CN101199836B - Stage releasing CsA solid tiny milk agent and tiny milk curing method thereof - Google Patents
Stage releasing CsA solid tiny milk agent and tiny milk curing method thereof Download PDFInfo
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- CN101199836B CN101199836B CN2007101353693A CN200710135369A CN101199836B CN 101199836 B CN101199836 B CN 101199836B CN 2007101353693 A CN2007101353693 A CN 2007101353693A CN 200710135369 A CN200710135369 A CN 200710135369A CN 101199836 B CN101199836 B CN 101199836B
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Abstract
The invention discloses a stage-releasing-type cyclosporine A solid micro-emulsion preparation and the solidification method of the micro-emulsion. With the containing cyclosporine A serving as the active component, the micro-emulsification technique and the micro-emulsion solidification technique are adopted to solidify the cyclosporine A micro-emulsion; then corresponding auxiliary material for delayed release is adopted to prepare into particles which can release at the specific intestine; the gastric juice soluble particles and the enteric soluble particles are mixed in a certain proportion to get the cyclosporine stage-releasing preparation which can be slowly released by stage. The new preparation overcomes the deficiency of the big fluctuation of the blood concentration of the ordinary preparation, prolongs the effective concentration time of the medicine and reduces the incidence of adverse reaction. The preparation method is applied to the industrialized production.
Description
One, technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof, specifically release type ciclosporin A solid microemulsion formulation of a kind of stage and microemulsion curing thereof.
Two, background technology
Ciclosporin A (Ciclosporin A) is a kind of fat-soluble ring-type 11 peptide compounds that mycete Tolypocladium inflatum generates.Be found in 1969, first Application was in clinical in 1978.Being mainly used in clinical immunosuppressant at present mainly is ciclosporin A, and this raw material has how tame pharmacy corporation production.The chemical name of ciclosporin is: 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]
Its structural formula is:
Ciclosporin selectively acts on the T lymphocyte activation initial stage.Can generate multiplicaiton factor interleukin II (IL-2) after helper T lymphocyte is activated, ciclosporin can suppress its generation; But it does not have influence to suppressor T lymphocyte.Its another important function is to suppress lymphocyte to generate interferon.It does not have influence to the reticuloendothelial system phagocytic cell.Thereby ciclosporin is different from the effect of cytotoxic drug, and it is the cellular immunization of suppressor T cell mediation and the general defence capability of unlikely appreciable impact body only.The treatment of anti-rejection when ciclosporin is mainly used in organ transplantation at present and graft versus host disease (GVHD).Along with the continuous understanding to the ciclosporin mechanism of action, and clinical some disease is pathogenetic constantly clear and definite, and ciclosporin not only is applied to anti-rejection at present.In recent years, this medicine is aspect treatment immune system diseases associated, and particularly the autoimmune disease aspect has also obtained sure evaluation.
Ciclosporin is mainly used in clinically:
1. inhibition organ transplant rejection is as the at first anti-rejection drugs after the various organ transplantations.
2. treat autoimmune disease and atrophic diseases, as crohn, ulcerative colitis, psoriasis, myasthenia gravis, rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus (sle), polymyositis, insulin dependent diabetes mellitus (IDDM), infiltrative exophthalmos etc.
3. hematopathy such as aplastic anemia, pure red cell aplasia anemia.
In recent years, ciclosporin typical hospital dosage at home rises year by year, the present preparation of ciclosporin mainly contains three kinds of ciclosporin injection, ciclosporin soft capsule and ciclosporin oral liquids, wherein with the ciclosporin soft capsule and the oral liquid consumption maximum of oral administration, because organ transplantation patient main method of oral immunity inhibitor that adopts after operation overcomes the organ rejection, the patient of other autoimmune diseases also needs long-term oral administration.Because ciclosporin is the medicine of indissoluble in the water, and it is also lower to gastrointestinal tract mucous permeability, so the method that initial preparation has adopted vegetable oil to add emulsifying agent prepares the pre-concentration emulsion formulation, the emulsifying under the effect at gastrointestinal motility jointly of the liquid of said preparation in oral back and gastrointestinal tract, and by the further emulsifying of bile, at last by intestinal absorption.But this preparation can cause bigger individual variation because of patient's intestinal physiology difference and the different of choleresis, therefore U.S. Novartis Co.,Ltd has released new microemulsifying formulations in recent years, add the better emulsifying agent of effect in this microemulsifying formulations and helped Emulsion, improved the composition of oil phase, the microemulsion of preparation is more stable, particle diameter is littler after the emulsifying, make its absorption in gastrointestinal tract less be subjected to the influence of individual variation, thereby bioavailability is improved, and the individual variation of absorption has obtained reducing.
Ciclosporin existing problem in clinical practice is to need constantly monitoring blood drug level, and untoward reaction such as injury of kidney and nerve injury easily take place when blood drug level surpasses treatment concentration, and blood drug level rejection will take place when being lower than treatment concentration.The blood drug level of ciclosporin being treated window has at present clinically had more understanding, requires paddy concentration greater than 120ng/ml generally speaking, and the highest blood drug level should be lower than 600ng/ml (concentration range is different according to assay method).The ciclosporin oral liquid (sandimmun neoral) of listing adopts the method administration of 2 administrations on the one at present, the peak time of sandimmun neoral is about 1 hour, therefore back short-term drug level height and the low problem of later stage drug level might occur taking medicine, after taking medicine, patient have the time blood drug level of half to be under the treatment window, caused the organ rejection risk, if and patient forgets and take medicine, bigger organ rejection risk will be caused.There is clinical research to show,, will obtains more stable blood drug level, thereby when guaranteeing curative effect, overcome untoward reaction if ciclosporin is adopted the low dosage multiple dosing.But multiple dosing on the one must bring inconvenience, especially organ transplantation patient in the medication for taking medicine all the life to the patient, and multiple dosing was less feasible on 1st.The method that solves is exactly that ciclosporin is made the preparation with release characteristics, once-a-day or obtain comparatively stable effective blood drug concentration after the twice-daily administration.Traditional slow controlled-release technology mainly contains skeleton release or the film controlled release is put, and require medicine dissolution better, be absorbed with rule, and the medicine of ciclosporin to be a slightly solubility and absorption do not have rule has only the purpose that adopts microemulsion system just can reach dissolving and stable absorption.But microemulsion formulation is comparatively novel, and still no-trump ciclosporin microemulsion is made the research report with release characteristic preparation at present.
Common Emulsion curing technology commonly used at present has spray drying method, freeze-drying and carrier absorption method.Spray drying method since the Emulsion viscosity big, in spray-drying process the loss bigger, generally be not used; Freeze-drying is that Emulsion is added a certain amount of excipient after the lyophilizing of long period forms, and the excipient dosage that this kind method needs is bigger, and freeze-drying time is long, and the cost height is produced comparatively complicated; Carrier absorption solidification method is simple and easy to do, is Emulsion solidification method commonly used at present, but the made Emulsion drug release of present Emulsion solidification method is incomplete, and the curing of microemulsion is attempted as yet.
As if 02809524.3 has mentioned with resin microemulsion has been solidified in the at present relevant ciclosporin patent, and with elder generation among the present invention microemulsion being solidified back reuse resin with other materials, to do skeleton different, and directly are difficult to molding with resin solidification.Patent 96195173.7 is mentioned with poloxamer medicine is made reuse resin coating behind the solid dispersion, and the ciclosporin in this system has not been a microemulsion system, and is different fully with the present invention.Mentioned the solidified technology of microemulsion in the patent 01807863, but this technology adopts spray drying method, production is complicated, loss is big, and the microemulsion after also will not solidifying is simultaneously made delayed release preparation.
Three, summary of the invention
Ciclosporin A solid microemulsifying formulations with stage release characteristics provided by the invention is intended to obtain haemoconcentration stably for the patient after taking medicine, technical problem to be solved is that ciclosporin A is progressively discharged in gastric juice and in the intestinal stage by stage, and the curing of microemulsion.
The alleged stage release type ciclosporin A solid microemulsion formulation of the present invention is by ciclosporin A microemulsion stage release type solid microemulsion formulation of obtaining than mix homogeneously by 1: 2～2: 1 quality of the enteric coated particles that discharges in intestinal of preparation and the gastric-soluble particle that discharges in gastric juice respectively after solidifying.
Preferred enteric coated particles and gastric-soluble particle compare mix homogeneously by 1: 1 quality.
The microemulsion that obtains in the organic facies that described ciclosporin A microemulsion is dissolved in oil phase, surfactant and is helped Emulsion to form by ciclosporin A, each component is got following weight portion:
0.5～1.5 part of ciclosporin A
2～4 parts of oil phases
4～8 parts in surfactant
Help 2～4 parts of Emulsions
The preferred organic facies that constitutes with decanoyl/octanoyl glycerides, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol, wherein decanoyl/octanoyl glycerides is a kind of medium-chain triglyceride, has self emulsifying effect preferably, polyoxyethylene hydrogenated Oleum Ricini is a present proving effect emulsifying agent preferably, be good wherein with polyoxyethylene hydrogenated Oleum Ricini RH40, co-emulsifier has been selected stability propylene glycol preferably, ciclosporin A microemulsion good stability with this organic facies preparation, self-emulsifying ability is higher, is the slightly opalescent liquid of clarification with the arbitrary proportion dilution in water.The abbreviation that described hot capric acid glyceride is sad triglyceride and capric acid triglyceride.
0.5～1.5 part of ciclosporin
2～4 parts of decanoyl/octanoyl glycerides
4～8 parts of polyoxyethylene hydrogenated Oleum Ricini
2～4 parts of propylene glycol
The curing of described ciclosporin A microemulsion is to be cured with known carrier absorption method, with the difference of existing method is to be cured with the carrier absorption method add the absorption improving agent in the ciclosporin A microemulsion after, the addition of absorption improving agent is 20 ~ 100wt% of organic facies in the microemulsion, preferred 30 ~ 60wt%.Described carrier is selected from micropowder silica gel, microcrystalline Cellulose, dextrin, lactose, calcium hydrogen phosphate, polyvinylpyrrolidone etc., and preferred micropowder silica gel and microcrystalline Cellulose are especially the strongest with hydrophilic micropowder silica gel absorbability.But there is very big problem in the microemulsion after the absorption aspect self emulsifying, because adsorbing material to the absorption of medicine, has caused the microemulsion after solidifying to be difficult to form again microemulsion in water, the result causes the dissolution rate of solidfied material Chinese medicine to be reduced to 50～70%.In order to address this problem, the applicant added the recovery that the absorption improving agent helps to solidify microemulsion before microemulsion absorption.The absorption improving agent is selected from hydrophilic high molecular material and comprises hydroxypropyl emthylcellulose or water-soluble cellulose analog derivatives such as hydroxy methocel or hydroxypropyl cellulose or hydroxy methocel, perhaps polyvinylpyrrolidone and derivant thereof are wherein with the polyvinylpyrrolidone best results.Each composition weight mark is:
0.5～1.5 part of ciclosporin A
8～16 parts of organic faciess
3～8 parts of absorption improving agent
4～8 parts in carrier
Preferably:
Ciclosporin A 0.5-1.5 part
Decanoyl/octanoyl glycerides 2-4 part
Polyoxyethylene hydrogenated Oleum Ricini 4-8 part
Propylene glycol 2-4 part
Polyvinylpyrrolidone 3-8 part
Micropowder silica gel 4-8 part
Therefore after having prepared solidified ciclosporin A microemulsion, adopt the processing method of known delivery formulations to be made into enteric coated particles and two kinds of delayed release granules of gastric-soluble particle.Enteric coated particles can postpone drug release about 2 hours, because granule emptying time under one's belt is quite fixing, was approximately 2 hours, so can utilize this time difference with the enteric coated particles administration that combines with gastric-soluble particle, reached the purpose that the stage discharges medicine.Promptly two kinds of granules progressively discharge medicine in the gastrointestinal tract transport process, reach the purpose that discharges stage by stage.
Enteric coated particles and gastric-soluble particle can be matrix type granule or coating type granular.Its component is as follows:
Solidify microemulsion part 60-80%w/w
Resin matrix or coating part 20-40%w/w
Framework material that enteric coated particles is used or coating material (general designation enteric resin) are selected from:
EUDRAGIT L 100-55 or EUDRAGIT L 30D-55 or EUDRAGIT L 100 or polyacrylic resin II etc.
Framework material that gastric-soluble particle is used or coating material (general designation gastric solubleness resin) are selected from:
EUDRAGI E 100 or EUDRAGIT EPO or polyacrylic resin IV etc.
Concrete preparation process is as follows:
(1) ciclosporin A is dissolved in the organic facies.
(2) will adsorb improving agent and add mixing in the ciclosporin A microemulsion.
(3) add the carrier absorption solidification.
(4) resin solution is added limit granulation limit drying in the solidified carrier.Maybe will solidify and in the coating machine, use the resin solution coating after microemulsion is granulated.
(5) enteric coated particles is mixed according to a certain percentage with gastric-soluble particle.
The present invention discharged about 50% in 2 hours with enteric coated particles and the solid microemulsion formulation of making after gastric-soluble particle mixes by a certain percentage in external acid medium, 2 hours accumulative total discharges about 80% after being transformed into the enteric medium, accumulative total discharged more than 90% in 4 hours, had realized discharging stage by stage, the steady purpose of blood drug level.The present invention has successfully adopted a kind of curing technology of easy suitable suitability for industrialized production that microemulsion system is solidified but has not destroyed its characteristic, adopts to postpone release tech with its prepared composition stage delivery formulations on solidified basis.In solidification process, creatively use a kind of hydrophilic material, successfully solve carrier absorption solidification method Chinese medicine and discharged incomplete problem, prepared and can not only keep the microemulsion characteristic but also have the plain A of environmental protection of better solidification effect to solidify microemulsion.On this basis ciclosporin A is formed in the granule that different gastrointestinal tract sections discharge, reaches the purpose that makes medicine progressively discharge and obtain steady blood drug level.
A kind of novelty, significant ciclosporin drug delivery system are provided for clinical.
Four, description of drawings
Fig. 1 is the blood drug level-time graph behind oral embodiment 1 of beagle dog and the ciclosporin oral liquid 100mg, and abscissa is the oral back time, and vertical coordinate is a blood drug level.Both compare, take the present embodiment medicine after animal blood drug level steady, blood peak concentration/blood paddy concentration ratio is less than the ciclosporin oral liquid.
Five, the specific embodiment
Example 1
Enteric coated particles
Ciclosporin A 1kg
Decanoyl/octanoyl glycerides 2kg
Polyoxyethylene hydrogenated Oleum Ricini 5kg
Propylene glycol 3kg
Polyvinylpyrrolidone K30 4kg
Micropowder silica gel 5kg
Homemade II resin 6kg
Gastric-soluble particle
Ciclosporin A 1kg
Decanoyl/octanoyl glycerides 2kg
Polyoxyethylene hydrogenated Oleum Ricini 5kg
Propylene glycol 3kg
Polyvinylpyrrolidone K30 4kg
Micropowder silica gel 5kg
Homemade IV resin 4kg
Ciclosporin A is joined in decanoyl/octanoyl glycerides, the propylene glycol, stir and make dissolving, add polyoxyethylene hydrogenated Oleum Ricini, stirring and evenly mixing adds polyvinylpyrrolidone K30 and stirring fast, makes its abundant dispersing and dissolving in solution, add micropowder silica gel subsequently, stir to make and adsorb into solid.The II resin is joined after with an amount of dissolve with ethanol in the microemulsion absorption solid, stir and make mix homogeneously, make granule, fling to ethanol and obtain solidified enteric coated particles.Make with quadrat method and to make granule with the alcoholic solution of IV resin after solidifying microemulsion, obtain solidified gastric-soluble particle after flinging to ethanol.Two kinds of granules are measured behind the content according to getting final product in 1: 1 mixed of ciclosporin.
Example 2
Enteric coated particles
Ciclosporin A 1kg
Decanoyl/octanoyl glycerides 2kg
Polyoxyethylene hydrogenated Oleum Ricini 5kg
Propylene glycol 3kg
Polyvinylpyrrolidone K30 4kg
Micropowder silica gel 5kg
Starch 5kg
Homemade II resin 6kg
PEG?400 0.5kg
Pulvis Talci 1kg
Ethanol 80kg
Gastric-soluble particle
Ciclosporin A 1kg
Decanoyl/octanoyl glycerides 2kg
Polyoxyethylene hydrogenated Oleum Ricini 5kg
Propylene glycol 3kg
Polyvinylpyrrolidone K30 4kg
Micropowder silica gel 5kg
Homemade IV resin 4kg
Ciclosporin A is joined in decanoyl/octanoyl glycerides, the propylene glycol, stir and make dissolving, add polyoxyethylene hydrogenated Oleum Ricini, stirring and evenly mixing adds polyvinylpyrrolidone K30 and stirring fast, makes its abundant dispersing and dissolving in solution, add micropowder silica gel subsequently, stir to make and adsorb into solid.Will be solidified microemulsion granulate with polyvinylpyrrolidone K30 alcoholic solution after adding starch, granule places the round as a ball limit oven dry of coating pan limit, treat that granule reaches certain roundness after, with II resin alcoholic solution coating, the coating weightening finish reaches 10-20%.40 ℃ of curing of coated granule got final product after 12 hours.The method preparation that gastric-soluble particle and example 1 are identical.
Checking example 1
Particulate dissolution determination: the ciclosporin A granule that will be equivalent to 100mg places the 1000ml dissolution medium, 37 ℃ of following 100r/min stir, preceding 2 hours dissolution medium is the 0.1M hydrochloric acid solution, being replaced with pH after the sampling in 2 hours is 6.8 buffer, continue to stir 2,4 hours sampling and measuring after changing medium.Assay method is a high-efficient liquid phase technique.
| 2 hours (0.1M hydrochloric acid) | 4 hours (pH6.8 buffer) | 6 hours |
| Example 1 | ?53％ | 86％ | 98％ |
| Example 2 | ?52％ | 89％ | 98％ |
Checking example 2
Particulate animal pharmacokinetics research: give 6 beagle dogs with granule and the commercially available ciclosporin oral liquid of embodiment 1, each oral administration 100mg, the administration of binary cycle intersection, got blood in 1,2,3,4,6,8,10,12,24 hour before the administration and after the administration, measure ciclosporin blood drug level with the HPLC method.The result shows that the ciclosporin oral liquid has bigger peak concentration, and the peak concentration of example 1 is low, and blood drug level is steady.See accompanying drawing 1.
Claims (6)
1. stage release type ciclosporin A solid microemulsion formulation, it is characterized in that: be the enteric coated particles that in intestinal, discharges that after solidifying, prepares respectively by the ciclosporin A microemulsion, with the gastric-soluble particle that in gastric juice, discharges, the solid microemulsion formulation that obtains than mix homogeneously by 1: 2～2: 1 quality; Wherein
Enteric coated particles
Ciclosporin A 0.5-1.5 part
Organic facies 8-16 part
Absorption improving agent 3-8 part
Carrier 4-8 part
Enteric resin 4-8 part;
Gastric-soluble particle
Ciclosporin A 0.5-1.5 part
Organic facies 8-16 part
Absorption improving agent 3-8 part
Carrier 4-8 part
Gastric solubleness resin 2-6 part;
Described organic facies constitutes with decanoyl/octanoyl glycerides, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol, and described absorption improving agent is a polyvinylpyrrolidone.
2. a kind of stage release type ciclosporin A solid microemulsion formulation according to claim 1, it is characterized in that: the particulate mass ratio of enteric coated particles and gastric solubleness is 1: 1.
3. a kind of stage release type ciclosporin A solid microemulsion formulation according to claim 1 and 2 is characterized in that:
Enteric coated particles
Ciclosporin A 0.5-1.5 part
Decanoyl/octanoyl glycerides 2-4 part
Polyoxyethylene hydrogenated Oleum Ricini 4-8 part
Propylene glycol 2-4 part
Absorption improving agent 3-8 part
Carrier 4-8 part
Enteric resin 4-8 part;
Gastric-soluble particle
Ciclosporin A 0.5-1.5 part
Decanoyl/octanoyl glycerides 2-4 part
Polyoxyethylene hydrogenated Oleum Ricini 4-8 part
Propylene glycol 2-4 part
Absorption improving agent 3-8 part
Carrier 4-8 part
Gastric solubleness resin 2-6 part.
4. a kind of stage release type ciclosporin A solid microemulsion formulation according to claim 3 is characterized in that:
Enteric coated particles
1 part of ciclosporin A
2 parts of decanoyl/octanoyl glycerides
40 5 parts of polyoxyethylene hydrogenated Oleum Ricini RH
3 parts of propylene glycol
4 parts of polyvinylpyrrolidone K30
5 parts of micropowder silica gels
6 parts of enteric resins;
Gastric-soluble particle
1 part of ciclosporin A
2 parts of decanoyl/octanoyl glycerides
40 5 parts of polyoxyethylene hydrogenated Oleum Ricini RH
3 parts of propylene glycol
4 parts of polyvinylpyrrolidone K30
5 parts of micropowder silica gels
4 parts of gastric solubleness resins.
5. the microemulsion curing of stage release type ciclosporin A solid microemulsion formulation as claimed in claim 1, be meant that the ciclosporin A microemulsion formulation with the method that the carrier absorption method is cured, is characterized in that: be to be cured with the carrier absorption method add the absorption improving agent in the ciclosporin A microemulsion after; The addition of described absorption improving agent is 20～100wt% of organic facies, and described absorption improving agent is selected from hydrophilic high molecular material, and hydrophilic high molecular material is selected from polyvinylpyrrolidone.
6. curing according to claim 5 is characterized in that: the addition of absorption improving agent is 30～60wt% of organic facies.
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| CN101406452B (en) * | 2008-11-14 | 2012-10-17 | 沈阳药科大学 | Ciclosporin A microemulsion formulation for injection and preparation method thereof |
| CN102600076B (en) * | 2012-03-15 | 2016-03-23 | 胡容峰 | Ciclosporin A solid self-microemulsion particle and preparation method thereof |
| CN104483376A (en) * | 2014-12-30 | 2015-04-01 | 青岛市市立医院 | Method for screening drug action target position of cyclosporine A in immunized T cell |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079907A (en) * | 1991-06-27 | 1993-12-29 | 山道士有限公司 | Pharmaceutical composition |
| CN1679916A (en) * | 2000-04-10 | 2005-10-12 | 诺瓦提斯公司 | Pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079907A (en) * | 1991-06-27 | 1993-12-29 | 山道士有限公司 | Pharmaceutical composition |
| CN1679916A (en) * | 2000-04-10 | 2005-10-12 | 诺瓦提斯公司 | Pharmaceutical compositions |
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