GB2363572A

GB2363572A - Pharmaceutical composition containing cyclosporin

Info

Publication number: GB2363572A
Application number: GB0121845A
Authority: GB
Inventors: Yonghua Zhang
Original assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Current assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Priority date: 1999-03-09
Filing date: 2000-03-02
Publication date: 2002-01-02
Anticipated expiration: 2020-03-02
Also published as: WO2000053212A1; DE10084344T1; GB2363572B; CN1167462C; BR0010454A; GB0121845D0; AU2792700A; KR20010112315A; CN1265920A

Abstract

The present invention relates to a pharmaceutical composition containing cyclosporin, the active ingredient of which is cyclosporin, which characterized in that choosing a pharmaceutical organic acid such as medium or long chain saturated or unsatured fatty acid, substituted carboxylic acid etc., or an admixture of one or more acids or fish oil as a hydrophobic ingredient, depending on the need of various dosage form, not adding water or adding appropriate amount water to made a hydrophilic medium, the formulation of the composition is suitable in preparation of dosage forms such as soft capsule, paste, eye dops, oral liquid and injection etc.

Description

$ 57 S'- Title Pharmaceutical Composition containing cyclosporin

Field of the invention

The present invention relates to a pharmaceutical composition comprising a cyclosporin as an active ingredient; a solvent or co-surfactant such as ethanol or propylene glycol or mixture thereof, as solubilizer a hydrophilic surfactant having HLB value of 10-19;as lipophilic component one or a mixture of two or more selected from the group consisting of pharmaceutical organic acids such as medium/long chain saturated or unsaturated fatty acid and substituted carboxylic acid, or fish oil;and where appropriated, water for making hydrophilic substrate being present or absent The composition may be formulated into soft capsule, ointment, eye-drop, oral solution, injection and so on.

More particularly, the invention relates to a composition comprising cyclosporin which is insoluble in water The composition may be formulated into many formulations, such as soft capsule, ointment, eye-drop, oral solution, injection and so on In accordance with the present invention, here is provided information about the each component.

Background

The active ingredient is cyclosporin, also known as cyclosporin A or ciclosporine It is a cyclic polypeptide consisting of 11 amino acids.

Cyclosporin has now been as a novel and efficient immunosuppressive agent in the clinic field, especially in the prevention of organ rejection following organ and bone marrow transplantation and the therapy of various autoimrnune diseases It acts in the early lymphocyte proliferation phase and the action of inhibition for cell is reversible In additional, It doesn't affect hematopoietic function of bone marrow and not cause to decrease of amount of WBC and RBC Cyclosporin is white crystal powder which has molecular weight of 1202 64 It's highly hydrophobic and sparingly water- soluble,and as well dissolved in an organic solvent such as methanol, ethanol, acetone, ether, chloroform and the like Due to above-mentioned reasons, cyclosporine oral solution is poor absorbed and has low bioavailability In the 1980 's, the scientists of Sandoz Company dissolved cyclosporin with ethanol, then formulated an oil form in junction with vegetable oil and Labrafil M 1944 CS having HLB value of 3 After added some water in the formulation, the composition become unstable and turbid The sandoz's formulation containing cyclosporin is thus generally administered with dilution of milk or fuit juice The bioavailability of said formulation depends on the patent's body condition, individual difference etc The variation of bioavailability is in the range of about 4-60 % Therefore, it is very difficult for said formulation to retain an effective therapeutic concentration of Cyclosporin.

Further, the primary side effects of cyclosporin are hepatotoxic and nephrotoxic With the dosage increasing, said side effect become more serious Furthermore, the evaporation of ethanol during the preparation process and the storage of the soft capsule over time may also result in the precipitation of cyclosporin contained in the formulation, whereby bioavailability levels and stablility of cyclosporin are decreased.

In order to improve the bioavailability of Cyclosporin, reduce the marked difference in the individual and the inconvenience of diluting with milk or juice before the oral cyclosporine solution is administrated, numerous studies have been extensively conducted to discover an novel preparation suitable for cyclosporin well -distribution in the water with molecular state, which make absorption of cyclosporin not be affected by bile and the fat in food.

Accordingly, Sandoz Company has marketed a preparation of cycloprine in the form of a emulsion pre-concentrate which trademark as SANDIMUN NEORAL and Korea-America Pharmaceutical Company has also marketed a preparation of cycloprine in the form of a emulsion pre-concentrade which trademark as IMPLANTA.

Object of the invention The object of the present invention is to develop a liquid composition which enable the stability of cycloprine more higher.

The inventors of the present invention have studied about various surfactant, co-surfactaaant, solubilizar, and oil ingredient based on the research of solubilization for insoluble drugs and find a new liquid composition comprising cyclosporin, which is never disclosed in the prior art.

The present composition has many advantages such as improvement stability and no-influence with co-surfactant migration during the preparation process and the storage period, even when exposed or opened or in water-existing condition, it may still exhibit more stability than the known preparation The ratio of cyclosporin as an active ingredient is in the range of 0 5-15 % by weight based on the weight of composition.

Within the range, the composition is in the best emulsified state Thus, the new oral preparation containing cyclosporine in the present invention has great improvement on bioavailability than those of the prior art,and has the same bioequivalence with said Sandimmun Neoral on the market.

Summary of the present invnetion

The present invention relates to a pharmaceutical composition containing cyclosporin which comprises:

( 1) cyclosporin as active ingredient; ( 2) as solvent or co-surfactant ethanol, propylene glycol or mixture thereof; ( 3) as solubilizer hydrophilic surfactant having HLB value from 10 to 19;

( 4) as lipophilic component a pharmaceutical organic acid selected from the group consisting of saturated or unsaturated fatty acid having medium/long chain, substituted carboxylic acid or mixture thereof, or fish oil; ( 5) where appropriated, presence or absence of water or hydrophilic base containing water.

The composition may be formulated into various form such as soft capsule, soft cream, eye-drop, oral solution and injection etc.

Detailed description of the present invention.

According to the present invention, the solvent or co-surfactant for dissolving an insoluble drug is selected from the group consisting of ethanol, propylene glycol and the mixture thereof The ratio of ethanol: propylene glycol is 1:

0.1-10 (w/w),more preferablyl: O 5-5 (w/w) and most preferably 1: 1-3 (w/w).

According to the composition of present invention, the hydrophilic pharmaceutical surfactant having HLB from 10 to 19 is used as solubilizers for liposoluble drugs to achieve the balance between the hydrophilic component and the lipophilic component and form a steady emulsion These surfactants involve, for example, the derivatives of polyoxyethylene castor oil, such as Cremophor EL, Cremophor RH 40, Cremophor 60, or Tween type, such as Tween 80, Tween 65, Tween 20, and the Myrj such as Myrj 52 The derivatives of polyoxyethylene castor oil are preferred.

According to the composition of the present invention, said composition characterizes by using a pharmaceutical organic acids or fish oil as lipophilic component, wherein an organic acid is selected from the group consisting of saturated or unsaturated fatty acid having medium/long chain and substituted carboxylic acid or mixture thereof The lipophilic component make the composition of the present invention more stable and simple than that of prior art In the present invention, the above-mentioned carboxylic acid may be in esterfied or free form Among the all components, the lipophilic component may be the saturated acids having medium/long chain are C 8-28 carboxylic acid; the unsaturated acids having medium/long chain are C 10- 24 mono-, di-, or tri-olefine acid; the substituted carboxylic lactic; or the fish oil containing 70 % DHA As lipophilic component unsaturated fatty acids having the medium/long chain especially C 14-22 mono-, di-, or tri- olefine acid are preferred.

According to the present invention, the another character of the composition of present invention lies in that water is present or absent depending on different form of each composition The ratio of the active ingredient to the water is in the range of 1:0-1000 by weight For example,

adding certain water in to the oral solution containing cyclosporin can cut down the temperature of solidify or forming flocculation of a composition.

Accordingly, the character can be applied for the preparation of hydrophilic ointment and eye-drop.

According to the present invention, to meet the different requirement in the clinic application, the composition which contain cyclosporin or other fat-soluble drugs is formulated into soft gelatin capsule, ointment, eyedrop, oral solution, injection and so on.

Further, depending on the different requirement of the formulation, excipient or adjuvant may also be used, e g, anti-oxidant, flavoring agent, osmosis promoter, agent for adjusting p H, antiseptic and so on, and not limited to above-mentioned range The method of preparation of various formulations can be taken under the conventional method in the art.

The present invention will be more specifically illustrated by the following examples However, it should be understood that the present invention is not limited by these examples in any manner.

Example 1 The preparation of Cs A oral solution INGREDIENT QUANTITY(mg) Cyclosporin 100 Mixture of ethanol and propylene glycol 230 Polyoxyethylene castor oil 400 Oleate 220 Vitamin E 2 Purified water a q.

Total 100 Oml Example 2 The preparation of Cs A capsule INGREDIENT QUANTITY(mg) Cyclosporin 50 Mixture of ethanol and propylene glycol 100 Polyoxyethylene castor oil 200 Refined fish oil 130 Total 1300 capsules Example 3 The preparation of Cs A eye-drop INGREDIENT QUANTITY(mg) Cyclosporin 20 Mixture of ethanol and propylene glycol 50 Polyoxyethylene castor oil 90 Stearic magnesium 220 Vitamin E 1 Physiological saline a q.

Total 1000 ml A study on relative bioavailability was carried out by comparing the oral solution preparation prepared by the examplel (new cyclosporin oral solution, thereafter named as -New Cyspin) with the known cyclosporin soft capsule(named as Cyspinin below) and Sandimmun capsule.

A result of pharmacokinetic parameters derived from above comparision is obtained from 12 male health volunteers who received cyclosporin soft capsule (Cyspinin commercial), New Cyclosporine Oral Solutio ("New Cyspin") provided by Hang 7 hlou Zhongmeihuadong Pharmaceutical Co, Ltd.

and the Cyclosporine capsule named as Sandimrnmun Neoral ("Sandimmun Neoral" is commercial available) The obtained whole-blood concentration was detected by HPLC, followed by pharmacokinetical assay according to statistic matrix, by use of 3 P 87 and NDST computer programs The results showed: after oral administration of the Cyspinin, New Cyspin and Sandimmun Neoral, respectively, AUC (AUC is an area under curve of concentration of blood-drug vs time and is a main parameter for determing bioavilability in the art) were 11 43 2 49, 16 77 + 2 49 and 16 39 + 3.54 mg/lh, respectively; Cmax (peak valve of blood-drug concentration) were 1 56 O 25, 2 38 + 0 38 and 2 47 0 42 mg/1 respectively; and Tmax (time for achieving peak value of blood-drug concentration) were 2 04 0 54, 2 00 0 56 and 1 62 0 38 h respectively The major pharmacokinetic parameters AUC, Cmax and Tmax showed: remarkable difference existed between Cysipinin and New Cyspin, Sandimmun Neoral, but no remarkable difference existed between New Cyspin and Sandimmun Neoral The relative bioavailability of Cyspin and New Cyspin Vs Sandimmun Neoral was 73 4 25 2 %, 105 0 17 9 % The results of the study confirmed the bioequivalence of New Cyspin and Sandimmun Neoral in human body.

12 male health adult volunteers were selected to voluntarily receive the administration under complying with the requirement of " Guideline for Medical Preparation in Bioavailability Study Conducted on Human Body" issued by the Medical Administration Bureau of Health Ministry Routine laboratory tests showed that their blood, urine, liver and kidney functions, electrocardiogram and related immunological indexes were normal During the two weeks before the test and the period in test the testees were required to free from any drugs.

Cyclosporine Reference Standard, supplied by Hangzhou Zhongmei Huadong Pharmaceutical Co, Ltd ( 9201 C, Purity 0 976 mg/mg) Inside-label, Cyclosporin D (thereafter named as 'CSD'), purity 98 4 %, supplied by Sichuan Industrial Institute of Antibiotics and prepared to 1.2 mg/1 solution for being ready.

The volunteers should not take any food from supper the day before to 4 hours after administration There were totally 12 persons in the test, divided into 3 group, each group including 4 persons The first group took orally CYSPIN IN 500 mg, the second group took NEW CYSPIN 500 mg, the tird group took Sandimmun Neoral 500 mg, all taking together with 300 ml of juice The volunteers were given standard food with little fat 4 hours after administration Each volunteer undergo Cross-administration (Cyspin,New Cyspin & Sandimmun Neoral) one time with the interval of 7 days Collect venous blood respectively at 0 5, 1 0, 1 5, 2 0, 2 5, 3 0, 3 5, 4 0, 5 0, 8 0, 12 and 24 hours after orally administration Put the blood sample in the heparin- anticoagulating test tube, stored at 40 C for determination after shaking vigorously.

The blood samples obtained were detected by direct injection method, through column conversion 1 ml of whole blood sample was transferred into a 5 ml plastic centrifugal tube with plug, followed by accurately adding 1 0 ml of CSD working solution, 1 0 ml of methanol and 1 0 ml of hexane, successively, the mixture was allowed to be vertically blended for 1 min, and then centrifuged for 10 min ( 1600 r/min) The hexane phase in upper level was discarded while the clear solution in lower level was transferred into a 1.5 ml centrifugal tube and again centrifuged for 10 min ( 1600 r/min), 1 0 ml of the centrifuged solution was applied into the chromatography system for assay An RP 2 column ( 30 x 4 6 mm, 25-400 m) was applied as the purifying column, self-filled according to homogenization method The mobile phase for purification was a mixture of methanoland water ( 65:35), flow rate lml/min The purification time was defined as 10 min, tangential time lmin;

a Shim-pack CLC-OBD column ( 150 X 6 mm, 51 Dm) together with a precolumn (ODS, 1 OX 4 6 mm, 10 m) were applied for separation, column temperature 70 C; the mobile phase for assay was a mixture of acetonitrile and O 025 mol/l of Sulphonamide ( 82:18, p H 2 5), flow rate Iml/min, the wave length for detection was at 210 nm, and sensitivity of instrument was set at 0 02 AUFS The detected retention time of Cs A and Cs D were 9 2 min and 11.2 min, respectively Quantitative assay was conducted through measuring peak height by internal standard method, and a linear range existed from 0.025-3 mg/1, y= 1 04 X 10-3 x-4 06 X 10-3, R= O 9999, the signal-to- noise ratio was 3, the concentration limit of whole blood was O Olmg/1 In this range, respectively took 1 0 ml standard Cs A in high, middle and low concentration, followed by adding 1 0 ml of empty whole blood sample, 1 0 ml of CSD working solution, 1 0 ml of n-hexane, successively, the mixture was allowed to be vertically blended for 1 min According to the above- mentioned method, detected the high of Cs A (H) And then took 1 0 ml standard Cs A with the same concentration, adding 1 0 ml of water, 1 0 ml of Cs D working solution, after being vertically blended for 1 min, directly detected the high of Cs A (HO) Treated the H/HO as purification recovery, the average purification recovery was 98 5 % (Table 1 '), the average method recovery was 99 3 % (Table 2) Intra-day RSD was 23 % and day-to-day RSD was 2 6 % (Table 3) Figure 1 is the Curve of Mean Concentration vs Time.

In Figure 1, abscissa represents time after administration (hr), ordinate represents blood-drug concentration (mg/l), each point in trangle shows the curve of the average concentration after adminstration of sandimmun Neoral vs time, each point in square shows the curve of the average concentration after adminstration of cyspinin Neoral vs time, each point in rhomboid represents shows the curve of the average concentration after adminstration of New cyspin solution vs time.

Pharmacokinetic parameters and bioavailability F 1) The practical pharmacokinetic computer program which was used to control 3 P 87 and new medical statistic program NDST, formulated by the Chinese Society of Pharmacology, were adopted for statistic processing in a P-133 computer 1,2 -dimensional analogue-curves of fit were conducted respectively based on variation of blood cone The results declared:

pharmacokinetic result of oral administration of New Cyspin met the 1dimensional model The calculation of AUC, MRT, etc was conducted according to statistic matrix, Cmax and Tmax were obtained based on actual data of blood cone vs time, T 1/2 was calculated according to 1- dimensional model, and pair-t test was adopted for statistic processing, in which AUC of Cyspin, New Cyspin and Sandimmun Neoral were 11 43 + 2 48,16 77 + 2 49 and 16 39 3 54 mg/lh; Cmaxl 56 + O 25, 2 38 0 388 and 2 47 O 42 mg/1; Tmax 2 04 + O 54, 2 00 O 56 and 1 62 0 38 h.

2) Calculation of Bioavilability (F) F=(AUC of New Cyspin/AUC of Sandimmun Neoral) X 100 % The relative bioavailability of Cysipinin and New Cyspin vs Sandimmun Neoral was 73 4 + 25 2 %, 105 0 17 9 %, calculated by average, was 69 7 % and 102 3 %.

Table 1 The Purification Recovery of Cs A in the Whole Blood Samples (Tested by JPLC, N= 5) Cs A Cone (mg/1) H HO Purification Recovery (%) RSD (%) Average 0.101 729 740 98 51 2 01 0,504 3566 3641 97 95 1 83 98 51 2.018 14456 14593 99 06 1 05 Table 2 The Method Recovery of Cs A in the Whole Blood Samples (Tested by HPLC, N= 5) Adding (mg/l) Measurement (rg/l) Recovery (%) Average SD (%) 0.101 0 101 9981 0.504 0 496 98,41 99 31 0 64 2.018 2 012 99 70 Table 3 The Precision of Cs A in the Whole Blood Samples (Tested by HPLC) Concentration (mg/1) RSD (Intra-day) Times RSD (Day-to-day) Times 0.102 1 76 5 1 88 3 0.505 1 48 5 2 34 3 2.070 2 27 5 2 57 3

Claims

Claim

What is claimed is:

1.A pharmaceutical composition comprising:

1) a cyclosporin as active ingredient; 2) a solvent or a co-surfactant such as ethanol, propylene glycol and the mixture of them 3) a hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 to 19 as solubilizer; 4) lipophilic component which is one or a mixture of two or more selected from the group consisting of pharmaceutical organic acids such as medium/long chain saturated or unsaturated fatty acid and substitutive carboxylic acid, and fish oil as; 5) where appropriated, water for making the hydrophilic substrate is present or absent.

said composition is formulated into soft capsule, ointment, eye-drop, oral solution, injection, etc.

2 The composition according to claim i wherein said solvent or cosurfactant is ethanol, propylene glycol or a mixture of them.

3 The composition according to claim 1 wherein the ratio of said ethanol to propylene glycol is from 1:0 1 to 1:10 (w/w).

4 The composition according to claim 1 wherein the ratio of said ethanol to propylene glycol is from 1:0 5 to 1:5 (w/w).

The composition according to claim 1 wherein said the surfactant having the HLB value of 10 to 19 is the derivatives of polyoxyethylene castor oil, Tween, and Myrj.

6 The composition according to claim 1 wherein as the lipophilic component said medium/long chain saturated fatty acid is Cs-28 carboxylic acid.

7 The composition according to claim 1 wherein as the lipophilic component said medium/long chain unsaturated fatty acid is C O o 24 mono-, di-, or tri- olefine acid.

8 The composition according to claim 1 wherein as the lipophilic component said medium/long chain unsaturated fatty acid is C 14-22 mono, di-, or tri- olefine acid.

9 The composition according to claim 1 wherein said substituted carboxylic acid is lactic acid.

The composition according to claim 1 wherein as the lipophilic component said fish oil comprises 70 % DHA (w/w).

11 The composition according to claim 1 wherein said oil component is one or a mixture of two or more selected from the group consisting of pharmaceutical organic acids, such as medium/long chain saturated or unsaturated fatty acid and substituted carboxylic acid.

12 The composition according to claim 1 wherein said ratio of cyclosporin to the puried water is 1:0-1000 (w/w).

13 The composition according to claim 1 wherein said composition is formulated into soft capsule, ointment, eye-drop, oral solution, injection and so on.