CN102600076A - Cyclosporine A solid self-microemulsion particle and preparation method thereof - Google Patents
Cyclosporine A solid self-microemulsion particle and preparation method thereof Download PDFInfo
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- CN102600076A CN102600076A CN2012100787516A CN201210078751A CN102600076A CN 102600076 A CN102600076 A CN 102600076A CN 2012100787516 A CN2012100787516 A CN 2012100787516A CN 201210078751 A CN201210078751 A CN 201210078751A CN 102600076 A CN102600076 A CN 102600076A
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Abstract
The invention relates to the field of medical technology, in particular to a cyclosporine A solid self-microemulsion particle and a preparation method of the cyclosporine A solid self-microemulsion particle. The preparation method is characterized in that spherocrystal granulation technique is utilized, cyclosporine A self-microemulsion is added to a uniform suspension solution of a polymer material formed by the high polymer material, a dispersion carrier and a pore-forming agent by dissolution in a solvent, the suspension solution is added to a poor solvent containing a surfactant, and cyclosporine A solid self-microemulsion particle is prepared in liquid phase in one step. The cyclosporine A solid self-microemulsion particle comprises the following ingredients by weight: 0.25 to 1.5% of cyclosporine A, 4.0% of polyoxyethylene hydrogenated castor oil, 2.0% of caprylic/decanoic acid glycerol ester, 2.0% of propylene glycol, 1.0% of ethanol, 4.0% of dichloromethane, 0.5-1.1g of ethyl cellulose (or Eudragit RS100, RS100), 0.05 % of PEG4000 (polyethylene glycol 4000) and 0.5% of colloidal silicon dioxide.
Description
One, technical field
The invention belongs to medical technical field, relate to a kind of method for preparing of pharmaceutical preparation, exactly it is a kind of ciclosporin A solid self-microemulsion microgranule and preparation method thereof.A kind of specifically in liquid phase a step make ciclosporin A solid self-microemulsion microgranule.
Two, background technology
Ciclosporin A is a kind of immunosuppressant of strong effect, has been widely used in the anti-rejection of organ transplantation patient and autoimmune disease such as treatment of diseases such as psoriasis, rheumatoid arthritis such as liver, kidney, lung, bone marrow, pancreas at present.Ciclosporin A has larger molecular weight (1202.6), strong lipotropy (lgP=2.92) and low aqueous solubility (37 ℃, 1.73 μ g/ml); And highly relying on bile absorbs; And have gastrointestinal tract metabolism widely, thereby oral absorption is poor, bioavailability is low; Individual variation is big, has limited its extensive use clinically.The dosage form of listing is soft capsule, oral liquid and injection at present, and medicine is met waterishlogging in vivo and is conigenous emulsifying formation microemulsion, has improved the low patient's of reaching of bioavailability of medicament the big problem of individual variation.Can be automatic emulsified behind the oral chance gastro-intestinal Fluid of commercial preparation sandimmun neoral (Neoral) microemulsion about one-tenth 30nm; It is low to have improved the CyA oral administration biaavailability; The shortcoming that the pharmacokinetics variability is big; But contain a large amount of solubilizing agent Cremophor EL in the self-microemulsion and can cause a series of biologys and physiology's side effect; Like nephrotoxicity, anaphylaxis, hyperlipidemia, erythrocyte gathering etc., and according to therapeutic drug monitoring confirm to occur easily taking medicine back short-term drug level height and the low problem of later stage drug level.
Because the oil phase and the surfactant viscosity that contain in the self-microemulsion are big, the spray drying yield is low; The lyophilization rule has certain requirement to instrument and equipment, and cost is high, produces complicated; The general carrier absorption method generally need add a large amount of vehicle excipients, and the pressed powder drug loading that makes is lower and viscosity is bigger, is difficult to handle etc.This seminar intends explores the new way that the spherocrystal granulating technique prepares the solid self-microemulsion, does not all see to have in document and the patent at present to relate to the report that the spherocrystal granulating technique prepares the solid self-microemulsion.
Ciclosporin A is processed the solid self-micro emulsion formulation medicine will steadily be discharged slowly, the back blood drug level of avoiding taking medicine is too high and cause serious Liver and kidney toxicity, also can avoid the influence of liquid alcohol to soft capsule shell, improves oral administration biaavailability, improves curative effect.
Three, summary of the invention
The objective of the invention is deficiency to existing preparation; Ciclosporin A is processed the solid self-micro emulsion formulation can make medicine steadily discharge slowly; The back blood drug level of avoiding taking medicine is too high and cause serious Liver and kidney toxicity, also can avoid the influence of liquid alcohol to soft capsule shell, improves oral administration biaavailability; Improve curative effect, solidify self-microemulsion and conveniently store and carry.
The objective of the invention is to realize according to following scheme
The preparation of ciclosporin A solid self-microemulsion utilizes the spherocrystal granulating technique, macromolecule blocker, porogen is dissolved in the even suspension solution that forms macromolecular material in the solvent, under stirring condition; Add and contain in right amount in the aqueous solutions such as poor solvent of certain surface activating agent, stir, replenish suitable quantity of water through appropriate time; Continue to stir an amount of time, good solvent and bridging agent counterdiffusion mutually in water, emulsion droplet solidifies; Form microspheres with solid, room temperature is dry down, collects; The associating dispersible carrier is cured the ciclosporin A self-microemulsion, thereby prepares ciclosporin A solid self-microemulsion microgranule.
Ciclosporin A solid self-microemulsion wherein; It is characterized in that: utilize the spherocrystal granulating technique; The ciclosporin A self-microemulsion is joined macromolecular material, dispersible carrier, porogen be dissolved in the even suspension solution that forms macromolecular material in the solvent; Join in the poor solvent that contains surfactant, a step makes ciclosporin A solid self-microemulsion microgranule in liquid phase.
Preparation ciclosporin A solid self-microemulsion microgranule needs three solvent systems and surfactant to form.
Bridging agent: dichloromethane, chloroform;
Good solvent: independent or mixed solvent such as ethanol, acetone;
Poor solvent: water and aqueous medium thereof.
Surfactant: sodium lauryl sulphate, polyvinyl alcohol, poloxamer, tween 80 etc.
Macromolecular material selection cellulose derivative class is selected from one or more in hypromellose titanate esters, Hydroxypropyl Methyl Cellulose Phthalate, hypromellose, hydroxypropyl cellulose phthalate, the ethyl cellulose (10-40cp), preferred, ethyl (10-40cp) in the ciclosporin A solid self-microemulsion; Crylic acid resin or cellulose derivative class; Wherein crylic acid resin is selected from one or more among acrylic resin, Eudragit RL, Eudragit RS, Eudragit E, Eudragit L, the Eudragit S, preferred acrylic resins Eudragit E100, EudragitRS100, Eudragit RL100; Porogen selects for use PEG4000, polyethylene than in pyrrolidone, HPMC K4M, lactose, the mannitol powder one or more; Dispersible carrier is selected one or more of micropowder silica gel, Pulvis Talci, calcium carbonate, calcium phosphate, magnesium stearate for use.
The ciclosporin A solid self-microemulsion; It is characterized in that: said composition contains the weight of ciclosporin A self-microemulsion raw material and forms: ciclosporin A: 5%～20%; Polyoxyethylene hydrogenated Oleum Ricini: 30%～70%; Sad capric acid triglyceride: 10%～30%, propylene glycol: 10%～30%, ethanol: 5%～15%.
The ciclosporin A solid self-microemulsion is characterized in that: the weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 0.25～1.5, and polyoxyethylene hydrogenated Oleum Ricini: 4; Sad capric acid triglyceride: 2, propylene glycol: 2, ethanol: 1; Dichloromethane 4.0; Ethyl cellulose (10-40cp) 0.5g, PEG4000 0.05g, micropowder silica gel 0.5g.
The weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 1, and polyoxyethylene hydrogenated Oleum Ricini: 4, sad capric acid triglyceride: 2; Propylene glycol: 2, ethanol: 1, dichloromethane 4.0; Ethyl cellulose (10cp) 0.5g, PEG40000.05g, micropowder silica gel 0.5g.
The spherocrystal granulating technique prepares the ciclosporin A solid self-microemulsion, and its solidification temperature is 25 ℃～50 ℃, and rotating speed is 400～600rpm.The mass fraction of ciclosporin A in the solid self-microemulsion is 0.05～0.25.
Microsphere prepares the adding that adds the purpose porogen of porogen in the process, makes the microsphere of preparation with holes, thereby better, more adsorbs the ciclosporin A self-microemulsion, when guaranteeing to improve drug loading, but makes the microsphere that makes have the characteristic of vertical compression.
The sad capric acid triglyceride of oil phase in the adsorption process in the purpose ciclosporin A self-microemulsion of adding micropowder silica gel and the viscosity of surfactant polyoxyethylene hydrogenation castor oil are very big; And fusion at high temperature takes place easily; Adding carrier material makes medicine better adsorbed by porous microsphere; Improve solids flowability effectively, can be used for directly filling or tabletting.
The ciclosporin A solid self-microemulsion of preparation can form microemulsion in 37 ℃ aqueous solution, demonstrate blue opalescence.
Advantage of the present invention be can be in liquid phase a step make ciclosporin A and solidify self-microemulsion.Medicine can slowly discharge stably after said preparation got into gastrointestinal tract, reduced the serious Liver and kidney toxicity that quick releasing formulations such as oral liquid and soft capsule produce.Also avoid simultaneously in the soft capsule pure class I liquid I to the influence of softgel shell, and drug loading increase greatly, the solid self-microemulsion, better mobile because of it, can directly incapsulate or direct compression, production cost is low, favorable reproducibility, yield is high.
Description of drawings
Fig. 1 places under the transmission electron microscope and to observe ciclosporin A solid self-microemulsion microgranule outward appearance, form and take pictures
Fig. 2 laser particle size analyzer is measured ciclosporin A solid self-microemulsion diameter of particle and particle size distribution
The specific embodiment
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stir and promptly get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 0.5 ethyl cellulose, 0.05g PEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible; Add the ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; Continue to stir 10min, until full solidification.Do not take place stickingly glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
Embodiment 2
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: root takes by weighing ciclosporin A 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stirs and promptly gets the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible; Add above-mentioned ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; 10min is stirred in continuation, does not take place to glue to aggregate particle to stick natural drying 12h on sieve; Sieve and weigh, particle diameter concentrates on 100～～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
Embodiment 3
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 0.25g according to prescription, be dissolved in the 1.0ml ethanol, add the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stir and promptly get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 0.5mg ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible; Add above-mentioned ciclosporin A self-microemulsion 1.0g in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 1%PVA aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; 10min is stirred in continuation, does not take place to glue to aggregate particle to stick natural drying 12h on sieve; Sieve and weigh, particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid microemulsified slow-releasing preparation that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
Embodiment 4
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 1.25g according to prescription, be dissolved in the 1.0ml ethanol, add the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stir and promptly get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 1.0g Eudragit RS100,0.1gPEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible; Add the ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; 10min is stirred in continuation, does not take place to glue to aggregate particle to stick natural drying 12h on sieve; Sieve and weigh, particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stir and promptly get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 0.5g Eudragit RL100,0.05g HPMC K4M in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible; Add above-mentioned ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; 10min is stirred in continuation, does not take place to glue to aggregate particle to stick natural drying 12h on sieve; Sieve and weigh, particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
Embodiment 6
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 2.0g according to prescription, be dissolved in the 1.0ml ethanol, add the sad capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol more successively, stir and promptly get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 1.1g Eudragit RS100,0.05g HPMC K4M in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible; Above-mentioned ciclosporin A self-microemulsion adds an amount of micropowder silica gel in small beaker, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution; Temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h; 10min is stirred in continuation, does not take place to glue to aggregate particle to stick natural drying 12h on sieve; Sieve and weigh, particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid microemulsified slow-releasing preparation that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and tangible blue opalescence is arranged.Pressing drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), is release medium with the 900ml distilled water, and rotating speed is 50rpm, in accordance with the law operation.The scope of release degree is 20%～50% of a 2h release labelled amount, discharges 50%～75% of labelled amount in the 6h, discharges more than 90% of labelled amount in the 12h.
Claims (7)
1. claim 1 ciclosporin A solid self-microemulsion; It is characterized in that: utilize the spherocrystal granulating technique; The ciclosporin A self-microemulsion is joined macromolecular material, dispersible carrier, porogen be dissolved in the even suspension solution that forms macromolecular material in the solvent; Join in the poor solvent that contains surfactant, a step makes ciclosporin A solid self-microemulsion microgranule in liquid phase.
2. ciclosporin A solid self-microemulsion according to claim 1; It is characterized in that: said composition contains the weight of ciclosporin A self-microemulsion raw material and forms: ciclosporin A: 5%～20%; Polyoxyethylene hydrogenated Oleum Ricini: 30%～70%; Sad capric acid triglyceride: 10%～30%, propylene glycol: 10%～30%, ethanol: 5%～15%.
3. according to claim 1; 2 described a kind of ciclosporin A solid self-microemulsion; It is characterized in that: macromolecular material selection cellulose derivative class is selected from one or more in hypromellose titanate esters, Hydroxypropyl Methyl Cellulose Phthalate, hypromellose, hydroxypropyl cellulose phthalate, the ethyl cellulose (10-40cp), preferred, ethyl (10-40cp); Crylic acid resin or cellulose derivative class; Wherein crylic acid resin is selected from one or more among acrylic resin, Eudragit RL, EudragitRS, Eudragit E, Eudragit L, the Eudragit S, preferred acrylic resins Eudragit E100, Eudragit RS100, Eudragit RL100; Porogen selects for use PEG4000, polyethylene than in pyrrolidone, HPMC K4M, lactose, the mannitol powder one or more; Dispersible carrier is selected one or more of micropowder silica gel, Pulvis Talci, calcium carbonate, calcium phosphate, magnesium stearate for use.
4. ciclosporin A solid self-microemulsion according to claim 2 is characterized in that: the weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 0.25～1.5, and polyoxyethylene hydrogenated Oleum Ricini: 4.0; Sad capric acid triglyceride: 2.0, propylene glycol: 2.0, ethanol: 1.0; Dichloromethane 4.0; Ethyl cellulose (10-40cp) (or Eudragit RS100, RS100) 0.5～1.1g, PEG4000 0.05, micropowder silica gel 0.5.
5. ciclosporin A solid self-microemulsion according to claim 2 is characterized in that: the weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 1.0, and polyoxyethylene hydrogenated Oleum Ricini: 4.0; Sad capric acid triglyceride: 2.0, propylene glycol: 2.0, ethanol: 1.0; Dichloromethane 4.0; Ethyl cellulose (10cp) 0.5g, PEG4000 0.05g, micropowder silica gel 0.5g.
6. method for preparing according to claim 1 is characterized in that: the mass fraction of ciclosporin A in the solid self-microemulsion is 0.05～0.25.
7. curing according to claim 1 is characterized in that: the spherocrystal granulating technique prepares the ciclosporin A solid self-microemulsion, and its solidification temperature is 25 ℃～50 ℃, and rotating speed is 400～600rpm.
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| CN103315960A (en) * | 2012-03-19 | 2013-09-25 | 胡容峰 | Solid self-microemulsion based on spherical crystallization technique and preparation method thereof |
| KR101819310B1 (en) * | 2015-12-29 | 2018-01-18 | 단국대학교 천안캠퍼스 산학협력단 | Pharmaceutical composition comprising cyclosporine |
| CN110382552A (en) * | 2017-03-17 | 2019-10-25 | 陶氏环球技术有限责任公司 | Method for recycling esterified cellulose ether from mixture of reaction products |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103315960A (en) * | 2012-03-19 | 2013-09-25 | 胡容峰 | Solid self-microemulsion based on spherical crystallization technique and preparation method thereof |
| KR101819310B1 (en) * | 2015-12-29 | 2018-01-18 | 단국대학교 천안캠퍼스 산학협력단 | Pharmaceutical composition comprising cyclosporine |
| CN110382552A (en) * | 2017-03-17 | 2019-10-25 | 陶氏环球技术有限责任公司 | Method for recycling esterified cellulose ether from mixture of reaction products |
| US20220049022A1 (en) * | 2017-03-17 | 2022-02-17 | Dow Global Technologies Llc | Process for recovering an esterified cellulose ether from a reaction product mixture |
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