CN1245212C - Cyclosporin A dispersion solid and its preparation method - Google Patents
Cyclosporin A dispersion solid and its preparation method Download PDFInfo
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- CN1245212C CN1245212C CN 200410016445 CN200410016445A CN1245212C CN 1245212 C CN1245212 C CN 1245212C CN 200410016445 CN200410016445 CN 200410016445 CN 200410016445 A CN200410016445 A CN 200410016445A CN 1245212 C CN1245212 C CN 1245212C
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Abstract
The present invention relates to immunosuppressant ciclosporin A solid dispersion and a preparation method thereof, which belongs to the field of chemical medicine preparation. In the present invention, ciclosporin A is adopted as a medicine active component, a carrier material is added to the ciclosporin A to be respectively processed by adopting a solvent method, a solvent melting method, a grinding method, a spray drying method and a freeze drying method to prepare ciclosporin A solid dispersion, and the solid dispersion can be further prepared into capsules, tablets, granules, suppositories and dripping pills. The present invention can increase medicine solubility and a medicine dissolution speed, the solubility of a medicine in water and the accumulation and dissolution percentage of the medicine in a dissolution medium are respectively raised by 5 to 300 times and 3 to 15 times than those of a raw material medicine in 60 minutes, and the present invention can improve the absorption of a medicine in vivo.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of chemical compound ciclosporin A solid dispersion and preparation method thereof.
Technical background
Ciclosporin A (English name: Cyclosporine A, Cyclosporin A) its chemical name for the ring [[(E)-(2S, 3R, 4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octene acyl]-the amino butyryl of L-2-N-methyl glycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl], molecular formula C
62H
111N
11O
12Molecular weight: 1202.63, have following chemical constitution,
Ciclosporin A is a kind of lipotropy ring type polypeptide that extracts from fungus (Tolypocladium Inflatum Gams) in 1772, is made up of 11 aminoacid, is insoluble in water, fusing point 148-151 ℃.Found that ciclosporin A had immunosuppressive action in 1976, it is a potent immunosuppressant, began to be used for the renal transplant patient in 1978, be widely used in clinical organ transplantation since the eighties in 20th century, in order to improve the survival rate after transplanting, become one of current topmost immunosuppressant.
Ciclosporin A is the common drug after the organ transplantation still not, rejection when being widely used in heteroplastic transplantation of the same race such as control parenchymatous organ and bone marrow, and be applied to other treatment of diseases gradually, as autoimmune disease, cutaneous diseases, autoimmunity hematopathy, asthma and multiple myeloma etc.Main dosage form clinically has soft capsule (microemulsion, sandimmun neoral), oral liquid (oil solution) and injection at present.
Ciclosporin A dissolubility in water is minimum, dissolving hardly, and bioavailability is low, can't directly be prepared into qualified oral formulations by crude drug.
Summary of the invention
The purpose of this invention is to provide a kind of ciclosporin A solid dispersion, be specifically related to ciclosporin A solid dispersion that a kind of stripping is fast, bioavailability is high and preparation method thereof.The present invention has the advantage that stripping is fast, bioavailability is high, is convenient to the ciclosporin A that pharmacy corporation is produced multiple solid dosage forms.
It is active component that the present invention adopts ciclosporin A (Taishan City, Guangdong Province chemical pharmacy company limited), add carrier material, comprise polyvidone, polyethylene glycols, poloxamer, Gelucire44/14 and Gelucire50/13, Myrj 45 class, mannitol, microcrystalline Cellulose and cyclodextrin and derivant thereof, adopt solvent method, solvent-fusion method, polishing, spray drying method, freeze-drying to prepare the ciclosporin A solid dispersion respectively.
Ciclosporin A solid dispersion of the present invention can be distinguished preparation as follows:
1, solvent method also claims coprecipitation
Get carrier material and ciclosporin A, rate of charge is 4: 1-20: 1, add organic solvent dehydrated alcohol, chloroform, dichloromethane, 95% ethanol, acetone or methanol, and stir, make dissolving; Boil off most of solvent on Rotary Evaporators, bath temperature is 25-65 ℃, determines that by inventory and bath temperature evaporation time is 0.1-4h; Afterwards, put dry 10-30h in the vacuum drying oven, temperature can be between room temperature to 60 ℃; Dry thing is crossed the 60-120 mesh sieve and is got powder after grinding, and promptly gets solid dispersion of the present invention.
The gained solid dispersion can be made into tablet, capsule, granule, suppository or drop pill.Wherein film-making agent and capsule can add fluidizer and lubricant, comprise Pulvis Talci, Polyethylene Glycol, Stepanol MG, magnesium stearate, sodium lauryl sulphate, micropowder silica gel or their mixture, and consumption is the 0.1-5% of total recipe quantity; Disintegrating agent be can add and starch 5-20%, carboxymethyl starch sodium 1-6%, polyvinylpolypyrrolidone 0.5-6% or low-substituted hydroxypropyl cellulose 2-5% comprised; Can add other adjuvants, comprise pregelatinized Starch, lactose, microcrystalline Cellulose, starch, dextrin or their mixture, consumption accounts for the 15-60% of recipe quantity; Carrier material can be selected Polyethylene Glycol, poloxamer, polyvidone, Myrj 45 class and mannitol.
2, solvent-fusion method
Get carrier material, heating makes its fusion in 50-90 ℃ of water-bath, drip and stir ciclosporin A with organic solvent such as dehydrated alcohol, methanol, 95% ethanol, acetone, chloroform or ether dissolution, continue to stir 30-150 minute according to inventory, fused mass poured on culture dish or the stainless steel flat plate tiles ,-20 ℃ freezing 2-8 hour; Put vacuum drying oven dry 10-30 hour, temperature can be between room temperature to 65 ℃; Or frozen material placed exsiccator, room temperature was placed 1-5 days; Dry thing is pulverized, and crosses the 60-120 mesh sieve, promptly gets solid dispersion of the present invention.
The gained solid dispersion can be made into tablet, granule, capsule, suppository or drop pill.Wherein film-making agent and capsule can add fluidizer and lubricant, comprise Pulvis Talci, Stepanol MG, magnesium stearate, sodium lauryl sulphate, micropowder silica gel or their mixture, and consumption is the 0.1-5% of total recipe quantity; Can comprise starch 5-20%, carboxymethyl starch sodium 1-6%, polyvinylpolypyrrolidone 0.5-6% or low-substituted hydroxypropyl cellulose 2-5% with disintegrating agent; Can add other adjuvants, comprise pregelatinized Starch, lactose, microcrystalline Cellulose, starch, dextrin or their mixture, consumption accounts for the 15-60% of recipe quantity; Carrier material can be selected Polyethylene Glycol, poloxamer, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, Gelucire44/14 and Gelucire50/13, or wherein any two or three carrier mixes use.
3, polishing
Get carrier material and ciclosporin A, mixing is put in the mortar and is ground, rotating speed 100-600rpm, milling time 10-60min.Take out, cross the 80-100 mesh sieve, promptly get solid dispersion of the present invention.
Gained solid dispersion directly compressible, preparation capsule or wet method system granule tabletting.Wherein the mass ratio that feeds intake of carrier material and medicine is 4: 1-20: 1, and described carrier material can be selected Macrogol 4000, polyethylene glycol 6000, the plain PH M06 of plain PH302, Ai Wei of plain PH301, Ai Wei of plain PH101, Ai Wei of Ai Wei plain PH102, Ai Wei, the plain PH M15 of Ai Wei, the plain PH M25 of Ai Wei, the plain RC A591NF of Ai Wei plain KG801, Ai Wei, cyclodextrin and derivant, polyvidone class and lactose for use.
4, spray drying method
Get carrier material and ciclosporin A, mixing adds 60-90% ethanol, stirs and makes dissolving.Spray drying gets solid dispersion of the present invention.The gained solid dispersion can further be made tablet or capsule.
Wherein the weight ratio that feeds intake of carrier material and medicine is 4: 1-20: 1, and described carrier material can be selected polyvidone, polyethylene glycol 6000, Macrogol 4000, cyclodextrin and derivant thereof, Myrj 45 class, lactose and mannitol for use.
5, freeze-drying
Get carrier material, adding distil water stirs, and makes dissolving, and this solution and medicine ciclosporin A are put in the mortar altogether, grind, and rotating speed 100-600rpm, milling time is 20-70min.Lyophilization, freeze-drying time are 15-48h.Take out, grind, cross the 60-100 mesh sieve, promptly get solid dispersion of the present invention.
The gained solid dispersion can encapsulated, tabletting.Wherein, the weight ratio that feeds intake of carrier material and medicine is 4: 1-20: 1, and the distillation water yield is the heavy 10-100 of carrier material times.Described carrier material can be selected Macrogol 4000, polyethylene glycol 6000, poloxamer 407, poloxamer 188, Myrj 45 class, polyvidone class, lactose and mannitol for use.
Ciclosporin A solid of the present invention is disperseed the dissolubility of physical ability increase medicine, accelerates the dissolution rate of medicine.Medicine in water dissolubility and in dissolution medium 60 minutes accumulation stripping percentage rate improve 5-300 doubly and 3-15 times than material medicine respectively.Through the rat oral gavage administration, the pharmacokinetics experimental result shows this invention and sandimmun neoral (Neoral) bioequivalence in the body.
The present invention adopts differential scanning calorimetric analysis (DSC), X-ray diffraction analysis that prepared all kinds of solid dispersion are investigated.DSC result shows, does not all observe the fusing point peak of medicine in the described solid dispersion, and prompting should not adopt the DSC method that this solid dispersion is identified.The X-ray diffraction result shows that the ciclosporin A crude drug has strong diffraction maximum between 5-30 °, after making solid dispersion, except with poloxamer 188 being the solid dispersion external (carrier is 8: 1 with the ratio of medicine) of preparing carriers, the crystal diffraction peak of medicine disappears, show the medicine high degree of dispersion in carrier material, be scattered in wherein with molecular forms or unformed state.
The present invention adopts the stripping situation of dissolution in vitro measuring medicine, and the result shows that it is all right in external stripping, has clear improvement than crude drug.The result is as follows:
1, second method or the three therapeutic methods of traditional Chinese medicine (little agar diffusion method) mensuration medicine dissolution in vitro in the Chinese Pharmacopoeia version appendix in 2000 press in dissolution in vitro experiment.Medium is 0.01%W/V polyoxyethylene sorbitan monoleate, 0.1N HCl/ acetonitrile (7/3, volume ratio), 0.1% sodium lauryl sulphate (SDS) aqueous solution, pH7.4 phosphate buffer or distilled water, rotating speed 100rpm, 37 ± 0.5 ℃ of temperature.
2, the dissolution in vitro experiment is contrast with the ciclosporin A crude drug, measures ciclosporin A solid dispersion of the present invention in external stripping situation.The result shows that solid dispersion of the present invention cumulative in vitro stripping in 60 minutes percentage rate is 55.79-100.33% (labelled amount), has significance to improve than material medicine.Be the solid dispersion of preparing carriers with poloxamer 407, poloxamer 188, polyoxyethylene (40) stearate, Gelucire 50/13 and Gelucire 44/14 wherein, dissolution rate improves particularly remarkable.
Description of drawings
Fig. 1 is blood drug level-time graph in solid dispersion of the present invention and the Neoral rat body.
The specific embodiment
Embodiment 1
Get the 1g ciclosporin A and 8g polyoxyethylene (40) stearate is put in the beaker, add the 15ml dehydrated alcohol, stir and make dissolving fully.In 40 ℃ of water-baths, with Rotary Evaporators evaporation 25 minutes, with the solvent evaporate to dryness.Be transferred to and continue dry 24h (room temperature) in the vacuum drying oven, take out, grind, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 94.40 ± 1.51% (n=6).
Embodiment 2
Get the 1g ciclosporin A and 8g 30 POVIDONE K 30 BP/USP-29/32 is put in the beaker, add the 20ml dehydrated alcohol, stir and make dissolving fully.In 40 ℃ of water-baths, with Rotary Evaporators evaporation 25 minutes, with the solvent evaporate to dryness.Be transferred to and continue dry 24h (50 ℃) in the vacuum drying oven, take out, grind, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 55.79 ± 11.92% (n=6).
Embodiment 3
Get the 1g ciclosporin A and 10g poloxamer 407 is put in the beaker, add the 25ml dehydrated alcohol, stir and make dissolving fully.In 40 ℃ of water-baths, with Rotary Evaporators evaporation 25 minutes, with the solvent evaporate to dryness.Be transferred to and continue dry 24h (40 ℃) in the vacuum drying oven, take out, grind, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 91.83 ± 5.19% (n=6).
Embodiment 4
Get the 1g ciclosporin A and 12g poloxamer 407 is put in the beaker, add the 25ml dehydrated alcohol, stir and make dissolving fully.In 40 ℃ of water-baths, with Rotary Evaporators evaporation 25 minutes, with the solvent evaporate to dryness.Be transferred to and continue dry 24h (40 ℃) in the vacuum drying oven, take out, grind, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 87.67 ± 7.40% (n=6).
Embodiment 5
Get 10g poloxamer 188 in beaker, put in 70 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring with the 4ml anhydrous alcohol solution, finish, after continuing to be stirred to solvent and flinging to, pour in the culture dish rapidly and tile, place 4h in the refrigerator frozen coating, taking-up is put and is placed 24h (35 ℃) in the vacuum desiccator, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 90.40 ± 1.06% (n=6).
Embodiment 6
Get 11g poloxamer 188 in beaker, put in 70 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring with the 4ml anhydrous alcohol solution, finish, after continuing to be stirred to solvent and flinging to, pour in the culture dish rapidly and tile, place 4h in the refrigerator frozen coating, taking-up is put and is placed 24h (35 ℃) in the vacuum desiccator, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 92.14 ± 1.58% (n=6).
Embodiment 7
Get 12g poloxamer 188 in beaker, put in 70 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring with the 4ml anhydrous alcohol solution, finish, after continuing to be stirred to solvent and flinging to, pour in the culture dish rapidly and tile, place 4h in the refrigerator frozen coating, taking-up is put and is placed 24h (35 ℃) in the vacuum desiccator, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 99.32 ± 0.34% (n=6).
Embodiment 8
Get 8g poloxamer 407, in beaker, place in 90 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring, finish, after continuing to be stirred to solvent and flinging to the 4ml anhydrous alcohol solution, pour in the culture dish rapidly and tile, place 4h in the refrigerator frozen coating, take out to put and place 24h (40 ℃) in the vacuum desiccator, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 95.14 ± 3.77% (n=6).
Embodiment 9
Get 5g poloxamer 407, in beaker, place in 90 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring, finish, after continuing to be stirred to solvent and flinging to the 4ml anhydrous alcohol solution, pour in the culture dish rapidly and tile, place 4h in the refrigerator frozen coating, take out to put and place 24h (40 ℃) in the vacuum desiccator, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 100.33 ± 5.99% (n=6).
Get 6g polyoxyethylene (40) stearate in beaker, place in 70 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring, finish with the 4ml anhydrous alcohol solution, after continuing to be stirred to solvent and flinging to, pour in the culture dish rapidly and tile, place 4h, take out to put and place 24h in the vacuum desiccator in the refrigerator frozen coating, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 87.28 ± 4.19% (n=6).
Embodiment 11
Get 7g polyoxyethylene (40) stearate in beaker, place in 70 ℃ of water-baths, treat complete fusion, add medicine 1g while stirring, finish with the 4ml anhydrous alcohol solution, after continuing to be stirred to solvent and flinging to, pour in the culture dish rapidly and tile, place 4h, take out to put and place 24h in the vacuum desiccator in the refrigerator frozen coating, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 93.34 ± 4.28% (n=6).
Embodiment 12
Get 5g Gelucire 50/13 in beaker, put in 70 ℃ of water-baths, treat complete fusion, add 3g microcrystalline Cellulose (the plain PH302 of Ai Wei), stir evenly.Add medicine 1g while stirring, finish, after continuing to be stirred to solvent and flinging to the 4ml anhydrous alcohol solution, pour in the culture dish rapidly and tile, place 4h, take out to put and place 24h (room temperature) in the vacuum desiccator in the refrigerator frozen coating, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 80.12 ± 5.22% (n=6).
Embodiment 13
Get Gelucire 50/13 and Gelucire 44/14 each 2.5g in beaker, put in 70 ℃ of water-baths, treat complete fusion, add 3g microcrystalline Cellulose (the plain PH302 of Ai Wei), stir evenly.Add medicine 1g while stirring, finish, after continuing to be stirred to solvent and flinging to the 4ml anhydrous alcohol solution, pour in the culture dish rapidly and tile, place 4h, take out to put and place 24h (room temperature) in the vacuum desiccator in the refrigerator frozen coating, treat embrittlement, take out the pulverizing back and cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 85.34 ± 4.12% (n=6).
Embodiment 14
Get 0.5g ciclosporin A and 6g microcrystalline Cellulose (the plain PH302 of Ai Wei), put altogether in the mortar, grind, rotating speed is 200rpm, and milling time is 3h, crosses 100 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 72.96 ± 5.09% (n=6).
Embodiment 15
Get the ciclosporin A that 0.5g crosses 80 mesh sieves,, filter, get the medicine group with 90% ethanol 50ml dissolving.Get 5g 30 POVIDONE K 30 BP/USP 29/32,, filter, get carrier material solution with 75% ethanol 500ml dissolving.With drug solution and carrier solution mixing under agitation, electricity consumption thermal spray exsiccator carries out spray drying.Inlet temperature is 60 ℃, application of sample speed 20ml/min.Make dry loose powdered shape solid dispersion.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 71.46 ± 8.8% (n=6).
Embodiment 16
Get 0.25g ciclosporin A and 5g 30 POVIDONE K 30 BP/USP 29/32 and put altogether in the mortar, grind, rotating speed 300rpm, milling time 3g crosses 100 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 83.14 ± 3.98% (n=6).
Embodiment 17
Get the 1.5g polyethylene glycol 6000, add distilled water 150ml, stir and make dissolving fully, this solution and 0.125g ciclosporin A are placed mortar altogether, grind rotating speed 200rpm, milling time 80min.Medicinal liquid is transferred in the 500ml round-bottomed flask pre-freeze, lyophilization 52h.Take out, pulverize, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 67.77 ± 2.52% (n=6).
Embodiment 18
Get 1.5g 30 POVIDONE K 30 BP/USP 29/32, add distilled water 150ml, stir and make dissolving fully, this solution and 0.125g ciclosporin A are placed mortar altogether, grind rotating speed 200rpm, milling time 80min.Medicinal liquid is transferred in the 500ml round-bottomed flask pre-freeze, lyophilization 50h.Take out, pulverize, cross 80 mesh sieves, promptly.This invention solid dispersion 60min cumulative in vitro stripping percentage rate is 67.31 ± 8.70% (n=6).
Claims (15)
1, ciclosporin A solid dispersion, it is characterized in that containing active component ciclosporin A and carrier material, described carrier material comprises Gelucire44/14 and Gelucire50/13, Myrj 45 class, mannitol, microcrystalline Cellulose and cyclodextrin and derivant thereof.
2, ciclosporin A solid dispersion as claimed in claim 1, the weight ratio that it is characterized in that described carrier material and ciclosporin A is 4: 1-20: 1.
3, the method for preparing the described ciclosporin A solid dispersion of claim 1 is characterized in that by solvent method or solvent-fusion method or polishing or spray drying method or freeze-drying preparation.
4, the preparation method of claim 3, wherein solvent method is by following step,
Get carrier material and ciclosporin A, rate of charge is 4: 1-20: 1, and add organic solvent and stir, make dissolving; Rotation boils off solvent, and water-bath 25-65 ℃, evaporation 0.1-4h, vacuum drying 10-30h, temperature is a room temperature to 60 ℃, dry thing grinds, and crosses the 60-120 mesh sieve and gets powder.
5, preparation method as claimed in claim 4, wherein said organic solvent are dehydrated alcohol, chloroform, dichloromethane, 95% ethanol, acetone or methanol, and described carrier material is the Myrj 45 class.
6, preparation method as claimed in claim 3, wherein solvent-fusion method is by following step,
Get carrier material, 50-90 ℃ of heating in water bath makes its fusion, drips ciclosporin A liquid, stirs 30-150 minute, and fused mass is poured out tiling, put-20 ℃ freezing 2-8 hour; Vacuum drying 10-30 hour, temperature was between the room temperature to 60 ℃; Or frozen material put in the exsiccator, placed 1-5 days under the room temperature; Pulverize dry thing, cross the 60-120 mesh sieve.
7, preparation method as claimed in claim 6, wherein said carrier material are Gelucire 44/14, Gelucire 50/13 and Myrj 45 class.
8, preparation method as claimed in claim 3, wherein polishing is by following step,
Get carrier material and ciclosporin A, mixing is put in the mortar altogether, grinds rotating speed 100-600rpm, milling time 10-60min.Take out, cross the 80-100 mesh sieve.
9, preparation method as claimed in claim 8, wherein said carrier material are microcrystalline Cellulose and cyclodextrin and derivant thereof.
10, preparation method as claimed in claim 3, wherein spray drying method is by following step, gets carrier material and ciclosporin A, mixing adds 60-90% ethanol, stirs to make dissolving, spray drying.
11, by the preparation method of claim 10, wherein said carrier material is Myrj 45 class, cyclodextrin and derivant thereof and mannitol.
12, preparation method as claimed in claim 3, wherein freeze-drying is by following step,
Get carrier material, add distilled water, stir, make dissolving, solution and medicine ciclosporin A are placed mortar altogether, grind, rotating speed 100-600rpm grinds 20-70min, lyophilization, and 15-48h takes out, and grinds again, crosses the 60-100 mesh sieve.
13, as the preparation method of claim 12, wherein said carrier material is cyclodextrin and derivant and mannitol.
14, ciclosporin A solid dispersion as claimed in claim 1 can be made into tablet, capsule, granule, drop pill or suppository.
15, ciclosporin A solid dispersion as claimed in claim 14, wherein film-making agent and capsule, add fluidizer and lubricant, comprise Pulvis Talci, Polyethylene Glycol, Stepanol MG, magnesium stearate, sodium lauryl sulphate, micropowder silica gel or their mixture, consumption is the 0.1-5% of total recipe quantity; Or the adding disintegrating agent, comprise starch 5-20%, carboxymethyl starch sodium 1-6%, polyvinylpolypyrrolidone 0.5-6% or low-substituted hydroxypropyl cellulose 2-5%; Or add other adjuvants, and comprising pregelatinized Starch, lactose, microcrystalline Cellulose, starch, dextrin or their mixture, consumption accounts for the 15-60% of recipe quantity.
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| CN100431601C (en) * | 2005-04-25 | 2008-11-12 | 北京大学 | Cyclosporine microball preparation for treating endophthalmitis |
| CN101219114B (en) * | 2005-06-24 | 2010-06-02 | 云南白药集团股份有限公司 | Pennogenin compounds solid state molecule dispersion preparation |
| CN101081213B (en) * | 2007-06-26 | 2010-10-06 | 中山大学 | Butane diacid(5-androstene-17-ketone- 3beta -hydroxyl group ) diester solid dispersoid and method for making same and applications thereof |
| CN101129362B (en) * | 2007-08-16 | 2010-10-06 | 江苏信孚药业有限公司 | Sirolimus dispersible tablets and method of producing the same |
| CN101716135B (en) * | 2010-01-08 | 2012-11-14 | 山西医科大学 | Soy isoflavone solid dispersion suppository and preparation method thereof |
| CN102166201B (en) * | 2011-04-25 | 2013-05-01 | 江苏大学 | Oral ciclosporin A sustained-release agent and preparation method thereof |
| CN102764258B (en) * | 2011-10-21 | 2013-09-25 | 四川百利药业有限责任公司 | Preparation method of candesartan cilexetil amlodipine compound tablet |
| CN108354905A (en) * | 2018-05-22 | 2018-08-03 | 江西中医药大学 | A kind of andrographolide solid dispersion of stabilization and preparation method thereof and preparation |
| CN113081970A (en) * | 2021-05-07 | 2021-07-09 | 聊城大学 | Cyclosporine solid dispersion and preparation method of tablet thereof |
| CN113384535A (en) * | 2021-07-12 | 2021-09-14 | 河南金大众生物工程有限公司 | Florfenicol solid dispersion and preparation method thereof |
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