Indian Patents. 216033:"A NOVEL CYCLOSPORIN COMPOSITION"

Title of Invention	"A NOVEL CYCLOSPORIN COMPOSITION"
Abstract	The invention describes a homogenous alcohol free composition of Cyclosporin in a hydrophilic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils.

Full Text	INTRODUCTION The present invention relates to pharmaceutical compositions comprising Cyclosporin as active ingredient. The present invention also relates to novel alcohol free, free flowing, clear and transparent compositions comprising Cyclosporin as an active ingredient. The novel compositions are characterized in having increased bio-availability when the drug is formulated in a solubilised system and also amenable to convenient commercial production. BACKGROUND OF THE INVENTION Cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the Cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as Cyclosporin A and commercially available under several brands. Ciclosporin is the Cyclosporin of formula A. (Formula Removed) wherein - MeBmt- represents the N-Methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L) threonyl residue of formula B. (B) (Formula Removed) in which -x-y- is --CH =CH- (trans). Naturally occurring and semi-synthetic Cyclosporins, their classification, nomenclature etc. are known [c.f Traber et al. 1, Helv. Chim Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. (65 no. 162, 1655-1667 (1982)); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (1980); and von Wart-burg et al., Progress in allergy, 38, 28-45 1986)]. US Patent Nos 4,108,985, 4,210,581 and 4,220,641; European Patent Publication Nos. 0034567 and 0056782; International Patent Publication no. WO 86/02080; Wenger 1, Transp. Proc. 15, Suppl. 1; 2230(1983); Wenger. 2, Angew. Chem. Int. Ed., 24,77 (1985); and Wenger 3, Progress in Chemistry of Organic natural products 50, 123(1986). Other Cyclosporins are known from U.S Patents 4,639,434; 4,703,033; 4,764,503, 4,885,276; 5,116,816; 5,122,511; 5,525,590; 5,643,870 and 5,767,069. So far the primary area of clinical investigation for Cyclosporins and in particular, Ciclosporin has been as an immunosuppressive agent, in particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin and corneal transplants and, in particular, allogenic organ transplants. In this field Cyclosporins, in particular ciclosporins have achieved a remarkable success. Among all the Cyclosporins, Cyclosporin A ( also known as Cyclosporine or Ciclosporin) has established its utility in the area of organ transplant and therapy of autoimmune diseases. At the same time, applicability of Cyclosporins including Ciclosporin to various autoimmune diseases and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are wide-spread in the literature. Specific auto-immune diseases for which Cyclosporin and Ciclosporin therapy has been proposed or applied include, autoimmune hematological disorder (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus ervthematosus, poly-chondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthirits and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy). Further areas of investigation for cyclosporins include potential applicability as an anti-parasitic, in particular anti-protozoal agent, with possible uses suggested including treatment of malaria, coccidiomycosis and schistosomiasis and, yet more recently, use as an agent for reversing or abrogating anti-neoplastic agent resistance in tumours and the like. Although Cyclosporin A is the most widely used amongst all the immunosuppresants available so far, it suffers from a serious drawback of poor bio-availability. Cyclosporin blood levels have to be maintained within a specified range to achieve the effective therapy. The required range varies according to the clinical status of the patient. Because of poor and variable bioavailability daily dosages needed to achieve the desired blood levels need to be varied considerably in the existing dosage forms of Cyclosporin and a concomitant monitoring of blood levels is essential. This adds an additional cost to the therapy. In order to improve the bio-availability several attempts have been made to improve formulations of Cyclosporin. The oral dosage forms known in the market (i.e. those employing ethanol, olive oil as carrier medium in conjunction with Labrafll as surfactant (see US patent no. 4, 388, 307) are unpleasant tasting galenic forms. The bio-availability levels using these dosage forms are low and exhibit wide inter-and intra-individual variations. Such dosage forms provide an average absolute bioavailability of ca 30%. Reported variation in bio-availability between subjects varies between a few percent for some patients to as much as 90% or more for others. Also a marked change in bio-availability for individuals with time is frequently observed. US Patent no. 4,388,307 also describes a drink solution containing Cyclosporin in a base of Labrafll, Miglyol, Ethanol, Corn/olive oil. However, such preparation suffered from the drawback that it can be presented only as a liquid for dilution in drinking water/fluid before use, otherwise it is very difficult to give an accurate dose. Bioavailability levels achieved using the systems s very low and exhibits wide variations between individuals, individual patient type and even for single individuals at different times during the course of therapy. Han Gua Patent (Chinese Patent No. 94191895.5) explains the active compound of Cyclosporin, fatty acid sugar ester and diluent carrier having good bio-availability. However, this compound suffers from the drawback that diluent degrades due to hygroscopicity of sugar ester and the stability is not of desired standards, (See also Pharmaceutical Research, Volume 6, No. 11, 1989, P958, "Solid Surfactant Solution of active Ingredients in Sugar Ester" and International Journal of Pharmaceutics, Vol. 92, 1993, P197," Application of sucrose laurate a new pharmaceutical excipient, in Peroral formulation of Cyclosporin A"). Chinese Patent 9419189.5 having equivalent EP 0702562 describes a powder dosage form of Cyclosporin possessing comparatively higher stability and to some extent bio-availability when compared to the earlier formulations. This art describes adsorption of Cyclosporin A with appropriate solvents onto an adsorbent along with a nonionic hydrophillic surfactant. The final product does not contain the solvent as this evaporates during the process of manufacturing. Thus this product does not suffer from the disadvantage arising out of solvent evaporation during shelf life and hence stability problems. The various pharmaceutical surfactants, polyhydric alcohols and solvents are well known to the art. The adsorbent used is Colloidal Silicon Dioxide. The blood level arising out of such product have been compared with the standard formulations as per US patent no. 4, 388, 307 with significant improvement in bioavailability. However, if compared with the micro-emulsion based formulations these formulations do not show any advantage as the drug is adsorbed on solid surface and needs an additional process of dissolution prior to become bioavailable. The effect of sucrose laurate on the gastrointestinal absorption of Cyclosporine is also described (Lerk-PC; Sucker-H, International Journal of Pharmaceutics; 1993; 92; (May 3); 197-202). The evaluation of the dosage form containing sucrose Laurate was found to enhance the in vitro absorption of Cyclosporine when normal epithelial tissue and Peyer's patch tissue of guinea pigs were used. Compared to the commercially available drinking solution, absorption was raised by a factor of 10. Excess amount of surfactant reduced drug absorption. Despite large excess of Sucrose laurate, the absorption of Cyclosporin was still superior to the drinking solution. Choleic acid was also found to increase absorption by a factor of 5-6. A comparison of the absorption between normal epithelial and Peyer's patch tissues indicated that the absorption by endocytosis does not contribute significantly to the overall absorption of Cyclosporin. It was concluded that preliminary formulation experiments showed that a solid oral dosage form of Cyclosporin could be made using sucrose laurate as an excipient. Abdallah-HY; Mayersohn-M. Pharmaceutical Research; 199l;8(Apr);518-522 reported several formulations of Cyclosporin were prepared and examined in vitro and in dogs A tablet formulation was then selected for comparison with the commercial oil solution placed in a soft gelatin capsule in a randomized crossover study in dogs. Compared with an intravenous dose of the drug, absolute bioavailability was 46+11.1 and 45+ 9.9% for the capsules and tablets, respectively. Maximum concentration, time to reach maximum concentration and mean absorption time were not significantly different between the 2 formulations. It was concluded that the tablet formulation of Cyclosporin is equivalent in dogs to the commercial dosage form packed into soft gelatin capsules. US patent no. 505 1402 describes that Cyclosporin may be rendered more soluble by the concomitant administration of a-Cyclodextrin, either separately, but essentially simultaneously or, preferably, in admixture. US Patent No. 4990337 describes a formulation comprising a Cyclosporin in admixture with at least one mono or diglyceride of a C6-C10 fatty acid sufficient to dissolve the Cyclosporin. The resulting solution can then easily be emulsified in water or an aqueous fluid. Freeze dried liposome mixture containing Cyclosporin has been described in US Patent no. 4963362. This invention provides a freeze-dried potential liposome mixture having an amphipathic lipid and a Cyclosporin or derivative thereof for use in possible liposome delivery of Cyclosporin into cells. A method to produce the freeze-dried mixture is also disclosed. When reconstituted to yield liposomes in an aqueous medium, substantially all of the Cyclosporin present in the freeze-dried mixture is encapsulated in the liposomes. Other galenic improvements in Cyclosporin emulsion formulations recorded in prior arts such as EP0724452 discloses a pharmaceutical composition which contains cyclosporine A and alpha -tocopherol or one of its derivatives. EP0712631 describes a oral multiple emulsion pre-concentrate comprising a surfactant, ethanol, a lipophilic and/or an amphiphilic solvent, characterized by the composition comprising Cyclosporin, tocopheryl polyethylene glycol carboxylic acid ester, ethanol, lipophilic solvent and/or an amphiphilic solvent, and if desired co-tenside. EP0711550 discloses a cyclosporin soft capsule composition comprising cyclosporin as an active ingredient, dimethylisosorbide as a cosurfactant, one component or a mixture of two or more components selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component, and a surfactant having HLB (Hydrophilic-lipophilic balance) value of 10 to 17. EP0650721 discloses an oral microemulsion composition for suppression of an immunological response comprising an immunosuppressive amount of cyclosporin and a sufficient amount of dimethylisosorbide, oil and surfactant to form a microemulsion suitable for oral administration. WO9423733 describes an oral administration pharmaceutical compositions that are easy to produce and have a good bioavailability and comprises cyclosporine as active substance an alkylene polyether or polyester, and may optionally contain an alkylene polyol, an alkylene glycol, a polyalkylene glycol, an alkyl diether or partial ether of a low molecular mono- or polyoxyalkane diol and/or a vegetable oil or its hydrogenated or hydrolysed product. EP0694308 discloses a cyclosporin-containing oil-in-water type emulsion composition comprising cyclosporin, a polyalkyl ester of polycarboxylic acid in the form of a liquid at ordinary temperature, an oil component having an I.O.B. of 0 to 0.25 in the form of a liquid at ordinary temperature, and a surfactant, EP0656212 discloses cyclosporin-containing liquid compositions for oral or parenteral administration comprising cyclosporin, a polyoxyethylene glycerol fatty acid monoester and a mono- and/or polyhydric alcohol(s). These compositions are stable, well tolerated and have better bioavailability. EP0651995 describes a pharmaceutical preparation which contains one or more cyclosporins, one or more oils of natural origin, 3-sn-phosphatidylethanolamine and water. Three Patent Applications namely European Patent App.No. 94110184.2, 95117171.9 and PCT/EP95/04187 describe the use of Dimethylisosorbide as a co-surfactant or a hydrophillic phase along with other ingredients to enhance the absorption of Cyclosporin. One of the most significant attempt to improve bio-availability of Cyclosporin from its dosage form is the described in US patent no. 5, 342, 625. This art describes use of microemulsion pre-concentrate consisting of a three phase systems i.e. (1) a hydrophilic phase component (2) a lipophilic phase component and (3) a surfactant. Such composition has alcohol as an essential ingredient. Such composition upon dilution with water provides an oil-in-water microemulsion with an average particle size of less than 1000A0. Such an enhanced surface area results in increased bio-availability of Cyclosporin when compared with conventional dosage forms. A comparison of bio-availability from micro-emulsion dosage form (Composition I from US patent no. 5, 342, 625) with the conventional ethanol/oil based dosage form (Composition X from US patent no. 5,342,625) earlier reported in US patent no. 4, 388, 307 has been performed in healthy human volunteers and reported in US patent no. 5,342, 625. Bio-availability level of 149.0% (± 48) is recorded for composition I as compared to composition X (for which bio-availability achieved is set as 100%). The mean AUC levels from composition I were 40% higher when compared to those from composition X but still had a high variation of 20%. Alcohol is an essential part of composition as is evident from the products available in the market (Sandimun [US Pat. No. 4, 388, 307] and Neoral [US Pat. No. 5,342, 625]) both of which contain Alcohol. Such compositions suffer from severe drawback of instability due to evaporation of a low boiling solvent like Alcohol. This is particularly true as the products are used in home environment, which cannot be precisely controlled with respect to temperature. Although very expensive cumbersome technology (such as cold formed Aluminium/ Aluminium Blister packs) is adopted to protect these products, yet the problem of instability is not completely solved. The stability problems are evident from strict storage conditions and usage requirements as declared either on the labels or package inserts of commercial products Sandimun, and Neoral drink solutions and capsules. Some of the examples are : 1. There is a requirement of storage of product below 30°C at the same time refrigeration is prohibited. This means that a patient using this product in a tropical country need to have an air-conditioned home environment. This is not only a limiting factor in use of this product but sometimes in economically backward countries it may not be possible that every person using the product has an air-conditioned storage area. Sometimes factors like prolong electricity failure and mechanical and electrical defects in air-conditioning system can cause instability problems to these products rendering them unstable for use. 2. There is also an a statement in Packing insert of Sandimun and Neoral drink solutions that " Sandimun Neoral solution should be used within 2 months of opening the bottle and be stored between 15° and 30°C, preferably not below 20°C for prolonged periods, as it contains oily components of natural origin which tend to solidify at low temperatures. A jelly-like formation may occur below 20°C, which is however reversible at temperatures up to 30°C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the pipette remains accurate." indicating instability problems. US Patent no. 5, 639, 724 discloses pharmaceutical compositions comprising Cyclosporin, transesterification product of a natural vegetable oil with glycerol, which is exemplified in the specification as MAISINE (transesterification product of corn oil and glycerol) which is an essential component of the compositions. The cyclosporin must be mixed with a transesterification product of a natural vegetable oil with glycerol. These compositions are not useful as drink solutions because of formation of jelly like, lumps, since the transesterification product is a jelly like substance at room temperature. Such composition also preferably require the use of alcohol. This compositions compares its bioavailability with that of older and inferior compositions based on US patent no. 4, 388, 307 and does not compare bioavailability with a more recently marketed compositions (NEORAL) as defined in US patent no. 5, 342, 625. US Patent No. 5,639,724 discloses the use of Labrafil as a preferred ingredient to be added to the composition of Cyclosporin and MAISINE for a drink solution. However, this patent does not address the problem of flake like substances formed by the presence of MAISINE even though Labrafil has been added to the composition. The formulation of emulsion as well as microemulsion present their own technological problems relating to thermodynamic instability. Such problems may be partially solved presenting the product in a microemulsion pre-concentrate form wherein the microemulsfying occurs in vivo only. However, such systems may also present variability problems due to variations existing in GI tract of patients. Any person skilled in the art attempting to make compositions without the use of alcohol and without careful and extensive experimentation and study of desired chemicals to be added to Cyclosporin will end with compositions which are highly viscous and which tend to solidify at normal room temperature conditions. Such compositions are undesirable not only due to physical unstability but also that they cannot be formulated as liquids whose dose can be measured exactly under normal conditions. The major consideration here is the accurate measurement of dose in Cyclosporin which is an essential feature because of the narrow therapeutic condition of the drug i.e. below threshold the organ rejection occurs and above a particular level the drug causes severe toxic reactions. None of the above mentioned inventions teaches the art of dissolving cyclosporin including Cyclosporin A (which is a water insoluble hydrophobic drug) in a hydrophilic medium. This looks improbable and a person skilled in the art cannot conceive beyond an emulsion and/or microemulsion. All the earlier approaches to enhance the bioavailability of Cyclosporin were towards making the drug in a emulsifying form (US Patent no 4, 388, 307) or substantially increasing the surface area by converting into microemulsion (US Patent No. 5, 342, 625). Our attempt has been to affect solution of cyclosporin in a hydrophilic environment using micellar concept of a surfactant and a co-surfactant such that such compositions are substantially devoid of fatty materials and hence also devoid of the defects associated with such fatty materials. Compositions according to this invention may be formulated for oral administration including but not limited to drink solutions or formulated as hard or soft gelatin capsules. The capsules may be gelatin or cellulose or two piece hard shell capsules. Drink solution formulations may be diluted with water or aqueous medium and the lipophilic Cyclosporin drug is maintained in a solubilized state, hence making the drug bioavailable in therapeutic concentrations. It will be most appropriate to formulate Cyclosporin compositions in a way that the drug gets converted into a solubilized system on dilution in vivo. Compositions of the invention when administered orally in the form of a drink solution or soft gelatin capsules get diluted with the gastrointestinal fluids to form micellar solutions such that the hydrophilic end of the surfactant and the cosurfactant are oriented towards hydrophilic environment of gastrointestinal fluid and the drug molecules are entrapped in the hydrophobic portions of the surfactant micelles. Such micellar solubilised systems, when in contact with the mucosa of the gastrointestinal tract, release the drug leading to absorption, thus providing an increased and less variable bioavailability. The inventors have invented compositions in which hydrophobic drug like Cyclosporin can be dissolved in a hydrophillic medium by careful selection of the hydrophilic medium, surfactants and manner of addition such that a hydrophobic drug can get dissolved in an array of surfactant molecules arranged in a manner that their hydrophilic portions are oriented outside i.e. towards the hydrophilic medium resulting in clear stable solution based formulation. Such products when they come in contact with biological fluids result in total solubilazationof Cyclosporin at molecular levels thereby increasing the surface area of Cyclosporin and such diluted solutions of Cyclosporin are highly bioavailable. Such compositions do not form emulsions on dilution. Such systems will definitely be more uniform and bio-available than microemulsions from where the drug has to partition out of the lipophillic phase for absorption. Oral solution concentrates are to be diluted prior to intake and are used as start up therapies. These dosage forms provide more flexibility in dosage adjustments to achieve the optimum therapeutic concentrations as desired by the physicians. The second type of dosage forms are unit dosage forms for example capsules, generally soft or hard gelatin capsules or cellulose capsules or two piece hard shell capsules. SUMMARY OF THE INVENTION In accordance with the present invention there is described a homogenous substantially alcohol free, composition of Cyclosporin which comprises a Cyclosporin in a hydrophillic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range : Cyclosporin : 1-25 %w/w Propylene Glycol : 5 - 50% w/w Esters of propylene glycol with C4 to C12 fatty acids : 10 - 40% w/w Polyoxyethylene hydrogenated Castor oils : 25 - 60% w/w DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention there is described a homogenous substantially alcohol free, composition of Cyclosporin which comprises a Cyclosporin in a hydrophillic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range: Cyclosporin : l-25%w/w Propylene Glycol : 5 _ 50% w/w Esters of propylene glycol with C4 to C12 fatty acids : 10 - 40% w/w Polyoxyethylene hydrogenated Castor oils : 25 - 60% w/w In another preferred embodiment of the invention the composition further comprises Triacetin or Glycerol triacetate. The glycerol triacetate may be present in the range of 0% to 10% w/w. In another embodiment of the present invention the composition further comprises Oleic Acid in the range of 0 to 15% w/w. In another embodiment of the present invention the composition further comprises Antioxidants i in the range of 0 to 2% w/w. The antioxidants could be selected from Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), Tocopherylacetate or a mixture thereof. In preferred embodiment of the invention is a composition comprising : Cyclosporin : 5-15%w/w Propylene Glycol : 15 - 45% w/w Esters of propylene glycol with C4 to C12 fatty acids : 15-35% w/w Polyoxyethylene hydrogenated Castor oils : 30 - 50% w/w In another embodiment of the invention the compositions are clear, stable, transparent, easily flowable and easily measurable at a wide range of temperature of 15° to 45°C. The amount of all of the ingredients of the composition disclosed above equals to 100%. The systems of the present invention are single phase systems in contrast to emulsion/microemulsions wherein essentially Lipophillic phase is emulsified or microemulsified with Hydrophilic phase using surfactant. The expression "single phase" should be implied to mean a phase wherein the drug is solubilized in Hydrophilic phase using suitable blend of surfactant (s)/ co-surfactant (s). The cyclosporins used in the compositions may be selected from cyclosporin A, cyclosporin D, cyclosporin G or any other known cyclosporin. It is preferred that cyclosporin A be used. Dosage forms that are soft gelatin capsules pose unique technology problems when the solutions to be encapsulated are microemulsion preconcentrate. There is a tendency to loose weight due to the migration of materials with free hydroxy groups into the capsule shell thus causing precipitation of drug due to loss of solvent. In the present invention this problem has been solved by adding to the said composition of the invention substantially 10-25% excess of the "carrier medium" thereby compensating for the loss of weight due to migration. At the same time the amount of plasticizers in the capsule shell are reduced by the amount equivalent to the excess carrier medium added in the capsule. The term "base" or "carrier medium" should be implied to mean everything added to the composition except the drug. The composition is incorporated into the capsule shell by conventional procedures as described in standard texts. ( "The theory and practice of Industrial Pharmacy" by Leon Lachman et al. Third edition, LEA AND FEBIGER, USA ) The Soft Gelatin and two piece hard shell Capsules have a very distinct advantage of ease of carrying and administration as compared with oral solutions. These dosage forms hence contribute to a very large segment of commercial market. To aid the filling of the composition into two piece hard shell capsules suitable hydrophilic viscosity imparting agents known in the art, may be added. These may be selected from natural gums like Xanthan gum, Karaya gum, Guar gum, Acacia and the like or semi-synthetic or synthetic polymers like cellulosics e.g. hydrxypropyl cellulose. Hydroxypropylmethyl cellulose, Carboxy methyl cellulose; Acrylates like polymethyl methacrylic acid; carbomers like Carbopol' 934, Carbopol 940 (BF Goodrich, USA). Such compositions of the present invention which are solubilized systems and substantially free of C1-5 alkanols such as ethanol are distinctly advantageous over the ones described in US patent no. 5, 342, 625 with respect to manufacturing and distribution in the tropical countries. It is most beneficial in context of hot tropical countries where absence of C1-5 alkanols such as ethanols are more due to evaporation. Preferably the (dransesterification product of a natural vegetable oil triglycerides and a Polyalkalene polyolpis Apricot Kernel/coconut oil Polyethylene glycol 6 esters. More preferably the Apricot Kernel/coconut oil Polyethylene Glycol 6 esters are selected from the group containing Labrafil Ml944 and Labrasol. Preferably the Polyoxyethylene hydrogenated castor oil is polyoxyethylene 40 Hydrogenated Castor oil. Especially suitable is product available under the Trade name Cremophor RH 40. The term " easily measurable" has been used due to the characteristic features of the drug Cyclosporin. Cyclosporin requires accurate dose measurement because of its narrow therapeutic index. Most of the drink solution packs are provided with a pipette or a syringe for accurate dose measurement. This warrants that the solution is a sufficiently thin liquid to permit ease of measurement and not a semi solid mass and also it should be devoid of any flakes, jelly like formations or other sediments which can cause non-homogeneity in the dose. The composition of our invention possesses all the desired characteristics and hence is easily measurable as far as the dose requirements is concerned. Compositions according to this invention may be formulate'd as drink solutions or diluted as a drink solution or formulated as soft gelatin capsules or as two piece hard shell capsules. Several compositions as per this invention with different ranges of ingredients were subjected to commercial production trials and shelf-life stability studies and the inventors were successful in arriving at a composition which was easy to manufacture and stable for long periods of time when tested by accelerated stability studies. Moreover when tested on healthy human volunteers, the composition(s) of this invention was found to have excellent bio-availability of Cyclosporin and were also found to be bioequivalent with commercial product. The comparative results are collected in Table I & II. The invention will now be described with reference to the accompanying examples which should not be construed to limit the scope of the invention : EXAMPLE 1 (PRIOR ART) COMPONENT AMOUNT a) Cyclosporin 100 mg(=ca. 10.5%) b) Maisine 550 mg (= ca. 57.8%) c) Labrafil M 2125 300 mg(=ca. 33.5%) TOTAL 950 mg The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation. EXAMPLE 2 (PRIOR ART) COMPONENT AMOUNT a) Cyclosporin 100 mg (= ca. 10.5%) b) Maisine 490 mg (= ca. 52%) c) Labrafil M 2125 300 mg (= ca. 31.5%) d) Cremophore RH40 60 mg (= ca. 6.3%) TOTAL 950 mg The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation. EXAMPLE 3 (PRIOR ART) COMPONENT AMOUNT a) Cyclosporin 100mg(=ca. 10.5%) b) Maisine 850 mg (= ca. 52%) TOTAL 950 mg The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation. EXAMPLE 4 (PRIOR ART) COMPONENT AMOUNT a) Cyclosporin l00mg b) Propylene Glycol 200 mg c) Cremophore RH40 350 mg d) Labrafil Ml944 200 mg e) Maisine 150mg TOTAL l000mg The composition obtained was a clear, homogenous liquid at a temperatures between 25° to 30°C, but at temperatures below 20°C jelly like flakes separated out. Examples 5 to 11 relate to cyclosporin compositions used as drink solution and soft gelatin capsules. Examples 12 to 19 relate to Cyclosporin compositions which can be used as a drink solution or can be suitable encapsulated. Example 5 COMPONENT AMOUNT a) Cyclosporin 200 mg b) Propylene Glycol 240 mg c) Cremophore RH40 430 mg d) Labrafll Ml944 110mg e) Oleic Acid 20 mg TOTAL l000mg This is a clear and homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafll Ml944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 6 COMPONENT AMOUNT a) Cyclosporin 200 mg b) Propylene Glycol 257 mg c) Cremophore RH40 425 mg d) Labrafll Ml 944 90 mg e) Oleic Acid 28 mg TOTAL l000mg This is a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 7 COMPONENT AMOUNT a) Cyclosporin 150mg b) Propylene Glycol 260 mg c) Cremophore RH40 460 mg d) Labrafil Ml944 110mg e) Oleic Acid 20 mg TOTAL l000mg The composition is a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 8 COMPONENT AMOUNT a) Cyclosporin 50 mg b) Propylene Glycol 350 mg c) Cremophore RH40 420 mg d) Labrafil Ml944 ll0mg e) Triacetin 20 mg f) Oleic Acid 50 mg TOTAL l000mg Above composition gives a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 and Oleic acid were then added to the bulk and mixed. Triacetin was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 9 COMPONENT AMOUNT a) Cyclosporin 10 mg b) Propylene Glycol 400 mg c) Cremophore RH40 420 mg d) Labrafil Ml944 150mg e) Oleic Acid 20 mg TOTAL 1000 mg Above composition gives a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Propylene Glycol was heated upto 55 to 60°C and Cyclosporin was dissolved therein. Cremophor RH40 was added to the bulk and mixed. Labrafil M1944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 10 COMPONENT AMOUNT a) Cyclosporin l00mg b) Propylene Glycol 240 mg c) Cremophore RH40 480 mg d) Labrafil Ml944 160mg e) Oleic Acid 20 mg TOTAL l000mg Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Labrafll Ml944 and added to the bulk and mixed. Triacetin was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 11 Process for making Soft Gelatin Capsules of Cyclosporin The compositions as mentioned in the prior art suffer from a disadvantage of migration of carrier medium comprising solvents containing free -OH groups particularly ethanol into the shell leading to precipitation of drug in the capsules. If alcohol is removed it also leads to precipitation of drug. To overcome this problem we have surprisingly found in the composition of the present invention that by increasing the amount of carrier medium in the core composition by about 20% at the time of encapsulation and reducing the amount of plasticizers (Sorbitol and Glycerine) in the capsule shell composition by 20 % yields soft gelatin capsules which on storage attain equilibrium and remain stable throughout the shelf life as exemplified below: Batch size : 1,00,000 capsules Core Composition a) Cyclosporin : 5 kg b) Carrier Medium* : 55 kg ""Includes 20% extra carrier medium Composition of carrier medium i) Propylene Glycol : 10.8kg ii) Cremophore RH40 : 24.9kg Hi) Labrafll Ml944 : 18.l kg iv) Oleic acid : 1.2kg Capsule shell composition i) Gelatin : 50kg ii) Sorbitol 8 kg iii) Glycerine 8 kg iv) Methyl Paraben 240 g v) Propyl Paraben 140 g vi) Water 45 kg vii) Colour 400 g Example 12 Cyclosporin - l00mg Propylene Glycol - 200 mg Cremophor RH 40 - 400 mg' Labrasol - 30 mg Labrafil - 180mg Oleic acid - 70 mg Triacetin - 19.75 mg Tocopherylacetate - 0.25 mg l000mg Heat Propylene Glycol to 55-60°C. Add cyclosporin and stir well till dissolved. Heat Cremophor RH 40 to 45°C and add to the bulk. Then add Labrafil and Labrasol, Oleic Acid and Triacetin followed by tocopherylacetate and stir to make a homogenous mixture. The resultant mixture is then filtered. Example 13 Composition for two piece hard shell capsule Cyclosporin - 25 mg Propylene Glycol - 41.5mg Cremophor RH 40 - 122.2 mg Labrasol - 9.15 mg Labrafil - 76.35 mg Oleic acid - 19.30 mg Triacetin - 19.40mg Tocopherylacetate - 6.10mg 319 mg The above composition may be filled in two piece hard capsules made up of materials like gelatin or cellulosics (e.g. Hydroxy propyl methyl cellulose based capsules like (LICAPS™) using suitable modified machines for filling liquids in two piece hard capsules. The capsules may be sealed using Qualiseal technology. The capsule shell may further comprise plasticizers, colorants, release modifiers, and the like. Example 14 Cyclosporin - 10 gms Propylene Glycol - 18 gms Cremophor RH 40 - 42 gms Propylene glycol laurate - 30 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol laurate was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 15 Cyclosporin - 10 gms Propylene Glycol - 20 gms Cremophor RH 40 - 40 gms Propylene glycol dicaprylate/dicaprate - 30 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol dicapryalate/dicaprylate was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 16 Cyclosporin - 10 gms Propylene Glycol - 18 gms Cremophor RH 40 - 42 gms Propylene glycol dioctanoate - 30 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol dioctanoate was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 17 Cyclosporin - l0gms Propylene Glycol - 15 gms Cremophor RH 40 - 40 gms Propylene glycol laurate - 17 gms Propylene glycol dicaprylate/dicaprate - 15 gms Triacetin - 3 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol laurate was then added to the bulk mixture and mixed. To this was added propylene glycol dicaprylate/dicaprate followed by Oleic acid. The resultant mixture was then filtered. Example 18 Cyclosporin - 10 gms, Cremophor RH 40 - 42 gms Propylene glycol monolaurate - 30 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol monolaurate was then added to the bulk mixture and mixed. The resultant mixture was then filtered. Example 19 Cyclosporin - 10 gms Propylene Glycol - 17 gms Cremophor RH 40 - 40 gms Propylene glycol monolaurate - 20 gms > Oleic Acid - 10 gms Triacetin - 2.93 gms Tocopheryl Acetate - 0.07 gms Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol monolaurate was then added to the bulk mixture and mixed. To this was added Oleic acid, Triacetin and Tocopherylacetate. The resultant mixture was then filtered. We claim : I. A homogenous alcohol free composition of C'yclosporin which comprises a C'yclosporin in a hydrophilic carrier medium comprising propylene glycol. transesterification product of a natural vegetable oil triglycerides and a polyalkalene polyol and polyoxycthylene hydrogenated castor oils wherein the ingredients are present in the following range: Cyclosporin , : 1 25 % \\7\Propylene glycol : 5 50 % w/w I ransesterification product of a natural vegetable oil : 10 - 40 % vv/vv triglycerides and a polyalkalene polyol Polyoxyethylene hydrogenated castor oils : 25 60% w/w 2. A composition as claimed in claim 1. wherein the ingredients are present in the following range : Cyclosporin : 5- 15% w/w Props lenc glycol : 15 45 % w/w I ranscstcrification product of a natural vegetable oil : 15 35 % w/w Iriulytvrides and a polyalkalene polyol Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w 3. A composition as claimed in claim 1. which comprises transesterification product of a natural vegetable oil triglycerides and a polyalkalene polyol. 4. A composition as claimed in claim I. uherein the composition optionally comprises agents selected from glycerol triacetate, oleic acid, butylated hydroxyanisole. butylated hydroxytoluene, tocopherylacetate or a mixture thereof. 5. A composition as claimed in claim 4, wherein glycerol triacetate is present in the range ol'O to 10% w/w. 6. A composition as claimed in claim 4. wherein oleic acid is present in the range of 0 to 1 5% w/w. 7. A composition as claimed in claim I, which can be formulated as a drink solution or incorporated into soft gelatin capsules or hard gelatin capsules or hard cellulose capsules or packed in a suitable device to affect measurable unit dosage dispensing. 8. A composition as claimed in claim 1, wherein the Cyclosporin is Ciclosporin A. 9. A homogenous alcohol free composition of Cyclosporin substantially as herein described with reference to the foregoing description and the accompanying Examples.

Full Text

INTRODUCTION
The present invention relates to pharmaceutical compositions comprising Cyclosporin as active ingredient. The present invention also relates to novel alcohol free, free flowing, clear and transparent compositions comprising Cyclosporin as an active ingredient. The novel compositions are characterized in having increased bio-availability when the drug is formulated in a solubilised system and also amenable to convenient commercial production.
BACKGROUND OF THE INVENTION
Cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the Cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as Cyclosporin A and commercially available under several brands. Ciclosporin is the Cyclosporin of formula A.
(Formula Removed)
wherein - MeBmt- represents the N-Methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L) threonyl residue of formula B.
(B) (Formula Removed)
in which -x-y- is --CH =CH- (trans).
Naturally occurring and semi-synthetic Cyclosporins, their classification, nomenclature etc. are known [c.f Traber et al. 1, Helv. Chim Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. (65 no. 162, 1655-1667 (1982)); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (1980); and von Wart-burg et al., Progress in allergy, 38, 28-45 1986)]. US Patent Nos 4,108,985, 4,210,581 and 4,220,641; European Patent Publication Nos. 0034567 and 0056782; International Patent Publication no. WO 86/02080; Wenger 1, Transp. Proc. 15, Suppl. 1; 2230(1983); Wenger. 2, Angew. Chem. Int. Ed., 24,77 (1985); and Wenger 3, Progress in Chemistry of Organic natural products 50, 123(1986). Other Cyclosporins are known from U.S Patents 4,639,434; 4,703,033; 4,764,503, 4,885,276; 5,116,816; 5,122,511; 5,525,590; 5,643,870 and 5,767,069.
So far the primary area of clinical investigation for Cyclosporins and in particular, Ciclosporin has been as an immunosuppressive agent, in particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin and corneal transplants and, in particular, allogenic organ transplants. In this field Cyclosporins, in particular ciclosporins have achieved a remarkable success. Among all the Cyclosporins, Cyclosporin A ( also known as Cyclosporine or Ciclosporin) has established its utility in the area of organ transplant and therapy of autoimmune diseases.
At the same time, applicability of Cyclosporins including Ciclosporin to various autoimmune diseases and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are wide-spread in the literature. Specific auto-immune diseases for which Cyclosporin and Ciclosporin therapy has been proposed or applied include, autoimmune hematological disorder (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus ervthematosus, poly-chondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic
arthirits and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
Further areas of investigation for cyclosporins include potential applicability as an anti-parasitic, in particular anti-protozoal agent, with possible uses suggested including treatment of malaria, coccidiomycosis and schistosomiasis and, yet more recently, use as an agent for reversing or abrogating anti-neoplastic agent resistance in tumours and the like.
Although Cyclosporin A is the most widely used amongst all the immunosuppresants available so far, it suffers from a serious drawback of poor bio-availability. Cyclosporin blood levels have to be maintained within a specified range to achieve the effective therapy. The required range varies according to the clinical status of the patient.
Because of poor and variable bioavailability daily dosages needed to achieve the desired blood levels need to be varied considerably in the existing dosage forms of Cyclosporin and a concomitant monitoring of blood levels is essential. This adds an additional cost to the therapy.
In order to improve the bio-availability several attempts have been made to improve formulations of Cyclosporin. The oral dosage forms known in the market (i.e. those employing ethanol, olive oil as carrier medium in conjunction with Labrafll as surfactant (see US patent no. 4, 388, 307) are unpleasant tasting galenic forms. The bio-availability levels using these dosage forms are low and exhibit wide inter-and intra-individual variations. Such dosage forms provide an average absolute bioavailability of ca 30%. Reported variation in bio-availability between subjects varies between a few percent for some patients to as much as 90% or more for others. Also a marked change in bio-availability for individuals with time is frequently observed.
US Patent no. 4,388,307 also describes a drink solution containing Cyclosporin in a base of Labrafll, Miglyol, Ethanol, Corn/olive oil. However, such preparation suffered from the drawback that it can be presented only as a liquid for dilution in drinking water/fluid before use, otherwise it is very difficult to give an accurate dose. Bioavailability levels achieved using the systems s very low and exhibits wide variations between individuals, individual patient type and even for single individuals at different times during the course of therapy.
Han Gua Patent (Chinese Patent No. 94191895.5) explains the active compound of Cyclosporin, fatty acid sugar ester and diluent carrier having good bio-availability. However, this compound suffers from the drawback that diluent degrades due to hygroscopicity of sugar ester and the stability is not of desired standards, (See also Pharmaceutical Research, Volume 6, No. 11, 1989, P958, "Solid Surfactant Solution of active Ingredients in Sugar Ester" and International Journal of Pharmaceutics, Vol. 92, 1993, P197," Application of sucrose laurate a new pharmaceutical excipient, in Peroral formulation of Cyclosporin A").
Chinese Patent 9419189.5 having equivalent EP 0702562 describes a powder dosage form of Cyclosporin possessing comparatively higher stability and to some extent bio-availability when compared to the earlier formulations. This art describes adsorption of Cyclosporin A with appropriate solvents onto an adsorbent along with a nonionic hydrophillic surfactant. The final product does not contain the solvent as this evaporates during the process of manufacturing. Thus this product does not suffer from the disadvantage arising out of solvent evaporation during shelf life and hence stability problems. The various pharmaceutical surfactants, polyhydric alcohols and solvents are well known to the art. The adsorbent used is Colloidal Silicon Dioxide. The blood level arising out of such product have been compared with the standard formulations as per US patent no. 4, 388, 307 with significant improvement in bioavailability. However, if compared with the micro-emulsion based formulations these formulations do not show any advantage as the drug is adsorbed on solid surface and needs an additional process of dissolution prior to become bioavailable.
The effect of sucrose laurate on the gastrointestinal absorption of Cyclosporine is also described (Lerk-PC; Sucker-H, International Journal of Pharmaceutics; 1993; 92; (May 3); 197-202). The evaluation of the dosage form containing sucrose Laurate was found to enhance the in vitro absorption of Cyclosporine when normal epithelial tissue and Peyer's patch tissue of guinea pigs were used. Compared to the commercially available drinking solution, absorption was raised by a factor of 10. Excess amount of surfactant reduced drug absorption. Despite large excess of Sucrose laurate, the absorption of Cyclosporin was still superior to the drinking solution. Choleic acid was also found to increase absorption by a factor of 5-6. A comparison of the absorption between normal epithelial and Peyer's patch tissues indicated that the absorption by endocytosis does not contribute significantly to the overall absorption of Cyclosporin. It was
concluded that preliminary formulation experiments showed that a solid oral dosage form of Cyclosporin could be made using sucrose laurate as an excipient.
Abdallah-HY; Mayersohn-M. Pharmaceutical Research; 199l;8(Apr);518-522 reported several formulations of Cyclosporin were prepared and examined in vitro and in dogs A tablet formulation was then selected for comparison with the commercial oil solution placed in a soft gelatin capsule in a randomized crossover study in dogs. Compared with an intravenous dose of the drug, absolute bioavailability was 46+11.1 and 45+ 9.9% for the capsules and tablets, respectively. Maximum concentration, time to reach maximum concentration and mean absorption time were not significantly different between the 2 formulations. It was concluded that the tablet formulation of Cyclosporin is equivalent in dogs to the commercial dosage form packed into soft gelatin capsules.
US patent no. 505 1402 describes that Cyclosporin may be rendered more soluble by the concomitant administration of a-Cyclodextrin, either separately, but essentially simultaneously or, preferably, in admixture.
US Patent No. 4990337 describes a formulation comprising a Cyclosporin in admixture with at least one mono or diglyceride of a C6-C10 fatty acid sufficient to dissolve the Cyclosporin. The resulting solution can then easily be emulsified in water or an aqueous fluid.
Freeze dried liposome mixture containing Cyclosporin has been described in US Patent no. 4963362. This invention provides a freeze-dried potential liposome mixture having an amphipathic lipid and a Cyclosporin or derivative thereof for use in possible liposome delivery of Cyclosporin into cells. A method to produce the freeze-dried mixture is also disclosed. When reconstituted to yield liposomes in an aqueous medium, substantially all of the Cyclosporin present in the freeze-dried mixture is encapsulated in the liposomes.
Other galenic improvements in Cyclosporin emulsion formulations recorded in prior arts such as EP0724452 discloses a pharmaceutical composition which contains cyclosporine A and alpha -tocopherol or one of its derivatives. EP0712631 describes a oral multiple emulsion pre-concentrate comprising a surfactant, ethanol, a lipophilic and/or an amphiphilic solvent, characterized by the composition comprising Cyclosporin, tocopheryl polyethylene glycol
carboxylic acid ester, ethanol, lipophilic solvent and/or an amphiphilic solvent, and if desired co-tenside. EP0711550 discloses a cyclosporin soft capsule composition comprising cyclosporin as an active ingredient, dimethylisosorbide as a cosurfactant, one component or a mixture of two or
more components selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component, and a surfactant having HLB (Hydrophilic-lipophilic balance) value of 10 to 17. EP0650721 discloses an oral microemulsion composition for suppression of an immunological response comprising an immunosuppressive amount of cyclosporin and a sufficient amount of dimethylisosorbide, oil and surfactant to form a microemulsion suitable for oral administration. WO9423733 describes an oral administration pharmaceutical compositions that are easy to produce and have a good bioavailability and comprises cyclosporine as active substance an alkylene polyether or polyester, and may optionally contain an alkylene polyol, an alkylene glycol, a polyalkylene glycol, an alkyl diether or partial ether of a low molecular mono- or polyoxyalkane diol and/or a vegetable oil or its hydrogenated or hydrolysed product. EP0694308 discloses a cyclosporin-containing oil-in-water type emulsion composition comprising cyclosporin, a polyalkyl ester of polycarboxylic acid in the form of a liquid at ordinary temperature, an oil component having an I.O.B. of 0 to 0.25 in the form of a liquid at ordinary temperature, and a surfactant, EP0656212 discloses cyclosporin-containing liquid compositions for oral or parenteral administration comprising cyclosporin, a polyoxyethylene glycerol fatty acid monoester and a mono- and/or polyhydric alcohol(s). These compositions are stable, well tolerated and have better bioavailability. EP0651995 describes a pharmaceutical preparation which contains one or more cyclosporins, one or more oils of natural origin, 3-sn-phosphatidylethanolamine and water.
Three Patent Applications namely European Patent App.No. 94110184.2, 95117171.9 and PCT/EP95/04187 describe the use of Dimethylisosorbide as a co-surfactant or a hydrophillic phase along with other ingredients to enhance the absorption of Cyclosporin.
One of the most significant attempt to improve bio-availability of Cyclosporin from its dosage form is the described in US patent no. 5, 342, 625. This art describes use of microemulsion pre-concentrate consisting of a three phase systems i.e. (1) a hydrophilic phase component (2) a lipophilic phase component and (3) a surfactant. Such composition has alcohol as an essential ingredient. Such composition upon dilution with water provides an oil-in-water microemulsion
with an average particle size of less than 1000A0. Such an enhanced surface area results in increased bio-availability of Cyclosporin when compared with conventional dosage forms. A comparison of bio-availability from micro-emulsion dosage form (Composition I from US patent no. 5, 342, 625) with the conventional ethanol/oil based dosage form (Composition X from US patent no. 5,342,625) earlier reported in US patent no. 4, 388, 307 has been performed in healthy human volunteers and reported in US patent no. 5,342, 625. Bio-availability level of 149.0% (± 48) is recorded for composition I as compared to composition X (for which bio-availability achieved is set as 100%). The mean AUC levels from composition I were 40% higher when compared to those from composition X but still had a high variation of 20%.
Alcohol is an essential part of composition as is evident from the products available in the market (Sandimun [US Pat. No. 4, 388, 307] and Neoral [US Pat. No. 5,342, 625]) both of which contain Alcohol. Such compositions suffer from severe drawback of instability due to evaporation of a low boiling solvent like Alcohol. This is particularly true as the products are used in home environment, which cannot be precisely controlled with respect to temperature. Although very expensive cumbersome technology (such as cold formed Aluminium/ Aluminium Blister packs) is adopted to protect these products, yet the problem of instability is not completely solved. The stability problems are evident from strict storage conditions and usage requirements as declared either on the labels or package inserts of commercial products Sandimun, and Neoral drink solutions and capsules. Some of the examples are :
1. There is a requirement of storage of product below 30°C at the same time refrigeration is
prohibited. This means that a patient using this product in a tropical country need to have
an air-conditioned home environment. This is not only a limiting factor in use of this
product but sometimes in economically backward countries it may not be possible that
every person using the product has an air-conditioned storage area. Sometimes factors
like prolong electricity failure and mechanical and electrical defects in air-conditioning
system can cause instability problems to these products rendering them unstable for use.
2. There is also an a statement in Packing insert of Sandimun and Neoral drink solutions
that " Sandimun Neoral solution should be used within 2 months of opening the bottle
and be stored between 15° and 30°C, preferably not below 20°C for prolonged periods, as
it contains oily components of natural origin which tend to solidify at low temperatures.

A jelly-like formation may occur below 20°C, which is however reversible at temperatures up to 30°C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the pipette remains accurate." indicating instability problems.
US Patent no. 5, 639, 724 discloses pharmaceutical compositions comprising Cyclosporin, transesterification product of a natural vegetable oil with glycerol, which is exemplified in the specification as MAISINE (transesterification product of corn oil and glycerol) which is an essential component of the compositions. The cyclosporin must be mixed with a transesterification product of a natural vegetable oil with glycerol. These compositions are not useful as drink solutions because of formation of jelly like, lumps, since the transesterification product is a jelly like substance at room temperature. Such composition also preferably require the use of alcohol. This compositions compares its bioavailability with that of older and inferior compositions based on US patent no. 4, 388, 307 and does not compare bioavailability with a more recently marketed compositions (NEORAL) as defined in US patent no. 5, 342, 625. US Patent No. 5,639,724 discloses the use of Labrafil as a preferred ingredient to be added to the composition of Cyclosporin and MAISINE for a drink solution. However, this patent does not address the problem of flake like substances formed by the presence of MAISINE even though Labrafil has been added to the composition.
The formulation of emulsion as well as microemulsion present their own technological problems relating to thermodynamic instability. Such problems may be partially solved presenting the product in a microemulsion pre-concentrate form wherein the microemulsfying occurs in vivo only. However, such systems may also present variability problems due to variations existing in GI tract of patients.
Any person skilled in the art attempting to make compositions without the use of alcohol and without careful and extensive experimentation and study of desired chemicals to be added to Cyclosporin will end with compositions which are highly viscous and which tend to solidify at normal room temperature conditions. Such compositions are undesirable not only due to physical unstability but also that they cannot be formulated as liquids whose dose can be measured exactly under normal conditions.
The major consideration here is the accurate measurement of dose in Cyclosporin which is an essential feature because of the narrow therapeutic condition of the drug i.e. below threshold the organ rejection occurs and above a particular level the drug causes severe toxic reactions.
None of the above mentioned inventions teaches the art of dissolving cyclosporin including Cyclosporin A (which is a water insoluble hydrophobic drug) in a hydrophilic medium. This looks improbable and a person skilled in the art cannot conceive beyond an emulsion and/or microemulsion.
All the earlier approaches to enhance the bioavailability of Cyclosporin were towards making the drug in a emulsifying form (US Patent no 4, 388, 307) or substantially increasing the surface area by converting into microemulsion (US Patent No. 5, 342, 625).
Our attempt has been to affect solution of cyclosporin in a hydrophilic environment using micellar concept of a surfactant and a co-surfactant such that such compositions are substantially devoid of fatty materials and hence also devoid of the defects associated with such fatty materials. Compositions according to this invention may be formulated for oral administration including but not limited to drink solutions or formulated as hard or soft gelatin capsules. The capsules may be gelatin or cellulose or two piece hard shell capsules. Drink solution formulations may be diluted with water or aqueous medium and the lipophilic Cyclosporin drug is maintained in a solubilized state, hence making the drug bioavailable in therapeutic concentrations.
It will be most appropriate to formulate Cyclosporin compositions in a way that the drug gets converted into a solubilized system on dilution in vivo. Compositions of the invention when administered orally in the form of a drink solution or soft gelatin capsules get diluted with the gastrointestinal fluids to form micellar solutions such that the hydrophilic end of the surfactant and the cosurfactant are oriented towards hydrophilic environment of gastrointestinal fluid and the drug molecules are entrapped in the hydrophobic portions of the surfactant micelles. Such micellar solubilised systems, when in contact with the mucosa of the gastrointestinal tract, release the drug leading to absorption, thus providing an increased and less variable bioavailability. The inventors have invented compositions in which hydrophobic drug like Cyclosporin can be dissolved in a hydrophillic medium by careful selection of the hydrophilic
medium, surfactants and manner of addition such that a hydrophobic drug can get dissolved in an array of surfactant molecules arranged in a manner that their hydrophilic portions are oriented outside i.e. towards the hydrophilic medium resulting in clear stable solution based formulation. Such products when they come in contact with biological fluids result in total solubilazationof Cyclosporin at molecular levels thereby increasing the surface area of Cyclosporin and such diluted solutions of Cyclosporin are highly bioavailable. Such compositions do not form emulsions on dilution. Such systems will definitely be more uniform and bio-available than microemulsions from where the drug has to partition out of the lipophillic phase for absorption.
Oral solution concentrates are to be diluted prior to intake and are used as start up therapies. These dosage forms provide more flexibility in dosage adjustments to achieve the optimum therapeutic concentrations as desired by the physicians. The second type of dosage forms are unit dosage forms for example capsules, generally soft or hard gelatin capsules or cellulose capsules or two piece hard shell capsules.
SUMMARY OF THE INVENTION
In accordance with the present invention there is described a homogenous substantially alcohol free, composition of Cyclosporin which comprises a Cyclosporin in a hydrophillic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range :
Cyclosporin : 1-25 %w/w
Propylene Glycol : 5 - 50% w/w
Esters of propylene glycol with C4 to C12 fatty acids : 10 - 40% w/w
Polyoxyethylene hydrogenated Castor oils : 25 - 60% w/w
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention there is described a homogenous substantially alcohol free, composition of Cyclosporin which comprises a Cyclosporin in a hydrophillic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range:
Cyclosporin : l-25%w/w
Propylene Glycol : 5 _ 50% w/w
Esters of propylene glycol with C4 to C12 fatty acids : 10 - 40% w/w
Polyoxyethylene hydrogenated Castor oils : 25 - 60% w/w
In another preferred embodiment of the invention the composition further comprises Triacetin or Glycerol triacetate. The glycerol triacetate may be present in the range of 0% to 10% w/w.
In another embodiment of the present invention the composition further comprises Oleic Acid in the range of 0 to 15% w/w.
In another embodiment of the present invention the composition further comprises Antioxidants
i
in the range of 0 to 2% w/w.
The antioxidants could be selected from Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), Tocopherylacetate or a mixture thereof.
In preferred embodiment of the invention is a composition comprising :
Cyclosporin : 5-15%w/w
Propylene Glycol : 15 - 45% w/w
Esters of propylene glycol with C4 to C12 fatty acids : 15-35% w/w
Polyoxyethylene hydrogenated Castor oils : 30 - 50% w/w
In another embodiment of the invention the compositions are clear, stable, transparent, easily flowable and easily measurable at a wide range of temperature of 15° to 45°C.
The amount of all of the ingredients of the composition disclosed above equals to 100%.
The systems of the present invention are single phase systems in contrast to emulsion/microemulsions wherein essentially Lipophillic phase is emulsified or microemulsified with Hydrophilic phase using surfactant. The expression "single phase" should be implied to
mean a phase wherein the drug is solubilized in Hydrophilic phase using suitable blend of surfactant (s)/ co-surfactant (s).
The cyclosporins used in the compositions may be selected from cyclosporin A, cyclosporin D, cyclosporin G or any other known cyclosporin. It is preferred that cyclosporin A be used.
Dosage forms that are soft gelatin capsules pose unique technology problems when the solutions to be encapsulated are microemulsion preconcentrate. There is a tendency to loose weight due to the migration of materials with free hydroxy groups into the capsule shell thus causing precipitation of drug due to loss of solvent. In the present invention this problem has been solved by adding to the said composition of the invention substantially 10-25% excess of the "carrier medium" thereby compensating for the loss of weight due to migration. At the same time the amount of plasticizers in the capsule shell are reduced by the amount equivalent to the excess carrier medium added in the capsule. The term "base" or "carrier medium" should be implied to mean everything added to the composition except the drug.
The composition is incorporated into the capsule shell by conventional procedures as described in standard texts. ( "The theory and practice of Industrial Pharmacy" by Leon Lachman et al. Third edition, LEA AND FEBIGER, USA )
The Soft Gelatin and two piece hard shell Capsules have a very distinct advantage of ease of carrying and administration as compared with oral solutions. These dosage forms hence contribute to a very large segment of commercial market. To aid the filling of the composition into two piece hard shell capsules suitable hydrophilic viscosity imparting agents known in the art, may be added. These may be selected from natural gums like Xanthan gum, Karaya gum, Guar gum, Acacia and the like or semi-synthetic or synthetic polymers like cellulosics e.g. hydrxypropyl cellulose. Hydroxypropylmethyl cellulose, Carboxy methyl cellulose; Acrylates like polymethyl methacrylic acid; carbomers like Carbopol' 934, Carbopol 940 (BF Goodrich, USA).
Such compositions of the present invention which are solubilized systems and substantially free of C1-5 alkanols such as ethanol are distinctly advantageous over the ones described in US patent no. 5, 342, 625 with respect to manufacturing and distribution in the tropical countries.
It is most beneficial in context of hot tropical countries where absence of C1-5 alkanols such as
ethanols are more due to evaporation.
Preferably the (dransesterification product of a natural vegetable oil triglycerides and a
Polyalkalene polyolpis Apricot Kernel/coconut oil Polyethylene glycol 6 esters. More preferably the Apricot Kernel/coconut oil Polyethylene Glycol 6 esters are selected from the group containing Labrafil Ml944 and Labrasol.
Preferably the Polyoxyethylene hydrogenated castor oil is polyoxyethylene 40 Hydrogenated Castor oil. Especially suitable is product available under the Trade name Cremophor RH 40.
The term " easily measurable" has been used due to the characteristic features of the drug
Cyclosporin. Cyclosporin requires accurate dose measurement because of its narrow therapeutic
index. Most of the drink solution packs are provided with a pipette or a syringe for
accurate dose measurement. This warrants that the solution is a sufficiently thin liquid to permit ease of measurement and not a semi solid mass and also it should be devoid of any flakes, jelly like formations or other sediments which can cause non-homogeneity in the dose. The composition of our invention possesses all the desired characteristics and hence is easily measurable as far as the dose requirements is concerned.
Compositions according to this invention may be formulate'd as drink solutions or diluted as a drink solution or formulated as soft gelatin capsules or as two piece hard shell capsules.
Several compositions as per this invention with different ranges of ingredients were subjected to commercial production trials and shelf-life stability studies and the inventors were successful in arriving at a composition which was easy to manufacture and stable for long periods of time when tested by accelerated stability studies.
Moreover when tested on healthy human volunteers, the composition(s) of this invention was found to have excellent bio-availability of Cyclosporin and were also found to be bioequivalent
with commercial product. The comparative results are collected in Table I & II.

The invention will now be described with reference to the accompanying examples which should not be construed to limit the scope of the invention :
EXAMPLE 1 (PRIOR ART)
COMPONENT AMOUNT
a) Cyclosporin 100 mg(=ca. 10.5%)
b) Maisine 550 mg (= ca. 57.8%)
c) Labrafil M 2125 300 mg(=ca. 33.5%)
TOTAL 950 mg
The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation.
EXAMPLE 2 (PRIOR ART)
COMPONENT AMOUNT
a) Cyclosporin 100 mg (= ca. 10.5%)
b) Maisine 490 mg (= ca. 52%)
c) Labrafil M 2125 300 mg (= ca. 31.5%)
d) Cremophore RH40 60 mg (= ca. 6.3%)
TOTAL 950 mg
The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation.
EXAMPLE 3 (PRIOR ART)
COMPONENT AMOUNT
a) Cyclosporin 100mg(=ca. 10.5%)
b) Maisine 850 mg (= ca. 52%)
TOTAL 950 mg
The mixture obtained was a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation.
EXAMPLE 4 (PRIOR ART)
COMPONENT AMOUNT
a) Cyclosporin l00mg
b) Propylene Glycol 200 mg
c) Cremophore RH40 350 mg
d) Labrafil Ml944 200 mg
e) Maisine 150mg
TOTAL l000mg
The composition obtained was a clear, homogenous liquid at a temperatures between 25° to 30°C, but at temperatures below 20°C jelly like flakes separated out.
Examples 5 to 11 relate to cyclosporin compositions used as drink solution and soft gelatin capsules. Examples 12 to 19 relate to Cyclosporin compositions which can be used as a drink solution or can be suitable encapsulated.
Example 5
COMPONENT AMOUNT
a) Cyclosporin 200 mg
b) Propylene Glycol 240 mg
c) Cremophore RH40 430 mg
d) Labrafll Ml944 110mg
e) Oleic Acid 20 mg
TOTAL l000mg
This is a clear and homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules.
Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafll Ml944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 6
COMPONENT AMOUNT
a) Cyclosporin 200 mg
b) Propylene Glycol 257 mg
c) Cremophore RH40 425 mg
d) Labrafll Ml 944 90 mg
e) Oleic Acid 28 mg
TOTAL l000mg
This is a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules.
Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 was added to the bulk and mixed. Oleic
acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered.

Example 7
COMPONENT AMOUNT
a) Cyclosporin 150mg
b) Propylene Glycol 260 mg
c) Cremophore RH40 460 mg
d) Labrafil Ml944 110mg
e) Oleic Acid 20 mg
TOTAL l000mg
The composition is a clear, homogenous solution which remains clear and stable at temperatures
between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable

for formulating as a drink solution or soft gelatin capsules.
Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 8
COMPONENT AMOUNT
a) Cyclosporin 50 mg
b) Propylene Glycol 350 mg
c) Cremophore RH40 420 mg
d) Labrafil Ml944 ll0mg
e) Triacetin 20 mg
f) Oleic Acid 50 mg
TOTAL l000mg
Above composition gives a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules.
Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C. Cyclosporin was dissolved in the resultant mixture. Labrafil Ml944 and Oleic acid were then added to the bulk and mixed. Triacetin was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 9
COMPONENT AMOUNT
a) Cyclosporin 10 mg
b) Propylene Glycol 400 mg
c) Cremophore RH40 420 mg
d) Labrafil Ml944 150mg
e) Oleic Acid 20 mg
TOTAL 1000 mg
Above composition gives a clear, homogenous solution which remains clear and stable at temperatures between 15° to 45°C without any jelly like flake formation. Hence this composition is suitable for formulating as a drink solution or soft gelatin capsules.
Propylene Glycol was heated upto 55 to 60°C and Cyclosporin was dissolved therein. Cremophor RH40 was added to the bulk and mixed. Labrafil M1944 was added to the bulk and mixed. Oleic acid was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 10
COMPONENT AMOUNT
a) Cyclosporin l00mg
b) Propylene Glycol 240 mg
c) Cremophore RH40 480 mg
d) Labrafil Ml944 160mg
e) Oleic Acid 20 mg
TOTAL l000mg
Propylene Glycol was mixed with Cremophor RH40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Labrafll Ml944 and added to the bulk and mixed. Triacetin was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 11
Process for making Soft Gelatin Capsules of Cyclosporin
The compositions as mentioned in the prior art suffer from a disadvantage of migration of carrier medium comprising solvents containing free -OH groups particularly ethanol into the shell leading to precipitation of drug in the capsules. If alcohol is removed it also leads to precipitation of drug.
To overcome this problem we have surprisingly found in the composition of the present invention that by increasing the amount of carrier medium in the core composition by about 20% at the time of encapsulation and reducing the amount of plasticizers (Sorbitol and Glycerine) in the capsule shell composition by 20 % yields soft gelatin capsules which on storage attain equilibrium and remain stable throughout the shelf life as exemplified below:
Batch size : 1,00,000 capsules Core Composition
a) Cyclosporin : 5 kg
b) Carrier Medium* : 55 kg
""Includes 20% extra carrier medium
Composition of carrier medium
i) Propylene Glycol : 10.8kg
ii) Cremophore RH40 : 24.9kg
Hi) Labrafll Ml944 : 18.l kg
iv) Oleic acid : 1.2kg
Capsule shell composition
i) Gelatin : 50kg
ii) Sorbitol 8 kg
iii) Glycerine 8 kg
iv) Methyl Paraben 240 g
v) Propyl Paraben 140 g
vi) Water 45 kg
vii) Colour 400 g
Example 12
Cyclosporin - l00mg
Propylene Glycol - 200 mg
Cremophor RH 40 - 400 mg'
Labrasol - 30 mg
Labrafil - 180mg
Oleic acid - 70 mg
Triacetin - 19.75 mg
Tocopherylacetate - 0.25 mg
l000mg
Heat Propylene Glycol to 55-60°C. Add cyclosporin and stir well till dissolved. Heat Cremophor RH 40 to 45°C and add to the bulk. Then add Labrafil and Labrasol, Oleic Acid and
Triacetin followed by tocopherylacetate and stir to make a homogenous mixture. The resultant
mixture is then filtered.
Example 13
Composition for two piece hard shell capsule
Cyclosporin - 25 mg
Propylene Glycol - 41.5mg
Cremophor RH 40 - 122.2 mg
Labrasol - 9.15 mg
Labrafil - 76.35 mg
Oleic acid - 19.30 mg
Triacetin - 19.40mg
Tocopherylacetate - 6.10mg
319 mg
The above composition may be filled in two piece hard capsules made up of materials like gelatin or cellulosics (e.g. Hydroxy propyl methyl cellulose based capsules like (LICAPS™) using suitable modified machines for filling liquids in two piece hard capsules. The capsules may be sealed using Qualiseal technology. The capsule shell may further comprise plasticizers, colorants, release modifiers, and the like.
Example 14
Cyclosporin - 10 gms
Propylene Glycol - 18 gms
Cremophor RH 40 - 42 gms
Propylene glycol laurate - 30 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and
Cyclosporin was dissolved in the resultant. Propylene glycol laurate was then added to the bulk
mixture and mixed. The resultant mixture was then filtered.
Example 15
Cyclosporin - 10 gms
Propylene Glycol - 20 gms
Cremophor RH 40 - 40 gms
Propylene glycol dicaprylate/dicaprate - 30 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and
Cyclosporin was dissolved in the resultant. Propylene glycol dicapryalate/dicaprylate was then
added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 16
Cyclosporin - 10 gms
Propylene Glycol - 18 gms
Cremophor RH 40 - 42 gms
Propylene glycol dioctanoate - 30 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol dioctanoate was then added to the bulk mixture and mixed. The resultant mixture was then filtered.
Example 17
Cyclosporin - l0gms
Propylene Glycol - 15 gms
Cremophor RH 40 - 40 gms
Propylene glycol laurate - 17 gms
Propylene glycol dicaprylate/dicaprate - 15 gms
Triacetin - 3 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and
Cyclosporin was dissolved in the resultant. Propylene glycol laurate was then added to the bulk
mixture and mixed. To this was added propylene glycol dicaprylate/dicaprate followed by Oleic
acid. The resultant mixture was then filtered.
Example 18
Cyclosporin - 10 gms,
Cremophor RH 40 - 42 gms
Propylene glycol monolaurate - 30 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and
Cyclosporin was dissolved in the resultant. Propylene glycol monolaurate was then added to the
bulk mixture and mixed. The resultant mixture was then filtered.
Example 19
Cyclosporin - 10 gms
Propylene Glycol - 17 gms
Cremophor RH 40 - 40 gms
Propylene glycol monolaurate - 20 gms >
Oleic Acid - 10 gms
Triacetin - 2.93 gms
Tocopheryl Acetate - 0.07 gms
Propylene Glycol was mixed with Cremophor RH 40 and heated upto 55 to 60°C and Cyclosporin was dissolved in the resultant. Propylene glycol monolaurate was then added to the bulk mixture and mixed. To this was added Oleic acid, Triacetin and Tocopherylacetate. The resultant mixture was then filtered.

We claim :
I. A homogenous alcohol free composition of C'yclosporin which comprises a C'yclosporin in a hydrophilic carrier medium comprising propylene glycol. transesterification product of a natural vegetable oil triglycerides and a polyalkalene polyol and polyoxycthylene hydrogenated castor oils wherein the ingredients are present in the following range:
Cyclosporin , : 1 25 % \\7\Propylene glycol : 5 50 % w/w
I ransesterification product of a natural vegetable oil : 10 - 40 % vv/vv
triglycerides and a polyalkalene polyol
Polyoxyethylene hydrogenated castor oils : 25 60% w/w
2. A composition as claimed in claim 1. wherein the ingredients are present in the following range :
Cyclosporin : 5- 15% w/w
Props lenc glycol : 15 45 % w/w
I ranscstcrification product of a natural vegetable oil : 15 35 % w/w
Iriulytvrides and a polyalkalene polyol
Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w
3. A composition as claimed in claim 1. which comprises transesterification product of a natural
vegetable oil triglycerides and a polyalkalene polyol.
4. A composition as claimed in claim I. uherein the composition optionally comprises agents selected from glycerol triacetate, oleic acid, butylated hydroxyanisole. butylated hydroxytoluene, tocopherylacetate or a mixture thereof.
5. A composition as claimed in claim 4, wherein glycerol triacetate is present in the range ol'O to 10% w/w.

6. A composition as claimed in claim 4. wherein oleic acid is present in the range of 0 to 1 5% w/w.
7. A composition as claimed in claim I, which can be formulated as a drink solution or
incorporated into soft gelatin capsules or hard gelatin capsules or hard cellulose capsules or
packed in a suitable device to affect measurable unit dosage dispensing.
8. A composition as claimed in claim 1, wherein the Cyclosporin is Ciclosporin A.
9. A homogenous alcohol free composition of Cyclosporin substantially as herein described with reference to the foregoing description and the accompanying Examples.

Documents:

777-del-1999-abstract.pdf

777-DEL-1999-Claims.pdf

777-del-1999-correspondence-others.pdf

777-del-1999-correspondence-po.pdf

777-del-1999-description (complete).pdf

777-del-1999-form-1.pdf

777-del-1999-form-13.pdf

777-del-1999-form-19.pdf

777-del-1999-form-2.pdf

777-del-1999-form-26.pdf

777-del-1999-form-4.pdf

777-del-1999-form-5.pdf

777-del-1999-petition-138.pdf

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Patent Number

216033

Indian Patent Application Number

777/DEL/1999

PG Journal Number

13/2008

Publication Date

28-Mar-2008

Grant Date

05-Mar-2008

Date of Filing

25-May-1999

Name of Patentee

PANACEA BIOTEC LIMITED

Applicant Address

B-1, EXT./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. AMARJIT SINGH	PANACEA BIOTEC LIMITED., B-1, EXT./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110 044.
2	JAIN RAJESH	DIRECTOR, PANACEA BIOTEC LIMITED., B-1, EXT./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110 044.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA