WO2006001035A2 - Synergistic liposomal tamoxifen composition for topical application and method of preparing thereof. - Google Patents

Abstract

The present invention related to a Multilamellar vesicular composition containing tamoxifen for its transepidermal delivery.

Description

Title of the Invention Synergistic Liposomal Tamoxifen Composition For Topical Application And Method Of Preparing Thereof Field of invention: The present invention relates to synergistic liposomal tamoxifen composition for topical application and method of preparing thereof, for the treatment of localized skin problems including cutaneous melanoma (i.e. skin cancer), keloids, excessive dermal scarring, hypertrophic scars of acne, and psoriasis etc.

In particular, present invention relates to the field of carrier-based drug delivery wherein the drug molecules are accommodated at various levels within the carrier system (i.e. drug is encapsulated or non- encapsulated) so that its transport to the target site is effected in a most desirable manner. The delivery system is structured by selecting the appropriate components of varied physico-chemical nature, and designing them in an architectural pattern which suits for the purpose. This invention is appropriate for the treatment of localized skin problems including cutaneous melanoma (skin cancer), keloids, excessive dermal scarring, hypertrophic scars of acne and psoriasis, where the delivery of the drug, i.e. tamoxifen is effected in the trans- epidermal and dermal layers of the skin, by way of generating microstructures in-situ with the help of some bio-friendly and most suitable components. Description of the prior art Tamoxifen citrate is a non-steroidal estrogen receptor antagonist, known to be especially useful in the treatment of hormone-dependent tumours, and especially in the treatment of breast cancer in women. Tamoxifen is a first-line agent in the treatment of advanced breast cancer in postmenopausal patients and is alternative to first-line ovarian ablation in premenopausal women. Tamoxifen is also useful in the treatment of anovulatory infertility in women and idiopathic oligospermia in males. Tamoxifen has been used extensively to treat advanced breast cancer since its introduction in the early 1970' s and over the last decade, has been used as adjuvant treatment in the early stage disease. Benefits of adjuvant tamoxifen therapy in early stage breast cancer include increased overall survival as well as disease free survival for women over 50 years of age, with or without the concomitant use of cytotoxic chemotherapy. In addition to suppressing the post operative relapse of early stage breast cancer, adjuvant therapy with tamoxifen appears to prevent the development of second primary breast tumors in women, following resection of an initial primary breast cancer. In early breast cancer, it induces a 25% reduction in relapse rates and a 17% reduction in mortality. It also prolongs the disease free and overall survival time of patients with primary tumors. The therapeutic effect is more pronounced in women with Estrogen receptor positive tumors and with therapy duration longer than 2 years. The beneficial effects are most apparent among post menopausal women with ER positive tumors, but prolongation of disease free survival has been demonstrated among women with ER negative disease in several trials. The drug is official in Indian Pharmacopoeia, British Pharmacopoeia, United States Pharmacopoeia and British Pharmaceutical Codex. Tamoxifen is a first-line agent in the treatment of advanced breast cancer in postmenopausal patients and is alternative to first-line ovarian ablation in premenopausal women. Tamoxifen is also useful in the treatment of anovulatory infertility in women and idiopathic oligospermia in males. Recently efforts have been made to explore its newer applications i.e., in the treatment of localized skin problems such as cutaneous melanoma (skin cancer), keloids, excessive dermal scarring, hypertrophic scars of acne, and psoriasis. For example, in a study conducted by Zhao et al and El-Kattan et al (2001), enhanced transdermal delivery of tamoxifen, employing different penetration enhancers has been reported. Similarly, Hu.D. et al (1998), found topical administration of TAM to be effective in the treatment of excessive dermal scarring. In another study by Maenpaa et al (1993) on topical application of TAM employing different melanoma models, percutaneous administration of TAM yielded higher local tissue concentrations with minimal systemic absorption. Similarly, Soe et al. (1997) evaluated the therapeutic advantage with percutaneous application of TAM for the treatment of tumors. Significantly high local (subcutaneous and skin) concentration of the drug has been achieved, with lesser drug distribution to other organs. Mechanism of action of Tamoxifen: The antiestrogenic effect of Tamoxifen may be related to its ability to compete with estrogen for binding sites in target tissues such as the breast. It inhibits estrogen dependent secretion of transforming growth factor alpha and epidermal growth factor, by breast cancer cells and stimulates production of transforming growth factor beta. Both transforming growth factor alpha and epidermal growth factor bind to receptors in the cell membrane and promote breast cancer cell proliferation. Transforming growth factor beta inhibits growth of many epithelial cell lines, including estrogen receptor -negative breast cancer cells. The drug has been shown to inhibit or reverse mammary carcinoma in rats induced by dimethylbenzanthracene (DMBA). It also decreases the frequency of tumor development when administered with DMBA. In humans, tamoxifen has been shown to inhibit cell reproduction in estrogen-dependent breast cancer cell cultures. The drug produces no significant effect in tumor cultures without estrogen receptors. There is evidence to suggest that tamoxifen acts within a tumor cell, possibly by blocking estrogen receptors. Other mechanisms of action have also been suggested, possibly involving inhibition of messenger RNA by the tamoxifen-estrogen receptor complex within tumor cells. It has been hypothesized that antiestrogen controls the growth of breast cancer by interacting directly in cancer cells with the estrogen receptors rather than antiestrogen binding protein. Tamoxifen Citrate Prof ile Chemical Name: 1 (p-dimethylaminoethoxyphenyl) trans-l-(p-hy-droxyphenyl)-2- phenylbut-1-ene Empirical Formula: C32H37NO8 CAS Registry No: 54965-24-1 Molecular weight: 563.65 Description: a white or almost white crystalline powder Melting Point: 140-142⁰C pKa : 8.85 Solubility: Slightly soluble in water, acetone and in chloroform. Very slightly soluble in ethanol. Soluble in methanol. Polymorphism Tamoxifen exhibits polymorphism. Its crystals exist in two polymorphic forms. The normally available compound is present as the meta stable polymorph. On crystallisation from protic solvents, the compound forms crystals of the stable polymorph. Pharmacopoeial Status: LP, B.P, U.S.P & B.P.C Storage: Preserve in well- closed, light - resistant container Pharmacokinetics: Tamoxifen is well-absorbed from the gastrointestinal tract. Peak concentration occurs 4-7 hours after oral dosing. Peak concentration after single oral doses of 20 mg are about 40 μ/1. The drug is metabolized in the liver and only small amounts are excreted in the urine. The distribution half life is 7 to 14 hours. It is more than 99% protein bound in serum predominantly to albumin. In patients with breast cancer, the concentration of tamoxifen and its metabolites in pleural, pericardial and peritoneal effusion fluid are between 20 and 100% of those in serum, but only trace amounts enter the cerebrospinal fluid. The drug concentration in breast cancer tissue exceeds that in serum. The volume of distribution is 50-60 I/kg. The elimination is biphasic, with an initial half-life of around 7 hours and a terminal half-life of 7-11 days, and at least 4 weeks of treatment are required to reach steady state drug concentrations. Preliminary pharmacokinetics in woman using radio labeled tamoxifen citrate has shown that most of the radioactivity is slowly excreted in the faeces with only small amounts appearing in the urine. The drug is excreted mainly as conjugates, with unchanged drug and hydroxylated metabolites accounting for 30% of the total amount. Blood levels of total radioactivity following single oral dose of approximately 0.3 mg/kg reached peak values of 0.06-0.14 micrograms/ mL at 4-7 hours after dosing, with 20% -30% of the drug present as tamoxifen. There was an initial half -life of 7-14 hours with secondary peaks four or more days later. The prolongation of blood levels and faecal excretion is believed to be due to enterohepatic circulation. Tamoxifen administered orally, undergoes extensive hepatic metabolism, and is converted during its .passage through the liver to numerous metabolites including 1-[4-(2-N- dimethylaminoethoxy)phenyl]-l-(4-hydroxy-phenyl)-2-phenylbut-l-( Z)-ene (the primary alchohol), N-desmethyl tamoxifen, 4-hydroxy tamoxifen, 4-hydroxy-N-desmethyl tamoxifen, N-desdimethyl tamoxifen. The metabolite, 4- hydroxytamoxifen is the active form of the product at the molecular level. It is produced in much lower quantity and for this reason this 4-hydroxy derivative directly administered orally appears to be more rapidly degraded than tamoxifen and for this reason it is useless to administer it by this route. Also, it has a much shorter half-life than either the parent compound or the N-desmethyl metabolite. In addition, it is also known that the 4-hydroxy derivative is from twenty to one hundred times more active than tamoxifen as an anti-estrogen at the level of the estrogen receptors. However, the administration orally or parenterally, other than percutaneously, leads to a diffusion of this product throughout the organism, causing— inter alia~a detrimental paradoxical stimulation of the ovaries. It possesses—in addition to its property of blocking the 6

C^{1 1}T f hormonal site of the estrogen receptor (anti-estrogen action)~a stimulatory action on the receptors for another hormone involved in the good trophic quality of the breast, progesterone. N-desmethyl tamoxifen is the principal metabolite of tamoxifen. Its half -life in humans is 14 days. Although serum concentration of N-desmethyl tamoxifen is equal or more than the parent compound, it has a low binding affinity for estrogen receptors and is a less potent estrogen antagonist than tamoxifen. Major excretory route is via the bile as metabolites and enterohepatic recirculation occurs. Less than 1% is excreted in the urine. Dosage form and routes of administration TAM is generally administered through oral and parenteral route. It is available commercially in various oral formulations (mainly tablet dosage form). The normal oral dose of tamoxifen citrate for the treatment of breast cancer is 10-20 mg twice a day. Initial recommended doses are 10 mg twice a day followed by increases to 20 mg twice a day in one month if no response is evident. Higher daily doses (80 mg) have not generally resulted in greater improvement when used to treat breast cancer. The use of higher doses (40 mg) per day of tamoxifen citrate in a woman with metastatic breast cancer to the lung resulted in higher anti-tumor effect. Oral doses of 20 to 40 mg per day and two divided doses are recommended for the treatment of patients with advanced breast cancer and as adjuvant therapy. Increasing the dose to 90 mg daily may produce better response rates in postmenopausal patients with refractory breast cancer. It has shown that dose adjustments are not needed in mild to moderate renal failure. Adverse effects associated with tamoxifen: Tamoxifen is generally administered through oral and parenteral route. Despite being quite effective on oral administration, it exhibits certain side effects like distaste for food, abdominal cramps, nausea and vomiting. Various other documented adverse reactions associated with therapeutic doses of tamoxifen citrate include, but are not limited to, thrombocytopenia, leukopenia, anemia, thromboembolism, arterial thrombosis, mesenteric artery thrombosis, agranulocytosis, lightheadedness, depression, dizziness, headache, lassitude, mental confusion, delusions, hypercalcemia, galactorrhea, nausea, vomiting, pruritus vulvae, vaginal bleeding, endometriosis, priapism, oligospermia, optic disc swelling, retinal hemorrhages, retinopathy, skin rash, flushing and skeletal pain. Its other infrequent side effects include endometrial carcinoma, ocular problems, thromboembolic disorders and acquired drug resistance on long-term therapy. Although no cases of tamoxifen citrate overdose have been reported in humans, however in one report the animals receiving 100 to 200 times the recommended daily dose of developed respiratory difficulties and convulsions.

Drawbacks of the prior art As tamoxifen is known to exhibit side effects through systemic delivery routes such as oral and parenteral, it is desired to deliver the drug using alternative route, preferably topical, particularly when the conditions to be treated are topical, i.e., affecting the skin tissues. Thus to treat skin problems, it was but natural to find the possibility of delivering the molecules using topical preparations or vehicles. The work carried out in this direction, i.e., topical treatment of varied skin diseases using tamoxifen so far includes the following:

• Hu. D. et al. in 1998 have found that topical administration of TAM is effective in the treatment of excessive dermal scarring. (Hu, D., Hughes, M. A. and Cherry, G. W., Topical tamoxifen-a potential therapeutic regime in treating excessive dermal scarring? Br J Plast Surg, 5: 462-469, 1998;

• Maenpaa et al. in the year 1993 have found that topical application of TAM employing different melanoma models, percutaneous administration of TAM yielded higher local tissue concentrations with minimal systemic absorption. In addition cytostatic effect has also been observed in a variety of human melanomatous cell lines). (Maenpaa, J., Dooley, T., Wurz, G., VandeBerg, J., Robinson, E., Emshoff, V., Sipila, P., Wiebe, V., Day, C. and DeGregorio, M., Topical toremifine: a new approach for cutaneous melanoma. Cancer Chemother Pharmacol, 32: 392-395, 1993).

• Similarly, Soe et al. (1997) evaluated the therapeutic advantage with percutaneous application of TAM for the treatment of tumors. Significantly high local (subcutaneous and skin) concentration of the drug has been achieved, with lesser drug distribution to other organs. (Soe, L., Wurz, G. T., Maenpaa, J. U., Hubbard, G. B., Cadman, T. B., Wiebe, V. J., Theon, A. P. and DeGregorio, M. W., Tissue distribution of transdermal toremifene. Cancer Chemother Pharmacol, 39: 513-520, 1997).

• Besides TAM, the percutaneous application of 4-hydroxy tamoxifen, an active metabolite of TAM, has also been found to exhibit anticancer activity. (Kuttenn, F. and Mauvais-Jarvis, P., Intratumoral levels and metabolism of 4-hydroxytamoxifen after percutaneous administration at the breast level. C R Acad Sd III, 300: 457-462, 1985; Mauvais-Javis, P., Baudot, N., Castaigne, D., Banzet, P. and Kuttenn, F., trans-4-Hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast. Cancer Res, 46: 1521-1525, 1986); Sauvez, F., Drouin, D. S., Attia, M., Bertheux, H. and Forster, R., Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats. Carcinogenesis, 20: 843-850, 1999).

■ A US Patent 4,851,433 prescribes the use of tamoxifen per se, or an acid-addition salt of tamoxifen, for example the tamoxifen hydrochloride, tamoxifen hydrobromide, tamoxifen citrate or tamoxifen D-gluconate, for the relief of psoriasis in a topical formulation. A suitable topical formulation for example an ointment, cream or lotion containing upto 10% by weight of therapeutic agent and typically in the range, for example 0.1 to 5 % by weight which can normally be applied to the skin, has been disclosed containing penetration enhancers like dimethyl sulphoxide, N-methyl-2-pyrrolidinone or 1- dodecylazacycloheptan-2-one. ■ In another report, Heard CM et al., found improved in vitro transcutaneous delivery of Tamoxifen and polyunsaturated fatty acids from non-aqueous gels containing Tamoxifen and varying amounts(5%, 10%, 15%) of borage oil. Addition of borage oil to Tamoxifen could be a valuable addition to the current treatment of breast cancer. However, oral administration of both drugs, either in combination or as single doses poses potential problem, as the wide distribution of tamoxifen in the body can lead to undesirable effect on CNS, uterus and liver. (Charles M Heard,Costantino Congiatu, Simon J Gallagher, John Harwood, Clare Karia, Chris Mc Guigan, MartaNemcova, Tereza Nouskova, π-π Complexation between Tamoxifen and borage oil/ γ linolenic acid and its effect on topical delivery) ■ Patent US 4919937 describes the topical administration of 4- hydroxytamoxifen in an aqueous or alcoholic gel. In this study, Mauvais-Jarvis et al., describe the topical administration of an alcoholic solution of 4-Hydroxy tamoxifen was applied as 60% strength alcoholic solution, this compound applied on the skin overlying cancerous mammary tumors proved capable of passing through the cutaneous barrier and being taken up on the receptor molecules in these tumors. The Applicants have observed that, in contrast, tamoxifen cannot be activated to its 4-hydroxy derivative by the percutaneous route, since the breast does not have at its disposal, like the liver, the enzymes needed for the conversion. ■ Another US Patent 5,904,930 describes transdermal system in the form of a patch that comprises a tamoxifen derivative and an absorption-promoting additive for systemic administration.

Similarly, enhanced transdermal delivery of TAM, employing different penetration enhancers, i.e_v terpene enhancers like menthone, has been reported by Zhao et al and El-Kattan et al in the year 2001 (the results are positive) (Zhao, K., Singh, S. and Singh, J., Effect of menthone on the in-vitro percutaneous absorption of tamoxifen and skin reversibility. Int J Pharm, 219: 177-181, 2001.; El-Kattan, A. F., Asbill, C. S., Kim, N. and Michniak, B. B., The effect of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. Int J Pharm, 215: 229-240, 2001).

• In another report, enhanced percutaneous absorption of Tamoxifen using penetration enhancers like oleic acid/ethanol and oleic acid/ propylene glycol has been reported by S.Gao, J.Singh ( Effect of Oleic acid/ethanol and oleic acid/ propylene glycol on the in vitro percutaneous absorption of 5-fluorouracil and tamoxifen and the macroscopic barrier property of procine epidermis, hit J ofPharm 165( 1998) 45-55. Drawbacks of prior art Tamoxifen as an anti estrogen is commonly used in the palliative treatment of breast cancer. It is commonly administred by oral route but the drug is not reliably absorbed orally because it is highly insoluble in water. Secondly, it undergoes extensive first pass metabolism thereby reducing the bioavailability of the drug. Tamoxifen administered orally is converted during its passage through the liver to numerous metabolites, including l-[4-(2-N-dimethylaminoethoxy)phenyl]-l-(4- hydroxy-phenyl)-2-phenylbut-l-( Z)-ene, also named 4- hydroxytamόxifen, which is the active form of the product at the molecular level. On the other hand, this 4-hydroxy derivative directly administered orally appears to be more rapidly degraded than tamoxifen and for this reason it is useless to administer it by this route. In addition, it is also known that the 4-hydroxy derivative is from twenty to one hundred times more active than tamoxifen as an anti- estrogen at the level of the estrogen receptors. However, the administration orally or parenterally, other than percutaneously, leads to a diffusion of this product throughout the organism, causing—inter alia~a detrimental paradoxical stimulation of the ovaries. Oral administration appears to be of restricted efficacy due to the destruction of the compound itself through its passage in the liver, while injection, leading to the introduction of the said compound into the blood circulation, can induce the detrimental ovarian effects, through a systemic action. So, novel dosage form and new route of administration is envisaged for use of tamoxifen in the treatment of breast cancer. It has been noted that tamoxifen possesses a high potential in treating skin disorders. It is estimated that 90% of patients who initially respond to tamoxifen will acquire resistance to his drug within one year.lt is atleast partially possible to overcome tamoxifen resistance if selective estrogen receptor modulators ( SERM ) or new non steroidal antiestrogens like Faslodex, Raloxifene,Toemifene, Droloxifene, ERA-923 or the prodrug are used. Another possibility to prevent or overcome resistance is to change the application form of tamoxifen for therapeutic purposes. The transport of the anti-estrogen to, into and within the tumor cells seems to be a very critical factor for the development of tamoxifen resistance. Thus, Despite being effective there had been no attempts to find a proper delivery vehicle, which can carry the tamoxifen molecules and make them available in a desired physico-chemical state for an improved therapeutic action. The efforts made so far did not show the role and influence of vehicle on topical delivery of tamoxifen, while this is supposed to be a very crucial factor. Probably this could be the key reason that the work in this area began almost a decade ago but did not advance as expected. And no such commercial formulation is available till date. Therefore, in the view of aforementioned deficiencies attendant with the prior art methods for the treatment of breast cancer using tamoxifen, it should be apparent that their still exists a need in the art for a rapid , reliable, safe and cvonvienient method of administering tamoxifen in the treatment of breast cancer. Also, the chemicals or substances such as menthone, used in the previous studies to help enhance skin-transport of tamoxifen, are not supposed to be skin-friendly and may affect the skin tissues. Objectives of the present invention The object of the present invention is to achieve the transepidermal delivery of tamoxifen by administering it via the topical route in order to explore and exploit the potential of tamoxifen in the treatment of skin disorders such as psoriasis, cutaneous melanoma (skin cancer), keloids, excessive dermal scarring, hypertrophic scars of acne etc. The objective had been set to design and develop a vehicle, which could present tamoxifen to an affected pathophysiological site in a most desired manner. The effective and safer delivery using phospholipid- based vesicular (liposomal) systems has been envisaged, which possess considerable potential for topical drug delivery. Liposomal systems as drug delivery carriers generate the required physico-chemical atmosphere (i.e., skin hydration in lipid rich environment) in the skin layers, which in turn also favour the retention of the drug at the affected site for a prolonged period of time (i.e., depot or reservoir effect), thereby having a synergistic effect. Detailed description of the invention Method The drug along with the lipid components namely, phospholipid, cholesterol are dissolved in sufficient amount of dicholromethane in a round bottom flask. The flask is then attached to the rotavapor for evaporation of the solvent and formation of a thin film. The flask is subjected to overnight vacuum for complete removal of the residual solvent. The dry, thin film is then hydrated with saline solution . The suspension is added to the required amount of methylcellulose so as to gel the entire system. The addition of methylcellulose is a crucial step, wherein methylcellulose is made into slurry at high temperature (60 to 65°C) and then added to the entire system at a substantially lower temperature (0 to 5°C). This transition in temperature allows to form a gel product in a quicker succession so as to encage the vesicles within the gel matrix to help maintain the uniformity. The various parameters which influence the quality of the product include the level of the drug, lipid, solvent, nature of the hydration medium, hydration temperature and the process variables such as rotational speed, temperature and the surface area of the glass support etc. Drug entrapment studies were carried out by separating the unentrapped drug from the prepared liposomes using mini column centrifugation method and Percent drug loading (PDL) for the prepared liposomes has been calculated. Prepared liposomal batches were monitored for their morphological attributes and size distribution profile. The ability of vesicles to retain the drug (i.e., drug-retentive behavior) was assessed by keeping the liposomal suspensions at four different temperature conditions, i.e., 4-8°C (Refrigerator; RF), 25±2°C (Room temperature; RT), 37±2°C and 45+2⁰C for a period of 5 weeks. Skin permeation studies with TAM-containing liposomal formulations (liposome suspension and liposomes incorporated in Carbopol gel), were carried out using abdominal skin of LACA mice. The results obtained were compared with that of non-lip osomal formulations of TAM, i.e., aqueous solution and Carbopol gel, containing equivalent amounts of TAM. The ability of vesicles to help retain the drug within the skin milieu (i.e., depot-effect) was investigated by determining the amount of drug retained in the skin samples employed in permeation studies. Outcome of the investigations (Results)

The formula and the preparatory conditions (like hydration media and temperature, instrument parameters) for the process development were optimized to obtain the product with best quality and performance. The liposomes formed were found to be multilamellar in nature, multilamellarity of the vesicles was confirmed by optical photomicrograph of liposomes obtained at suitable magnification (1000X). These multilamellar vesicles are observed to be more suitable for topical delivery. The mean vesicle diameter, using laser light scattering technique for liposomes was found to be 5.3 μm. Liposomes exhibit normal size distribution with homogenous population in the range of 1 to 13 μm, 90% of the liposomal population equal or below 12.9μm. The maximum drug entrapment was noted to be 57.5% i.e., 38.3 μg of drug per mg of lipids, for liposomes composed of hydrogenated phosphatidylcholine and cholesterol, employing 66.6 μg drug per mg of lipids during preparation, and the loaded drug remain solubilized in the lipid-phase or bilayers). Skin permeation studies were carried out using abdominal skin of LACA mice, and employing modified Franz diffusion cell. Significantly higher skin permeation of Tamoxifen from liposomal formulations (flux values 63.67 μg/cm²/h and 59.87 μg/cm²/h for liposomal suspension and liposomal gel has been achieved, as compared to solution (21.65 μg/cm²/h) and Carbopol gel (24.55 μg/cm²/h) containing tamoxifen. Also, the performance included the ability of the formulation to retain the drug within the skin layers vis-a-vis conventional dosage forms. Higher magnitude of tamoxifen retention in the skin layers was noted with liposomal formulations vis-a-vis non-liposomal formulations of the drug. Liposomes stored at 2 to 8 ° C were found to be most stable, with only 5% drug loss over the storage period of 5 weeks. The storage conditions (i.e., 4-8°C or Refrigeration conditions) were optimized to maintain the originality of the product. Conclusions: ■ TAM is a drug of choice in the treatment of breast cancer which is administered through oral and parenteral route. ■ Recently, TAM has been shown to possess the potential in treating the patho-physiological conditions other than skin viz. as cutaneous melanoma, keloids, hypertrophic scars, excessive dermal scarring and psoriasis. ^■ The attempts so far made for the topical delivery of tamoxifen are inadequate. No proper science or engineering has been considered at its delivery level, which is supposed to be a major aspect. ■ Realizing the potential of TAM as well as the need to develop a properly designed delivery vehicle, which can deliver the molecules to the affected site, the project was taken up. ■ In order to provide the proper delivery of TAM, liposomes were choosen as carrier systems which have been noted to be superior over conventional topical preparations. Phospholipids, being the major component of liposomal systems, can easily get integrated with the skin lipids and maintain the desired hydration conditions to improve drug penetration and localization in the skin layers. ^■ Successful attempts have been made to incorporate the TAM in liposomes. ■ The studies included the optimization of lipid composition, which would yield the desired nature of carriers such as size and physical stability. ■ Also, the designed systems were able to penetrate the skin layers, which can form the depots or reservoirs within the skin layers. Thus by virtue of facilitated transport of drug molecules into the skin and its prolonged stay at the affected site, the liposomal formulation is supposed to perform as desired, i.e., with improved efficacy and safety as well, as the drug would not be available for systemic absorption. ■ The formulated systems have been taken up for preliminary clinical trials. Though the study is not complete, but the initial results are quite encouraging. Specific Examples Composition of the prepared liposomal product:

Brief Description of the Prepared Product

Claims

We claim : 1. A Multilamellar vesicular composition containing tamoxifen for its transepidermal delivery. 2. Multilamellar vesicular composition of TAM, and the said composition contains concentric bilayered vesicles dispered therein, the said vesicles having an average particle size in the micron range of lμm to lOμm. 3. The multilamellar vesicular composition as claimed in claim 1, is used for the topical treatment of skin problems such as psoriasis, cutaneous melanoma (skin cancer), keloids, excessive dermal scarring, hypertrophic scars of acne etc. 4. Inter and intra multilamellar vesicular composition as claimed in claim 1, wherein the said lipid phase of said vesicle contains phospholipid and cholesterol. 5. Inter and intra multilamellar vesicular composition as claimed in claim 3, wherein said phospholipid is saturated in nature and provides a controlled release of TAM from the composition. 6. Multilamellar vesicular composition as claimed in claim 1, having incorporated therein a hydrocolloid gelling agent in an amount sufficient to form a gel. 7. Multilamellar vesicular composition as claimed in claim 5, wherein said hydrocolloid gelling agent is methylcellulose. 8. Inter and intra multilamellar vesicular composition as claimed in claim 6, wherein said methylcellulose is present in an amount ranging from 0.5% to 3.0% by weight based upon the total weight of the composition. 9. Inter and intra multilamellar vesicular composition as claimed in claim 1, wherein said aqueous phase comprises normal saline.