Wockhardt Limited | Rhein or diacerein compositions |
| EP2471515A3 (en) * | 2007-09-14 | 2012-12-26 | Wockhardt Limited | Rhein or diacerein compositions |
| EP3207921A1 (en) * | 2007-09-14 | 2017-08-23 | Wockhardt Limited | Rhein or diacerein compositions |
| WO2009040702A2 (en) * | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| WO2009040702A3 (en) * | 2007-09-27 | 2009-08-06 | Wockhardt Research Center | Pharmaceutical compositions of rhein or diacerein |
| AU2008303277B2 (en) * | 2007-09-27 | 2013-04-04 | Wockhardt Limited | Pharmaceutical compositions of rhein or diacerein |
| RU2484816C2 (en) * | 2007-09-27 | 2013-06-20 | Вокхардт Рисерч Сентер | Pharmaceutical compositions of rhein or diacerein |
| CN104188951A (en) * | 2014-09-18 | 2014-12-10 | 上海慈瑞医药科技有限公司 | Diacerein composition and preparing method thereof |
| CN104188951B (en) * | 2014-09-18 | 2016-09-28 | 上海慈瑞医药科技有限公司 | A kind of diacetyl rhein compositions and preparation method thereof |
| CN114796149A (en) * | 2022-04-27 | 2022-07-29 | 苏州中化药品工业有限公司 | Diacerein capsule with high bioavailability and preparation method thereof |
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