Indian Patents. 261190:"MICROEMULSION ORGANOGEL SYSTEM FOR SITE-SPECIFIC DELIVERY OF CYCLOSPORIN"

Title of Invention	"MICROEMULSION ORGANOGEL SYSTEM FOR SITE-SPECIFIC DELIVERY OF CYCLOSPORIN"
Abstract	A microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules, a polar/aqueous phase, and appropriate organic solvents wherein cyclosporin is in liposolubilzed state in the organogels.

Full Text	Field of invention The present invention relates to a microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules a polar/aqueous phase and appropriate organic solvents wherein cyclosporin is in hposolubilzed state in the micellar network of organogel More specifically, the present invention relates to topical drug delivery system, containing cyclosporin A, in the form of supramolecularly structured "lecithin organogels', wherein cyclosporin is entrapped in the three-dimensional network of swollen cylindrical reverse micelles These micellar systems are prepared by m-situ self-emulsification process which comprises of cyclosporin as an active ingredient, amphipathic phospholipids and other appropriate ingredients such as surfactants, polar agents etc Background of the Invention The cyclosporins were discovered in the year 1970 by researchers in an attempt to identify new antimicrobial agents These comprise a recognized class of pharmaceutically active, cyclic undecapeptides They are a group of natural oligopeptides ranging from cyclosporin A to cyclosporin Z The parent compound of this class is well-established pharmaceutical agent "Cyclosporin A" or Cyclosporin (also spelled as, cyclosponne or ciclosponn) Cyclosporin A (CysA), a potent immunosuppressive agent, was first isolated from two strains of imperfect fungi Cylmdrocopan lucidum Booth and Tolypocladium inflation Gams CysA is a specific, macromolecular lipophilic, cyclic, water-insoluble, non-polar undecapeptide consisting of 11 amino acids that inhibit the transcription of T-cell activation genes and/or signal transduction pathways involved in the T-cell activation The compound is a selective immunosuppresant and a potent anti-inflammatory agent, and has demonstrated great clinical success in inhibiting T-cell mediated immune processes such as allograft rejection, graft-versus-host disease, and autoimmune disease when administered systemically CysA acts in the cell nucleus by binding to intracellular receptor termed cyclophilm This Cyclosporin A-cyclophilin complex inhibits the calcmeunn (calcium and calmodulin dependent phosphatase), a key enzyme involved in calcium dependent signaling process Inhibition of calcmeunn prevents the transcription of lnterleukin-2 (IL -2) and other lymphokme genes Thus blockade of IL-2 and other lymphokine (T-cell growth factors) production by T-helper cells results in the impairment of IL-2 driven proliferation of activated T-cells in response to specific A class of cytosolic binding proteins (immunophihns) for cyclosporins has been identified, which are peptidyl-prolyl-cis- trans-isomerases and have been implicated in signaling pathways for T cell activation In addition to the use of CysA in organ transplantation, the systemic administration of CysA is also effective in the treatment of a large number of autoimmune diseases Some specific examples of the autoimmune diseases and disorders to which CysA can be employed include psoriasis vulgaris, pustular psoriasis, contact dermatitis, atopic dermatitis alopecia areata, arthritis, autoimmune hematologic disorder, chronic bronchial asthma systemic lupus erythematosus, polymyositis systemic scleroderma Wegner's syndrome, myasthenia gravis, autoimmune intestinal diseases (spontaneous ulcerative colitis, Crohn's disease) sarcoidosis, multiple sclerosis, juvenile diabetes, uveitis, psoriatic arthritis, glomerular nephritis Organogels, also known as microemulsion organogel systems, are thermodynamtcally stable, clear viscoelastic biocompatible and isotropic gels composed of phospholipids (lecithin) appropriate organic solvent, and a polar solvent Organogels, the jelly-like phases consist of a 3-dimensional network of entangled reverse cylindrical (polymer-like) micelles, which immobilizes the continuous or macroscopic external organic phase, thus turning a liquid into a gel The formation of a 3-dimensional network in the organogel is the result of transition at the micellar level in a low viscous Newtonian liquid consisting of lecithin reverse micelles in nonpolar organic liquid This spherical reverse micellar state of lipid aggregates turns on to form elongated tubular micelles with the addition of water and subsequently entangles to form a temporal 3-dimensional network in the solution bulk The latter serves to immobilize the external organic phase thus producing a gel form or the jelly-like state of the initial non-viscous solution However, the transparency and optical isotropy of the organogel remains as before The incorporation of synthetic polymeric surfactant (e g , pluronics) in LOs, have been reported for their usefulness as cosurfactants and stablizers In addition, it has been shown that the inclusion of pluronics makes the organogellmg feasible with lecithin of relatively lesser purity too The term "pluronic" refers to a series of nonionic, closely related block copolymers of ethylene oxide and propylene oxide Also known as poloxamers, poloxamer polyols, or lutrols, these copolymers are primarily used in pharmaceutical formulations as cosurfactants, emulsifiers solubilizers, suspending agents, and stabilizers These pluronic containing LOs have been termed as pluronic lecithin organogels poloxamer organogels pluronic organogels, PLO gel, or simply PLOs LOs have generated considerable interest over the years as a potential topical drug delivery vehicle The coexistence of organic and aqueous phase by means of a structurally well-defined micellar network of phospholipids, a large mterfacial area, and the possibility to entrap solutes within the gel matrix, along with long-term stability, makes them useful for a variety of applications The topical applications of various drugs containing LO systems have been demonstrated to significantly enhance the skin permeation and absorption of both lipophilic and hydrophilic substances The organized microstructural matrix, amphiphilicity, supersolubihzmg capacity and interaction of the biolipids with skin tissues are some of the major promoting factors for an enhanced transport of drug molecules into or across the skin Therapeutic compounds of different chemical and physicochemical background such as muscle relaxants, steroids, hormones, analgesics antiemetics, cardiovascular agents antithyroid drugs, and some macromolecules have been incorporated in the LOs and yielded quite promising encouraging results with respect to dermal- as well as transdermal drug delivery Drawbacks Of The Prior Art A Problems related to the systemic delivery of cyclosporin i) Pharmacodynamic implications According to the conventional method for treatment of autoimmune dermatological disorder such as psoriasis or atopic dermatitis, CysA is administered per oral either in an amount of 3-6mgAg/day for 2 months, or in an amount of 14mg/kg/day for 2 weeks, as a short-term therapy Alternatively, as a long-term therapy cyclosporin is administered in an amount of 1-4mg/kg/day for 12 to 25 months However, it is known that CysA when administered systemically (per oral or intravenous administration) over a long period of time results is harmful The reversible side effects are renal tubular cell damage or nephrotoxicity Acute cyclosporin nephrotoxicity is accompanied morphologically by tubular lesions characterised by inclusion bodies, isometric vacuolation and microcalcification That leads to a decrease in the glomerular filtration rate, which can be identified by the rapid increase in serum creatinine in patients treated with cyclosporin Other frequent side effects of CysA treatments include hepatotoxicity, hypertension, granulomatous hepatitis, hypochromic or microcytic anaemia, marrow hyperplasia lymphopenia, hyperkalemia, hyperuncaemia, anaemia hypertrichosis, gingival hyperplasia, gastrointestinal side effects, tremors and paraesthesia n) Pharmaceutical complications The cyclosporins are highly lipophilic substances and poorly soluble in water, e g solubility of cyclosporin A is Moreover, by virtue of these two inherent physico-chemical characteristics, the pharmaceutical compositions of cyclosporin A with customary solid or liquid pharmaceutical carriers often have disadvantages In view of their better solubility in fatty oils and alcohol, Sandimmune® (Novartis, Basel, Switzerland) was developed employing these type of ingredients as solubility enhancers for oral use in the form of an emulsion concentrate, which after administration require patient's own bile for the absorption of drug The said emulsion concentrate consists of 100 mg cyclosporin dissolved in 1 ml of a mixture of oil, ethanol and an emulsifier, namely macrogel glycerol trioleate linolate However Sandimmune s reliance on patient's bile leads to great mtrapatient and mterpatient absorption variability and bioavailability varies between 1% to 89% with an average of 30% In addition to the oral solution formulation, Sandimmun® is also available in capsule (soft gelatin capsules) form The capsules contain 25mg/100mg cyclosporin A dissolved in a mixture of oil, ethanol and emulsifier Of late, this Sandimmun® coarse emulsion formulation has been replaced with Sandimmun Neoral® microemulsion Neoral® is a microemulsion preconcentrate, which after oral administration, forms a relatively homogenous microemulsion in aqueous fluids simulating a mixed micellar phase However, even using Neoral®, there are bioavailability problems and no change in the side effect profile of the drug, while Neoral® administration in patients requires individual therapeutic drug monitoring Upon systemic (oral/parenteral) administration, merely 3 5ng/mg concentration of CysA is able to reach the actual site of action (i e , the skin) even when CysA is administered in a dose as high as 14mg/kg/day This again demands the dosage form with some innovative strategy which can help localize more number of drug molecules at the site of action through a more directed and convenient approach such as topical delivery As an example of the aforementioned ramifications, within the specialty of dermatology, it would be extremely desirable and advantageous that cyclosporin is administered topically rather than systemically, to treat autoimmune, putative autoimmune or immunoinflammatory and related diseases of the skin, including, for example, psoriasis, eczema, dermatitis etc and also to effect site-specific immunosuppression (SSIS), i e , for the induction of localized site-specific immunsuppression which would inhibit the mechanisms leading to graft rejection Thus oral administration of cyclosponne has not been a very successful proposition owing to poor, erratic bioavailability and of course the undesired bio-distribution leading to adverse effects B Problems related to the topical delivery of cyclosponne To overcome the difficulties related to the systemic administration of cyclosporins, topical formulations of cyclosporins is extremely advantageous and desirable However, it is extremely difficult to formulate cyclosporin into topical preparations so as to achieve the desired therapeutic effect, unlike water soluble or low-molecular weight pharmaceutically effective therapeutic substances And furthermore, various attempts to provide therapeutically effective topical formulations of cyclosporins have hitherto failed or proved unsatisfactory for usage in particular conditions One of the reasons for this difficulty is that, like any other peptide, the skin penetration/permeation of CysA is hindered by the barrier property of stratum corneum Another reason for this difficulty is because the cyclosporin is insoluble in water and also there is the restriction upon the kind of organic solvents in which the cyclosporin can be dissolved As such specific organic solvents, a lower alkanol such as ethanol onsopropanol may be generally employed However, such a lower alkanol is highly irritative to the skin when it is employed for topical preparations in a relatively high concentration, hence affect the safety and biocompatibility of the topical formulation On the other hand, when the lower alcohol is employed in a relatively low concentration in topical preparations, the ability of the cyclosporin to get dispersed uniformly may be impaired, which significantly affects the therapeutic effect of any topical formulation Due to such characteristic physico-chemical properties of cyclosporin, it has been reported that most of the prior cyclosporin topical preparations cannot permeate the stratum corneum for lack of skin permeability and therefore, cannot sufficiently provide the desired clinical effect Various proposals have been made in the prior art for application of cyclosporins in topical form, and a number of topical formulations have been described However, attempts at topical application have failed to provide any demonstrably effective therapy For example, although in the literature, the cyclosporin is said to have a topical action in theory but its efficacy was only observed after six months' treatment Moreover dimethyl sulphoxide (DMSO) had to be used as solvent at the concentration of 50%, which is unacceptable for a treatment like that of psoriasis Intralesional injections were also explored, and demonstrated the theoretical efficacy of the substance, although its use proved totally impracticable for treatment purposes Similarly, a Japanese Laid-open Patent Publication No 5-310591 (November 22, 1993) discloses the cyclosporin topical preparation formulated by using a volatile lower alcohol However, this preparation has disadvantages that the stability of the preparation during long-term storage is low, and when the preparation is applied to the skin, alcohol is rapidly volatilized to cause the precipitation of cyclosporin, which results in the suboptimal pharmacological efficacy Further, European Patent 2218334B describes cyclosporin topical preparation containing C12-24 mono- or polyfatty acid or alcohol as an absorption-enhancing agent However, the formulation does not the have skin permeability to the desired extent Japanese Patent Laid-open Publication No 2-17,127 discloses compositions, which contain, as essential components, cyclosporin and a mono- or polyunsaturated fatty acid or an unsaturated alcohol, each having from 12 to 24 carbon atoms The mono- and polyunsaturated fatty acids may include, for example, vaccenic acid, linoleic acid, linolenic acid elatdic acid erucic acid, and the like The unsaturated alcohol may include, for example, vaccenyl alcohol, linoleyl alcohol, linolenyl alcohol, elaidyl alcohol erucyl alcohol and the like Further, it describes the compositions may be effective to various skin diseases However, the publication does not specify its pharmaceutical effects and refers merely to the ability of the cyclosporin to infuse or penetrate through the skin The publication is thoroughly silent about the extent, for example to which the cyclosporin is effective against any dermatological disorder such as psoriasis Additionally, several other cases have been reported where attempts had been made to use topical cyclosporin in skin diseases, but mixed results have been obtained Similarly, a conventional "microemulsion preconcentrate" or "emulsion" type topical formulation disclosed in US patent 6024978 has been shown to exhibit anti-inflammatory activity when applied topically in guinea pigs There are reports of contact-type dermatitis, for example in Arch Dermato-1 125 568 (1989) which reports to the effect that cyclosporin is employed for a human DNCB test with no effect Further, Contact Dermatitis 19, 129-132 (1988) makes a review on three formulations a 10% cyclosporin formulation in Labrafil (polyoxyl-5-oleate, olive oil and ethanol) a 5% cyclosponn formulation in castor oil, and a 5% cyclosporin formulation m castor oil containing 20% propylene glycol, however it states the results of this review are not so satisfactory, and that a more effective solvent is required In addition, Contact Dermatitis,20, 155-156 (1988) states that none of three cyclosporin formulations (i e , cone 0 1%, 1% and 10% w/w) are effective at all against contact dermatitis Pharmacological effect of cyclosporin upon psoriasis is described, in Clinical Research, 34 1007A (1986), in which it is described that topical administration of cyclosporin is not effective for the therapy to psoriasis, although neither the concentration of cyclosporin nor the composition thereof are specified It is also described in Lancet, 1, 806 (1987) that a 2% by weight cyclosporin (on ointment base) is as effective upon psoriasis as placebo Further, J Amer Acad Dermatol, 18, 378-379 (1988) describes that a 5% cyclosporin solution in olive oil is equal to the sole use of olive oil that is employed as the base in the previous case In addition, J Amer Acad Dermatol, 22, 126-127 (1990) states that a gel comprising 10% cyclosporin, 43% olive oil 10% ethanol 30% polyoxyl-5-oleate and 7% colloidal silica did not produce any effect upon psoriasis Furthermore, it is reported in Brit J Derm 122 113-114 (1990) that a 5% (by weight) cyclosporin ointment was not effective US Patent 4996193 discloses topical conventional formulations of CysA in the concentration range of 2 5-5% w/w containing different co-solvents, emulsifiers and penetration enhancers However it has been disclosed that this topical formulation is exhibits its immunosuppressant activity only when combined with systemic administration of CysA for first eight to ten days of the therapy, i e , CysA is administered at a dose of 8mg/kg/day for 10 days prior to topical application It mentions that this initial systemic dose od CysA is necessary to induce the systemic maintenance phase of immuno-nonresponsiveness, which is then further supported by the topical formulation disclosed in the invention Another conventional ointment formulation of cyclosporin A has been disclosed in WO 0547229 and US patent 5504069 It is shown that CysA present in the concentration range of 1-10%w/w are effective against atopic dermatitis and psoriatic arthritis in humans However the formulation has been tested in only one or two patients, and also contains high amounts of surfactants and alcohols (such as ethanol), which may affect its safety on long-term applications as well as stability on, prolonged periods of storage US patent 6022852 describes a-tocopherol containing topical conventional formulation of CysA (1 0% w/w) It has been disclosed that a-tocopherol and its derivatives are excellent solubilizers for CysA and may also help in permeation of the drug through intact skin However no in-vitro, ex-vivo or m-vivo studies have been earned out to evaluate the performance of the formulation EP patent 0793966 describes a conventional topical formulation of CysA, wherein CysA has been emulsified in a carbopol gel employing vegetable oils and surfactants Moreover the formulation contains penetration enhancers such as DMSO which are known for their adverse effects on the skin such as irritation and damage to the barrier function of the skin Moreover, no skin irritation stability and clinical studies have been carried to prove the utility of the formulation for dermatological applications Similar type of formulations has also been disclosed in US patent 5807820, containing very large amounts of CysA (upto 10% w/w) EP patent 1230917 disclosed Invasomes of CysA for topical applications, which are uni, ohgo, or multilamellar vesicles of 50-70nm size composed of phospholipids and ethanol containing 5%w/w CysA along with a mixture of D-hmonene, cmeol, and citral The formulation has been found to exhibit significant immunosuppressant activity in animals models US patent 6890901 describes a liposomal composition of CysA for topical applications However the composition disclosed is a mixture of liposomes and hyaluronic acid (HA) and it has been mentioned that hyaluronic acid has a key role in the efficacy and stability of the formulation This composition has been compared with plain liposomal formulation, for stability and in-vitro performance, and it has been disclosed that the latter composition (i e without HA) is neither effective nor stable Moreover, the formulation disclosed has not been evaluated for its m-vivo or clinical performance In addition to significant therapeutic effect of CysA in some deap seated skin disorders reports on alopecia aereata have also been published e g in Lancet 2, 803-804 (1986) where it is described that a 2% cyclosporin oily solution was effective In addition, Lancet, 2, 971-972 (1986) reports that a 5% (w/w) cyclosporin formulation in oil was effective against alopecia areata Acta Derm Venereol, 69,252-253 (1989) describes a 10% cyclosporin oily preparation was not effective Furthermore, J Amer Acad Dermatol, 22, 251-253 (1989) reports that a 5% cyclosporin formulation was effective against male alopecia, although no specific compositions are described therein Therefore, as long as the literature, as described hereinabove, has been reviewed, it is considerably difficult to conclude that any of the cyclosporin topical preparations described in numerous prior references and patents exhibit a significant therapeutic effect on dermatologic diseases as specified hereinabove Even if it could be said that cyclosporin would be effective against the skin diseases, it can be said that cyclosporin need to be employed in a considerably large amount In other words, no topical cyclosporin preparations could so far achieve the object to utilize cyclosporin effectively via topical route of administration On the other hand the drug (CysA) may have shown the effective and safer response on its topical delivery but did not find the way on account of its high molecular weight, high degree of lipophilicity, and difficulty of penetrating the intact skin, especially the horny layer Hence, a topical preparation containing a therapeutically adequate amount of cyclosporin A in combination with substances that promote the permeation of cyclosporin A through the intact skin is desirable In addition, the combination should not interfere in the healing process of the skin rather it should be supportive in nature The topical delivery would help localize or target the drug molecules to specific target sites, such as skin layers in case of some deep-seated dermatological disorders i e , where the disease is limited to the skin In other words, if the focus of a disease is restricted to a layer of the dermis, topical administration through the epidermis is more advantageous than other ways of administration because local rise in the concentration of drug molecules at or near the desired target would result in enhanced interaction with focal responding immunocytes and in turn enhance the therapeutic efficacy (potentiation) to a significant extent Thereby the dose of cyclosporin to be administered can be reduced and hence the systemic side effects can be minimized to a considerable extent In other words, there is an urgent need for efficacious topical formulations of CysA particularly that react with immunophilin cytosolic binding proteins through topical route, for the management of some autoimmune dermatological disorders In addition, there is also a need for utilizing the same, in the prevention of localized tissue site-specific inflammatory immune reactions An example includes prevention of skin allograft rejection and contact hypersensitivity reactions at a local level, localized tissue auto-or alio- inflammatory/immune responses, and tissue or organ allografts In particular, a methodology that locally provides allograft acceptance and attenuates T-cell mediated events is highly desirable The present invention is directed to such formulations and methods of use Present invention obviates the drawbacks of the prior art by providing a microemulsion organogel system for effective drug delivery comprising Cyclosporin Object of the present invention The object of the present invention is to provide an efficacious topical formulation of CysA to react with immunophilin cytosolic binding proteins through topical route, for the management of some autoimmune dermatological disorders Another object of the present invention is to provide an efficacious topical formulation effective in the prevention of localized site-specific inflammatory immune reactions Yet another object of the present invention is to provide a microemulsion organogel system for effective delivery of Cyclosporin A through stratum corneum Further, object of the invention is to provide an effective method for the preparation of the process for preparing the microemulsion organogel system Summary of the invention The present invention relates to a microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules, a polar/aqueous phase, and appropriate organic solvents wherein cyclosporin is in hposolubilzed state in the organogels The slightly water-soluble biologically active compound is Cyclosporin, more preferably Cyclosporin A Cyclosporin is present in an effective amount of about 0 5-5 0% w/w The said gelator molecules are amphipathic surfactants Further the amphipathic surfactants are phospholipids The phospholipids are selected from the group consisting of natural lecithins like egg lecithin or soy lecithin more preferably unsaturated lecithin The phospholipids may be used either alone or as mixture of phospholipids The organic solvents are selected from the group consisting of monovalent alcohol fatty acid ester, divalent fatty acid ester, and linear, branched or cyclic alkanes The present invention has optimum skin permeability, so that cyclosporin can efficiently reach the target lesion, through the stratum corneum, and also may create a depot effect in the skin layers and therefore may attain the above-mentioned purpose The cyclosporin A contained in the said carrier systems of the present invention can provide significant therapeutic effects for autoimmune or allergic skin disorders, merely by applying them to the affected part of the skin Further, these topical preparations are non-irritant to the skin, so that they are highly safe In relation to topical applications, the present invention further enables the preparation of novel topical formulations comprising cyclosporins as active ingredient, and permitting improved treatment for autoimmune diseases affecting the skin, or diseases of the skin having an autoimmune aetiology The galenic products of the invention are in particular applicable to treatment of dermatological disease, e g as aforesaid, involving morbid proliferation and/or keratinisation of the epidermis, especially to treatment of psoriasis, atopic dermatitis, contact dermatitis or allergic contact dermatitis etc Topically applicable compositions in accordance with the invention may also be of use in the treatment of alopecia, e g for use in the promotion of hair growth Further the topical preparations can assist adapt a skin piece grafted to the site of skin grafting The topical preparations according to the present invention may be administered by applying them directly to the affected part of the skin thereof once or several times, e g thrice, per day The number of applications may appropriately be increased or reduced depending upon the extent of the disease to be applied Detailed description of the preferred embodiments of invention The present invention provides novel galenic products for topical, in particular for trans-epidermal administration, comprising a cyclosporin as an active ingredient, which overcomes the difficulties hitherto encountered in the topical delivery of this peptide due to its inherent physico-chemical characteristics such as large molecular weight, high lipophilhcity and poor aqueous solubility In accordance with the present invention, cyclosporin A is formulated as "organogels", which are thermodynamically stable, clear, viscoelastic, biocompatible gels, composed of phospholipids (lecithin) and appropriate organic solvent, wherein cyclosporin is in hposolubihzed state More particularly, the cyclosporin A is formulated as a microemulsion gel system, which is identifiable as possessing one or more of the following characteristics They are composed of self-assembled supramolecular arrangement of surfactant molecules, formed spontaneously or substantially spontaneously when their components are brought into contact that is without any input of external energy e g heating or the use of high shear equipment or other substantial agitation and exhibit thermodynamic stability In one aspect of the invention, the said "organogel systems" are prepared by a process which comprises incorporation of a critical amount of a specific polar agent such as water, to a solution of gelator molecules (in optimum concentration) in a specific organic solvent, e g , linear branched and cyclic alkanes, ethers and esters, fatty acids and amines In another aspect of the invention, the organogel system are prepared by spontaneous emulsification of organic phase consisting of appropriate organic solvent and a specific amount of amphipathic surfactant as gelator molecules such as phospholipid with a certain specific amount of aqueous phase with or without co-surfactant Particularly, the present invention relates to a topical pharmaceutical composition containing (i) cyclosporin, (ii) organic phase, (in) surfactant or gelator molecules, (iv) polar (aqueous) phase, and (v) a co-surfactant (i) Cyclosporin The pharmacologically active ingredient used in the composition according to the present invention is cyclosporin Cyclosporin A is most preferable since its clinical effectiveness and pharmacological properties are well established in the art Suitable formulations containing CysA can be prepared so that CysA would be present in an amount of0 5-10 0%w/w In addition to the cyclosporin as active ingredient, the "microemulsion gel or Lecithion organogel" compositions of the invention will appropriately comprise (11) Gelating agent The organogel matrix of the present invention chiefly consists of amphipathic surfactant such a phospholipids as gelator molecules A wide variety of phospholipids can be used in the present invention, however, non-immunogenic and biodegradable lipids are preferred, for example the natural lecithins such as egg lecithin or soy lecithin or synthetic lecithins such as saturated synthetic lecithins Either a single phospholipid or a mixture of phospholipids may be used It is therefore understood that any reference herein to lecithin or phosphatidylcholine is intended to include any combination of lecithin-like phospholipids as is well known in the art It is to be understood that the soy lecithin of the present invention is a preferred lecithin source and may be dissolved in appropriate organic solvent to achieve a final concentration in the composition from approximately 20%-90%, with a more preferred final concentration of from approximately 10%-60% (m) Organic phase An appropriate organic solvent provides the desired solvent action onto the gelator molecules Specific organic solvents, which may be incorporated (in certain specific amount) for the compositions of the present invention, includes monovalent alcohol-fatty acid ester in liquid state at ambient temperature, for example a monovalent fatty acid ester such as ethyl mynstate, isopropyl mynstate, iso propyl mynstate, isopropyl laurate isopropyl caprylate, isopropyl palmirate, and a divalent fatty acid ester such as, dnsopropyl adipate diisooctyl adipate branched and cyclic alkanes such as isooctane and n-hexadecane (iv) Aqueous phase The same includes purified or pharmaceutical grade water, glycerol or ethylene glycol (v) Co-surfactant The aqueous phase may also contain a co-surfactant as additional emulsifier and structure stabilizing agent, or any other adjuvant, selected from the group consisting of the following (i) Polyoxypropylene-polyoxyethyklene block co-polymer, (u) Ethoxy diglycol e g of the type known and commercially available and sold collectively under the trademark "TRANSCUTOL P" (Gattefosse, Elmsford NY) (m) Glycolysed ethoxylated C8/C10 glycendes, le polyethylene glycol caprylate/caprate e g of the type known and commercially available and sold collectively under the trademark Labrasol (Gattefosse, Elmsford NY) iv) Vegetable oil-polyethylene glycol-6 (PEG) complex which is trans-estenfication product of natural triglycerides (kernel oil) and polyethylene glycol e g of the type known and commercially available and sold collectively under the trademark Labrafil (e g Labrafil M 1944 CS, Gattefosse, Elmsford NY) (v) Polyoxyethylene-sorbitan-fatty acid esters e g of the type known as "Tweens (vi) Polyoxyethylene stearic acid esters of the type known as "Mynj" (vii) Polyoxyethylene fatty acid ethers of the type known as "Bnj" (vii) Any other optional adjuvant such as charge inducers pH modifier etc (ix) Any additional agent(s) to modify the permeation kinetics of the developed organogel systems such as impart such as urea, sahcyclic acid, lactic acid etc The structure stabilizer is a preferably a polymeric surfactant i e , Pluronic, in the concentration range of 10-25% w/w The Cyclosporin is made available in the dermal site in a controlled release fashion, as the drug gradually partitions, from the elongated cylindrical or tubular micellar/fibnilar network of the organogel, into the skin The microemulsion organogel system of cyclosporin is locally effective in abrogating inflammatory reactions and autoimmune skin disorders Further, the microemulsion organogel system of cyclosporin is particularly effective in clearing lesions in plaque type psoriasis with good patient tolerabihty The present composiotion has also been found to be clinically useful in subacute eczema and lichen planus The topical pharmaceutical compositions of the present invention can be used to achieve site-specific/local immunosuppression Topical drug delivery mechanistics of the present invention Cyclosporin A, one of the most useful drug candidate in the prevention of allograft rejection has already made an indispensable place in the armoury of the physicians and surgeaons But for certain localized medical problems such as dermatological disorders selected from the group consisting of but not limited to psoriasis, atopic dermatitis contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus etc, it is highly desirable to provide a dosage form which can help deliver these molecules exactly onto the target-receptor site or at least in the vicinity of affected cells or tissues Hence, the main objective of the invention centers on designing and developing a topical formulation for the directed delivery of the cyclosporme by overcoming the difficulties related to the physico-chemical nature of the peptidal drug candidate This sets the objective of searching an appropriate formulation comprising of appropriate interior architectural design, employing the desired biofnendly components as well as the necessary strategic preparatory process In order to accomplish the objective of topically delivering the cyclosporin molecules into and across the skin layers, most of the formulations described in the prior art have employed physico-chemical techniques (such as solvents, surfactants, detergents etc) or physical approaches such as iontophoresis, electorporation or sonophoresis, for the penetration enhancement of the active molecules It is generally believed that many of these penetration enhancing agents or techniques fluidize the polar head groups and/or nonpolar tail group within the multilayered lipid bilayers of the skin However these approaches are not really effective for highly lipophilic large molecular compounds such as proteins and peptides such as cyclosporins In other words the drug molecules do not penetrate in pharmaceutical^ useful quantities through the epithelia employing these permeation-enhancing approaches Moreover these penetration enhancers such as DMSO Azones or Oleic acid etc induce some degree of disturbance or even destruction to the protective and barrier function of the skin and therefore hinder rather than assist the healing process of the skin such as in psoriasis or eczema The topical drug delivery system disclosed in the present invention has advantages in that employing the said carrier systems targeted delivery of the CysA is achieved for the effective management of deep seated dermal disorders, especially some autoimmune inflammatory disorders affecting skin layers by virtue of the following mechanistics displayed by the developed microstructured carriers a Molecular mixing and "swelling effect" Micellar phospholipids mix with the intercellular lipids matrix of the stratum conrneum and thus cause swelling of the intercellular spaces thus accumulating the drug outside the cell membrane, which enhance the drug-target interactions, and also causes the formation of depots in the skin layers b Modification of stratum corneum barrier The phospholipids constituents of carriers induce some physicochemical changes in the bilayer packing of stratum corneum and deeper skin strata, thereby causing a large increase in the 'lecithin alkyl chain disorder" thus leading to enhanced penetration of the drug molecules c Adsorption and fusion of carriers to the stratum corneum The same promotes the penetration and accumulation of the drug in the skin strata d "Transcutaneous hydration force" effect There is enhanced penetration of the reverse micelles (containing drug) under the 'transcutaneous hydration force" caused by the water concentration gradient between the skin surface and the skin interior e Increased skin moistunzation The aqua-hpoidal biphasic state of the earners, as well as the phospholipids per se improve the hydration state of the skin and results in loosening of the dense lipidic lamellae of stratum corneum thus allowing enhanced penetration of the drug molecules f Reduced clearance of the encapsulated drug from skin layers In general, highly lipophilic drugs are immediately cleared away by the epithelial blood capillaries, as soon as the drug molecules cross the stratum corneum However, drug molecules entrapped in the micellar carriers are less prone to clearance from the site of action, which leads to enhanced and prolonged presence of the drug molecules at the desired site of action Lecithin organogels as a potential phospholipid-structured system for topical drug delivery A review AAPS PharmScitech 2005, (in press), Wilhmann H, LUISI PL Lecithin organogels as matrix for transdermal transport of drugs Biochem BiophyRes Commun 1991, 177897-900 Pharmaceutical and clinical advantages of the present invention > The cyclosporin containing topical formulations according to the present invention are charactenzed by the features that these carrier-based compositions are entirely different from those of the conventional topical formulations described in the aforesaid prior art and can achieve the objectives of the present invention in an effective way by using a reduced amount/concentration of cyclosporins > Another advantage of the present invention over the pnor art includes the fact that the topical application of cyclosporin is effective in abrogating inflammatory reactions and autoimmune skin disorders without interfering with other cellular processes > A further advantage of the present invention is that selectively delivering the cyclosporin to the specific tissue i e , skin, localize the drug molecules in the area of cellular activity and targets the drug molecules to the focal responding immunocytes and inflammatory cells thus results in enhanced efficacy and negligible or no associated systemic toxicities In other words, using the carrier system of the present invention, high levels of CsA can be localized at the tissue site undergoing immune activation to inhibit immunocytes A depot effect of the active substance in the dermal tissues is achieved, so that the drug effectively partitions into the skin and inhibit functional immune response (T-cell activation and inflammatory reactions) at a local level without significant influence on the systemic immunity > In the compositions/formulations of the present invention, the CysA is supposed to acquire entirely a new set of physico-chemical cover hence said to be modified without getting any fundamental changes in the chemical skeleton In other words, the carrier system provides for an adopted modified physico-chemical properties leading to a substantially enhanced performance Thus the entire profile of the drug gets favorably modified as if a newer molecule has been evolved, with a new potential in the same molecule > The compositions/formulations of the present invention are not only therapeutically effective, but also assist the healing process e g in case of psoriasis or eczema Because of the presence of phospholipids, being the major component of organogel micellar systems These can easily get integrated with the skin lipids and help regenerate the bioactive state of the skin thereby having a synergistic effect > The compositions/formulations of the present invention are highly stable > The compositions/formulations of the present invention are devoid of any irritation to the skin and hence are highly safe for long-term applications > The compositions/formulations of the present invention are easily administered topically The invention will now be explained with the help of examples without limiting the scope of the invention Example 1 For a topical lecithin organogel preparation of cyclosporin there were employed the components as follows (i) Cyclosporin A 200mg (n) lecithin 1gm (in) Isopropyl palmitate 1 5 gm (iv) Purified water 1000 µl Component (i), and (n) were dissolved in component (in) at a temperature of 50-60°C to obtain a uniform solution Subsequently component (iv) was added gradually, with gentle stirring, to obtain an isotropic lecithin organogel formulation Example 2 Topical organogel composition with preservatives was prepared in a similar manner as in example 1, with the preservative selected from the following (i) propyl paraben (n) methyl paraben (in) potassium sorbate (iv) sorbic acid Example 3 For a topical pluronic lecithin organogel preparation of cyclosporin, there were employed the components as follows (i) Cyclosporin A 2 g (II) lecithin 10 gm (in) Isopropyl palmitate 15 gm (iv) Sorbicacid 1gm (v) Pluronic F 127 14gm (vi) Purified water 57 gm (VII) Potassium Sorbate 1 gm Organic phase was prepared by mixing Component (i), (n) and (iv) in component (in) at a temperature of 50-60°C to obtain a uniform solution Aqueous phase was prepared by dissolving component (v) into component (vi) by keeping overnight in refrigerator Subsequently component (vn) was added The organic and aqueous phases were mixed in varying ratios (from 1 1 to 1 5) to obtain cyclosponne loaded plurnic lecithin organogels or PLOs In a manner similar to the preceding examples, different compositions were prepared by varying the components as follows (i) varying the effective concentration of Cyclosporin (in the range of 1% - 3 0%w/w) (II) Varying the amounts of lecithin (in) Using saturated lecithin in place of unsaturated lecithin (iv) Using different grades of Pluronic, and varying the concentration of pluronic from 10% to 25% on weight/weight basis (v) Incorporating additional adjuvants like skin depots forming agent viz Transcutol P in the concentration range of 3-7% (vi) Optionally adding other agents for synergistic therapeutic effect like urea (2-5% w/w) lactic acid (5-10%w/w), corticosteroid (0 025% to 0 05%) etc Example 4 Case 1 A female patient, 55 years old was affected with stable plaque psoriasis since 7 years, with bilaterally symmetrical psoriatic plaques on forehmbs, with a lesion area of Case 2 A male patient, 62 years old was affected with oral lichen planus Cyclosponne PLO 1 5% % w/w according to the example 4 of present invention was applied, once a day The application of 1 5% cyclosponne PLO cleared the clinical signs and symptoms of oral lichen planus within 04 weeks Case 3 A male patient, 26 years old was affected with subacute eczema on both the legs A 2% cyclosponne PLO formulation according to the present invention was applied, once a day, on one side with the corresponding placebo on the other side All the clinical signs and symptoms of subacute eczema disappeared with the application of 2% w/w cyclosponne PLO within 07 weeks whereas no significant therapeutic effect was observed in case of placebo treated site It will be understood that the scope of this invention is not limited by the above-described preferred embodiments It will be understood that while various specific embodiments of the present invention have been described modifications and substitutions may be made by those skilled in the art without departing from the true spirit and scope of the present invention Accordingly, any modified or substituted variants of the present invention should be understood to fall within the scope of the invention in as much as the invention has been described by way of illustration only and not limitation We claim: 1. A microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules, a polar/aqueous phase, and appropriate organic solvents wherein cyclosporin is in liposolubilzed state in the organogels. 2. A microemulsion organogel system as claimed in claim 1 wherein the slightly water-soluble biologically active compound is Cyclosporin, more preferably Cyclosporin A. 3. A microemulsion organogel system as claimed in claim 1 wherein cyclosporin is present in an effective amount of about 0.5-5.0% w/w. 4. A microemulsion organogel system as claimed in claim 1 wherein the said gelator molecules are amphipathic surfactants. 5. A microemulsion organogel system as claimed in claim 4 wherein the said amphipathic surfactants are phospholipids. 6. A microemulsion organogel system as claimed in claim 5 wherein phospholipids are selected from the group consisting of natural lecithins like egg lecithin or soy lecithin, more preferreably unsaturated lecithin present in an effective amount of 5-30%w/w. 7. A microemulsion organogel system as claimed in claim 5 wherein either a single phospholipid or a mixture of phospholipids is used. 8. A microemulsion organogel system as claimed in claim 1 wherein organic solvents are selected from the group consisting of monovalent alcohol fatty acid ester, divalent fatty acid ester, and linear, branched or cyclic alkanes. 9. A microemulsion organogel system as claimed in claim 9 wherein monovalent alcohol-fatty acid ester are selected from ethyl myristate, isopropyl myristate, iso propyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmirate, 10. A microemulsion organogel system as claimed in claim 9 wherein divalent fatty acid ester is selected from diisopropyl adipate, diisooctyl adipate. 11. A microemulsion organogel system as claimed in claim 9 wherein branched and cyclic alkanes are selected from isooctane and n-hexadecane. 12. A microemulsion organogel system as claimed in claim 1 wherein aqueous phase optionally contains cosurfactant as additional emulsifier and structure stabilizing agent, or other adjuvant. 13. A microemulsion organogel system as claimed in claim 13 wherein cosurfactant are selected from the group consisting Polyoxypropylene-polyoxyethyklene, Ethoxy diglycol, Glycolysed ethoxylated C8/C10 glycerides, Vegetable oil-polyethylene glycol-6 (PEG) complex, Polyoxyethylene-sorbitan-fatty acid esters, Polyoxyethylene stearic acid esters, Polyoxyethylene fatty acid ethers. 14. A microemulsion organogel system as claimed in claim 13 wherein the structure stabilizer is a preferably a polymeric surfactant i.e., Pluronic, in the concentration range of 10-25% w/w. 15. A microemulsion organogel system as claimed in claim 13 wherein other optional adjuvant are charge inducers, pH modifiers etc. 16. A microemulsion organogel system as claimed in claim 1 wherein other additional agent(s) to modify the skin permeation kinetics of the developed organogel are urea, salicyclic acid, lactic acid etc. 17. A topical pharmaceutical composition comprising the microemulsion organogel system as claimed in claim 1 along with the pharmaceutical^ acceptable carriers. ig exam] 20. A microemulsion organogel system for site-specific delivery of cyclosporin substantially as herein described with reference to the foregoi

Full Text

Field of invention
The present invention relates to a microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules a polar/aqueous phase and appropriate organic solvents wherein cyclosporin is in hposolubilzed state in the micellar network of organogel
More specifically, the present invention relates to topical drug delivery system, containing cyclosporin A, in the form of supramolecularly structured "lecithin organogels', wherein cyclosporin is entrapped in the three-dimensional network of swollen cylindrical reverse micelles These micellar systems are prepared by m-situ self-emulsification process which comprises of cyclosporin as an active ingredient, amphipathic phospholipids and other appropriate ingredients such as surfactants, polar agents etc
Background of the Invention
The cyclosporins were discovered in the year 1970 by researchers in an attempt to identify new antimicrobial agents These comprise a recognized class of pharmaceutically active, cyclic undecapeptides They are a group of natural oligopeptides ranging from cyclosporin A to cyclosporin Z
The parent compound of this class is well-established pharmaceutical agent "Cyclosporin A" or Cyclosporin (also spelled as, cyclosponne or ciclosponn) Cyclosporin A (CysA), a potent immunosuppressive agent, was first isolated from two strains of imperfect fungi Cylmdrocopan lucidum Booth and Tolypocladium inflation Gams
CysA is a specific, macromolecular lipophilic, cyclic, water-insoluble, non-polar undecapeptide consisting of 11 amino acids that inhibit the transcription of T-cell activation genes and/or signal transduction pathways involved in the T-cell activation
The compound is a selective immunosuppresant and a potent anti-inflammatory agent, and has demonstrated great clinical success in inhibiting T-cell mediated immune processes such as allograft rejection, graft-versus-host disease, and autoimmune disease when administered systemically
CysA acts in the cell nucleus by binding to intracellular receptor termed cyclophilm This Cyclosporin A-cyclophilin complex inhibits the calcmeunn (calcium and calmodulin dependent phosphatase), a key enzyme involved in calcium dependent signaling process Inhibition of calcmeunn prevents the transcription of lnterleukin-2 (IL -2) and other lymphokme genes Thus blockade of IL-2 and other lymphokine (T-cell growth factors) production by T-helper cells results in the impairment of IL-2 driven proliferation of activated T-cells in response to specific A class of cytosolic binding proteins (immunophihns) for cyclosporins has been identified, which are peptidyl-prolyl-cis- trans-isomerases and have been implicated in signaling pathways for T cell activation
In addition to the use of CysA in organ transplantation, the systemic administration of CysA is also effective in the treatment of a large number of autoimmune diseases Some specific examples of the autoimmune diseases and disorders to which CysA can be employed include psoriasis vulgaris, pustular psoriasis, contact dermatitis, atopic dermatitis alopecia areata, arthritis, autoimmune hematologic disorder, chronic bronchial asthma systemic lupus erythematosus, polymyositis systemic scleroderma Wegner's syndrome, myasthenia gravis, autoimmune intestinal diseases (spontaneous ulcerative colitis, Crohn's disease) sarcoidosis, multiple sclerosis, juvenile diabetes, uveitis, psoriatic arthritis, glomerular nephritis
Organogels, also known as microemulsion organogel systems, are thermodynamtcally stable, clear viscoelastic biocompatible and isotropic gels composed of phospholipids (lecithin) appropriate organic solvent, and a polar solvent Organogels, the jelly-like phases consist of a 3-dimensional network of entangled reverse cylindrical (polymer-like) micelles, which immobilizes the continuous or macroscopic external organic phase, thus turning a liquid into a gel The formation of a 3-dimensional network in the organogel is the result of transition at the micellar level in a low viscous Newtonian liquid consisting of lecithin reverse micelles in nonpolar organic liquid This spherical reverse micellar state of lipid aggregates turns on to form elongated tubular micelles with the addition of water and subsequently entangles to form a temporal 3-dimensional network in the solution bulk The latter serves to immobilize the external organic phase thus producing a gel form or the jelly-like state of the initial non-viscous solution However, the transparency and optical isotropy of the organogel remains as before
The incorporation of synthetic polymeric surfactant (e g , pluronics) in LOs, have been reported for their usefulness as cosurfactants and stablizers In addition, it has been shown that the inclusion of pluronics makes the organogellmg feasible with lecithin of relatively lesser purity too The term "pluronic" refers to a series of nonionic, closely related block copolymers of ethylene oxide and propylene oxide Also known as poloxamers, poloxamer polyols, or lutrols, these copolymers are primarily used in pharmaceutical formulations as cosurfactants, emulsifiers solubilizers, suspending agents, and stabilizers These pluronic containing LOs have been termed as pluronic lecithin organogels poloxamer organogels pluronic organogels, PLO gel, or simply PLOs
LOs have generated considerable interest over the years as a potential topical drug delivery vehicle The coexistence of organic and aqueous phase by means of a structurally well-defined micellar network of phospholipids, a large mterfacial area, and the possibility to entrap solutes within the gel matrix, along with long-term stability, makes them useful for a variety of applications The topical applications of various drugs containing LO systems have been demonstrated to significantly enhance the skin permeation and absorption of both lipophilic and hydrophilic substances The organized microstructural matrix, amphiphilicity, supersolubihzmg capacity and interaction of the biolipids with skin tissues are some of the major promoting factors for an enhanced transport of drug molecules into or across the skin Therapeutic compounds of different chemical and physicochemical background such as muscle relaxants, steroids, hormones, analgesics antiemetics, cardiovascular agents antithyroid drugs, and some macromolecules have been incorporated in the LOs and yielded quite promising encouraging results with respect to dermal- as well as transdermal drug delivery
Drawbacks Of The Prior Art
A Problems related to the systemic delivery of cyclosporin
i) Pharmacodynamic implications
According to the conventional method for treatment of autoimmune dermatological disorder such as psoriasis or atopic dermatitis, CysA is administered per oral either in an amount of 3-6mgAg/day for 2 months, or in an amount of 14mg/kg/day for 2 weeks, as a short-term therapy Alternatively, as a long-term therapy cyclosporin is administered in an amount of 1-4mg/kg/day for 12 to 25 months
However, it is known that CysA when administered systemically (per oral or intravenous administration) over a long period of time results is harmful The reversible side effects are renal tubular cell damage or nephrotoxicity Acute cyclosporin nephrotoxicity is accompanied morphologically by tubular lesions characterised by inclusion bodies, isometric vacuolation and microcalcification That leads to a decrease in the glomerular filtration rate, which can be
identified by the rapid increase in serum creatinine in patients treated with cyclosporin
Other frequent side effects of CysA treatments include hepatotoxicity, hypertension, granulomatous hepatitis, hypochromic or microcytic anaemia, marrow hyperplasia lymphopenia, hyperkalemia, hyperuncaemia, anaemia hypertrichosis, gingival hyperplasia, gastrointestinal side effects, tremors and paraesthesia
n) Pharmaceutical complications
The cyclosporins are highly lipophilic substances and poorly soluble in water, e g solubility of cyclosporin A is Moreover, by virtue of these two inherent physico-chemical characteristics, the pharmaceutical compositions of cyclosporin A with customary solid or liquid pharmaceutical carriers often have disadvantages
In view of their better solubility in fatty oils and alcohol, Sandimmune® (Novartis, Basel, Switzerland) was developed employing these type of ingredients as solubility enhancers for oral use in the form of an emulsion concentrate, which after administration require patient's own bile for the absorption of drug The said emulsion concentrate consists of 100 mg cyclosporin dissolved in 1 ml of a mixture of oil, ethanol and an emulsifier, namely macrogel glycerol trioleate linolate However Sandimmune s reliance on patient's bile leads to great mtrapatient and mterpatient absorption variability and bioavailability varies between 1% to 89% with an average of 30%
In addition to the oral solution formulation, Sandimmun® is also available in capsule (soft gelatin capsules) form The capsules contain 25mg/100mg cyclosporin A dissolved in a mixture of oil, ethanol and emulsifier
Of late, this Sandimmun® coarse emulsion formulation has been replaced with Sandimmun Neoral® microemulsion Neoral® is a microemulsion preconcentrate, which after oral administration, forms a relatively homogenous microemulsion in aqueous fluids simulating a mixed micellar phase However, even using Neoral®, there are bioavailability problems and no change in the side effect profile of the drug, while Neoral® administration in patients requires individual therapeutic drug monitoring
Upon systemic (oral/parenteral) administration, merely 3 5ng/mg concentration of CysA is able to reach the actual site of action (i e , the skin) even when CysA is administered in a dose as high as 14mg/kg/day This again demands the dosage form with some innovative strategy which can help localize more number of drug molecules at the site of action through a more directed and convenient approach such as topical delivery
As an example of the aforementioned ramifications, within the specialty of dermatology, it would be extremely desirable and advantageous that cyclosporin is administered topically rather than systemically, to treat autoimmune, putative autoimmune or immunoinflammatory and related diseases of the skin, including, for example, psoriasis, eczema, dermatitis etc and also to effect site-specific immunosuppression (SSIS), i e , for the induction of localized site-specific immunsuppression which would inhibit the mechanisms leading to graft rejection
Thus oral administration of cyclosponne has not been a very successful proposition owing to poor, erratic bioavailability and of course the undesired bio-distribution leading to adverse effects
B Problems related to the topical delivery of cyclosponne
To overcome the difficulties related to the systemic administration of cyclosporins, topical formulations of cyclosporins is extremely advantageous and desirable
However, it is extremely difficult to formulate cyclosporin into topical preparations so as to achieve the desired therapeutic effect, unlike water soluble or low-molecular weight pharmaceutically effective therapeutic substances
And furthermore, various attempts to provide therapeutically effective topical formulations of cyclosporins have hitherto failed or proved unsatisfactory for usage in particular conditions
One of the reasons for this difficulty is that, like any other peptide, the skin penetration/permeation of CysA is hindered by the barrier property of stratum corneum
Another reason for this difficulty is because the cyclosporin is insoluble in water and also there is the restriction upon the kind of organic solvents in which the cyclosporin can be dissolved As such specific organic solvents, a lower alkanol such as ethanol onsopropanol may be generally employed However, such a lower alkanol is highly irritative to the skin when it is employed for topical preparations in a relatively high concentration, hence affect the safety and biocompatibility of the topical formulation On the other hand, when the lower alcohol is employed in a relatively low concentration in topical preparations, the ability of the cyclosporin to get dispersed uniformly may be impaired, which significantly affects the therapeutic effect of any topical formulation
Due to such characteristic physico-chemical properties of cyclosporin, it has been reported that most of the prior cyclosporin topical preparations cannot permeate the stratum corneum for lack of skin permeability and therefore, cannot sufficiently provide the desired clinical effect
Various proposals have been made in the prior art for application of cyclosporins in topical form, and a number of topical formulations have been described However, attempts at topical application have failed to provide any demonstrably effective therapy
For example, although in the literature, the cyclosporin is said to have a topical action in theory but its efficacy was only observed after six months' treatment Moreover dimethyl sulphoxide (DMSO) had to be used as solvent at the concentration of 50%, which is unacceptable for a treatment like that of psoriasis
Intralesional injections were also explored, and demonstrated the theoretical efficacy of the substance, although its use proved totally impracticable for treatment purposes
Similarly, a Japanese Laid-open Patent Publication No 5-310591 (November 22, 1993) discloses the cyclosporin topical preparation formulated by using a volatile lower alcohol However, this preparation has disadvantages that the stability of the preparation during long-term storage is low, and when the preparation is applied to the skin, alcohol is rapidly volatilized to cause the precipitation of cyclosporin, which results in the suboptimal pharmacological efficacy
Further, European Patent 2218334B describes cyclosporin topical preparation containing C12-24 mono- or polyfatty acid or alcohol as an absorption-enhancing agent However, the formulation does not the have skin permeability to the desired extent
Japanese Patent Laid-open Publication No 2-17,127 discloses compositions, which contain, as essential components, cyclosporin and a mono- or polyunsaturated fatty acid or an unsaturated alcohol, each having from 12 to 24 carbon atoms The mono- and
polyunsaturated fatty acids may include, for example, vaccenic acid, linoleic acid, linolenic acid elatdic acid erucic acid, and the like The unsaturated alcohol may include, for example, vaccenyl alcohol, linoleyl alcohol, linolenyl alcohol, elaidyl alcohol erucyl alcohol and the like Further, it describes the compositions may be effective to various skin diseases However, the publication does not specify its pharmaceutical effects and refers merely to the ability of the cyclosporin to infuse or penetrate through the skin The publication is thoroughly silent about the extent, for example to which the cyclosporin is effective against any dermatological disorder such as psoriasis
Additionally, several other cases have been reported where attempts had been made to use topical cyclosporin in skin diseases, but mixed results have been obtained
Similarly, a conventional "microemulsion preconcentrate" or "emulsion" type topical formulation disclosed in US patent 6024978 has been shown to exhibit anti-inflammatory activity when applied topically in guinea pigs
There are reports of contact-type dermatitis, for example in Arch Dermato-1 125 568 (1989) which reports to the effect that cyclosporin is employed for a human DNCB test with no effect Further, Contact Dermatitis 19, 129-132 (1988) makes a review on three formulations a 10% cyclosporin formulation in Labrafil (polyoxyl-5-oleate, olive oil and ethanol) a 5% cyclosponn formulation in castor oil, and a 5% cyclosporin formulation m castor oil containing 20% propylene glycol, however it states the results of this review are not so satisfactory, and that a more effective solvent is required In addition, Contact Dermatitis,20, 155-156 (1988) states that none of three cyclosporin formulations (i e , cone 0 1%, 1% and 10% w/w) are effective at all against contact dermatitis
Pharmacological effect of cyclosporin upon psoriasis is described, in Clinical Research, 34 1007A (1986), in which it is described that topical administration of cyclosporin is not effective for the therapy to psoriasis, although neither the concentration of cyclosporin nor the composition thereof are specified
It is also described in Lancet, 1, 806 (1987) that a 2% by weight cyclosporin (on ointment base) is as effective upon psoriasis as placebo Further, J Amer Acad Dermatol, 18, 378-379 (1988) describes that a 5% cyclosporin solution in olive oil is equal to the sole use of olive oil that is employed as the base in the previous case In addition, J Amer Acad Dermatol, 22, 126-127 (1990) states that a gel comprising 10% cyclosporin, 43% olive oil 10% ethanol 30% polyoxyl-5-oleate and 7% colloidal silica did not produce any effect upon psoriasis Furthermore, it is reported in Brit J Derm 122 113-114 (1990) that a 5% (by weight) cyclosporin ointment was not effective
US Patent 4996193 discloses topical conventional formulations of CysA in the concentration range of 2 5-5% w/w containing different co-solvents, emulsifiers and penetration enhancers However it has been disclosed that this topical formulation is exhibits its immunosuppressant activity only when combined with systemic administration of CysA for first eight to ten days of the therapy, i e , CysA is administered at a dose of 8mg/kg/day for 10 days prior to topical application It mentions that this initial systemic dose od CysA is necessary to induce the systemic maintenance phase of immuno-nonresponsiveness, which is then further supported by the topical formulation disclosed in the invention
Another conventional ointment formulation of cyclosporin A has been disclosed in WO 0547229 and US patent 5504069 It is shown that CysA present in the concentration range of 1-10%w/w are effective against atopic dermatitis and psoriatic arthritis in humans However the formulation has been tested in only one or two patients, and also contains high amounts of surfactants and alcohols (such as ethanol), which may affect its safety on long-term applications as well as stability on, prolonged periods of storage
US patent 6022852 describes a-tocopherol containing topical conventional formulation of CysA (1 0% w/w) It has been disclosed that a-tocopherol and its derivatives are excellent solubilizers for CysA and may also help in permeation of the drug through intact skin However no in-vitro, ex-vivo or m-vivo studies have been earned out to evaluate the performance of the formulation
EP patent 0793966 describes a conventional topical formulation of CysA, wherein CysA has been emulsified in a carbopol gel employing vegetable oils and surfactants Moreover the formulation contains penetration enhancers such as DMSO which are known for their adverse effects on the skin such as irritation and damage to the barrier function of the skin Moreover, no skin irritation stability and clinical studies have been carried to prove the utility of the formulation for dermatological applications Similar type of formulations has also been disclosed in US patent 5807820, containing very large amounts of CysA (upto 10% w/w)
EP patent 1230917 disclosed Invasomes of CysA for topical applications, which are uni, ohgo, or multilamellar vesicles of 50-70nm size composed of phospholipids and ethanol containing 5%w/w CysA along with a mixture of D-hmonene, cmeol, and citral The formulation has been found to exhibit significant immunosuppressant activity in animals models
US patent 6890901 describes a liposomal composition of CysA for topical applications However the composition disclosed is a mixture of liposomes and hyaluronic acid (HA) and it has been mentioned that hyaluronic acid has a key role in the efficacy and stability of the formulation This composition has been compared with plain liposomal formulation, for stability and in-vitro performance, and it has been disclosed that the latter composition (i e without HA) is neither effective nor stable Moreover, the formulation disclosed has not been evaluated for its m-vivo or clinical performance
In addition to significant therapeutic effect of CysA in some deap seated skin disorders reports on alopecia aereata have also been published e g in Lancet 2, 803-804 (1986) where it is described that a 2% cyclosporin oily solution was effective In addition, Lancet, 2, 971-972 (1986) reports that a 5% (w/w) cyclosporin formulation in oil was effective against alopecia areata
Acta Derm Venereol, 69,252-253 (1989) describes a 10% cyclosporin oily preparation was not effective Furthermore, J Amer Acad Dermatol, 22, 251-253 (1989) reports that a 5% cyclosporin formulation was effective against male alopecia, although no specific compositions are described therein
Therefore, as long as the literature, as described hereinabove, has been reviewed, it is considerably difficult to conclude that any of the cyclosporin topical preparations described in numerous prior references and patents exhibit a significant therapeutic effect on dermatologic diseases as specified hereinabove Even if it could be said that cyclosporin would be effective against the skin diseases, it can be said that cyclosporin need to be employed in a considerably large amount
In other words, no topical cyclosporin preparations could so far achieve the object to utilize cyclosporin effectively via topical route of administration On the other hand the drug (CysA) may have shown the effective and safer response on its topical delivery but did not find the way on account of its high molecular weight, high degree of lipophilicity, and difficulty of penetrating the intact skin, especially the horny layer
Hence, a topical preparation containing a therapeutically adequate amount of cyclosporin A in combination with substances that promote the permeation of cyclosporin A through the intact skin is desirable In addition, the combination should not interfere in the healing process of the skin rather it should be supportive in nature
The topical delivery would help localize or target the drug molecules to specific target sites, such as skin layers in case of some deep-seated dermatological disorders i e , where the disease is limited to the skin In other words, if the focus of a disease is restricted to a layer of the dermis, topical administration through the epidermis is more advantageous than other ways of administration because local rise in the concentration of drug molecules at or near the desired target would result in enhanced interaction with focal responding immunocytes and in turn enhance the therapeutic efficacy (potentiation) to a significant extent Thereby the dose of cyclosporin to be administered can be reduced and hence the systemic side effects can be minimized to a considerable extent
In other words, there is an urgent need for efficacious topical formulations of CysA particularly that react with immunophilin cytosolic binding proteins through topical route, for the management of some autoimmune dermatological disorders
In addition, there is also a need for utilizing the same, in the prevention of localized tissue site-specific inflammatory immune reactions An example includes prevention of skin allograft rejection and contact hypersensitivity reactions at a local level, localized tissue auto-or alio- inflammatory/immune responses, and tissue or organ allografts In particular, a methodology that locally provides allograft acceptance and attenuates T-cell mediated events is highly desirable The present invention is directed to such formulations and methods of use
Present invention obviates the drawbacks of the prior art by providing a microemulsion organogel system for effective drug delivery comprising Cyclosporin
Object of the present invention
The object of the present invention is to provide an efficacious topical formulation of CysA to react with immunophilin cytosolic binding proteins through topical route, for the management of some autoimmune dermatological disorders
Another object of the present invention is to provide an efficacious topical formulation effective in the prevention of localized site-specific inflammatory immune reactions
Yet another object of the present invention is to provide a microemulsion organogel system for effective delivery of Cyclosporin A through stratum corneum
Further, object of the invention is to provide an effective method for the preparation of the process for preparing the microemulsion organogel system
Summary of the invention
The present invention relates to a microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules, a polar/aqueous phase, and appropriate organic solvents wherein cyclosporin is in hposolubilzed state in the organogels
The slightly water-soluble biologically active compound is Cyclosporin, more preferably Cyclosporin A
Cyclosporin is present in an effective amount of about 0 5-5 0% w/w
The said gelator molecules are amphipathic surfactants Further the amphipathic surfactants are phospholipids
The phospholipids are selected from the group consisting of natural lecithins like egg lecithin or soy lecithin more preferably unsaturated lecithin The phospholipids may be used either alone or as mixture of phospholipids
The organic solvents are selected from the group consisting of monovalent alcohol fatty acid ester, divalent fatty acid ester, and linear, branched or cyclic alkanes
The present invention has optimum skin permeability, so that cyclosporin can efficiently reach the target lesion, through the stratum corneum, and also may create a depot effect in the skin layers and therefore may attain the above-mentioned purpose
The cyclosporin A contained in the said carrier systems of the present invention can provide significant therapeutic effects for autoimmune or allergic skin disorders, merely by applying them to the affected part of the skin Further, these topical preparations are non-irritant to the skin, so that they are highly safe
In relation to topical applications, the present invention further enables the preparation of novel topical formulations comprising cyclosporins as active ingredient, and permitting improved treatment for autoimmune diseases affecting the skin, or diseases of the skin having an autoimmune aetiology The galenic products of the invention are in particular applicable to treatment of dermatological disease, e g as aforesaid, involving morbid proliferation and/or keratinisation of the epidermis, especially to treatment of psoriasis, atopic dermatitis, contact dermatitis or allergic contact dermatitis etc
Topically applicable compositions in accordance with the invention may also be of use in the treatment of alopecia, e g for use in the promotion of hair growth Further the topical preparations can assist adapt a skin piece grafted to the site of skin grafting
The topical preparations according to the present invention may be administered by applying them directly to the affected part of the skin thereof once or several times, e g thrice, per day The number of applications may appropriately be increased or reduced depending upon the extent of the disease to be applied
Detailed description of the preferred embodiments of invention
The present invention provides novel galenic products for topical, in particular for trans-epidermal administration, comprising a cyclosporin as an active ingredient, which overcomes the difficulties hitherto encountered in the topical delivery of this peptide due to its inherent physico-chemical characteristics such as large molecular weight, high lipophilhcity and poor aqueous solubility
In accordance with the present invention, cyclosporin A is formulated as "organogels", which are thermodynamically stable, clear, viscoelastic, biocompatible gels, composed of phospholipids (lecithin) and appropriate organic solvent, wherein cyclosporin is in hposolubihzed state
More particularly, the cyclosporin A is formulated as a microemulsion gel system, which is identifiable as possessing one or more of the following characteristics They are composed of self-assembled supramolecular arrangement of surfactant molecules, formed spontaneously or substantially spontaneously when their components are brought into contact that is without any input of external energy e g heating or the use of high shear equipment or other substantial agitation and exhibit thermodynamic stability
In one aspect of the invention, the said "organogel systems" are prepared by a process which comprises incorporation of a critical amount of a specific polar agent such as water, to a solution of gelator molecules (in optimum concentration) in a specific organic solvent, e g , linear branched and cyclic alkanes, ethers and esters, fatty acids and amines
In another aspect of the invention, the organogel system are prepared by spontaneous emulsification of organic phase consisting of appropriate organic solvent and a specific amount of amphipathic surfactant as gelator molecules such as phospholipid with a certain specific amount of aqueous phase with or without co-surfactant
Particularly, the present invention relates to a topical pharmaceutical composition containing (i) cyclosporin, (ii) organic phase, (in) surfactant or gelator molecules, (iv) polar (aqueous) phase, and (v) a co-surfactant
(i) Cyclosporin The pharmacologically active ingredient used in the composition according to the present invention is cyclosporin Cyclosporin A is most preferable since its clinical effectiveness and pharmacological properties are well established in the art Suitable formulations containing CysA can be prepared so that CysA would be present in an amount of0 5-10 0%w/w
In addition to the cyclosporin as active ingredient, the "microemulsion gel or Lecithion organogel" compositions of the invention will appropriately comprise
(11) Gelating agent The organogel matrix of the present invention chiefly consists of amphipathic surfactant such a phospholipids as gelator molecules A wide variety of phospholipids can be used in the present invention, however, non-immunogenic and biodegradable lipids are preferred, for example the natural lecithins such as egg lecithin or soy lecithin or synthetic lecithins such as saturated synthetic lecithins Either a single phospholipid or a mixture of phospholipids may be used It is therefore understood that any reference herein to lecithin or phosphatidylcholine is intended to include any combination of lecithin-like phospholipids as is well known in the art
It is to be understood that the soy lecithin of the present invention is a preferred lecithin source and may be dissolved in appropriate organic solvent to achieve a final concentration in the composition from approximately 20%-90%, with a more preferred final concentration of from approximately 10%-60%
(m) Organic phase An appropriate organic solvent provides the desired solvent action onto the gelator molecules Specific organic solvents, which may be incorporated (in certain specific amount) for the compositions of the present invention, includes monovalent alcohol-fatty acid ester in liquid state at ambient temperature, for example a monovalent fatty acid ester such as ethyl mynstate, isopropyl mynstate, iso propyl mynstate, isopropyl laurate isopropyl caprylate, isopropyl palmirate, and a divalent fatty acid ester such as, dnsopropyl adipate diisooctyl adipate branched and cyclic alkanes such as isooctane and n-hexadecane
(iv) Aqueous phase The same includes purified or pharmaceutical grade water, glycerol or ethylene glycol
(v) Co-surfactant The aqueous phase may also contain a co-surfactant as additional emulsifier and structure stabilizing agent, or any other adjuvant, selected from the group consisting of the following
(i) Polyoxypropylene-polyoxyethyklene block co-polymer,
(u) Ethoxy diglycol e g of the type known and commercially available and sold collectively under the trademark "TRANSCUTOL P" (Gattefosse, Elmsford NY)
(m) Glycolysed ethoxylated C8/C10 glycendes, le polyethylene glycol caprylate/caprate e g of the type known and commercially available and sold collectively under the trademark Labrasol (Gattefosse, Elmsford NY)
iv) Vegetable oil-polyethylene glycol-6 (PEG) complex which is trans-estenfication product of natural triglycerides (kernel oil) and polyethylene glycol e g of the type known and commercially available and sold collectively under the trademark Labrafil (e g Labrafil M 1944 CS, Gattefosse, Elmsford NY)
(v) Polyoxyethylene-sorbitan-fatty acid esters e g of the type known as "Tweens
(vi) Polyoxyethylene stearic acid esters of the type known as "Mynj"
(vii) Polyoxyethylene fatty acid ethers of the type known as "Bnj"
(vii) Any other optional adjuvant such as charge inducers pH modifier etc
(ix) Any additional agent(s) to modify the permeation kinetics of the developed organogel systems such as impart such as urea, sahcyclic acid, lactic acid etc
The structure stabilizer is a preferably a polymeric surfactant i e , Pluronic, in the concentration range of 10-25% w/w
The Cyclosporin is made available in the dermal site in a controlled release fashion, as the drug gradually partitions, from the elongated cylindrical or tubular micellar/fibnilar network of the organogel, into the skin
The microemulsion organogel system of cyclosporin is locally effective in abrogating inflammatory reactions and autoimmune skin disorders Further, the microemulsion organogel system of cyclosporin is particularly effective in clearing lesions in plaque type psoriasis with good patient tolerabihty The present composiotion has also been found to be clinically useful in subacute eczema and lichen planus
The topical pharmaceutical compositions of the present invention can be used to achieve site-specific/local immunosuppression
Topical drug delivery mechanistics of the present invention
Cyclosporin A, one of the most useful drug candidate in the prevention of allograft rejection has already made an indispensable place in the armoury of the physicians and surgeaons But for certain localized medical problems such as dermatological disorders selected from the group consisting of but not limited to psoriasis, atopic dermatitis contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus etc, it is highly desirable to provide a dosage form which can help deliver these molecules exactly onto the target-receptor site or at least in the vicinity of affected cells or tissues
Hence, the main objective of the invention centers on designing and developing a topical formulation for the directed delivery of the cyclosporme by overcoming the difficulties related to the physico-chemical nature of the peptidal drug candidate This sets the objective of searching an appropriate formulation comprising of appropriate interior architectural design, employing the desired biofnendly components as well as the necessary strategic preparatory process
In order to accomplish the objective of topically delivering the cyclosporin molecules into and across the skin layers, most of the formulations described in the prior art have employed physico-chemical techniques (such as solvents, surfactants, detergents etc) or physical approaches such as iontophoresis, electorporation or sonophoresis, for the penetration enhancement of the active molecules It is generally believed that many of these penetration enhancing agents or techniques fluidize the polar head groups and/or nonpolar tail group
within the multilayered lipid bilayers of the skin However these approaches are not really effective for highly lipophilic large molecular compounds such as proteins and peptides such as cyclosporins In other words the drug molecules do not penetrate in pharmaceutical^ useful quantities through the epithelia employing these permeation-enhancing approaches Moreover these penetration enhancers such as DMSO Azones or Oleic acid etc induce some degree of disturbance or even destruction to the protective and barrier function of the skin and therefore hinder rather than assist the healing process of the skin such as in psoriasis or eczema
The topical drug delivery system disclosed in the present invention has advantages in that employing the said carrier systems targeted delivery of the CysA is achieved for the effective management of deep seated dermal disorders, especially some autoimmune inflammatory disorders affecting skin layers by virtue of the following mechanistics displayed by the developed microstructured carriers
a Molecular mixing and "swelling effect" Micellar phospholipids mix with the intercellular lipids matrix of the stratum conrneum and thus cause swelling of the intercellular spaces thus accumulating the drug outside the cell membrane, which enhance the drug-target interactions, and also causes the formation of depots in the skin layers
b Modification of stratum corneum barrier The phospholipids constituents of carriers induce some physicochemical changes in the bilayer packing of stratum corneum and deeper skin strata, thereby causing a large increase in the 'lecithin alkyl chain disorder" thus leading to enhanced penetration of the drug molecules
c Adsorption and fusion of carriers to the stratum corneum The same promotes the penetration and accumulation of the drug in the skin strata
d "Transcutaneous hydration force" effect There is enhanced penetration of the reverse micelles (containing drug) under the 'transcutaneous hydration force" caused by the water concentration gradient between the skin surface and the skin interior
e Increased skin moistunzation The aqua-hpoidal biphasic state of the earners, as well as the phospholipids per se improve the hydration state of the skin and results in loosening of the dense lipidic lamellae of stratum corneum thus allowing enhanced penetration of the drug molecules
f Reduced clearance of the encapsulated drug from skin layers In general, highly lipophilic drugs are immediately cleared away by the epithelial blood capillaries, as soon as the drug molecules cross the stratum corneum However, drug molecules entrapped in the micellar carriers are less prone to clearance from the site of action, which leads to enhanced and prolonged presence of the drug molecules at the desired site of action Lecithin organogels as a potential phospholipid-structured system for topical drug delivery A review AAPS PharmScitech 2005, (in press), Wilhmann H, LUISI PL Lecithin organogels as matrix for transdermal transport of drugs Biochem BiophyRes Commun 1991, 177897-900
Pharmaceutical and clinical advantages of the present invention
> The cyclosporin containing topical formulations according to the present invention are charactenzed by the features that these carrier-based compositions are entirely different from those of the conventional topical formulations described in the aforesaid prior art and can achieve the objectives of the present invention in an effective way by using a reduced amount/concentration of cyclosporins
> Another advantage of the present invention over the pnor art includes the fact that the topical application of cyclosporin is effective in abrogating inflammatory reactions and autoimmune skin disorders without interfering with other cellular processes
> A further advantage of the present invention is that selectively delivering the cyclosporin to the specific tissue i e , skin, localize the drug molecules in the area of cellular activity and targets the drug molecules to the focal responding immunocytes and inflammatory cells thus results in enhanced efficacy and negligible or no associated systemic toxicities In other words, using the carrier system of the present invention, high levels of CsA can be localized at the tissue site undergoing immune activation to inhibit immunocytes A depot effect of the active substance in the dermal tissues is achieved, so that the drug effectively partitions into the skin and inhibit functional immune response (T-cell activation and inflammatory reactions) at a local level without significant influence on the systemic immunity
> In the compositions/formulations of the present invention, the CysA is supposed to acquire entirely a new set of physico-chemical cover hence said to be modified without getting any fundamental changes in the chemical skeleton In other words, the carrier system provides for an adopted modified physico-chemical properties leading to a substantially enhanced performance Thus the entire profile of the drug gets favorably modified as if a newer molecule has been evolved, with a new potential in the same molecule
> The compositions/formulations of the present invention are not only therapeutically effective, but also assist the healing process e g in case of psoriasis or eczema Because of the presence of phospholipids, being the major component of organogel micellar systems These can easily get integrated with the skin lipids and help regenerate the bioactive state of the skin thereby having a synergistic effect
> The compositions/formulations of the present invention are highly stable
> The compositions/formulations of the present invention are devoid of any irritation to the skin and hence are highly safe for long-term applications
> The compositions/formulations of the present invention are easily administered topically
The invention will now be explained with the help of examples without limiting the scope of the invention
Example 1
For a topical lecithin organogel preparation of cyclosporin there were employed the components as follows
(i) Cyclosporin A 200mg
(n) lecithin 1gm
(in) Isopropyl palmitate 1 5 gm
(iv) Purified water 1000 µl
Component (i), and (n) were dissolved in component (in) at a temperature of 50-60°C to obtain a uniform solution Subsequently component (iv) was added gradually, with gentle stirring, to obtain an isotropic lecithin organogel formulation
Example 2
Topical organogel composition with preservatives was prepared in a similar manner as in example 1, with the preservative selected from the following
(i) propyl paraben
(n) methyl paraben
(in) potassium sorbate
(iv) sorbic acid
Example 3
For a topical pluronic lecithin organogel preparation of cyclosporin, there were employed the components as follows
(i) Cyclosporin A 2 g
(II) lecithin 10 gm
(in) Isopropyl palmitate 15 gm
(iv) Sorbicacid 1gm
(v) Pluronic F 127 14gm
(vi) Purified water 57 gm
(VII) Potassium Sorbate 1 gm
Organic phase was prepared by mixing Component (i), (n) and (iv) in component (in) at a temperature of 50-60°C to obtain a uniform solution Aqueous phase was prepared by dissolving component (v) into component (vi) by keeping overnight in refrigerator Subsequently component (vn) was added The organic and aqueous phases were mixed in varying ratios (from 1 1 to 1 5) to obtain cyclosponne loaded plurnic lecithin organogels or PLOs
In a manner similar to the preceding examples, different compositions were prepared by varying the components as follows
(i) varying the effective concentration of Cyclosporin (in the range of 1% - 3 0%w/w)
(II) Varying the amounts of lecithin
(in) Using saturated lecithin in place of unsaturated lecithin
(iv) Using different grades of Pluronic, and varying the concentration of pluronic from
10% to 25% on weight/weight basis (v) Incorporating additional adjuvants like skin depots forming agent viz Transcutol P
in the concentration range of 3-7% (vi) Optionally adding other agents for synergistic therapeutic effect like urea (2-5%
w/w) lactic acid (5-10%w/w), corticosteroid (0 025% to 0 05%) etc
Example 4
Case 1
A female patient, 55 years old was affected with stable plaque psoriasis since 7 years, with bilaterally symmetrical psoriatic plaques on forehmbs, with a lesion area of Case 2
A male patient, 62 years old was affected with oral lichen planus Cyclosponne PLO 1 5% % w/w according to the example 4 of present invention was applied, once a day The application of 1 5% cyclosponne PLO cleared the clinical signs and symptoms of oral lichen planus within 04 weeks
Case 3
A male patient, 26 years old was affected with subacute eczema on both the legs A 2% cyclosponne PLO formulation according to the present invention was applied, once a day, on one side with the corresponding placebo on the other side All the clinical signs and symptoms of subacute eczema disappeared with the application of 2% w/w cyclosponne PLO within 07 weeks whereas no significant therapeutic effect was observed in case of placebo treated site
It will be understood that the scope of this invention is not limited by the above-described preferred embodiments It will be understood that while various specific embodiments of the present invention have been described modifications and substitutions may be made by those skilled in the art without departing from the true spirit and scope of the present invention Accordingly, any modified or substituted variants of the present invention should be understood to fall within the scope of the invention in as much as the invention has been described by way of illustration only and not limitation

We claim:
1. A microemulsion organogel system for site-specific delivery of cyclosporin composed of gelator molecules, a polar/aqueous phase, and appropriate organic solvents wherein cyclosporin is in liposolubilzed state in the organogels.
2. A microemulsion organogel system as claimed in claim 1 wherein the slightly water-soluble biologically active compound is Cyclosporin, more preferably Cyclosporin A.
3. A microemulsion organogel system as claimed in claim 1 wherein cyclosporin is present in an effective amount of about 0.5-5.0% w/w.
4. A microemulsion organogel system as claimed in claim 1 wherein the said gelator molecules are amphipathic surfactants.
5. A microemulsion organogel system as claimed in claim 4 wherein the said amphipathic surfactants are phospholipids.
6. A microemulsion organogel system as claimed in claim 5 wherein phospholipids are selected from the group consisting of natural lecithins like egg lecithin or soy lecithin, more preferreably unsaturated lecithin present in an effective amount of 5-30%w/w.
7. A microemulsion organogel system as claimed in claim 5 wherein either a single phospholipid or a mixture of phospholipids is used.
8. A microemulsion organogel system as claimed in claim 1 wherein organic solvents are selected from the group consisting of monovalent alcohol fatty acid ester, divalent fatty acid ester, and linear, branched or cyclic alkanes.
9. A microemulsion organogel system as claimed in claim 9 wherein monovalent alcohol-fatty acid ester are selected from ethyl myristate, isopropyl myristate, iso propyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmirate,
10. A microemulsion organogel system as claimed in claim 9 wherein divalent fatty acid ester is selected from diisopropyl adipate, diisooctyl adipate.
11. A microemulsion organogel system as claimed in claim 9 wherein branched and cyclic alkanes are selected from isooctane and n-hexadecane.
12. A microemulsion organogel system as claimed in claim 1 wherein aqueous phase optionally contains cosurfactant as additional emulsifier and structure stabilizing agent, or other adjuvant.
13. A microemulsion organogel system as claimed in claim 13 wherein cosurfactant are selected from the group consisting Polyoxypropylene-polyoxyethyklene, Ethoxy diglycol, Glycolysed ethoxylated C8/C10 glycerides, Vegetable oil-polyethylene glycol-6 (PEG) complex, Polyoxyethylene-sorbitan-fatty acid esters, Polyoxyethylene stearic acid esters, Polyoxyethylene fatty acid ethers.
14. A microemulsion organogel system as claimed in claim 13 wherein the structure stabilizer is a preferably a polymeric surfactant i.e., Pluronic, in the concentration range of 10-25% w/w.
15. A microemulsion organogel system as claimed in claim 13 wherein other optional adjuvant are charge inducers, pH modifiers etc.
16. A microemulsion organogel system as claimed in claim 1 wherein other additional agent(s) to modify the skin permeation kinetics of the developed organogel are urea, salicyclic acid, lactic acid etc.
17. A topical pharmaceutical composition comprising the microemulsion organogel system as claimed in claim 1 along with the pharmaceutical^ acceptable carriers.
ig exam]
20. A microemulsion organogel system for site-specific delivery of cyclosporin substantially as herein described with reference to the foregoi

Documents:

2515-del-2005-abstract.pdf

2515-del-2005-Claims-(24-05-2013).pdf

2515-del-2005-claims.pdf

2515-del-2005-Correspondence Others-(08-05-2013).pdf

2515-del-2005-Correspondence Others-(11-06-2012).pdf

2515-del-2005-Correspondence Others-(22-06-2012).pdf

2515-del-2005-Correspondence Others-(24-05-2013).pdf

2515-del-2005-correspondence-others.pdf

2515-del-2005-description (complete).pdf

2515-del-2005-description (provisional).pdf

2515-del-2005-Form-1-(11-06-2012).pdf

2515-del-2005-form-1.pdf

2515-del-2005-form-13.pdf

2515-del-2005-form-2.pdf

2515-del-2005-Form-3-(11-06-2012).pdf

2515-del-2005-form-3.pdf

2515-del-2005-form-5.pdf

2515-del-2005-gpa.pdf

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Patent Number

261190

Indian Patent Application Number

2515/DEL/2005

PG Journal Number

24/2014

Publication Date

13-Jun-2014

Grant Date

11-Jun-2014

Date of Filing

16-Sep-2005

Name of Patentee

LIFECARE INNOVATIONS PVT. LTD

Applicant Address

B-589, SUSHANT LOK-1, GURGAON-HARYANA-122002, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. SUNIL DOGRA	DEPARTMENT OF DERMATOLOGY, VENEREOLOGY & LAPROLOGY, POST GRADUAL INSTITUTE OF MEDICAL EDUCATION & RESEARCH, CHANDIGARH 160 012, INDIA.
2	DR. OM PRAKASH KATARE	PHARMACEUTICAL SCIENCES, PUNJAB UNIVERSITY, CHANDIGARH-160 014, INDIA.
3	RAJIV KUMAR	PHARMACEUTICAL SCIENCES, PUNJAB UNIVERSITY, CHANDIGARH-160 014, INDIA.
4	BHOOP, BHUPINDER SINGH	PHARMACEUTICAL SCIENCES, PUNJAB UNIVERSITY, CHANDIGARH-160 014, INDIA.
5	DR. INDERJEET KAUR	DEPARTMENT OF DERMATOLOGY, VENEREOLOGY & LAPROLOGY, POST GRADUAL INSTITUTE OF MEDICAL EDUCATION & RESEARCH, CHANDIGARH 160 012, INDIA.

PCT International Classification Number

A61K 38/12

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA