Title of Invention	"A HOMOGE NOUS ALCOHOL FREE TRANSPARENT COMPOSITION COMPRISING CYCLOSPORIN & PROCESS OF PREPARATION THEREOF"
Abstract	The present invention discloses a homogenous alcohol-free, transparent composition comprising a Cyclosporin in a hydrophilic carrier medium and process of preparing such composition. The said hydrophilic carrier medium comprises propylene glycol and polyoxyethylene hydrogenated castor oils additionally with a transesterification product of a natural vegetable oil triglyceride and polyalkylene polyol and/or triacetin.

Title of Invention

"A HOMOGE NOUS ALCOHOL FREE TRANSPARENT COMPOSITION COMPRISING CYCLOSPORIN & PROCESS OF PREPARATION THEREOF"

Abstract

The present invention discloses a homogenous alcohol-free, transparent composition comprising a Cyclosporin in a hydrophilic carrier medium and process of preparing such composition. The said hydrophilic carrier medium comprises propylene glycol and polyoxyethylene hydrogenated castor oils additionally with a transesterification product of a natural vegetable oil triglyceride and polyalkylene polyol and/or triacetin.

Full Text	INTRODUCTION The present invention also relates to a novel homogenous alcohol free, free flowing, clear and transparent pharmaceutical composition comprising a Cyclosporin as active ingredient. The novel composition is characterised in having increased bioavailability 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. (A) (Formula Removed) wherein - MeBmt- represents the N-Methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L) threonyl residue of formula B. (B) (Formula Removed) (S) CH3 in which -x-y- is --CH =CH- (trans). So far the primary area of clinical investigation for 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 Cyclosporin has achieved a remarkable success in its usage. At the same time, applicability of Cyclosporin 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 arthrit is deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are widespread in the literature. Specific auto-immune diseases for which 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 erythematosus, 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 have been 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. A detailed write-up on the variety of naturally occurring and semi-synthetic Cyclosporins, their classification, nomenclature etc. has already been published [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 (1982); and von Wart-burg et al., Progress in Allergy, 38, 28-45 (1986)]. U.S. Pat. Nos. 4,108,985, 4,210,581 and 4,220,641; European Patent Publication Nos. 0 034 567 and 0 056 782; 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). 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. Although Cyclosporin is used most widely amongst all the immunosuppressants available so far, it suffers from a serious drawback of poor bio-availability. The oral dosage forms existing lately in the market (i.e. those employing ethanol, olive oil as carrier medium in conjunction with Labrafil as surfactant (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 bioavaiiability 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 bioavaiiability for individuals with time is frequently observed. 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 bioavaiiability daily dosages need 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 bioavaiiability several attempts have been made to improve formulations of Cyclosporin. US patent no. 4,388,307 has proposed a method of preparation of drinks solution containing Cyclosporin in a base of Labrafil, Miglyol, Ethanol, Corn/olive oil. However, such preparation suffered from the draw back 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 is 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 (Reference from Chinese Patent No. 94191895.5) explains the active compound of Cyclosporin, fatty acid sugar ester and diluent carrier having good bioavailability. 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 bioavailability when compared to the earlier formulations. This Patent claims a bioavailability of the Composition as 62% higher than that of the composition of US Patent 4,388,307 of Sandoz. This art describes adsorption of Cyclosporin A with appropriate solvents on to a adsorbent along with a nonionic hydrophilic 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 Cyclosporin 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 Cyclosporin 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. Several formulations of Cyclosporin were prepared and examined in vitro and in dogs Abdallah-HY; Mayersohn-M. Pharmaceutical Research; 1991;8(Apr); 518-522. 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 was 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. 5051402 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 of Cyclosporin alongwith mixture of mono or diglyceride fatty acids. They may be rendered more soluble or dispersible in aqueous media by first dissolving them in at least one mono-or diglyceride of a C6-Ci0 fatty acids, and the resulting solution can then easily be emulsified in water or an aqueous fluid. It is presumed that the more soluble preparations may have increased bioavailability. 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 are recorded in prior art are the use of tocopherol derivatives (EP 0724452), tocopheryl polyethylene glycol carboxylic acid ester (EP 0712631), dimethyl isosorbide (EP 0711550, EP 0650721), alkylene polyether or polyester (WO 9423733), emulsion compositions (EP 0694308), anhydromannitol, Oley ether, lactoglyceride, citroglycerides (EP 656212), phosphatidyl ethanolamine (EP 0651995), as surfactants and stabilizers etc. Three Patent Applications namely European Patent App. No. 94110184.2, 95117171.9 and PCT/EP95/04187 describe the use of Dimethyl Isosorbide. While European Patent App. No. 94110184.2 and 95117171.9 use dimethyl isosorbide as a co-surfactant, PCT/EP95/04187 describe the use of dimethyl isosorbide or a hydrophilic phase component. One of the most significant attempts to improve bioavailability of Cyclosporin from its dosage form is 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 bioavailability of Cyclosporin when compared with conventional dosage forms. A comparison of bioavailability from micro-emulsion dosage form (Composition I from US patent no. 5,342,625) with the conventional ethanol-oil based dosage form (Composition 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. Bioavailability 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 ADC 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 needs 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 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 feature of the compositions. This composition necessitates that Cyclosporin be mixed with a transesterification product of a natural vegetable oil with glycerol. Such composition is not fit for drink solution because of formation of jelly like lumps, since the transesterification product is a jelly like substance at room temperature. Such composition also preferably uses alcohol. This composition 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 recent marketed composition (NEORAL) as defined in US patent no.5, 342, 625. The formulation of emulsion as well as microemulsion present their own technological problems relating to thermodynamic instability. Such problems may be partially solved by presenting the product in a microemulsion pre-concentrate form wherein the micro emulsification occurs in vivo only. However, such systems may also present variability problems due to wide variations existing in Gl tract of patients. Any person skilled in the art attempting to make composition without 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 abovementioned inventions teaches the art of dissolving Cyclosporin (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 a microemulsion. All the earlier approaches to enhance the bioavailability to Cyclosporin were towards making the drug in an emulsified form (US Patent no.4, 388, 307) or substantially increasing the surface area by converting into microemulsion (US Patent No.5, 342, 625). MAISINE is a fatty material, which gets out not only when combined with Cyclosporin but even when comprising Labrafil along with MAISINE. In the body of the specification of US Patent No.5, 639, 724 Labrafil has been disclosed as a preferred ingredient to be added to the composition of Cyclosporin and MAISINE for drink solution. However, this patent does not address the problem of formation of flake like substances formed by the presence of MAISINE even though Labrafil has been added to the composition. 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. Our composition when diluted with water or aqueous medium retains the lipophilic Cyclosporin drug in a solubilized state. Hence making the drug bioavailable in therapeutic concentrations and with reproducibility. 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. The composition 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 solubilized 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. Such systems will definitely be more uniform and bio-available than microemulsions from where the drug has to partition out of Lipophilic phase for absorption. Moreover, the inventors have done a detailed study of the type of products developed out of the technology based on microemulsion based systems. The product existing in the commercial market are presented into two types of oral dosage forms. One type is the oral solution concentrates to be diluted prior to intake 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 gelatin capsules. These type of dosage forms are used as continuation therapies once the dosage adjustments have been done. The inventors have, by careful experimentation and expenditure of mental faculties been able to invent a composition in which hydrophobic drug like Cyclosporin can be theoretically dissolved in a hydrophilic 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 solutions. Such products when they come in contact with biological fluids result in total solubilization of Cyclosporin at molecular levels thereby increasing the surface area of Cyclosporin and such diluted solutions of Cyclosporin are highly bioavailable. Such compositions do not remain in emulsion or in microemulsion form. In another embodiment of the invention there is disclosed an improved process for making soft gelatin capsules containing Cyclosporin as active ingredient in a carrier composition comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range: Cyclosporin : about 10 % w/w Propylene glycol : 10 - 40% w/w A transesterification product of a natural vegetable : 10 - 30% w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w Which comprises adding to the said composition substantially 10-25% excess of the base thereby compensating for the loss of weight due to migration of materials with free hydroxy groups into the capsule shell thus preventing precipitation of drug due to loss of solvent and reducing substantially 10-25% of the polyols such as Sorbitol and glycerol which are used as plasticizers from the capsule shell. The term "base" or "carrier medium" should be implied to mean everything added to the composition except the drug. The amount of plasticizers in the capsule shell are reduced by the amount equivalent to the excess carrier medium added in the capsule. 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 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. Such dosage form that is soft gelatin capsules pose unique technology problems when the compositions to be encapsulated are microemulsion pre-concentrate. The present invention relates to formulation of Cyclosporin in compositions such that the drug is presented in solubilized systems of surfactant micelles appropriately stabilised in specific hydrophilic phase. SUMMARY OF THE INVENTION In accordance with the present invention there is described a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and easily measurable at a wide range of temperature of 15° to 45°C which comprises a Cyclosporin in a hydrophilic carrier medium comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyaikylene polyol, and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range : Cyclosporin : about 10 % w/w Propylene Glycol : 10-40% w/w A transesterification product of a natural vegetable : 10 - 30% w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w Preferably the transesterification product of a natural vegetable oil triglycerides and a polyalkylene polyol is Apricot Kernel Oil Polyethylene glycol 6 esters. More preferably the Apricot Kernel Oil Polyethylene glycol 6 ester is Labrafil M1944. Preferably the polyoxyethylene hydrogenated castor oil is Cremophor RH 40. Preferably the ingredients in the present compositions are present in the following range Cyclosporin : about 10% w/w Propylene Glycol : 15 - 30 % w/w A transesterification product of a natural vegetable : 15-28% w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 15 - 45% w/w More preferably the composition in accordance with the present invention comprises the ingredients in the following range : Cyclosporin : about 10% w/w Propylene Glycol : 25 % w/w A transesterification product of a natural vegetable : 25 % w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 40% w/w DETAILED DESCRIPTION OF THE INVENTION The systems of the present invention are single phase systems in contrast to emulsion/microemulsions wherein essentially lipophilic 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 solubilised in Hydrophilic phase using suitable surfactant (s)/ co-surfactant (s). The compositions in this invention are substantially free of ethanol. It is most beneficial in context of hot tropical countries where absence of d.5 alkanols such as ethanols are more due to evaporation. Such compositions of the present invention which are solubilized systems and substantially free of 61.5 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. STATEMENT OF THE INVENTION In accordance with the present invention there is described a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and easily measurable at a wide range of temperature of 15° to 45°C which comprises a Cyclosporin in a hydrophilic carrier medium comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol, polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range: Cyclosporin : 10 % w/w Propylene Glycol : 10 - 40% w/w A transesterification product of a natural vegetable : 10-30% w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w Preferably the transesterification product of a natural vegetable oil triglyceride and a Polyalkylene polyol is Apricot Kernel Oil Polyethylene glycol 6 esters. More preferably the Apricot Kernel Oil Polyethylene Glycol 6 ester is Labrafil M1944. Preferably the polyoxyethylene hydrogenated castor oil is Cremophor RH 40. Preferably the ingredients in the present compositions are present in the following range: Cyclosporin : about 10 % w/w Propylene Glycol : 15 - 30 % w/w A transesterification product of a natural vegetable : 15-28% w/w oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 15 - 45 % w/w More preferably the composition in accordance with the present invention comprises the ingredients in the following range : Cyclosporin : about 10% w/w Propylene Glycol : 25 % w/w A transesterification product of a natural : 25 % w/w vegetable oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 40 % w/w Very small amounts of Antioxidants usually in the range of 0.005% to 0.01% w/w may be present as a part of one of the ingredients of the composition. The amount of the ingredients of the composition disclosed above equals to 100%. The formulation can be prepared so as to be diluted as a drink solution or incorporated into soft gelatin capsules. 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 therapeutics 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-homogenity in the dose. The composition of our invention possesses all the desired characteristics and hence is easily measurable as far as the dose requirement is concerned. In accordance with another embodiment of the invention a composition is disclosed which is a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and easily measurable at a wide range of temperature of 15° to 45°C which comprises a Cyciosporin in a hydrophilic carrier medium comprising Triacetin, Propylene Glycol and Polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range : Cyciosporin : about 10 % w/w Propylene Glycol : 10 - 40% w/w Triacetin : 10-30% w/w Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w Very small amounts of Antioxidants usually in the range 0.005 % to 0.01 % w/w may be present as a part of one of the ingredients of the composition. The amounts of the ingredients to the composition disclosed above equals to 100%. The formulation can be prepared so as to be diluted as a drink solution or incorporated into soft gelatin capsules. A "drink solution" should be implied to mean a homogenous clear transparent, stable, flowable and easily measurable liquid at a wide range of temperature i.e. from 15° C to 45°C which can be packed in a suitable container from which requisite amount can be withdrawn with the help of a pipette or syringe. Preferable the polyoxyethylene hydrogenated castor oil is Cremophor RH 40. Preferably such composition further comprises Oleic acid. Such Oleic acid may be present in the range from 0 - 10 % w/w. 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 bioavailability of Cyclosporin and were also found to be bioequivalent with commercial products. The comparative results are collected in Table l&ll. 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) LabrafilM2125 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) Cremophor 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 100 mg (= 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 100mg b) Propylene Glycol 200 mg c) Cremophor RH40 350 mg d) LabrafilM1944 200 mg e) Maisine 150mg TOTAL 1000 mg The composition obtained was a clear, homogenous liquid at temperatures between 25° to 30°C, but at temperatures below 20°C jelly like flakes separated out. Manufacturing process for compositions 1 to 4 - The components is thoroughly admixed in a conventional manner. The mixture so obtained is a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation and not for a drink solution. EXAMPLE 5 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 200 mg c) Cremophor RH40 415mg d) LabrafilM1944 285 mg TOTAL 1000mg 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. EXAMPLE 6 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 150mg c) Cremophor RH40 500 mg d) LabrafilM1944 250 mg TOTAL 1000mg 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. EXAMPLE 7 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 250 mg c) Cremophor RH40 350 mg d) LabrafilM1944 300 mg TOTAL 1000mg 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. EXAMPLE 8 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 200 mg c) Cremophor RH40 425 mg d) LabrafilM1944 275 mg TOTAL 1000mg 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. EXAMPLE 9 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 100mg c) Cremophor RH40 415mg d) LabrafilM1944 285 mg e) Triacetin 100mg TOTAL 1000mg 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. EXAMPLE 10 COMPONENT AMOUNT a) Cyclosporin 100mg b) Propylene Glycol 250 mg c) Cremophor RH40 450 mg d) Triacetin 150mg e) Oleic Acid 50 mg TOTAL 1000mg The quantity of a) required for a single dose is dissolved in the remaining components using conventional techniques. Heating the mass up to 60°C may be used to aid dissolution of a). Above composition gives a clear, homogenous solution which remains clear and stable at temperature between 15° to 45° without any jelly like flake formation hence this composition is suitable for formulating as a drink solution or soft gelatin capsules. Manufacturing process for compositions 5 to 10 - Cyclosporin was dissolved in propylene Glycol with constant stirring. Preferably the mixture was heated upto 60°C to aid dissolution process. To such mixture were added the remaining ingredients with constant stirring. The resultant solution was filtered through a 2 n glass fibre filter. 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 lac 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) Cremophor RH40 : 24.9 kg iii) Labrafil M1944 : 18.1kg iv) Triacetin : 1.2kg Capsule shell composition i) Gelatin 50 kg ii) Sorbitol 8 kg iii) Glycerine 8 kg iv) Methyl Paraben 240 g v) Propyl Paraben 140g vi) Water 45 kg vii) Colour 400 g We claim: 1. A homogenous alcohol free, transparent composition comprising a Cyclosporin in a hydrophilic carrier medium such as herein described characterized in that the said hydrophilic carrier medium comprises propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol, and polyoxyethylene hydrogenated castor oils, wherein the said ingredients are present in the following range: Cyclosporin : 10%w/w Propylene Glycol : 10-40%w/w A transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol : 10-30%w/w such as herein described Polyoxyethylene hydrogenated castor oils : 30-50 % w/w and optionally comprising Oleic acid. 2. A composition as claimed in claim 1, wherein the ingredients are present in the following range : Cyclosporin : 10% w/w Propylene Glycol : 25 % w/w A transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol : 25 % w/w Polyoxyethylene hydrogenated castor oils : 40 % w/w 3. A composition as claimed in claim 1, the said hydrophilic carrier medium comprises propylene glycol, triacetin and polyoxyethylene hydrogenated castor oils, wherein the said ingredients are present in the following range: Cyclosporin : 10% w/w Propylene Glycol : 10-40% w/w Triacetin : 10-30% w/w Polyoxyethylene hydrogenated castor oils : 30-50 % w/w 4. A composition as claimed in claim 1, wherein oleic acid is present in the range from 0-10%w/w. 5. A composition claimed in claims 1 to 4, which is in the form of a soft gelatin capsule or a drink solution. 6. A process for making a composition as claimed in claim 1, comprising Cyclosporin in a hydrophilic carrier medium, with constant stirring and heating in the range of 30-60° C the said hydrophilic carrier medium comprises propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol, and polyoxyethylene hydrogenated castor oils, wherein the ingredients are present in the following range: Cyclosporin : 10%w/w Propylene Glycol : 10-40%w/w A transesterification product of a natural : 10-30 % w/w vegetable oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 30-50 % w/w which comprises adding to the said composition 10 - 25% excess of the carrier medium. 7. A process for making a composition as claimed in claim 6, wherein the composition is in the form of a soft gelatin capsule comprising, Cyclosporin in a hydrophilic carrier medium, characterised in that the said carrier medium comprises propylene glycol, triacetin and polyoxyethylene hydrogenated castor oils, wherein the ingredients are present in the following range: Cyclosporin : 10% w/w Propylene Glycol : 10-40% w/w A transesterification product of a natural : 10-30 % w/w vegetable oil triglyceride and a polyalkylene polyol Polyoxyethylene hydrogenated castor oils : 30-50 % w/w which comprises adding to the said composition 10 - 25% excess of the carrier medium and reducing 10 - 25% of polyols which are used as plasticizers in the capsule shell. 8. A homogenous alcohol free, transparent composition comprising Cyclosporin substantially as herein described with reference to the foregoing description, the accompanying examples. 9. A process for making a composition, wherein the composition is in the form of a soft gelatin capsule containing Cyclosporin as active ingredient substantially as herein described with reference to the foregoing description, the accompanying examples and drawings.

Full Text

INTRODUCTION
The present invention also relates to a novel homogenous alcohol free, free flowing, clear and transparent pharmaceutical composition comprising a Cyclosporin as active ingredient. The novel composition is characterised in having increased bioavailability 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.
(A)
(Formula Removed)
wherein - MeBmt- represents the N-Methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L) threonyl residue of formula B.
(B) (Formula Removed)

(S) CH3
in which -x-y- is --CH =CH- (trans).
So far the primary area of clinical investigation for 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 Cyclosporin has achieved a remarkable success in its usage.
At the same time, applicability of Cyclosporin 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 arthrit is deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are widespread in the literature. Specific auto-immune diseases for which 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 erythematosus, 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 have been 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.
A detailed write-up on the variety of naturally occurring and semi-synthetic
Cyclosporins, their classification, nomenclature etc. has already been published [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 (1982); and von Wart-burg et al., Progress in Allergy, 38, 28-45 (1986)]. U.S. Pat. Nos. 4,108,985, 4,210,581 and 4,220,641; European Patent Publication Nos. 0 034 567 and 0 056 782; 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). 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.
Although Cyclosporin is used most widely amongst all the immunosuppressants available so far, it suffers from a serious drawback of poor bio-availability.
The oral dosage forms existing lately in the market (i.e. those employing ethanol, olive oil as carrier medium in conjunction with Labrafil as surfactant (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 bioavaiiability 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 bioavaiiability for individuals with time is frequently observed.
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 bioavaiiability daily dosages need 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 bioavaiiability several attempts have been made to improve formulations of Cyclosporin.
US patent no. 4,388,307 has proposed a method of preparation of drinks solution containing Cyclosporin in a base of Labrafil, Miglyol, Ethanol, Corn/olive oil. However, such preparation suffered from the draw back 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 is 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 (Reference from Chinese Patent No. 94191895.5) explains the active compound of Cyclosporin, fatty acid sugar ester and diluent carrier having good bioavailability. 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 bioavailability when compared to the earlier formulations. This Patent claims a bioavailability of the Composition as 62% higher than that of the composition of US Patent 4,388,307 of Sandoz. This art describes adsorption of Cyclosporin A with appropriate solvents on to a adsorbent along with a nonionic hydrophilic 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 Cyclosporin 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 Cyclosporin 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.
Several formulations of Cyclosporin were prepared and examined in vitro and in dogs Abdallah-HY; Mayersohn-M. Pharmaceutical Research; 1991;8(Apr); 518-522. 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 was 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. 5051402 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 of Cyclosporin alongwith mixture of mono or diglyceride fatty acids. They may be rendered more soluble or dispersible in aqueous media by first dissolving them in at least one mono-or diglyceride of a C6-Ci0 fatty acids, and the resulting solution can then easily be emulsified in water or an aqueous fluid. It is presumed that the more soluble preparations may have increased bioavailability.
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 are recorded in prior art are the use of tocopherol derivatives (EP 0724452), tocopheryl polyethylene glycol carboxylic acid ester (EP 0712631), dimethyl isosorbide (EP 0711550, EP 0650721), alkylene polyether or polyester (WO 9423733), emulsion compositions (EP 0694308), anhydromannitol, Oley ether, lactoglyceride, citroglycerides (EP 656212), phosphatidyl ethanolamine (EP 0651995), as surfactants and stabilizers etc.
Three Patent Applications namely European Patent App. No. 94110184.2, 95117171.9 and PCT/EP95/04187 describe the use of Dimethyl Isosorbide. While European Patent App. No. 94110184.2 and 95117171.9 use dimethyl isosorbide as a co-surfactant, PCT/EP95/04187 describe the use of dimethyl isosorbide or a hydrophilic phase component.
One of the most significant attempts to improve bioavailability of Cyclosporin from its dosage form is 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 bioavailability of Cyclosporin when compared with conventional dosage forms. A comparison of bioavailability from micro-emulsion dosage form (Composition I from US patent no. 5,342,625) with the conventional ethanol-oil based dosage form (Composition 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. Bioavailability 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 ADC 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 needs 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 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 feature of the compositions. This composition necessitates that Cyclosporin be mixed with a transesterification product of a natural vegetable oil with glycerol. Such composition is not fit for drink solution because of formation of jelly like lumps, since the transesterification product is a jelly like substance at room temperature. Such composition also preferably uses alcohol. This composition 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 recent marketed composition (NEORAL) as defined in US patent no.5, 342, 625.
The formulation of emulsion as well as microemulsion present their own technological problems relating to thermodynamic instability. Such problems may be partially solved by presenting the product in a microemulsion pre-concentrate form wherein the micro emulsification occurs in vivo only. However, such systems may also present variability problems due to wide variations existing in Gl tract of patients.
Any person skilled in the art attempting to make composition without 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 abovementioned inventions teaches the art of dissolving Cyclosporin (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 a
microemulsion.
All the earlier approaches to enhance the bioavailability to Cyclosporin were towards making the drug in an emulsified form (US Patent no.4, 388, 307) or substantially increasing the surface area by converting into microemulsion (US Patent No.5, 342, 625).
MAISINE is a fatty material, which gets out not only when combined with Cyclosporin but even when comprising Labrafil along with MAISINE.
In the body of the specification of US Patent No.5, 639, 724 Labrafil has been disclosed as a preferred ingredient to be added to the composition of Cyclosporin and MAISINE for drink solution. However, this patent does not address the problem of formation of flake like substances formed by the presence of MAISINE even though Labrafil has been added to the composition.
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. Our composition when diluted with water or aqueous medium retains the lipophilic Cyclosporin drug in a solubilized state. Hence making the drug bioavailable in therapeutic concentrations and with reproducibility.
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. The composition 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 solubilized 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.
Such systems will definitely be more uniform and bio-available than microemulsions
from where the drug has to partition out of Lipophilic phase for absorption.
Moreover, the inventors have done a detailed study of the type of products developed out of the technology based on microemulsion based systems.
The product existing in the commercial market are presented into two types of oral dosage forms.
One type is the oral solution concentrates to be diluted prior to intake 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 gelatin capsules. These type of dosage forms are used as continuation therapies once the dosage adjustments have been done.
The inventors have, by careful experimentation and expenditure of mental faculties been able to invent a composition in which hydrophobic drug like Cyclosporin can be theoretically dissolved in a hydrophilic 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 solutions. Such products when they come in contact with biological fluids result in total solubilization of Cyclosporin at molecular levels thereby increasing the surface area of Cyclosporin and such diluted solutions of Cyclosporin are highly bioavailable. Such compositions do not remain in emulsion or in microemulsion form.
In another embodiment of the invention there is disclosed an improved process for making soft gelatin capsules containing Cyclosporin as active ingredient in a carrier composition comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol and polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range:
Cyclosporin : about 10 % w/w
Propylene glycol : 10 - 40% w/w
A transesterification product of a natural vegetable : 10 - 30% w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w
Which comprises adding to the said composition substantially 10-25% excess of the
base thereby compensating for the loss of weight due to migration of materials with free
hydroxy groups into the capsule shell thus preventing precipitation of drug due to loss of
solvent and reducing substantially 10-25% of the polyols such as Sorbitol and glycerol
which are used as plasticizers from the capsule shell.
The term "base" or "carrier medium" should be implied to mean everything added to the composition except the drug.
The amount of plasticizers in the capsule shell are reduced by the amount equivalent to the excess carrier medium added in the capsule.
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 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.
Such dosage form that is soft gelatin capsules pose unique technology problems when the compositions to be encapsulated are microemulsion pre-concentrate.
The present invention relates to formulation of Cyclosporin in compositions such that the drug is presented in solubilized systems of surfactant micelles appropriately stabilised in specific hydrophilic phase.
SUMMARY OF THE INVENTION
In accordance with the present invention there is described a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and
easily measurable at a wide range of temperature of 15° to 45°C which comprises a
Cyclosporin in a hydrophilic carrier medium comprising propylene glycol, a
transesterification product of a natural vegetable oil triglyceride and a polyaikylene
polyol, and polyoxyethylene hydrogenated castor oils wherein the ingredients are
present in the following range :
Cyclosporin : about 10 % w/w
Propylene Glycol : 10-40% w/w
A transesterification product of a natural vegetable : 10 - 30% w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w
Preferably the transesterification product of a natural vegetable oil triglycerides and a polyalkylene polyol is Apricot Kernel Oil Polyethylene glycol 6 esters. More preferably the Apricot Kernel Oil Polyethylene glycol 6 ester is Labrafil M1944.
Preferably the polyoxyethylene hydrogenated castor oil is Cremophor RH 40. Preferably the ingredients in the present compositions are present in the following range
Cyclosporin : about 10% w/w
Propylene Glycol : 15 - 30 % w/w
A transesterification product of a natural vegetable : 15-28% w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 15 - 45% w/w
More preferably the composition in accordance with the present invention comprises the
ingredients in the following range :
Cyclosporin : about 10% w/w
Propylene Glycol : 25 % w/w
A transesterification product of a natural vegetable : 25 % w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 40% w/w
DETAILED DESCRIPTION OF THE INVENTION
The systems of the present invention are single phase systems in contrast to emulsion/microemulsions wherein essentially lipophilic 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 solubilised in Hydrophilic phase using suitable surfactant (s)/ co-surfactant (s).
The compositions in this invention are substantially free of ethanol.
It is most beneficial in context of hot tropical countries where absence of d.5 alkanols such as ethanols are more due to evaporation.
Such compositions of the present invention which are solubilized systems and substantially free of 61.5 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.
STATEMENT OF THE INVENTION
In accordance with the present invention there is described a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and easily measurable at a wide range of temperature of 15° to 45°C which comprises a Cyclosporin in a hydrophilic carrier medium comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol, polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range:
Cyclosporin : 10 % w/w
Propylene Glycol : 10 - 40% w/w
A transesterification product of a natural vegetable : 10-30% w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w
Preferably the transesterification product of a natural vegetable oil triglyceride and a
Polyalkylene polyol is Apricot Kernel Oil Polyethylene glycol 6 esters. More preferably
the Apricot Kernel Oil Polyethylene Glycol 6 ester is Labrafil M1944. Preferably the polyoxyethylene hydrogenated castor oil is Cremophor RH 40.
Preferably the ingredients in the present compositions are present in the following
range:
Cyclosporin : about 10 % w/w
Propylene Glycol : 15 - 30 % w/w
A transesterification product of a natural vegetable : 15-28% w/w
oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 15 - 45 % w/w
More preferably the composition in accordance with the present invention comprises the
ingredients in the following range :
Cyclosporin : about 10% w/w
Propylene Glycol : 25 % w/w
A transesterification product of a natural : 25 % w/w
vegetable oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 40 % w/w
Very small amounts of Antioxidants usually in the range of 0.005% to 0.01% w/w may be present as a part of one of the ingredients of the composition.
The amount of the ingredients of the composition disclosed above equals to 100%.
The formulation can be prepared so as to be diluted as a drink solution or incorporated into soft gelatin capsules.
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 therapeutics 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-homogenity in the dose. The composition of our invention possesses all the desired characteristics and hence is easily measurable as far as the dose requirement is concerned.
In accordance with another embodiment of the invention a composition is disclosed which is a homogenous substantially alcohol free, transparent composition of Cyclosporin which is clear, stable, flowable and easily measurable at a wide range of temperature of 15° to 45°C which comprises a Cyciosporin in a hydrophilic carrier medium comprising Triacetin, Propylene Glycol and Polyoxyethylene hydrogenated castor oils wherein the ingredients are present in the following range :
Cyciosporin : about 10 % w/w
Propylene Glycol : 10 - 40% w/w
Triacetin : 10-30% w/w
Polyoxyethylene hydrogenated castor oils : 30 - 50% w/w
Very small amounts of Antioxidants usually in the range 0.005 % to 0.01 % w/w may be present as a part of one of the ingredients of the composition.
The amounts of the ingredients to the composition disclosed above equals to 100%.
The formulation can be prepared so as to be diluted as a drink solution or incorporated into soft gelatin capsules. A "drink solution" should be implied to mean a homogenous clear transparent, stable, flowable and easily measurable liquid at a wide range of temperature i.e. from 15° C to 45°C which can be packed in a suitable container from which requisite amount can be withdrawn with the help of a pipette or syringe.
Preferable the polyoxyethylene hydrogenated castor oil is Cremophor RH 40.
Preferably such composition further comprises Oleic acid. Such Oleic acid may be present in the range from 0 - 10 % w/w.
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 bioavailability of Cyclosporin and were also found to be bioequivalent with commercial products. The comparative results are collected in Table l&ll.
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) LabrafilM2125 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) Cremophor 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 100 mg (= 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 100mg
b) Propylene Glycol 200 mg
c) Cremophor RH40 350 mg
d) LabrafilM1944 200 mg
e) Maisine 150mg
TOTAL 1000 mg
The composition obtained was a clear, homogenous liquid at temperatures between 25° to 30°C, but at temperatures below 20°C jelly like flakes separated out.
Manufacturing process for compositions 1 to 4 - The components is thoroughly admixed in a conventional manner. The mixture so obtained is a semi-solid mass at room temperature suitable only for soft gelatin capsule formulation and not for a drink solution.
EXAMPLE 5
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 200 mg
c) Cremophor RH40 415mg
d) LabrafilM1944 285 mg
TOTAL 1000mg
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.
EXAMPLE 6
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 150mg
c) Cremophor RH40 500 mg
d) LabrafilM1944 250 mg
TOTAL 1000mg
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.
EXAMPLE 7
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 250 mg
c) Cremophor RH40 350 mg
d) LabrafilM1944 300 mg
TOTAL 1000mg
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.
EXAMPLE 8
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 200 mg
c) Cremophor RH40 425 mg
d) LabrafilM1944 275 mg
TOTAL 1000mg
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.
EXAMPLE 9
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 100mg
c) Cremophor RH40 415mg
d) LabrafilM1944 285 mg
e) Triacetin 100mg
TOTAL 1000mg
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.
EXAMPLE 10
COMPONENT AMOUNT
a) Cyclosporin 100mg
b) Propylene Glycol 250 mg
c) Cremophor RH40 450 mg
d) Triacetin 150mg
e) Oleic Acid 50 mg
TOTAL 1000mg
The quantity of a) required for a single dose is dissolved in the remaining components using conventional techniques. Heating the mass up to 60°C may be used to aid dissolution of a).
Above composition gives a clear, homogenous solution which remains clear and stable at temperature between 15° to 45° without any jelly like flake formation hence this composition is suitable for formulating as a drink solution or soft gelatin capsules.
Manufacturing process for compositions 5 to 10 - Cyclosporin was dissolved in propylene Glycol with constant stirring. Preferably the mixture was heated upto 60°C to aid dissolution process. To such mixture were added the remaining ingredients with constant stirring. The resultant solution was filtered through a 2 n glass fibre filter.
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 lac 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) Cremophor RH40 : 24.9 kg
iii) Labrafil M1944 : 18.1kg
iv) Triacetin : 1.2kg
Capsule shell composition
i) Gelatin 50 kg
ii) Sorbitol 8 kg
iii) Glycerine 8 kg
iv) Methyl Paraben 240 g
v) Propyl Paraben 140g
vi) Water 45 kg
vii) Colour 400 g

We claim:
1. A homogenous alcohol free, transparent composition comprising a Cyclosporin in
a hydrophilic carrier medium such as herein described characterized in that the
said hydrophilic carrier medium comprises propylene glycol, a transesterification
product of a natural vegetable oil triglyceride and a polyalkylene polyol, and
polyoxyethylene hydrogenated castor oils, wherein the said ingredients are
present in the following range:
Cyclosporin : 10%w/w
Propylene Glycol : 10-40%w/w
A transesterification product of a natural
vegetable oil triglyceride and a polyalkylene polyol : 10-30%w/w
such as herein described
Polyoxyethylene hydrogenated castor oils : 30-50 % w/w and
optionally comprising Oleic acid.
2. A composition as claimed in claim 1, wherein the ingredients are present in the
following range :
Cyclosporin : 10% w/w
Propylene Glycol : 25 % w/w
A transesterification product of a natural
vegetable oil triglyceride and a polyalkylene polyol : 25 % w/w
Polyoxyethylene hydrogenated castor oils : 40 % w/w
3. A composition as claimed in claim 1, the said hydrophilic carrier medium
comprises propylene glycol, triacetin and polyoxyethylene hydrogenated castor
oils, wherein the said ingredients are present in the following range:
Cyclosporin : 10% w/w
Propylene Glycol : 10-40% w/w
Triacetin : 10-30% w/w
Polyoxyethylene hydrogenated castor oils : 30-50 % w/w
4. A composition as claimed in claim 1, wherein oleic acid is present in the range
from 0-10%w/w.
5. A composition claimed in claims 1 to 4, which is in the form of a soft gelatin
capsule or a drink solution.
6. A process for making a composition as claimed in claim 1, comprising
Cyclosporin in a hydrophilic carrier medium, with constant stirring and heating in
the range of 30-60° C the said hydrophilic carrier medium comprises propylene
glycol, a transesterification product of a natural vegetable oil triglyceride and a
polyalkylene polyol, and polyoxyethylene hydrogenated castor oils, wherein the
ingredients are present in the following range:
Cyclosporin : 10%w/w
Propylene Glycol : 10-40%w/w
A transesterification product of a natural : 10-30 % w/w
vegetable oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 30-50 % w/w
which comprises adding to the said composition 10 - 25% excess of the carrier
medium.
7. A process for making a composition as claimed in claim 6, wherein the
composition is in the form of a soft gelatin capsule comprising, Cyclosporin in a
hydrophilic carrier medium, characterised in that the said carrier medium
comprises propylene glycol, triacetin and polyoxyethylene hydrogenated castor
oils, wherein the ingredients are present in the following range:
Cyclosporin : 10% w/w
Propylene Glycol : 10-40% w/w
A transesterification product of a natural : 10-30 % w/w
vegetable oil triglyceride and a polyalkylene polyol
Polyoxyethylene hydrogenated castor oils : 30-50 % w/w
which comprises adding to the said composition 10 - 25% excess of the carrier
medium and reducing 10 - 25% of polyols which are used as plasticizers in the
capsule shell.
8. A homogenous alcohol free, transparent composition comprising Cyclosporin
substantially as herein described with reference to the foregoing description, the
accompanying examples.
9. A process for making a composition, wherein the composition is in the form of a
soft gelatin capsule containing Cyclosporin as active ingredient substantially as
herein described with reference to the foregoing description, the accompanying
examples and drawings.

Documents:

2533-del-1997-abstract.pdf

2533-del-1997-claims.pdf

2533-del-1997-correspondence-others.pdf

2533-del-1997-correspondence-po.pdf

2533-del-1997-description (complete).pdf

2533-del-1997-form-1.pdf

2533-del-1997-form-13.pdf

2533-del-1997-form-19.pdf

2533-DEL-1997-Form-2.pdf

2533-del-1997-form-4.pdf

2533-del-1997-form-5.pdf

2533-del-1997-form-6.pdf

2533-del-1997-gpa.pdf

2533-del-1997-petition-138.pdf

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Patent Number

215244

Indian Patent Application Number

2533/DEL/1997

PG Journal Number

10/2008

Publication Date

07-Mar-2008

Grant Date

22-Feb-2008

Date of Filing

08-Sep-1997

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 LTD.B-1 EXT./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044.
2	JAIN RAJESH	DIRECTOR, PANACEA BIOTEC LTD.,B-1 EXT./A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044.

PCT International Classification Number

A61K 38/13

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA