CN1167462C - Medicinal composition containing cyclosporin - Google Patents
Medicinal composition containing cyclosporin Download PDFInfo
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- CN1167462C CN1167462C CNB991028481A CN99102848A CN1167462C CN 1167462 C CN1167462 C CN 1167462C CN B991028481 A CNB991028481 A CN B991028481A CN 99102848 A CN99102848 A CN 99102848A CN 1167462 C CN1167462 C CN 1167462C
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- pharmaceutical composition
- acid
- ciclosporin
- cyclosporin
- oily components
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
The present invention relates to a medicinal composition containing cyclosporin, wherein the active constituent of the medicinal composition is cyclosporin. The present invention is characterized in that medicinal organic acid, such as medium-chain and long-chain saturated or unsaturated fatty acid, substituted carboxylic acid, etc., or one or the mixture of multiple acid or fish oil is selected and used as an oleophilic constituent; no water or a proper amount of water can be added according to different requirements of each formulation so as to make a hydrophilic matrix. The formula of the composition is suitable for the preparation of formulations, such as soft capsule, ointment, eye drops, oral liquid, injection, etc.
Description
The present invention relates to a kind of pharmaceutical composition that contains ciclosporin, its active component is a ciclosporin; Ethanol or propylene glycol or its mixture are as solvent or surfactant adjuvant; With HLB value (hydrophil lipophil balance value) is that 10 to 19 hydrophilic surfactant active is solubilizing agent; Saturated or pharmaceutically acceptable organic acid such as unsaturated fatty acid, substituted carboxylic acid of long-chain or mixture that wherein one or more are sour or fish oil are as lipophilic ingredients in being characterized in selecting; According to the different requirements of each dosage form, can not add entry or add suitable water and make hydrophilic substrate, the prescription of said composition is applicable to the preparation of dosage forms such as soft capsule, ointment, eye drop, oral liquid and injection.
More particularly, the present invention relates to the compositions of ciclosporin insoluble drug, the prescription of said composition is applicable to the preparation of dosage forms such as soft capsule, ointment, eye drop, oral liquid and injection.Now the various components in the pharmaceutical composition of the present invention are illustrated respectively.
1. active component
Active component is a ciclosporin, ciclosporin claims that again cyclosporin A (is Cyclosporin A or Cyclosporine, be called for short CsA), be a kind of ring type polypeptide compound of forming by 11 amino acid residues, clinically be mainly used in the immunologic rejection treatment after organ transplantation, the bone marrow transplantation and the treatment of autoimmune disease.It is early stage that it acts on lymphopoiesis, and the inhibitory action of pair cell is reversible, and do not influence the hemopoietic function of bone marrow, can not cause bone marrow depression, leukocyte and thrombocytopenia, is a kind of novel, immunosuppressant efficiently.Ciclosporin is the white crystals sprills, and its molecular weight is 1202.64, is the hydrophobic material of high lipophilic, and is almost insoluble in water, and easily molten in organic solvents such as methanol, ethanol, acetone, ether, chloroform.Be limited to above-mentioned reason, seldom be absorbed by the body after ciclosporin is oral, bioavailability is very poor.The beginning of the eighties, the scientist of Shandeshi company with ciclosporin with dissolve with ethanol after, with the HLB value be that 3 surfactant Labrafil M 1944 CS and vegetable oil are mixed and made into a kind of oily preparation.This preparation becomes emulsion form after adding water, but the very low instability of emulsion is generally all diluted with milk or fruit juice before taking temporarily.The oral administration biaavailability of this preparation is subjected to patient's body condition influence to a great extent, and individual variation is very big, and relative bioavailability is 4～60%.This preparation to remain valid treatment concentration be difficulty comparatively, the main side effects of ciclosporin is liver, nephrotoxicity in addition, consumption increases also can make toxic and side effects increase.Because this preparation makes solvent with ethanol, and ethanol content can change in time and cause the crystallize of ciclosporin in soft capsule processing and storage, thereby has reduced the bioavailability of ciclosporin, so less stable.
In order to improve the bioavailability of ciclosporin, reduce bioavailability between the individuality greatly different difference and oral before dilute the inconvenience that this ciclosporin fluid composition administration brings with fruit juice or milk, many researcheres are all attempted to develop a kind of ciclosporin that makes and can are distributed in the water equably with molecularity, thereby make ciclosporin not be subjected to the influence of bile secretion what and used food fat content, and then reduce the individual variation of ciclosporin and improve the new ciclosporin preparation of its bioavailability in the intravital absorption of people.With this end in view, " Shandeshi " drugmaker develops the ciclosporin fluid composition of microemulsified, pre-concentration and has made oral liquid and soft capsule, Hanmi Pharm Ind. Co., Ltd has also developed a kind of ciclosporin soft capsule of new recipe, at present these two kinds of capsules and " mountain pass scholar's " new oral liquid can obtain from the market, trade name be respectively " sandimmun neoral (sandimmun Neoral) " and " because of the Pulan he (Implanta) ".
The present invention is carrying out insoluble drug on the basis of solubilization studies, long term studies has been carried out in combination to many kinds of surfactants, surface activity auxiliary agent, solubilizing agent, oily components, thereby has found the new ciclosporin fluid composition that do not related in original technology.This compositions can make the stability of ciclosporin higher, and can not processed, the influence of surperficial coagent composition migration in the storage, even, also can keep better stability than existing ciclosporin preparation having under the situation that water exists or packing is not airtight.The ratio of the active component ciclosporin in the said composition can be 0.5～15% (weight), and in this proportion, the emulsifying situation in the compositions water is splendid.The bioavailability of new compound composition ciclosporin oral formulations improves a lot than original ciclosporin preparation, than capsule consistent bioequivalence is arranged with commercially available sandimmun neoral.
2. solvent or surfactant adjuvant
Among the present invention, selecting for use has the mixed liquor of better deliquescent ethanol or propylene glycol or ethanol and propylene glycol as active component solvent or surfactant adjuvant to fat-soluble medicine.Wherein the ratio of ethanol and propylene glycol is 1: 0.1～10 (weight ratios), and preferably mixing the ethanol of cosolvent and the ratio of propylene glycol is 1: 0.5～5 (weight ratios), and optimal proportion is 1: 1～3 (weight ratios).
3. be that 10 to 19 hydrophilic surfactant active is solubilizing agent with the HLB value.
In the compositions of the present invention, selecting the HLB value for use is 10 to 19 the medicinal hydrophilic surfactant active solubilizing agent for fat-soluble medicine, to promote that hydrophilic and oleophilic moiety reaches balance in the compositions, forms stable emulsion.This class HLB value is that 10～19 surfactant is a castor oil derivatives, as Cremophor EL, Cremophor RH40, Cremophor 60 or Tweens, as Tween 80, Tween 65, Tween 20 or wheat pool class, as Myrj 52.Particularly preferably be castor oil derivatives.
4. saturated or pharmaceutically acceptable organic acid such as unsaturated fatty acid, substituted carboxylic acid of long-chain or mixture that wherein one or more are sour or fish oil are as lipophilic ingredients in selecting.
In the present composition, the most distinctive is that the pharmaceutically acceptable organic acid such as saturated or unsaturated fatty acid, substituted carboxylic acid of long-chain in selecting for use or mixture that wherein one or more are sour or fish oil are as lipophilic ingredients.The application of this oiliness composition makes this compositions more stable than other compositions of original invention, and simpler and more direct.In the present invention, pharmaceutically acceptable organic acid such as saturated or unsaturated fatty acid, the substituted carboxylic acid of middle long-chain or mixture or the carboxylic acid in the fish oil that wherein one or more are sour can exist with the ester group state with the alcohols in the compositions, also can free state exist.Wherein the satisfied fatty acid as the middle long-chain of oily components is C
8～28Carboxylic acid is for the unsaturated fatty acid of the middle long-chain of oily components is C
10～24One, two, the fish oil of trienic acid, substituted carboxylic acid lactic acid, DHA content 70% etc.Preferably the saturated and unsaturated fatty acid as oily components is C
14～22One, two, trienic acid or its mixture.
5. according to the different requirements of each dosage form, can not add entry or add suitable water and make hydrophilic substrate.
Another unique distinction of the present invention is, can not add water according to the different use of compositions, also can add a certain proportion of water, and wherein the ratio of active component and water is 1: 0～1000 (weight ratios).As in the ciclosporin oral liquid, adding a certain proportion of water, can reduce the temperature that floccule is solidified or formed to compositions, make it under relatively low temperature, still can keep haze-free.These characteristics also can be used for the preparation of hydrophilic ointment and eye drop.
6. according to clinically different demands, the pharmaceutical composition that contains cyclosporin or other fat-soluble medicine of the present invention can be prepared into gelatin and be encapsulated as soft capsule, also can be made into dosage forms such as ointment, eye drop, oral liquid and injection.
When compositions of the present invention is made various dosage form, as required, can add needed adjuvant of concrete dosage form or additives, as antioxidant, flavoring agent, penetration enhancer, pH regulator agent, antiseptic or the like, be not subjected to the restriction of listed content.The preparation method of different dosage form can require according to the routine of this dosage form to carry out.
The following examples will be made a more detailed description to the present invention.But, should be understood that, these embodiment be not be used for limiting of the present invention.
The preparation of embodiment 1. ciclosporin oral liquids
Amounts of components (gram)
Ciclosporin 100
Ethanol and mixed with propylene glycol liquid 230
Polyoxyethylene castor oil 400
Oleic acid 220
Distilled water surplus
Make 1000 milliliters
Amounts of components (gram)
Ciclosporin 50
Ethanol and mixed with propylene glycol liquid 100
Polyoxyethylene castor oil 200
Refine fish oil 130
Make 1000 capsules
Amounts of components (gram)
Ciclosporin 20
Ethanol and mixed with propylene glycol liquid 50
Polyoxyethylene castor oil 90
Stearic acid 60
Vitamin E 1
The normal saline surplus
Make 1000 milliliters
The oral liquid (promptly new ciclosporin oral liquid----hereinafter is called for short new Cyclosporin A) of the foregoing description 1 preparation is contrast with former prescription ciclosporin capsule (being called for short the Cyclosporin A capsule) with the sandimmun neoral capsule, carried out Bioavailability of Human Body research, the result is as follows:
----pharmacokinetic parameter of microemulsified ciclosporin capsule----the sandimmun neoral capsule of new Cyclosporin A (being called for short new Cyclosporin A) and commercially available import (being called for short the sandimmun neoral capsule) compares to the development of 12 oral Zhongmei Huadong Pharmaceutical Co., Ltd. Hangzhou of men's health volunteer, ciclosporin capsule----the Cyclosporin A capsule (abbreviation Cyclosporin A capsule has sale on the market) that provides and new ciclosporin oral liquid.Whole blood concentration detects with the HPLC method, uses 3P87 and NDST program, carries out pharmacokinetic analysis and paired t-test by statistical moment.The result shows: AUC behind oral Cyclosporin A capsule, new Cyclosporin A and the sandimmun neoral capsule (area below blood drug level--the time graph is measured the major parameter of bioavailability) is respectively 11.43 ± 2.48,16.77 ± 2.49 and 16.39 ± 3.54mg/l*h; C
Max(concentration when blood drug level reaches peak value) 1.56 ± 0.25,2.38 ± 0.38 and 2.47 ± 0.42mg/l; T
Max(time when blood drug level reaches peak value) 2.04 ± 0.54,2.00 ± 0.56 and 1.62 ± 0.38h.AUC, C in three's the main pharmacokinetic parameters
Max, T
MaxAt Cyclosporin A capsule and new Cyclosporin A, sandimmun neoral capsule significant difference is arranged all; New Cyclosporin A and sandimmun neoral capsule be there was no significant difference then.Cyclosporin A capsule, new Cyclosporin A and the commercially available capsular relative bioavailability of sandimmun neoral are respectively 73.4 ± 25.2% and 105.0 ± 17.9%, and the result shows that new Cyclosporin A and sandimmun neoral capsule have bioequivalence in human body.
The healthy volunteer of 12 adult males of experimental selection.Check blood, routine urinalysis through clinical laboratory, liver, renal function, electrocardiogram and relevant amynologic index are all normal, after fully understanding pharmacology, drug effect and the untoward reaction of this medicine, signature volunteer Informed Consent Form.Tried all not take any medicine in the last fortnight and during being tried.Can not participate in hardwork with any medicine and ban on opium-smoking and the opium trade, wine, tea during being tried.
The ciclosporin reference substance provides (lot number is 9201C, Zhejiang Province's drug inspection, purity of 50 percent .976mg/mg) by Zhongmei Huadong Pharmaceutical Co., Ltd. Hangzhou
Interior mark, cyclosporin D (being called for short CsD, is the another kind of component in the cyclosporin, as interior mark), purity 98.4%, Sichuan Industrial Institute of Antibiotics provides, and is made into the solution for standby of 1.2mg/l
Used acetonitrile is homemade chromatographically pure one-level in the experiment, and Huangyan, Zhejiang chemical experiment factory produces.All the other reagent and organic solvent are homemade analytical pure level, and the methanol need that wherein are used to prepare the reverse purge flow phase are through redistillation, and institute's water is a ultra-pure water.
High performance liquid chromatograph is Tianjin, island LC-6A type, comprises the visible UV-detector of SPD-6AV; The CTO-6A column oven; The SCL-6A system controller; FCN-2AH high pressure transfer valve; The CR-4A data process machine.Homemade LD4-2 centrifuge and TGL-16 high speed centrifuge.The P-133 microcomputer.
Tried after the eve supper fasting to the administration 4 hours.12 people are divided into 3 groups at random, every group 4 people.The 1st group of 4 human oral Cyclosporin A capsule 500mg (20) wherein, second group of 4 new Cyclosporin A 500mg of human oral (5ml), the 3rd group of 4 human oral sandimmun neoral capsule 500mg (20), 3 groups all gulp down (dashing) clothes with 300ml fruit beverage liquid.Administration was eaten by unified standard food low fat after 4 hours.The experimenter accepts 3 intersection administrations (Cyclosporin A capsule, new Cyclosporin A, sandimmun neoral capsule), and respectively once, each intertrial interval is 7 days.Experimentation has emergency measures and doctor's monitoring.
Gathered nitrile arteries and veins blood behind the oral administration in 0.5,1.0,1.5,2.0,2.5,3.0,3.5,4.0,5.0,8.0,12 and 24 hour.Blood specimen is collected in anticoagulant heparin in vitro, is stored in-40 ℃ after after the powerful jolting and is equipped with and surveys.
Adopting post to switch whole blood sample direct injected method measures.Get whole blood sample 1ml in 5ml band plug plastic centrifuge tube, accurate CsD working solution 1.0ml, methanol 1.0ml and the normal hexane 1.0ml of adding, vortex mixing 1min, centrifugal 10min (16000r/min), discard the normal hexane layer, take off layer clear liquid in the 1.5ml centrifuge tube, centrifugal 10min (16000r/min) gets the analysis of 1.0ml sample introduction.It is RP2 post (30 * 4.6mm, 25～40 μ m) that decontaminating column adopts model, and the homogenate method is from filling out.Reverse purge flow is methanol mutually: water (65: 35), flow velocity 1ml/min.Clarification time is 10min, and the tangent time is 1min; Separate and adopt Shim-pack CLC-ODS post (150 * 6mm, 5 μ m), and add pre-column (model ODS, 10 * 4.6mm10 μ m), 70 ℃ of column temperatures, analysis mobile phase is acetonitrile: 0.025mol/l ammonium phosphate (82: 18, pH2.5), flow velocity is 1ml/min, and the detection wavelength is 210nm, and instrumental sensitivity is 0.02AUFS.The retention time that this law is measured CsA and CsD is 9.2min and 11.2min.It is quantitative to press the internal standard method ratio of peak, linear in 0.025～3mg/l scope, y=1.04*10-3x-4.06*10-3, and R=0.9999 is 3 in signal to noise ratio, minimum whole blood test concentration is 0.01mg/l.In this scope, get respectively height, in and the CsA titer 1ml of low concentration, add the blank whole blood of 1ml, CsD working solution 1ml and normal hexane 1ml, vortex mixing 1min handles the back by last method and measures, the peak height (H) of CsA; Get the CsA titer 1ml of same concentrations again, add 1ml water, CsD working solution 1ml, direct injected is measured behind the vortex mixing 1min, gets the peak height (H of CsA
0), with H/H
0For purifying the response rate, it on average purifies the response rate is 98.5% (table 1), and the averaging method response rate is 99.3% (table 2).Record equally in a few days that RSD is 2.3%, RSD is 2.6% (table 3) in the daytime.
Time graph is seen Fig. 1 to its average blood drug level----.Time after wherein abscissa is represented to take medicine (hour), vertical coordinate is represented blood drug level (mg/l).Average the blood drug level----time graph behind the sandimmun neoral soft capsule is taken in the representative of figure intermediate cam shape each point, average the blood drug level----time graph behind the Cyclosporin A soft capsule is taken in the representative of square each point, and average the blood drug level----time graph after the new Cyclosporin A oral liquid is taken in the representative of rhombus each point.
Pharmacokinetic parameter and bioavailability F value
(1) practical pharmacokinetics calculation procedure 3P87 and the new drug statistical procedure NDST that adopts Chinese Pharmacological Society to work out handles on the P-133 microcomputer.According to the variation of blood drug level, carry out one respectively, the two-compartment model curve fitting, the result shows: the pharmacokinetics of oral ciclosporin meets one-compartment model.Practical Calculation is pressed statistical moment and is calculated parameters such as AUC, MRT, C
MaxAnd T
MaxRead T according to actual blood drug level time data
1/2Pressing one-compartment model calculates; Statistical procedures adopts paired t-test.
Wherein the AUC of Cyclosporin A capsule, new Cyclosporin A and import sandimmun neoral is respectively 11.43 ± 2.48,16.77 ± 2.49 and 16.39 ± 3.54mg/l*h; C
Max1.56 ± 0.25,2.38 ± 0.38 and 2.47 ± 0.42mg/l; T
Max2.04 ± 0.54,2.00 ± 0.56 and 1.62 ± 0.38h.
(2) calculating of bioavailability (F value):
Cyclosporin A capsule, new Cyclosporin A and the capsular relative bioavailability of sandimmun neoral (F value) are respectively 73.4 ± 25.2% and 105.0 ± 17.9%, calculate by mean and are respectively 69.7% and 102.3%.
Table 1 is measured CsA content purification recovery counting rate meter (N=5) in the whole blood with HPLC post switching method
| CSA concentration H H0 purifies RSD (%) mean value (MF/L) rate (%) 0.101 729 740 98.51 2.01 0.504 3,566 3,641 97.95 1.83 98.51 2.018 14,456 14,593 99.06 1.05 that reclaims |
Table 2 is measured CsA content method recovery counting rate meter (N=5) in the whole blood with HPLC post switching method
| The addition amount of recording rate of recovery mean value SD (MF/L) (MG/L) spends (%) (%) 0.101 0.101 99.81 0.504 0.496 98.41 99.31 0.64 2.018 2.012 99.70 |
Table 3 is measured the accurate kilsyth basalt of CsA content in the whole blood with HPLC post switching method
| Concentration (MF/L) day interior RSD N (inferior) is RSD N (inferior) 0.102 1.76 5 1.88 3 0.505 1.48 5 2.34 3 2.070 2.27 5 2.57 3 in the daytime |
Claims (10)
1. pharmaceutical composition that contains ciclosporin, it comprises following main component:
(1) as the ciclosporin of active component;
(2) as ethanol or propylene glycol or its mixture of solvent or surfactant adjuvant;
(3) as the HLB value of solubilizing agent be 10 to 19 hydrophilic surfactant active;
(4) saturated or pharmaceutically acceptable organic acid such as unsaturated fatty acid, substituted carboxylic acid or mixture that wherein one or more are sour as the middle long-chain of oily components;
(5) according to the different requirements of each dosage form, can not add entry or add suitable water to make hydrophilic substrate, said composition can be prepared into dosage forms such as soft capsule, ointment, eye drop, oral liquid and injection.
2. according to wanting sharp 1 the pharmaceutical composition that requires, be 1: 0.1～10 (weight ratios) wherein as the ethanol that mixes cosolvent and the ratio of propylene glycol.
3. according to wanting sharp 1 the pharmaceutical composition that requires, be 1: 0.5～5 (weight ratios) wherein as the ethanol that mixes cosolvent and the ratio of propylene glycol.
4. according to the pharmaceutical composition of claim 1, wherein the HLB value is that 10～19 surfactant is castor oil derivatives or Tweens or wheat pool class.
5. according to the pharmaceutical composition of claim 1, wherein the middle chain saturated fatty acids as oily components is C
8～28Carboxylic acid.
6. according to the pharmaceutical composition of claim 1, be C wherein as long-chain unsaturated fatty acid in the oily components
10～24One, two, trienic acid.
7. according to the pharmaceutical composition of claim 6, be C wherein as the oily components unsaturated fatty acid
14～22One, two, trienic acid.
8. according to the pharmaceutical composition of claim 1, wherein the substituted carboxylic acid as oily components is a lactic acid.
9. according to the pharmaceutical composition of claim 1, wherein the ratio of active component and water is 1: 0～1000 (weight ratios).
10. according to the pharmaceutical composition of claim 1, wherein said composition can be prepared into gelatin and seal dosage forms such as soft capsule, ointment, eye drop, oral liquid and injection.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991028481A CN1167462C (en) | 1999-03-09 | 1999-03-09 | Medicinal composition containing cyclosporin |
| BR0010454-0A BR0010454A (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporine |
| GB0121845A GB2363572B (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporin |
| PCT/CN2000/000041 WO2000053212A1 (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporin |
| DE10084344T DE10084344T1 (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporin |
| KR1020017011483A KR20010112315A (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporin |
| AU27927/00A AU2792700A (en) | 1999-03-09 | 2000-03-02 | Pharmaceutical composition containing cyclosporin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991028481A CN1167462C (en) | 1999-03-09 | 1999-03-09 | Medicinal composition containing cyclosporin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1265920A CN1265920A (en) | 2000-09-13 |
| CN1167462C true CN1167462C (en) | 2004-09-22 |
Family
ID=5271009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB991028481A Expired - Lifetime CN1167462C (en) | 1999-03-09 | 1999-03-09 | Medicinal composition containing cyclosporin |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR20010112315A (en) |
| CN (1) | CN1167462C (en) |
| AU (1) | AU2792700A (en) |
| BR (1) | BR0010454A (en) |
| DE (1) | DE10084344T1 (en) |
| GB (1) | GB2363572B (en) |
| WO (1) | WO2000053212A1 (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2466432A1 (en) * | 2001-11-08 | 2003-05-15 | Atrium Medical Corporation | Intraluminal device with a coating containing a therapeutic agent |
| AU2004264958B2 (en) | 2003-08-13 | 2010-04-15 | Biocon, Ltd | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
| WO2006036969A2 (en) | 2004-09-28 | 2006-04-06 | Atrium Medical Corporation | Formation of barrier layer |
| US9012506B2 (en) | 2004-09-28 | 2015-04-21 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
| US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
| KR100678829B1 (en) * | 2004-12-06 | 2007-02-05 | 한미약품 주식회사 | Oral micro-emulsion composition comprising tacrolimus |
| CN100478025C (en) * | 2005-03-25 | 2009-04-15 | 中国科学院上海药物研究所 | Cyclosporia A microemulsion for eye and its preparation method |
| US9427423B2 (en) | 2009-03-10 | 2016-08-30 | Atrium Medical Corporation | Fatty-acid based particles |
| US9278161B2 (en) | 2005-09-28 | 2016-03-08 | Atrium Medical Corporation | Tissue-separating fatty acid adhesion barrier |
| CN101502641B (en) * | 2009-02-23 | 2012-05-02 | 姚定全 | Ciclosporin medicament composition for injection administration |
| US20110038910A1 (en) | 2009-08-11 | 2011-02-17 | Atrium Medical Corporation | Anti-infective antimicrobial-containing biomaterials |
| US10322213B2 (en) | 2010-07-16 | 2019-06-18 | Atrium Medical Corporation | Compositions and methods for altering the rate of hydrolysis of cured oil-based materials |
| US9867880B2 (en) | 2012-06-13 | 2018-01-16 | Atrium Medical Corporation | Cured oil-hydrogel biomaterial compositions for controlled drug delivery |
| KR101363776B1 (en) * | 2012-12-21 | 2014-02-17 | 이상필 | Transparent eye drops composition comprising cyclosporin |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL102236A0 (en) * | 1991-06-27 | 1993-01-14 | Ltt Inst Co Ltd | Topical preparations containing cyclosporin |
| GB9113872D0 (en) * | 1991-06-27 | 1991-08-14 | Sandoz Ag | Improvements in or relating to organic compounds |
| KR940002128Y1 (en) * | 1992-04-21 | 1994-04-06 | 배순훈 | Tape loading apparatus for vtr |
| US5603951A (en) * | 1994-11-09 | 1997-02-18 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| KR0167613B1 (en) * | 1994-12-28 | 1999-01-15 | 한스 루돌프 하우스, 니콜 케르커 | Cyclosporin-containing soft capsule compositions |
| DE19549852B4 (en) * | 1995-11-29 | 2009-06-04 | Novartis Ag | Cyclosporin containing preparations |
-
1999
- 1999-03-09 CN CNB991028481A patent/CN1167462C/en not_active Expired - Lifetime
-
2000
- 2000-03-02 WO PCT/CN2000/000041 patent/WO2000053212A1/en active Application Filing
- 2000-03-02 KR KR1020017011483A patent/KR20010112315A/en not_active Application Discontinuation
- 2000-03-02 DE DE10084344T patent/DE10084344T1/en not_active Withdrawn
- 2000-03-02 AU AU27927/00A patent/AU2792700A/en not_active Abandoned
- 2000-03-02 GB GB0121845A patent/GB2363572B/en not_active Expired - Lifetime
- 2000-03-02 BR BR0010454-0A patent/BR0010454A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| GB0121845D0 (en) | 2001-10-31 |
| AU2792700A (en) | 2000-09-28 |
| WO2000053212A1 (en) | 2000-09-14 |
| KR20010112315A (en) | 2001-12-20 |
| GB2363572B (en) | 2004-02-18 |
| DE10084344T1 (en) | 2002-07-11 |
| GB2363572A (en) | 2002-01-02 |
| BR0010454A (en) | 2002-01-08 |
| CN1265920A (en) | 2000-09-13 |
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Assignee: Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou Assignor: Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co., Ltd. Contract fulfillment period: 2008.7.5 to 2018.7.5 Contract record no.: 2008330000426 Denomination of invention: Medicinal composition containing cyclosporin Granted publication date: 20040922 License type: Exclusive license Record date: 2008.9.10 |
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Free format text: EXCLUSIVE LICENCE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.7.5 TO 2018.7.5 Name of requester: ZHONGMEI HUADONG PHARMACEUTICAL CO., LTD. HANGZHO Effective date: 20080910 |
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Effective date of registration: 20160418 Address after: 310012 West Lake international science and technology building, No. 391 Wen two road, Hangzhou, Zhejiang, C910, Xihu District Patentee after: Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co., Ltd. Patentee after: Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou Address before: Hangzhou City, Zhejiang province 310011 Moganshan Road No. 866 Patentee before: Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co., Ltd. |
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