WO2006001035A2 - Composition liposomale synergique a base de tamoxifene pour application topique et son procede de preparation - Google Patents

Composition liposomale synergique a base de tamoxifene pour application topique et son procede de preparation Download PDF

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Publication number
WO2006001035A2
WO2006001035A2 PCT/IN2005/000221 IN2005000221W WO2006001035A2 WO 2006001035 A2 WO2006001035 A2 WO 2006001035A2 IN 2005000221 W IN2005000221 W IN 2005000221W WO 2006001035 A2 WO2006001035 A2 WO 2006001035A2
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WO
WIPO (PCT)
Prior art keywords
tamoxifen
composition
drug
skin
multilamellar vesicular
Prior art date
Application number
PCT/IN2005/000221
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English (en)
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WO2006001035A3 (fr
Inventor
Om Prakash Katare
Vivek Ranjan Sinha
Amit Bhatia
Rajiv Kumar
Somesh Gupta
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Lifecare Innovations Pvt. Ltd.
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Application filed by Lifecare Innovations Pvt. Ltd. filed Critical Lifecare Innovations Pvt. Ltd.
Publication of WO2006001035A2 publication Critical patent/WO2006001035A2/fr
Publication of WO2006001035A3 publication Critical patent/WO2006001035A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • DMBA dimethylbenzanthracene
  • 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.
  • 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.
  • 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.
  • TAM 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.
  • 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.
  • 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.
  • Soe et al. 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).
  • 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.
  • penetration enhancers like dimethyl sulphoxide, N-methyl-2-pyrrolidinone or 1- dodecylazacycloheptan-2-one.
  • 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.
  • 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- hydroxytam ⁇ xifen, which is the active form of the product at the molecular level.
  • 4-hydroxytam ⁇ xifen which is the active form of the product at the molecular level.
  • 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.
  • 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.
  • 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.
  • 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.
  • SERM selective estrogen receptor modulators
  • 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.
  • 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.
  • PDL Percent drug loading
  • 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 ⁇ m. Liposomes exhibit normal size distribution with homogenous population in the range of 1 to 13 ⁇ m, 90% of the liposomal population equal or below 12.9 ⁇ m.
  • the maximum drug entrapment was noted to be 57.5% i.e., 38.3 ⁇ g of drug per mg of lipids, for liposomes composed of hydrogenated phosphatidylcholine and cholesterol, employing 66.6 ⁇ g 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.
  • TAM is a drug of choice in the treatment of breast cancer which is administered through oral and parenteral route.
  • 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.
  • the designed systems were able to penetrate the skin layers, which can form the depots or reservoirs within the skin layers.
  • 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

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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

La présente invention concerne une composition vésiculaire multilamellaire contenant du tamoxifène administrée par voie transépidermique.
PCT/IN2005/000221 2004-06-28 2005-06-28 Composition liposomale synergique a base de tamoxifene pour application topique et son procede de preparation WO2006001035A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1196DE2004 2004-06-28
IN1196/DEL/2004 2004-06-28

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WO2006001035A2 true WO2006001035A2 (fr) 2006-01-05
WO2006001035A3 WO2006001035A3 (fr) 2006-10-26

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851433A (en) * 1986-02-24 1989-07-25 Imperial Chemical Industries Plc Therapeutic agents containing tamoxifen and salts thereof
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
US20030083313A1 (en) * 1998-12-04 2003-05-01 Reinhard Zeisig Means of tumor therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851433A (en) * 1986-02-24 1989-07-25 Imperial Chemical Industries Plc Therapeutic agents containing tamoxifen and salts thereof
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
US20030083313A1 (en) * 1998-12-04 2003-05-01 Reinhard Zeisig Means of tumor therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BHATIA A ET AL: "Tamoxifen in topical liposomes: Development, characterization and in-vitro evaluation" JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES 2004 CANADA, vol. 7, no. 2, 2004, pages 252-259, XP008067541 ISSN: 1482-1826 *
ZEISIG REINER ET AL: "Reduction of tamoxifen resistance in human breast carcinomas by tamoxifen-containing liposomes in vivo" ANTI-CANCER DRUGS, vol. 15, no. 7, August 2004 (2004-08), pages 707-714, XP008067535 ISSN: 0959-4973 *

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