Title of Invention	"A PHARMACEUTICAL COMPOSITION FOR TREATING SOLID TUMORS AND A METHOD OF PREPARING SAME THEREOF"
Abstract	A method for treating solid tumors by administering at a site in a patient through anticancer chemotherapeutic composition having incorporated into a natural polymeric biocompatible matrix releasing the chemotherapeutic by diffusion or degradation over a period of at least eight hours in an amount effective to treat the solid tumor. A method and device for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The device consists of matrix which release drug over an extended time period while at the same time preserve the bioactivity of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes. The devices are implanted within or immediately adjacent to the tumors to be treated or the site where they have been surgically removed

Title of Invention

"A PHARMACEUTICAL COMPOSITION FOR TREATING SOLID TUMORS AND A METHOD OF PREPARING SAME THEREOF"

Abstract

A method for treating solid tumors by administering at a site in a patient through anticancer chemotherapeutic composition having incorporated into a natural polymeric biocompatible matrix releasing the chemotherapeutic by diffusion or degradation over a period of at least eight hours in an amount effective to treat the solid tumor. A method and device for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The device consists of matrix which release drug over an extended time period while at the same time preserve the bioactivity of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes. The devices are implanted within or immediately adjacent to the tumors to be treated or the site where they have been surgically removed

Full Text	A PHARMACEUTICAL COMPOSITION COMPRISING AN ANTICANCER CHEMOTHERAPEUTIC AGENT AND A BIODEGRADABLE NATURAL POLYMERIC CHITOSAN MATRIX FOR LOCAL DELIVERY OF DRUG FIELD OF INVENTION The present invention relates to a novel drug delivery system capable of delivering an active ingredient to a localized area having solid tumors over an extended period of time, said drug delivery system comprising a natural biodegradable polymeric matrix and the active ingredient, wherein the active ingredient is incorporated in the said matrix. More particularly, the present invention relates to a novel pharmaceutical composition for delivery of anticancer chemotherauptic agent such as paclitaxel to a localized area having solid tumors over an extended period of time, said pharmaceutical composition comprising a natural biodegradable polymeric chitosan matrix, and the anticancer chemotherauptic agent being incorporated in the chitosan matrix. The composition of the present invention introduces the anticancer agent within or immediately adjacent to the solid tumors to be treated. Further, the drug delivery system prevents high systemic levels of the agent and associated toxicities. BACKGROUND OF THE INVENTION Cancer is the major disease due to which many people are dying throughout the world the world. In USA, cancer remains second only to cardiac disease as a cause of death. Studies show that 20% of the Americans die due to cancer, half of whom die due to lung, brest and colon-rectal cancer. It is anticipated that the percentage will increase to l/3rd within the next couple of decades. Designing effective treatments for patients with cancer has represented a major challenge. The current regimen of surgical resection, external beam radiation therapy, and/or systemic chemotherapy has been partially successful in some kinds of malignancies, but has not produced satisfactory results in others. In some malignancies, such as brain malignancies, this regimen produces a median survival of less than one year. For example, 90% of resected malignant gliomas recur within two centimeters of the original tumor site within one year. PRIOR ART DESCRIPTION Though effective in some kinds of cancers, the use of systemic chemotherapy has had minor success in the treatment of cancer of the colon-rectum, esophagus, liver, pancreas, and kidney and melanoma. A major problem with systemic chemotherapy for the treatment of these types of cancer is that the systemic doses required to achieve control of tumor growth frequently result in unacceptable systemic toxicity. Efforts to improve delivery of chemotherapeutic agents to the tumor site have resulted in advances in organ-directed chemotherapy, as by continuous systemic infusion, for example. However, continuous infusions of anticancer drugs generally have not shown a clear benefit over pulse or short-term infusions. Implantable elastomer access ports with self-sealing silicone diaphragms have also been tried for continuous infusion, but extravasation remains a problem. Portable infusion pumps are now available as delivery devices and are being evaluated for efficacy. (See Harrison's Principles of Internal Medicine 431-446, E. Braunwald et al., ed., McGraw-Hill Book Co. (1987) for a general review). In the brain, the design and development of effective anti-tumor agents for treatment of patients with malignant neoplasms of the central nervous system have been influenced by two major factors: (i) the blood-brain barrier provides an anatomic obstruction, limiting access of drugs to these tumors; and (ii) the drugs given at high systemic levels are generally cytotoxic. Efforts to improve drug delivery to the tumor bed in the brain have included transient osmotic disruption of the blood brain barrier, cerebrospinal fluid perfusion, and direct infusion into a brain tumor using catheters. Each technique has had significant limitations. Disruption of the blood brain barrier increased the uptake of hydrophilic substances into normal brain, but did not significantly increase substance transfer into the tumor. Only small fractions of agents administered into the cerebrospinal fluid actually penetrated into the brain parenchyma. Drugs that have been used to treat tumors by infusion have been inadequate, did not diffuse an adequate distance from the site of infusion, or could not be maintained at sufficient concentration to allow a sustained diffusion gradient. The use of catheters has been complicated by high rates of infection, obstruction, and malfunction due to clogging. See T. Tomita, "Interstitial chemotherapy for brain tumors: review" J. Neuro-Oncology 10:57-74 (1991). Controlled release biocompatible polymers for local drug delivery have been utilized for contraception, insulin therapy, glaucoma treatment, asthma therapy, prevention of dental caries, and for cancer chemotherapy. (Langer et al., 1981) Brain tumors have been particularly refractory to chemotherapy. One of the chief reasons is the restriction imposed by the blood-brain barrier. Agents that appear active against certain brain tumors, such as gliomas, in vitro may fail clinical trials because insufficient drug penetrates the tumor. Although the blood-brain barrier is disrupted at the core of a tumor, it is largely intact at the periphery where cells actively engaged in invasion are located. Experimental intratumoral regimens include infusing or implanting therapeutic agents within the tumor bed following surgical resection, as described by Tamita, T, J. Neuro-Oncol. 10:57-74(1991). Delivery of a low molecular weight, lipid soluble chemotherapeutic, l,3-bis(2-chloroethyl)-l-nitrosourea (carmustine), in a polymer matrix implanted directly adjacent to brain tumors has some efficacy, as reported by Brem, et al., J. Neurosurg. 74:441-446 (1991); Brem, et al., Eur. J. Pharm. Biopharm. 39(l):2-7 1993; and Brem, et al., "Intra-operative Chemotherapy using biodegradable polymers: Safety and Effectiveness for Recurrent Glioma Evaluated by a prospective, Multi-Institutional Placebo-Controlled Clinical Trial" Proc. Amer. Soc. Clin. Oncology May 17, 1994. Polymer-mediated delivery of carmustine was superior to systemic delivery in extending survival of animals with intracranial 9L gliosarcoma and has shown some efficacious results in clinical trials. However, carmustine is a low molecular weight drug, crosses the blood-barrier and had previously been demonstrated to have some efficacy when administered systemically. Unfortunately, the predictability of the efficacy of chemotherapeutic agents remains low. Drugs that look effective when administered systemically to animals may not be effective when administered systemically to humans due to physiological differences and bioavailability problems, and drugs that are effective systemically may not be effective when administered locally. Due to low efficacy during local administration it becomes imperative to undertake to devise efficient drug delivery system which would reduce systemic toxicity and enhance bioavailability and efficacy. Many other chemotherapeutics which are efficacious when administered systemically must be delivered at very high dosages in order to avoid toxicity due to poor bioavailability. For example, paclitaxel (taxol) has been used systemically with efficacy in treating several human tumors, including ovarian, breast, and non-small cell lung cancer. However, maintenance of sufficient systemic levels of the drug for treatment of tumors has been associated with severe, in some cases "life-threatening" toxicity, as reported by Sarosy and Reed, J. Nat. Med. Assoc. 85(6):427-431 (1993). Paclitaxel is a high molecular weight (854), highly lipophilic deterpenoid isolated from the western yew, Taxus brevifolia, which is insoluble in water. It is normally administered intravenously by dilution into saline of the drug dissolved or suspended in polyoxyethylated caster oil. This carrier has been reported to induce an anaphylactic reaction in a number of patients (Sarosy and Reed (1993)) so alternative carriers have been proposed, such as a mixed micellar formulation for parenteral administration, described by Alkan-Onyuksel, et al., Pharm. Res. 11(2), 206-212 (1994). There is also extensive non-renal clearance, with indications that the drug is removed and stored peripherally. Pharmacokinetic evidence from clinical trials (Rowinsky, E. K.., et al., Cancer Res. 49:4640-4647 (1989)) and animal studies (Klecker, R. W., Proc. Am. Assoc. Cancer Res. 43:381 (1993)) indicates that paclitaxel penetrates the intact blood-brain barrier poorly, if at all, and that there is no increased survival from systemic intraperitoneal injections of paclitaxel into rats with intracranial gliomas. Paclitaxel has been administered in a polymeric matrix for inhibition of scar formation in the eye, as reported by Jampel, et al., Opthalmic Surg. 22, 676-680 (1991), but has not been administered locally to inhibit tumor growth. 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Glutaraldehyde cross-linked chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle. Biomaterials 16: 769-775. Jampel, et al., 1991. In Vitro Release of Hydrophobic Drugs From Polyanhydride Disks. Opthalmic Surg. 22: 676-680. Klecker, et al., 1993. Distribution and metabolism of .sup.3 H-taxol in the rat. Proc. Am. Assoc. Cancer Res. 43: 380. Langer, et al., 1981. Biocompatibility of polymeric delivery systems for macromolecules. J. Biomed. Mater. Res. 15: 267-277. Leong, et al., 1985. Bioerodible polyanhydrides as drug-carrier matrices, I: Characterization, degradation, and release characteristics. J. Med. Biomed. Mater. Res. 19:941. Liggins, et al., 1997, Solid-state characterization of paclitaxel. J. Pharm. Sci. 86: 1458-1463. Martin, 1994. Polymer science. In: Physical pharmacy. Physical chemical principles in the pharmaceutical sciences. Martin, A. (Ed.) Waverly International (Maryland), pp: 556-594. Miyazaki, et al., 1990. Pharmaceutical application of biomedical polymers. XXIX. Preliminary study on film dosage form prepared from chitosan for oral drug delivery. Acta Pharm. Nord. 2: 401-406. Nunthanid, et al., 2001. Physical properties and molecular behavior of chitosan films. Drug Dev. Ind. Pharm. 27: 143-157. Pillai and Panchagnula, 2001. Polymers in drug delivery. Cur. Opin. Chem. Biol. 5: 447-451. Ratner, et al., 1999. Characterization of deliver systems, surface analysis and controlled release systems. In: Encyclopaedia of controlled drug delivery. Mathiowitz, E. (Ed.) John Wiley and Sons, Inc. (New York), pp: 261-269. Rowinsky, et al., 1989. Phase I and Pharmacodynamic Study of Taxol in Refractory Acute Leukemias. Cancer Res. 49: 4640-4647. Sarosy and Reed, 1993. Taxol Dose Intensification and Its Clinical Implications. J. Nat. Med. Assoc. 85:427-431. Tamita, 1991. Interstitial chemotherapy for brain tumors: review. J. Neuro-Oncology 10: 57-74. Tomihata, et al., 1997. In vitro and in vivo degradation of films of chitin and its deacetylated derivatives. Biomaterials 18:567-575. OBJECTIVES OF THE INVENTION The main object of the present invention is to provide a drug delivery system, a chemotherapeutic composition and a method of producing like composition which provides for effective long-term release of anticancer agents that are not soluble in aqueous solutions or which have limited bioavailability in vivo for treatment of solid tumors. Another object is to overcome the problems of bioavailability, efficacy and systemic related toxicity in treatment of cancers. Yet another object of the invention relates to providing a drug delivery system, a composition and a method for the treatment of solid tumors through localized delivery with anticancer chemotherapeutic agents that avoids high systemic levels of the agent and associated toxicities. Yet another objective of the invention relates to the strategy to remove constraints encountered during drug delivery for solid tumors, thereby making efficient delivery of both low molecular and high molecular weight drugs. Yet another objective of the invention relates to the elimination the blood-brain barriers encountered during the delivery and enhances the local administration of the drug in humans and animals. SUMMARY OF THE INVENTION The present invention provides novel drug delivery system and a pharmaceutical composition for delivery of anticancer chemotherauptic agent such as paclitaxel to a localized area having solid tumors over an extended period of time, said drug delivery system comprising a natural biodegradable polymeric chitosan matrix, and the anticancer chemotherauptic agent being incorporated in the chitosan matrix, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability in vivo. The drug delivery system of the present invention releases the drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. The drug delivery system of the present invention is implanted within or immediately adjacent to the tumors to be treated or the site from where they have been surgically removed. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph of the cumulative percent release over time (hours) for paclitaxel from polymer films loaded with 33 % by weight paclitaxel in absence of (a) lysozyme and (b) in presence of lysozyme in the release medium. FIG. 2 is a graph of illustrating the mechanical strength of film as studied through force-time profiles (a) blank film and (b) paclitaxel-loaded film. FIG. 3. Differential scanning calorimetric studies to investigate physical transformations induced in chitosan and paclitaxel by comparing solid-sate features of pure components with that in films (a) paclitaxel, (b) chitosan powder, (c) blank film and (d) paclitaxel chitosan film. Thermogarms were obtained at a scan rate of 5°C/min. When paclitaxel chitosan film was heated to 190°C, cooled to 25°C and reheated, peaks I, II, III were found to be irreversible in nature. FIG. 4. Scanning electron photomicrographs of (A) paclitaxel, (B) recrystallized paclitaxel, (C) blank film, and (D) paclitaxel chitosan film obtained at different magnifications. Paclitaxel micrographs were that of commercial sample without any modification. Recrystallized paclitaxel was obtained by evaporation of hydro-ethanolic solution of paclitaxel and poloxamer 407 under identical conditions as used for film casting in the absence of chitosan. FIG 5. X-ray diffraction patterns of (a) blank chitosan film; (b) paclitaxel and (c) paclitaxel chitosan film at ambient temperature to examine solid-state features of paclitaxel in film. FIG 6. Histopathological examination for generalized inflammatory response to assess biocompatibility of s.c. implanted chitosan film in mice (A) control tissue and (B) paclitaxel chitosan film embedded tissue following implantation of the film after 60 days. Magnification x 250. Film is indicated by arrow in (B). Histological assessment is usually based on cellular infiltration between and around delivery system, edema, formation of granulation tissue and presence of multi-nucleated giant cells/macrophages. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a localized drug delivery system to solid tumors. This drug delivery system of the present invention provides for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability in vivo, are described. The drug delivery system of the present invention releases the active ingredient over an extended time period, while at the same time preserving the bioactivity and bioavailability of the agent. The drug delivery system of the present invention consists of biodegradable polymeric chitosan matrix having the active ingredient, paclitaxel incorporated in it. The drug delivery system of the present invention is implanted within or immediately adjacent to the tumors to be treated or the site where they have been surgically removed. One method of extending the duration of exposure of a tumor to a drug is to deliver the drug interstitially to the tumor. Controlled-infusion pumps and biodegradable polymer devices are currently being developed to deliver drugs in such a sustained fashion to tumors of the central nervous system. Interstitial delivery minimizes the systemic drug levels and side effects of an agent. Delivering chemotherapeutic drugs locally to a tumor is an effective method of prolonging tumor exposure to the drug while minimizing the drug's dose-limiting, systemic side effects, such as neutropenia. Interstitial drug delivery bypasses the limitations of the blood-brain barrier. Presently, it is unclear how well some drugs such as paclitaxel crosses the blood-brain barrier. As described herein, the present invention also provides a composition comprising a chemotherapeutic active agent, which is not water soluble and has poor bioavailability in vivo impregnated into a biocompatible and biodegradable polymeric matrix for use in treatment of solid tumors. The chemotherapeutic active agent is released by diffusion and/or degradation over a therapeutically effective time, usually not less than 1 month. More particularly, the present invention also provides a composition comprising paclitaxel, which is not water soluble and has poor bioavailability in vivo impregnated into a biocompatible and biodegradable polymeric chitosan matrix for use in treatment of solid tumors. The paclitaxel is released by diffusion and/or degradation over a therapeutically effective time, usually not less than 1 month. In some of the previous attempts, in order to develop a local drug delivery system based on paclitaxel, a biodegradable chitosan film was attempted. However, effective incorporation of the paclitaxel in the chitosan matrix was not achieved. This was mainly due to the fact that chitosan is only soluble in aqueous acidic solutions where as paclitaxel being a hydrophobic drug, is insoluble under similar conditions. Thus, it should be noted that the common view in the field is that paclitaxel cannot be incorporated in the polymeric chitosan matrix because of their differences in solubility. One of the interesting points to note there is that in all the initial studies conducted, liposomes were used as carriers for the incorporation of paclitaxel into the chitosan polymeric matrix. The Inventors also tried to incorporate paclitaxel in the biodegradable chitosan polymeric matrix with liposomes as the carrier. In early stages of formula optimization studies, the Inventors observed that when liposomes were used as the carrier, paclitaxel was not incorporated into film but crystallized out as needles due to lack of solubilization in aqueous chitosan solutions thus, confirming the finding of the earlier scientists. Despite the failure, the Inventors tried the process of incorporating the paclitaxel into the polymeric chitosan matrix under various conditions. The Inventors also tried changing the ingredients that are used during the process. After much trial and error, and to the surprise of the Inventors, they noticed that when the lipids (used as carrier) were replaced with poloxamer, crystallization of the paclitaxel as needles did not occur. They also noticed that the lipids were prone to oxidation and hydrolytic degradation processes which gets further accelerated under heat. However, the poloxamer was not prone to oxidation and hydrolytic degradation processes. The exact mechanism by which the incompatibility is obliterated is not known, but it is plausible that poloxamer micelles act by solubilization phenomenon that are further stabilized by ETOH. Accordingly, the present invention provides a pharmaceutical composition for preventing and/or treating solid tumors said composition comprising natural polymeric matrix, poloxamer and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, and plasticizers. In an embodiment of the present invention, the natural polymer matrix is biocompatible and biodegradable. In another embodiment of the present invention, the natural polymer matrix is hydrophilic, soluble in water, retains integrity for suitable time period, strong but flexible and does not crumble or fragment during use. In yet embodiment of the present invention, the anticancer chemotherapeutic agent is impregnated within, throughout and/or on the surface of the natural polymeric matrix. In still another embodiment of the present invention, the anticancer chemotherapeutic agent is released by diffusion, degradation of the polymer or in combination thereof. hi one more embodiment of the present invention, the anticancer chemotherapeutic agent is hydrophobic, high molecular weight, exhibit rapid non-renal clearance in vivo and have functional equivalent derivatives. In one another embodiment of the present invention, the anticancer chemotherapeutic agent/s includes an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), mercaptopurine, fludarabine, cytarabine, asparaginase, pentostatin, procarbazine, thiotepa, streptozocin, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel, etc.), an alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, carnptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative). In a further embodiment of the present invention, the anticancer chemotherapeutic agent/s include paclitaxel and its functionally effective derivatives like hydrophobic hydroxy esters of paclitaxel where one or more of the three hydroxyls of paclitaxel are modified with long chain alkyl or aromatic pendant groups. In an embodiment of the present invention, the anticancer chemotherapeutic agent is present in the polymeric matrix in one or more solid state forms such as amorphorus, semicrystalline, crystalline, hydrated and hydrated forms. In another embodiment of the present invention, the natural polymeric matrix used is polymeric chitosan matrix. In yet another embodiment of the present invention, the dosage of anticancer chemotherapeutic agent/s is 10-25 mg. In still another embodiment of the present invention, the polymer chitosan is 20-250 mg. In one more embodiment of the present invention, the Paclitaxel and chitosan ratio is 0.00001 to 1: 1 In one another embodiment of the present invention, the Paclitaxel and surfactant ratio is 0.00001 to 0.2: 1. In a further embodiment of the present invention, the Paclitaxel and lipids ratio is 0.00001 to 0.1: 1 In an embodiment of the present invention, the Paclitaxel and plasticizers ratio is 0.00001 to 1: 1 In another embodiment of the present invention, the preferred weight percent range of anticancer chemotherapeutic agent is 1% to 90 % In yet another embodiment of the present invention, the time duration for the treatment varies from one month to six months depending upon the size of implant, location and size of the tumor to be treated. In still another embodiment of the present invention, the anticancer chemotherapeutic agent is released by diffusion or degradation over a period of eight hours. The present invention also provides a method of preparing a biocompatible and biodegradable composition, said method comprising, incorporating an anticancer chemotherapeutic agent/s in a natural polymeric chitosan matrix in presence of poloxamer carrier and optionally along with additives selected from the group consisting of surfactant/s, and plasticizers In an embodiment of the present invention, the anticancer chemotherapeutic agent/s is implanted in the polymer matrix chitosan by using micellar entrapment during film casting while adjusting the polarity of the medium with ethanol. In another embodiment of the present invention, the anticancer chemotherapeutic agent/s is prepared by either by mixing the polymer with chemotherapeutic agent or mixing the chemotherapeutic agent in polymer with solvent by casting and then evaporating the solvent. The present invention further provides a method to treat and/or prevent cancer using composition comprising natural polymeric chitosan matrix and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, lipids and plasticizers and other chemotherapeutics, said method comprising steps of administering a pharmaceutically effective dosage of the composition to a subject, preferably humans. In an embodiment of the present invention, the chemotherapeutic agent is released with linear or first order kinetics. In another embodiment of the present invention, chemotherapeutic agent can be administered alone or in combination with, either before, simultaneously, or subsequent to, treatment using chemotherapeutic or radiation therapy or surgery. In still another embodiment of the present invention, the effective dosage of the chemotherapeutic agents be delivered with additional chemotherapeutics, antibiotics, antiviral, antinflammatories, targeting compounds, cytokines, immunotoxins, antitumor antibodies, anti-angiogenic agents, anti-edema, radiosensitizers, and combinations thereof. Polymeric Formulations The ideal polymeric matrix would combine the characteristics of hydrophilicity, stability, aqueous solubility and suitable degradation profile. The polymer must possess suitable molecular weight so that it retains its integrity for a suitable period of time when placed in a aqueous environment, such a the body, and be stable enough to be stored for an extended period before use. The ideal polymer must also be strong, yet flexible enough so that it does not crumble or fragment during use. Biocompatible polymers can be categorized as biodegradable and non-biodegradable. Biodegradable polymers degrade in vivo as a function of chemical composition, method of manufacture, and implant structure. Synthetic and natural polymers can be used. Examples of natural polymers include chitosan, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin. Drug can be impregnated within, throughout, and/or on the surface of the implant. Drug is released by diffusion, degradation of the polymer, or a combination thereof. Chemotherapeutic Agents A variety of different chemotherapeutic agents can be incorporated into the polymeric matrix. In general, drugs will be added to between 10 and 50% (w/w), although the optimum can vary widely depending on the drug, from 1% to 70%. The preferred memotherapeutic agents are hydrophobic agents like paclitaxel, which are insoluble in water, relatively insoluble in lipid (compared, for example, to carmustine), high molecular weight (i.e., of a molecular weight not normally crossing the blood brain barrier), exhibit rapid non-renal clearance in vivo, and have substantial systemic toxicity, and their functionally effective derivatives. As used herein, paclitaxel refers to paclitaxel and functionally equivalent derivatives thereof, which are water soluble. The preferred weight percent range of drug in polymer is from one to 90% and the preferred time of degradation is between one month and six months. Dosages must be optimized depending on the size of the implant, the location and size of the tumor to be treated, and the period over which drug is to be delivered. These calculations are routine for those skilled in the art of administering chemotherapy to tumor patients. In general, the effective dosage of a chemotherapeutic agent, which is administered locally by extended release, will be significantly less than the dosage for the same drug administered for shorter periods of time. Preparation of Polymeric-Drug Compositions Controlled release devices are typically prepared in one of several ways. For example, the polymer can be melted, mixed with the substance to be delivered, and then solidified by cooling. Such melt fabrication processes require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. Alternatively, the device can be prepared by solvent casting, where the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated, leaving the substance in the polymeric matrix. Similar devices can be made by phase separation or emulsification or even spray drying techniques. In still other methods, a powder of the polymer is mixed with the drug and then compressed to form an implant. The drug to polymer ratio which can be incorporated is 0.00001-1:1. The ratio of excipients, additives, surfactant/s, lipids or plasticizers incorporated ratio are Paclitaxel to surfactant is 0.00001-0.2:1, Paclitaxel to lipids ratio is 0.00001-0.1:1, Paclitaxel to plasticizers ratio is 0.00001-1:1. Administration to Patients The chemotherapeutic agents described herein or their functionally equivalent derivatives can be administered alone or in combination with, either before, simultaneously, or subsequent to, treatment using other chemotherapeutic or radiation therapy or surgery. A preferred embodiment is the local administration, by implantation of a biocompatible polymeric matrix loaded with the chemotherapeutic agent, or injection/infusion of micro-implants, using dosages determined as described herein. The dosages for functionally equivalent derivatives can be extrapolated from the in vitro and in vivo data. The polymeric implants can also be combined with other therapeutic modalities, including radiotherapy, other chemotherapeutic agents administered systemically or locally, and immunotherapy. The present invention will be further understood by reference to the following non-limiting examples. The examples demonstrate the incorporation and release of paclitaxel from polymeric implant prepared by casting method. EXAMPLE 1 Preparation of Paclitaxel Implant Paclitaxel being a hydrophobic drug, two different approaches were undertaken for its incorporation into chitosan films, which involved use of either phospholipids alone or poloxamer 407 in presence of ETOH. Initially, a 10 mg/ml chitosan solution was prepared in 1% (v/v) acetic acid and glycerol was also included as a plasticizer at chitosan:glycerol weight ratio of 2:1. In the first method, liposomes containing paclitaxel (spiked with radioactive component) were prepared by film hydration method and were subsequently dispersed in chitosan solution. Then film was cast by pouring the mixture on a glass plate (area 45.5 cm2) followed by drying under vacuum for 48 h at 37°C. While in the second method, required quantities of paclitaxel and poloxamer 407 were dissolved separately in 1 ml of ETOH, mixed together and the ethanolic solution was added to chitosan solution with agitation in order to disperse paclitaxel. Subsequently, the homogeneous suspension was cast into film by the method described above and dried at 60°C for 12 h. Typical compositions that may be attempted are shown in Table 1. EXAMPLE 2 Demonstration of Paclitaxel Delivery from the Biodegradable Matrix (film) into the release medium under in vitro conditions. The efficiency of the delivery of paclitaxel incorporated into a biodegradable polymer into the surrounding medium was assessed in vitro as follows. Preparation of polymer films. Polymeric films were prepared as described above except that 14C-labeled paclitaxel was also used along with non-radioactive paclitaxel in the implant preparation. Method: A definite weight of film was cut and placed in micro centrifuge tube of 1.5 ml capacity containing 1 ml of release medium of following composition at 37°C: phosphate buffered saline (140 mM, pH 7.4) with 0.1% sodium azide and 0.1% Tween 80. At predetermined time points, 100 ul of release medium was sampled with replacement to which 3 ml of scintillation cocktail was added and vortexed before liquid scintillation counting. The cumulative amount of paclitaxel released as a function of time was calculated. In addition, to simulate the in vivo conditions, release of paclitaxel in presence of lysozyme (2 mg/100 ml) was also studied. Results: In order to establish the ability of films to serve as depot formulations, release of paclitaxel from both lipid and poloxamer containing films was studied. It was observed that release was negligible from lipid containing films, while that containing poloxamer has shown a burst effect followed by no release. Films containing poloxamer released about 10% in 6 h and further release of paclitaxel was not observed till the study period of 144 h suggesting that the film has retained 90% of the payload (Fig. 1A). Since the release of paclitaxel was Under in vitro conditions, poloxamer film exhibited an initial burst effect followed by negligible release of paclitaxel thereafter (Fig. 1). The initial burst release from the films is attributed to the surface deposited paclitaxel while the subsequent lack of release might be due to nonerosion/degradation of film. As chitosan is insoluble in release medium used for the study, film failed to release drug and this trend was observed with all film preparations. Though the test medium contained Tween 80, release of paclitaxel was not observed since the resulting micelles (diameter of 20-30 nm) were inaccessible to the inner matrix of film. To simulate the biodegradation process, lysozyme was included in the release medium as chitosan is susceptible to degradation by this enzyme. The extent of degradation by lysozyme, was inversely proportional to the degree of deacetylation and molecular weight. However, presence of lysozyme had not significantly influenced the release of paclitaxel from films (Fig. 1). The primary mechanisms for release of drugs from matrix systems in vitro are swelling, diffusion and degradation while in vivo release is governed by both diffusion and biodegradation of matrix. It was reported that the in vitro and in vivo degradation of chitosan films prepared by solution casting method occurred less rapidly as their degree of deacetylation increases, and films which were greater than 73% deacetylated showed slower biodegradation. Since the grade of chitosan used was of high molecular weight with a degree of deacetylation >85%, significant retardation of release of paclitaxel from film is attributed to the polymer characteristics. In addition, diffusion was hindered by increased tortuosity of polymer accompanied by a swelling mechanism. EXAMPLE 3 An evaluation of tensile strength of film. The effect of paclitaxel on mechanical properties of chitosan films was assessed through tensile strength test. Tensile strength of film was measured using Texture analyzer TA-XT2i (Stable Micro Systems, UK) with the following acquisition parameters: (i) 2 mm/s pre-speed (ii) 1 mm/s test-speed (iii) 10 mm/s post-speed with an acquisition rate of 50 pts/s (iv) 5 kg load cell Film was secured with tensile grips and a trigger force of 5 g was applied. The resulting profiles were analyzed using texture expert version 1.22. Results: Mechanical strength of film is described in terms of tensile strength and brittle films are characterized by decrease in the percent of elongation at break. The area under curve is energy required to break polymeric material and tough polymers have larger areas requiring large amounts of energy for rupture. In order to understand the arrangement of polymer chains in presence of paclitaxel, force-time profiles of films were generated as shown in Fig. 2. Though force of elongation at break is slightly lowered in presence of paclitaxel in film (10.3 vs. 9.8 N), the area under the profile has been increased (31.3 vs. 45.9 Ns). For convenience of interpretation, each profile is further described in terms of ascending and descending portions. The time to plateau of the ascending portion of paclitaxel chitosan film was greater in comparison to control film. As brittleness is reflected in the time to plateau, greater time is indicative of lack of brittleness of film. In addition, the descending segment of the profile of control film was uniform, while that of paclitaxel film was irregular and protracted. The discontinuities in internal structure and variation in strength of film matrix may be the reason of the irregular descending portion of profile. Films exhibited sufficient mechanical strength when assessed in terms of force of breaking point and percent elongation at beak. Generally, stiff and brittle materials display a steep rise in stress strain curve (undergoing little or no cold flow) which extends only over narrow areas indicating that work required to beak them is small and have low impact resistance. The long elongated fibrous structures in paclitaxel chitosan film form an entangled network with chitosan polymer chains during film formation (see below) and, thereby alter the film property, namely the elongation at break. It was also observed that paclitaxel film ruptures gradually rather than abruptly (an extended profile), on application of force leading to increased area under stress curve imparting toughness to the film. These observations indicate that, chitosan films are not brittle in nature but tough and flexible, and discontinuities in film are caused by interruptions in film matrix by fibrous paclitaxel structures, EXAMPLE 4 Solid state characterization of paclitaxel impregnated with the biodegradable film matrix METHODS: Differential scanning calorimetry DSC studies were performed with a Mettler Toledo 82 le thermal analyzer (Switzerland) calibrated with indium as standard. For thermogram acquisition, sample sizes of 1-5 mg were scanned with a heating rate of 5°C/min over a temperature range of 25-300°C. In order to check the reversibility of transition, samples were heated to a point just above the corresponding transition temperature, cooled to room temperature and reheated up to 300°C. Scanning electron microscopy Paclitaxel samples and chitosan films were viewed using Jeol scanning electron microscope, JSM 1600 (Japan) for morphological examination. Powder samples of paclitaxel and films were mounted onto aluminum stubs using double sided adhesive tape and sputter coated with a thin layer of gold at 10 torr vacuum before examination (Jeol Fine coat, Ion sputter, JFC-1100). The specimens were scanned with an electron beam of acceleration potential of 1.2 kV and images were collected in secondary electron mode. X-ray diffraction studies Molecular arrangement of paclitaxel and chitosan in powder as well as in films was compared by powder X-ray diffraction patterns acquired at room temperature on a Philips PW 1729 diffractometer (Holland) using Cu Ko. radiation. The data was collected over an angular range from 3-50° 26 in continuous mode using a step size of 0.02° 26 and step time of 5 s. Results: Thermal studies of flints The DSC thermograms of paclitaxel, recrystallized paclitaxel, blank and paclitaxel chitosan films are shown in Fig. 3 and the observed thermal events are summarized in Table 2. Thermogram of paclitaxel showed an initial broad peak at 64.5"C due to removal of absorbed moisture or nonstructural water followed by a single endotherm at 223.6°C just prior to an exotherm of degradation peak (Fig. 3a). Another minor broad peak at 168.9°C was observed which may be due to the presence of small amounts of micro crystalline/amorphous form in the sample (since this peak was absent from second heating phase on DSC run when the sample was initially heated to 200°C, cooled back to 25°C and reheated, results not shown). In addition, DSC studies were also performed on dry powder (recrystallized paclitaxel) obtained by evaporation of paclitaxel poloxamer mixtures dispersed in aqueous acetic acid-ETOH solvent system (with same proportions as mentioned in Table 1) with the only difference being that chitosan was omitted. In DSC thermograms of recrystallized paclitaxel, a single endotherm of transition of poloxamer at 49.7°C along with two minor transitions were observed, however the melting peak of paclitaxel was found to shift to 197.4°C as against 223.6°C. On the other hand, the degradation peak of paclitaxel appeared at 219.6°C(Table2). Both blank and paclitaxel chitosan films exhibited four endothermic peaks in DSC thermograms. The transition of poloxamer in these films occurred at 48°C with no appreciable shift (Fig. 3c). Other peaks in the region of 85-88°C have resulted from loss of moisture on heating. In blank film, a small endotherm was present at 139.9°C, while in paclitaxel film an asymmetric peak representing thermal event of micro crystalline/amorphous form of paclitaxel was seen. This event was followed by a broad endothermic peak at 230.5°C in both the films which may be attributed to glycerol component (boiling point of glycerol = 182°C). However, thermal events of paclitaxel, namely melting and decomposition, which were previously noted in the region of 190-225°C were not observable in film (Fig. 3d). Further, decomposition of chitosan was observed as a broad exotherm in films at 274-280°C while the same was at 294.5°C for chitosan powder under identical experimental DSC conditions (Fig. 3b). Film morphology scanning electron microscopy studies SEM photomicrographs revealed that commercial sample of paclitaxel has plate like appearance while recrystallized sample appeared fibrous and elongated as shown in Fig. 4A and B. In addition, SEM photographs of control and paclitaxel films were also acquin : ind compared with that of paclitaxel samples. The morphology of control film was p! and the picture was dark indicating that it has a smooth surface (Fig. 4C). In contra > control film, features of paclitaxel chitosan film resembled to that of fibrous recrys :ed paclitaxel morphology (Fig.4D). This typical surface appearance suggests that p; ixel is not only dispersed in the film matrix but projected onto to surface of film. Edition, some irregular masses were also identified in the pictures of recrys: ed paclitaxel and film loaded with paclitaxel. X-ray . action studies X-ray -action is an authentic tool to study crystal lattice arrangements and yields very u: information on degree of crystallinity of samples. X-ray diffraction pattern of pac el, blank and paclitaxel film and were obtained and compared which revealc larked differences in the molecular state of paclitaxel (Fig. 5). The diffract un of blank chitosan film has shown two low intensity peaks at 19.1 and 23.3° 2 ith a characteristic broad hump in the range of 7° to 45° 29. This halo diffract pattern (broad hump) is an indication of predominantly amorphous form of chitosa films (Fig. 5a). In case of paclitaxel, diffractogram exhibited peaks at the follow; 8 values: 4.1,5.4, 5.8, 9.1, 10.2, 11.3, 12.3, 12.5° (Fig. 5b). Amongst these, the peal highest intensity was located at 5.8° 29 and the peaks at 11.3 and 12.5° 29 were br When diffraction pattern of paclitaxel in chitosan film was compared with thai of utaxel, the pattern differed to a large extent. A number of high angle diffracti -eaks were observed in paclitaxel chitosan film at the following 29 values: 4.1, 5.2, 10.8, 12.1, 12.6, 13.8, 14.6, 18.6, 20, 20.7, 21.6, 23.6° (Fig. 5c). The 12.6° 29 peak the highest intensity and hump in the baseline occurred from 7 to 45° 29 as observer chitosan film. It is probable that the new sharp diffraction peaks are result of new t\ of paclitaxel. As DSC useful tool to monitor the effects of additives on the thermal behavior of materials s technique was employed to derive qualitative information about the physicoci cat status of drug in films. The recrystallized paclitaxel showed two peaks, a 1 •ndotherm peak representative of transition temperature of poloxamer, and an exothi : peak for degradation of paclitaxel. The lack of a second endothermic pea*, in me L/oC run above 100°C suggests that paclitaxel was present as amorphous form (Table 2). Amorphous paclitaxel prepared by quench cool method was reported to have a glass transition temperature of 152.4°C. However, it appears that the reported form is not present in the film since a new peak at 172.5°C (which was not present in control films) was observed in paclitaxel chitosan films (Fig. 3). The melting/transition point of this peak was different from that of reported value suggesting that the peak arises due to melting/transition of a new solid-state form of paclitaxel. Further, the sample was subjected to a heat-cool cycle (25-190-25-300°C) in order to ascertain the nature of this thermal event. On the second heating phase of a heat-cool cycle, all peaks were absent from the recrystallized sample suggesting that these events are irrereversible and the peak at 172.5°C is representative of transition and not melting process. In addition, decomposition peak shifted to lower temperatures in film which may be indicative of loss of interpolymer chain interactions as chitosan films were reported to undergo thermal decomposition at 290-300°C. As observed from SEM photomicrographs, the crystals of paclitaxel (plate like) have a different appearance to that of recrystallized paclitaxel (elongated and fibrous) (Fig. 4). This dissimilarity suggests that the crystal habit and/or lattice of paclitaxel was modified during film casting. In addition, the micrographs of recrystallized paclitaxel and paclitaxel loaded film also showed scattered irregular masses. Since, the proportion of poloxamer was not sufficient to form dispersion with the total amount of paclitaxel, excess of paclitaxel was observed to precipitate in a different form (irregular masses). This implies that paclitaxel is present in film both as amorphous form (fibrous form) and non-amorphous form (irregular masses) which is further substantiated by DSC and X-ray diffraction studies. X-ray diffraction is an authentic tool to study the degree of crystallinity of pharmaceutical drugs and excipients. A lower °26 value indicates larger d-spacings while an increase in the number of high angle reflections indicate higher molecular state order. In addition, broadness of reflections, high noise and low peak intensities are characteristic of a poorly crystalline material. A broad hump in the diffraction pattern of chitosan extending over a large range of °20 suggests that chitosan is present in amorphous state in the film (Fig. 5a). The two broad peaks superimposed on hump were also observed in other studies which were attributed to hydrated and anhydrous crystals of chitosan in film. Film of paclitaxel has exhibited a greater number of peaks than observed for paclitaxel, and further, shifts were observed for majority of peaks, with the most intense peak located at higher °26 value in film (Fig. 5c). The dissimilarity in diffraction pattern is indicative of different crystalline form of paclitaxel in film while the more intense and several new diffraction peaks provide evidence on increased crystallinity of paclitaxel. It was previously reported that dehydration of paclitaxel resulted in the increased degree of crystallinity compared with hydrated form and similarly, the polymorphic change is expected during drying process of film formation. Hence, X-ray diffraction studies confirm film casting methodology resulted in conversion of paclitaxel into a new form (dehydrated/crystalline form) with a different crystal lattice arrangement compared with commercial sample (paclitaxel). EXAMPLE 5 Histology studies Method: Histology studies were done in order to examine the acute toxicity of film at the implantation site. After a two-month implantation period, mice were sacrificed by cervical dislocation and an incision was made in the implantation area. Then, the tissue in which film was imbibed was removed and stored in 50% formalin until processing. Subsequently, tissue processing involved dehydration through graded series of alcohols (70, 80, 95 and 100%) followed by xylene and then infiltration with paraffin. For, obtaining thin sections (3-5 urn), tissues were embedded on edge of paraffin blocks and were cut on a rotary microtome. These sections were deparafinized, rehydrated with graded alcohols (100, 95, 80, 75%) and stained with hemotoxylin/eosin for microscopic examination. Similarly, sections of paclitaxel chitosan film and tissue of healthy mouse were obtained to serve as control. Results: The tissue responses to implanted film were studied by microscopic examination of tissues in the implanted area (Fig.6). Lack of increase in number of macrophages at the site of implantation suggests that inflammatory responses were either minimal or absent. It has been previously reported that, the degree of deacetylation of chitosan was key factor in determining not only release rate but also inflammatory responses. Typically, gels composed from grades of low degrees of deacetylation had short residence times and higher inflammatory response while those with higher degree have longer residence time and minimal or no inflammation. In the present study, the grade of chitosan used for fabrication of film was >85% deacetylated, and hence, the high degree of deacetylation of chitosan may be the reason for reducing local inflammatory responses. Though under in vitro conditions, chitosan film retained integrity in the presence of lysozyme, it has demonstrated susceptibility to biodegradation under in vivo conditions in mice. Moreover, tissue examined at the site of implantation appeared normal (absence of significant infiltration of macrophages) signifying that film had not imposed any unfavorable influences to create hostile environment. Hence, these studies turned out to be very significant in understanding film host tissue responses with the result that normal physiological processes remain unaffected after implantation These data show that paclitaxel can be effectively utilized by local delivery with the controlled release polymer chitosan. Further, the data show that local controlled drug delivery allow the clinical use of this highly effective drug that could not be utilized systemically because of its toxicity and narrow therapeutic window. Modifications and variations of the compositions of the present invention and methods for use will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to fall within the scope of the appended claims. The drug delivery system can be used for known anticancer agents including an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), mercaptopurine, fludarabine, cytarabine, asparaginase, pentostatin, procarbazine, thiotepa, streptozocin, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel), etc.), an alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative). The delivery system allows 1 % to 70 % incorporation of the drug into the polymer matrix, preferably between 10 %v to 50 %. Further, the polymer retains 90% of the drug payload due to its high molecular weight and therefore the drug release is streamlined. The lysozyme, which acts as excipient enhances the further diffusion of the drug. The non-obvious factor contributes to the unexpected results from the properties of the composition, which is surprising to the person skilled in the art. The spectrum of non-obviousness is enhanced since the efficacy achieved is not the sum of the properties of the two compounds but the path these compounds follow by overcoming the blood-brain barrier and systemic toxicity to deliver the desired anticancer response without any unusual affects is unexpected by the person skilled in the art. The combination of polymer chitosan and the anticancer chemotherapeutic agent forms a constructive network, which is well identified and readily accepted by the carrier system i.e the blood and subsequently by the body. The inventiveness is a synergistic mutual association between the delivery mechanism and the subject, so as the subject receives a consistent dosage of the drug for about eight hours, without any systemic toxicity or loss in the efficacy.The drug delivery system also works in synchronization with other anticancer chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. Since cancer chemotherapy is often a combination therapy, one or more drugs from appropriate class from the above mentioned substances and any possible route may administer group/category of drugs and the treatment can continue for any desirable length of time, and it can be repeated, as appropriate to achieve the desired end results. Such results can include the attenuation of the progression of the cancer, shrinkage of such tumors, or, desirably, remission of all symptoms. The combination is therefore a non-obvious combination. Infact, the present combination provide unexpected result and the properties of the combination is surprising to the person skilled in the art. ADVANTAGES: 1. The polymer chitosan is biodegradable and biocompatible and retains its integrity for longer period. 2. The composition includes anticancer chemotherapeutic agents of both high and low molecular weights, exhibit non-renal and show non-toxic systemic clearence. 3. The drug delivery dosage is upto eight hours. 4. The drug delivery system overcomes the blood-brain barrier and is non- cytotoxic. 5. The packing of the drug is by micellar entrapment during film casting which incorporates the drug thereby increasing its delivery efficacy. 6. The synergistic network of drug delivery system allows its easy and non-toxic acceptance within the body. 7. The drug delivery system performs synergistically with other anticancer chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. 8. The chemotherapeutic agent is released from the natural polymer by degradation or diffusion. (Table Remove) WHAT IS CLAIMED 1. A pharmaceutical composition for preventing and/or treating solid tumors said composition comprising natural polymeric matrix, poloxamer and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, and plasticizers. 2. A pharmaceutical composition as claimed in claim 1, wherein the natural polymer matrix is biocompatible and biodegradable. 3. A pharmaceutical composition as claimed in claim 1, wherein the natural polymer matrix is hydrophilic, soluble in water, retains integrity for suitable time period, strong but flexible and does not crumble or fragment during use. 4. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent is impregnated within, throughout and/or on the surface of the natural polymeric matrix. 5. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent is released by diffusion, degradation of the polymer or in combination thereof. 6. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent is hydrophobic, high molecular weight, exhibit rapid non-renal clearance in vivo and have functional equivalent derivatives. 7. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent/s includes an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MIX), mercaptopurine, fludarabine, cytarabine, asparaginase, pentostatin, procarbazine, thiotepa, streptozocin, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel, etc.), an alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative). 8. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent/s include paclitaxel and its functionally effective derivatives like hydrophobic hydroxy esters of paclitaxel where one or more of the three hydroxyls of paclitaxel are modified with long chain alkyl or aromatic pendant groups. 9. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent is present in the polymeric matrix in one or more solid state forms such as amorphorus, semicrystalline, crystalline, hydrated and hydrated forms. 10. A pharmaceutical composition as claimed in claim 1, wherein the natural polymeric matrix used is polymeric chitosan matrix. 11. A pharmaceutical composition as claimed in claim 1, wherein the dosage of anticancer chemotherapeutic agent/s is 10-25 mg. 12. A pharmaceutical composition as claimed in claim 1, wherein the polymer chitosan is 20-250 mg. 13. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and chitosan ratio is 0.00001 to 1: 1 14. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and surfactant ratio is 0.00001 to 0.2: 1. 15. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and lipids ratio is 0.00001 to 0.1: 1 16. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and plasticizers ratio is 0.00001 to 1: 1 17. A pharmaceutical composition as claimed in claim 1, wherein the preferred weight percent range of anticancer chemotherapeutic agent is 1% to 90 % 18. A pharmaceutical composition as claimed in claim 1, wherein the time duration for the treatment varies from one month to six months depending upon the size of implant, location and size of the tumor to be treated. 19. A pharmaceutical composition as claimed in claim 1, wherein the anticancer chemotherapeutic agent is released by diffusion or degradation over a period of eight hours. 20. A method of preparing a biocompatible and biodegradable composition, said method comprising, incorporating an anticancer chemotherapeutic agent/s in a natural polymeric chitosan matrix in presence of poloxamer carrier and optionally along with additives selected from the group consisting of surfactant/s, and plasticizers 21. A method as claimed in claim 20, wherein anticancer chemotherapeutic agent/s is implanted in the polymer matrix chitosan by using micellar entrapment during film casting while adjusting the polarity of the medium with ethanol. 22. A method as claimed in claim 20, wherein anticancer chemotherapeutic agent/s is prepared by either by mixing the polymer with chemotherapeutic agent or mixing the chemotherapeutic agent in polymer with solvent by casting and then evaporating the solvent. 23. A method to treat and/or prevent cancer using composition comprising natural polymeric chitosan matrix and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, lipids and plasticizers and other chemotherapeutics, said method comprising steps of administering a pharmaceutically effective dosage of the composition to a subject, preferably humans. 24. The method as claimed in claim 23, wherein the chemotherapeutic agent is released with linear or first order kinetics. 25. A method as claimed in claim 23, wherein chemotherapeutic agent can be administered alone or in combination with, either before, simultaneously, or subsequent to, treatment using chemotherapeutic or radiation therapy or surgery. 26. A method as claimed in claim 23, wherein effective dosage of the chemotherapeutic agents be delivered with additional chemotherapeutics, antibiotics, antiviral, antinflammatories, targeting compounds, cytokines, immunotoxins, antitumor antibodies, anti-angiogenic agents, anti-edema, radiosensitizers, and combinations thereof.

Full Text

A PHARMACEUTICAL COMPOSITION COMPRISING AN ANTICANCER CHEMOTHERAPEUTIC AGENT AND A BIODEGRADABLE NATURAL POLYMERIC CHITOSAN MATRIX FOR LOCAL DELIVERY OF DRUG
FIELD OF INVENTION
The present invention relates to a novel drug delivery system capable of delivering an active ingredient to a localized area having solid tumors over an extended period of time, said drug delivery system comprising a natural biodegradable polymeric matrix and the active ingredient, wherein the active ingredient is incorporated in the said matrix. More particularly, the present invention relates to a novel pharmaceutical composition for delivery of anticancer chemotherauptic agent such as paclitaxel to a localized area having solid tumors over an extended period of time, said pharmaceutical composition comprising a natural biodegradable polymeric chitosan matrix, and the anticancer chemotherauptic agent being incorporated in the chitosan matrix. The composition of the present invention introduces the anticancer agent within or immediately adjacent to the solid tumors to be treated. Further, the drug delivery system prevents high systemic levels of the agent and associated toxicities.
BACKGROUND OF THE INVENTION
Cancer is the major disease due to which many people are dying throughout the world the world. In USA, cancer remains second only to cardiac disease as a cause of death. Studies show that 20% of the Americans die due to cancer, half of whom die due to lung, brest and colon-rectal cancer. It is anticipated that the percentage will increase to l/3rd within the next couple of decades.
Designing effective treatments for patients with cancer has represented a major challenge. The current regimen of surgical resection, external beam radiation therapy, and/or systemic chemotherapy has been partially successful in some kinds of malignancies, but has not produced satisfactory results in others. In some malignancies, such as brain malignancies, this regimen produces a median survival of less than one year. For example, 90% of resected malignant gliomas recur within two centimeters of the original tumor site within one year.

PRIOR ART DESCRIPTION
Though effective in some kinds of cancers, the use of systemic chemotherapy has had minor success in the treatment of cancer of the colon-rectum, esophagus, liver, pancreas, and kidney and melanoma. A major problem with systemic chemotherapy for the treatment of these types of cancer is that the systemic doses required to achieve control of tumor growth frequently result in unacceptable systemic toxicity. Efforts to improve delivery of chemotherapeutic agents to the tumor site have resulted in advances in organ-directed chemotherapy, as by continuous systemic infusion, for example. However, continuous infusions of anticancer drugs generally have not shown a clear benefit over pulse or short-term infusions. Implantable elastomer access ports with self-sealing silicone diaphragms have also been tried for continuous infusion, but extravasation remains a problem. Portable infusion pumps are now available as delivery devices and are being evaluated for efficacy. (See Harrison's Principles of Internal Medicine 431-446, E. Braunwald et al., ed., McGraw-Hill Book Co. (1987) for a general review).
In the brain, the design and development of effective anti-tumor agents for treatment of patients with malignant neoplasms of the central nervous system have been influenced by two major factors: (i) the blood-brain barrier provides an anatomic obstruction, limiting access of drugs to these tumors; and (ii) the drugs given at high systemic levels are generally cytotoxic. Efforts to improve drug delivery to the tumor bed in the brain have included transient osmotic disruption of the blood brain barrier, cerebrospinal fluid perfusion, and direct infusion into a brain tumor using catheters. Each technique has had significant limitations. Disruption of the blood brain barrier increased the uptake of hydrophilic substances into normal brain, but did not significantly increase substance transfer into the tumor. Only small fractions of agents administered into the cerebrospinal fluid actually penetrated into the brain parenchyma. Drugs that have been used to treat tumors by infusion have been inadequate, did not diffuse an adequate distance from the site of infusion, or could not be maintained at sufficient concentration to allow a sustained diffusion gradient. The use of catheters has been complicated by high rates of infection, obstruction, and malfunction due to clogging. See T. Tomita, "Interstitial chemotherapy for brain tumors: review" J. Neuro-Oncology 10:57-74 (1991).

Controlled release biocompatible polymers for local drug delivery have been utilized for contraception, insulin therapy, glaucoma treatment, asthma therapy, prevention of dental caries, and for cancer chemotherapy. (Langer et al., 1981) Brain tumors have been particularly refractory to chemotherapy. One of the chief reasons is the restriction imposed by the blood-brain barrier. Agents that appear active against certain brain tumors, such as gliomas, in vitro may fail clinical trials because insufficient drug penetrates the tumor. Although the blood-brain barrier is disrupted at the core of a tumor, it is largely intact at the periphery where cells actively engaged in invasion are located. Experimental intratumoral regimens include infusing or implanting therapeutic agents within the tumor bed following surgical resection, as described by Tamita, T, J. Neuro-Oncol. 10:57-74(1991).
Delivery of a low molecular weight, lipid soluble chemotherapeutic, l,3-bis(2-chloroethyl)-l-nitrosourea (carmustine), in a polymer matrix implanted directly adjacent to brain tumors has some efficacy, as reported by Brem, et al., J. Neurosurg. 74:441-446 (1991); Brem, et al., Eur. J. Pharm. Biopharm. 39(l):2-7 1993; and Brem, et al., "Intra-operative Chemotherapy using biodegradable polymers: Safety and Effectiveness for Recurrent Glioma Evaluated by a prospective, Multi-Institutional Placebo-Controlled Clinical Trial" Proc. Amer. Soc. Clin. Oncology May 17, 1994. Polymer-mediated delivery of carmustine was superior to systemic delivery in extending survival of animals with intracranial 9L gliosarcoma and has shown some efficacious results in clinical trials. However, carmustine is a low molecular weight drug, crosses the blood-barrier and had previously been demonstrated to have some efficacy when administered systemically.
Unfortunately, the predictability of the efficacy of chemotherapeutic agents remains low. Drugs that look effective when administered systemically to animals may not be effective when administered systemically to humans due to physiological differences and bioavailability problems, and drugs that are effective systemically may not be effective when administered locally. Due to low efficacy during local administration it becomes imperative to undertake to devise efficient drug delivery system which would reduce systemic toxicity and enhance bioavailability and efficacy.

Many other chemotherapeutics which are efficacious when administered systemically must be delivered at very high dosages in order to avoid toxicity due to poor bioavailability. For example, paclitaxel (taxol) has been used systemically with efficacy in treating several human tumors, including ovarian, breast, and non-small cell lung cancer. However, maintenance of sufficient systemic levels of the drug for treatment of tumors has been associated with severe, in some cases "life-threatening" toxicity, as reported by Sarosy and Reed, J. Nat. Med. Assoc. 85(6):427-431 (1993). Paclitaxel is a high molecular weight (854), highly lipophilic deterpenoid isolated from the western yew, Taxus brevifolia, which is insoluble in water. It is normally administered intravenously by dilution into saline of the drug dissolved or suspended in polyoxyethylated caster oil. This carrier has been reported to induce an anaphylactic reaction in a number of patients (Sarosy and Reed (1993)) so alternative carriers have been proposed, such as a mixed micellar formulation for parenteral administration, described by Alkan-Onyuksel, et al., Pharm. Res. 11(2), 206-212 (1994). There is also extensive non-renal clearance, with indications that the drug is removed and stored peripherally. Pharmacokinetic evidence from clinical trials (Rowinsky, E. K.., et al., Cancer Res. 49:4640-4647 (1989)) and animal studies (Klecker, R. W., Proc. Am. Assoc. Cancer Res. 43:381 (1993)) indicates that paclitaxel penetrates the intact blood-brain barrier poorly, if at all, and that there is no increased survival from systemic intraperitoneal injections of paclitaxel into rats with intracranial gliomas. Paclitaxel has been administered in a polymeric matrix for inhibition of scar formation in the eye, as reported by Jampel, et al., Opthalmic Surg. 22, 676-680 (1991), but has not been administered locally to inhibit tumor growth.
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OBJECTIVES OF THE INVENTION
The main object of the present invention is to provide a drug delivery system, a chemotherapeutic composition and a method of producing like composition which provides for effective long-term release of anticancer agents that are not soluble in aqueous solutions or which have limited bioavailability in vivo for treatment of solid tumors.
Another object is to overcome the problems of bioavailability, efficacy and systemic related toxicity in treatment of cancers.
Yet another object of the invention relates to providing a drug delivery system, a composition and a method for the treatment of solid tumors through localized delivery with anticancer chemotherapeutic agents that avoids high systemic levels of the agent and associated toxicities.
Yet another objective of the invention relates to the strategy to remove constraints encountered during drug delivery for solid tumors, thereby making efficient delivery of both low molecular and high molecular weight drugs.
Yet another objective of the invention relates to the elimination the blood-brain barriers encountered during the delivery and enhances the local administration of the drug in humans and animals.
SUMMARY OF THE INVENTION
The present invention provides novel drug delivery system and a pharmaceutical composition for delivery of anticancer chemotherauptic agent such as paclitaxel to a localized area having solid tumors over an extended period of time, said drug delivery

system comprising a natural biodegradable polymeric chitosan matrix, and the anticancer chemotherauptic agent being incorporated in the chitosan matrix, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability in vivo. The drug delivery system of the present invention releases the drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. The drug delivery system of the present invention is implanted within or immediately adjacent to the tumors to be treated or the site from where they have been surgically removed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the cumulative percent release over time (hours) for paclitaxel from polymer films loaded with 33 % by weight paclitaxel in absence of (a) lysozyme and (b) in presence of lysozyme in the release medium.
FIG. 2 is a graph of illustrating the mechanical strength of film as studied through force-time profiles (a) blank film and (b) paclitaxel-loaded film.
FIG. 3. Differential scanning calorimetric studies to investigate physical transformations induced in chitosan and paclitaxel by comparing solid-sate features of pure components with that in films (a) paclitaxel, (b) chitosan powder, (c) blank film and (d) paclitaxel chitosan film. Thermogarms were obtained at a scan rate of 5°C/min. When paclitaxel chitosan film was heated to 190°C, cooled to 25°C and reheated, peaks I, II, III were found to be irreversible in nature.
FIG. 4. Scanning electron photomicrographs of (A) paclitaxel, (B) recrystallized paclitaxel, (C) blank film, and (D) paclitaxel chitosan film obtained at different magnifications. Paclitaxel micrographs were that of commercial sample without any modification. Recrystallized paclitaxel was obtained by evaporation of hydro-ethanolic solution of paclitaxel and poloxamer 407 under identical conditions as used for film casting in the absence of chitosan.
FIG 5. X-ray diffraction patterns of (a) blank chitosan film; (b) paclitaxel and (c) paclitaxel chitosan film at ambient temperature to examine solid-state features of paclitaxel in film.

FIG 6. Histopathological examination for generalized inflammatory response to assess biocompatibility of s.c. implanted chitosan film in mice (A) control tissue and (B) paclitaxel chitosan film embedded tissue following implantation of the film after 60 days. Magnification x 250. Film is indicated by arrow in (B). Histological assessment is usually based on cellular infiltration between and around delivery system, edema, formation of granulation tissue and presence of multi-nucleated giant cells/macrophages.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a localized drug delivery system to solid tumors. This drug delivery system of the present invention provides for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability in vivo, are described. The drug delivery system of the present invention releases the active ingredient over an extended time period, while at the same time preserving the bioactivity and bioavailability of the agent. The drug delivery system of the present invention consists of biodegradable polymeric chitosan matrix having the active ingredient, paclitaxel incorporated in it. The drug delivery system of the present invention is implanted within or immediately adjacent to the tumors to be treated or the site where they have been surgically removed.
One method of extending the duration of exposure of a tumor to a drug is to deliver the drug interstitially to the tumor. Controlled-infusion pumps and biodegradable polymer devices are currently being developed to deliver drugs in such a sustained fashion to tumors of the central nervous system. Interstitial delivery minimizes the systemic drug levels and side effects of an agent. Delivering chemotherapeutic drugs locally to a tumor is an effective method of prolonging tumor exposure to the drug while minimizing the drug's dose-limiting, systemic side effects, such as neutropenia. Interstitial drug delivery bypasses the limitations of the blood-brain barrier. Presently, it is unclear how well some drugs such as paclitaxel crosses the blood-brain barrier.

As described herein, the present invention also provides a composition comprising a chemotherapeutic active agent, which is not water soluble and has poor bioavailability in vivo impregnated into a biocompatible and biodegradable polymeric matrix for use in treatment of solid tumors. The chemotherapeutic active agent is released by diffusion and/or degradation over a therapeutically effective time, usually not less than 1 month.
More particularly, the present invention also provides a composition comprising paclitaxel, which is not water soluble and has poor bioavailability in vivo impregnated into a biocompatible and biodegradable polymeric chitosan matrix for use in treatment of solid tumors. The paclitaxel is released by diffusion and/or degradation over a therapeutically effective time, usually not less than 1 month.
In some of the previous attempts, in order to develop a local drug delivery system based on paclitaxel, a biodegradable chitosan film was attempted. However, effective incorporation of the paclitaxel in the chitosan matrix was not achieved. This was mainly due to the fact that chitosan is only soluble in aqueous acidic solutions where as paclitaxel being a hydrophobic drug, is insoluble under similar conditions. Thus, it should be noted that the common view in the field is that paclitaxel cannot be incorporated in the polymeric chitosan matrix because of their differences in solubility. One of the interesting points to note there is that in all the initial studies conducted, liposomes were used as carriers for the incorporation of paclitaxel into the chitosan polymeric matrix.
The Inventors also tried to incorporate paclitaxel in the biodegradable chitosan polymeric matrix with liposomes as the carrier. In early stages of formula optimization studies, the Inventors observed that when liposomes were used as the carrier, paclitaxel was not incorporated into film but crystallized out as needles due to lack of solubilization in aqueous chitosan solutions thus, confirming the finding of the earlier scientists.
Despite the failure, the Inventors tried the process of incorporating the paclitaxel into the polymeric chitosan matrix under various conditions. The Inventors also tried changing the ingredients that are used during the process. After much trial and error,

and to the surprise of the Inventors, they noticed that when the lipids (used as carrier) were replaced with poloxamer, crystallization of the paclitaxel as needles did not occur.
They also noticed that the lipids were prone to oxidation and hydrolytic degradation processes which gets further accelerated under heat. However, the poloxamer was not prone to oxidation and hydrolytic degradation processes.
The exact mechanism by which the incompatibility is obliterated is not known, but it is plausible that poloxamer micelles act by solubilization phenomenon that are further stabilized by ETOH.
Accordingly, the present invention provides a pharmaceutical composition for preventing and/or treating solid tumors said composition comprising natural polymeric matrix, poloxamer and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, and plasticizers.
In an embodiment of the present invention, the natural polymer matrix is biocompatible and biodegradable.
In another embodiment of the present invention, the natural polymer matrix is hydrophilic, soluble in water, retains integrity for suitable time period, strong but flexible and does not crumble or fragment during use.
In yet embodiment of the present invention, the anticancer chemotherapeutic agent is impregnated within, throughout and/or on the surface of the natural polymeric matrix.
In still another embodiment of the present invention, the anticancer chemotherapeutic agent is released by diffusion, degradation of the polymer or in combination thereof.
hi one more embodiment of the present invention, the anticancer chemotherapeutic agent is hydrophobic, high molecular weight, exhibit rapid non-renal clearance in vivo and have functional equivalent derivatives.
In one another embodiment of the present invention, the anticancer chemotherapeutic agent/s includes an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), mercaptopurine, fludarabine, cytarabine, asparaginase, pentostatin, procarbazine,

thiotepa, streptozocin, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel, etc.), an alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, carnptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative).
In a further embodiment of the present invention, the anticancer chemotherapeutic agent/s include paclitaxel and its functionally effective derivatives like hydrophobic hydroxy esters of paclitaxel where one or more of the three hydroxyls of paclitaxel are modified with long chain alkyl or aromatic pendant groups.
In an embodiment of the present invention, the anticancer chemotherapeutic agent is present in the polymeric matrix in one or more solid state forms such as amorphorus, semicrystalline, crystalline, hydrated and hydrated forms.
In another embodiment of the present invention, the natural polymeric matrix used is polymeric chitosan matrix.
In yet another embodiment of the present invention, the dosage of anticancer chemotherapeutic agent/s is 10-25 mg.
In still another embodiment of the present invention, the polymer chitosan is 20-250 mg.
In one more embodiment of the present invention, the Paclitaxel and chitosan ratio is 0.00001 to 1: 1
In one another embodiment of the present invention, the Paclitaxel and surfactant ratio is 0.00001 to 0.2: 1.
In a further embodiment of the present invention, the Paclitaxel and lipids ratio is 0.00001 to 0.1: 1

In an embodiment of the present invention, the Paclitaxel and plasticizers ratio is 0.00001 to 1: 1
In another embodiment of the present invention, the preferred weight percent range of anticancer chemotherapeutic agent is 1% to 90 %
In yet another embodiment of the present invention, the time duration for the treatment varies from one month to six months depending upon the size of implant, location and size of the tumor to be treated.
In still another embodiment of the present invention, the anticancer chemotherapeutic agent is released by diffusion or degradation over a period of eight hours.
The present invention also provides a method of preparing a biocompatible and biodegradable composition, said method comprising, incorporating an anticancer chemotherapeutic agent/s in a natural polymeric chitosan matrix in presence of poloxamer carrier and optionally along with additives selected from the group consisting of surfactant/s, and plasticizers
In an embodiment of the present invention, the anticancer chemotherapeutic agent/s is implanted in the polymer matrix chitosan by using micellar entrapment during film casting while adjusting the polarity of the medium with ethanol.
In another embodiment of the present invention, the anticancer chemotherapeutic agent/s is prepared by either by mixing the polymer with chemotherapeutic agent or mixing the chemotherapeutic agent in polymer with solvent by casting and then evaporating the solvent.
The present invention further provides a method to treat and/or prevent cancer using composition comprising natural polymeric chitosan matrix and anticancer chemotherapeutic agent/s, optionally along with additives selected from the group consisting of surfactant/s, lipids and plasticizers and other chemotherapeutics, said method comprising steps of administering a pharmaceutically effective dosage of the composition to a subject, preferably humans.

In an embodiment of the present invention, the chemotherapeutic agent is released with linear or first order kinetics.
In another embodiment of the present invention, chemotherapeutic agent can be administered alone or in combination with, either before, simultaneously, or subsequent to, treatment using chemotherapeutic or radiation therapy or surgery.
In still another embodiment of the present invention, the effective dosage of the chemotherapeutic agents be delivered with additional chemotherapeutics, antibiotics, antiviral, antinflammatories, targeting compounds, cytokines, immunotoxins, antitumor antibodies, anti-angiogenic agents, anti-edema, radiosensitizers, and combinations thereof.
Polymeric Formulations
The ideal polymeric matrix would combine the characteristics of hydrophilicity, stability, aqueous solubility and suitable degradation profile. The polymer must possess suitable molecular weight so that it retains its integrity for a suitable period of time when placed in a aqueous environment, such a the body, and be stable enough to be stored for an extended period before use. The ideal polymer must also be strong, yet flexible enough so that it does not crumble or fragment during use.
Biocompatible polymers can be categorized as biodegradable and non-biodegradable. Biodegradable polymers degrade in vivo as a function of chemical composition, method of manufacture, and implant structure. Synthetic and natural polymers can be used. Examples of natural polymers include chitosan, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin. Drug can be impregnated within, throughout, and/or on the surface of the implant. Drug is released by diffusion, degradation of the polymer, or a combination thereof.
Chemotherapeutic Agents
A variety of different chemotherapeutic agents can be incorporated into the polymeric matrix. In general, drugs will be added to between 10 and 50% (w/w), although the optimum can vary widely depending on the drug, from 1% to 70%. The preferred

memotherapeutic agents are hydrophobic agents like paclitaxel, which are insoluble in water, relatively insoluble in lipid (compared, for example, to carmustine), high molecular weight (i.e., of a molecular weight not normally crossing the blood brain barrier), exhibit rapid non-renal clearance in vivo, and have substantial systemic toxicity, and their functionally effective derivatives. As used herein, paclitaxel refers to paclitaxel and functionally equivalent derivatives thereof, which are water soluble. The preferred weight percent range of drug in polymer is from one to 90% and the preferred time of degradation is between one month and six months. Dosages must be optimized depending on the size of the implant, the location and size of the tumor to be treated, and the period over which drug is to be delivered. These calculations are routine for those skilled in the art of administering chemotherapy to tumor patients. In general, the effective dosage of a chemotherapeutic agent, which is administered locally by extended release, will be significantly less than the dosage for the same drug administered for shorter periods of time.
Preparation of Polymeric-Drug Compositions
Controlled release devices are typically prepared in one of several ways. For example, the polymer can be melted, mixed with the substance to be delivered, and then solidified by cooling. Such melt fabrication processes require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. Alternatively, the device can be prepared by solvent casting, where the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated, leaving the substance in the polymeric matrix. Similar devices can be made by phase separation or emulsification or even spray drying techniques. In still other methods, a powder of the polymer is mixed with the drug and then compressed to form an implant. The drug to polymer ratio which can be incorporated is 0.00001-1:1. The ratio of excipients, additives, surfactant/s, lipids or plasticizers incorporated ratio are Paclitaxel to surfactant is 0.00001-0.2:1, Paclitaxel to lipids ratio is 0.00001-0.1:1, Paclitaxel to plasticizers ratio is 0.00001-1:1.

Administration to Patients
The chemotherapeutic agents described herein or their functionally equivalent derivatives can be administered alone or in combination with, either before, simultaneously, or subsequent to, treatment using other chemotherapeutic or radiation therapy or surgery. A preferred embodiment is the local administration, by implantation of a biocompatible polymeric matrix loaded with the chemotherapeutic agent, or injection/infusion of micro-implants, using dosages determined as described herein. The dosages for functionally equivalent derivatives can be extrapolated from the in vitro and in vivo data. The polymeric implants can also be combined with other therapeutic modalities, including radiotherapy, other chemotherapeutic agents administered systemically or locally, and immunotherapy.
The present invention will be further understood by reference to the following non-limiting examples. The examples demonstrate the incorporation and release of paclitaxel from polymeric implant prepared by casting method.
EXAMPLE 1
Preparation of Paclitaxel Implant
Paclitaxel being a hydrophobic drug, two different approaches were undertaken for its incorporation into chitosan films, which involved use of either phospholipids alone or poloxamer 407 in presence of ETOH. Initially, a 10 mg/ml chitosan solution was prepared in 1% (v/v) acetic acid and glycerol was also included as a plasticizer at chitosan:glycerol weight ratio of 2:1. In the first method, liposomes containing paclitaxel (spiked with radioactive component) were prepared by film hydration method and were subsequently dispersed in chitosan solution. Then film was cast by pouring the mixture on a glass plate (area 45.5 cm2) followed by drying under vacuum for 48 h at 37°C. While in the second method, required quantities of paclitaxel and poloxamer 407 were dissolved separately in 1 ml of ETOH, mixed together and the ethanolic solution was added to chitosan solution with agitation in order to disperse paclitaxel. Subsequently, the homogeneous suspension was cast into film by the method described above and dried at 60°C for 12 h. Typical compositions that may be attempted are shown in Table 1.

EXAMPLE 2
Demonstration of Paclitaxel Delivery from the Biodegradable Matrix (film) into the release medium under in vitro conditions.
The efficiency of the delivery of paclitaxel incorporated into a biodegradable polymer into the surrounding medium was assessed in vitro as follows.
Preparation of polymer films. Polymeric films were prepared as described above except that 14C-labeled paclitaxel was also used along with non-radioactive paclitaxel in the implant preparation.
Method: A definite weight of film was cut and placed in micro centrifuge tube of 1.5 ml capacity containing 1 ml of release medium of following composition at 37°C: phosphate buffered saline (140 mM, pH 7.4) with 0.1% sodium azide and 0.1% Tween 80. At predetermined time points, 100 ul of release medium was sampled with replacement to which 3 ml of scintillation cocktail was added and vortexed before liquid scintillation counting. The cumulative amount of paclitaxel released as a function of time was calculated. In addition, to simulate the in vivo conditions, release of paclitaxel in presence of lysozyme (2 mg/100 ml) was also studied.
Results: In order to establish the ability of films to serve as depot formulations, release of paclitaxel from both lipid and poloxamer containing films was studied. It was observed that release was negligible from lipid containing films, while that containing poloxamer has shown a burst effect followed by no release. Films containing poloxamer released about 10% in 6 h and further release of paclitaxel was not observed till the study period of 144 h suggesting that the film has retained 90% of the payload (Fig. 1A). Since the release of paclitaxel was Under in vitro conditions, poloxamer film exhibited an initial burst effect followed by negligible release of paclitaxel thereafter (Fig. 1). The initial burst release from the

films is attributed to the surface deposited paclitaxel while the subsequent lack of release might be due to nonerosion/degradation of film. As chitosan is insoluble in release medium used for the study, film failed to release drug and this trend was observed with all film preparations. Though the test medium contained Tween 80, release of paclitaxel was not observed since the resulting micelles (diameter of 20-30 nm) were inaccessible to the inner matrix of film. To simulate the biodegradation process, lysozyme was included in the release medium as chitosan is susceptible to degradation by this enzyme. The extent of degradation by lysozyme, was inversely proportional to the degree of deacetylation and molecular weight. However, presence of lysozyme had not significantly influenced the release of paclitaxel from films (Fig. 1).
The primary mechanisms for release of drugs from matrix systems in vitro are swelling, diffusion and degradation while in vivo release is governed by both diffusion and biodegradation of matrix. It was reported that the in vitro and in vivo degradation of chitosan films prepared by solution casting method occurred less rapidly as their degree of deacetylation increases, and films which were greater than 73% deacetylated showed slower biodegradation. Since the grade of chitosan used was of high molecular weight with a degree of deacetylation >85%, significant retardation of release of paclitaxel from film is attributed to the polymer characteristics. In addition, diffusion was hindered by increased tortuosity of polymer accompanied by a swelling mechanism.
EXAMPLE 3
An evaluation of tensile strength of film.
The effect of paclitaxel on mechanical properties of chitosan films was assessed
through tensile strength test. Tensile strength of film was measured using Texture
analyzer TA-XT2i (Stable Micro Systems, UK) with the following acquisition
parameters:
(i) 2 mm/s pre-speed
(ii) 1 mm/s test-speed
(iii) 10 mm/s post-speed with an acquisition rate of 50 pts/s
(iv) 5 kg load cell

Film was secured with tensile grips and a trigger force of 5 g was applied. The resulting profiles were analyzed using texture expert version 1.22.
Results: Mechanical strength of film is described in terms of tensile strength and brittle films are characterized by decrease in the percent of elongation at break. The area under curve is energy required to break polymeric material and tough polymers have larger areas requiring large amounts of energy for rupture. In order to understand the arrangement of polymer chains in presence of paclitaxel, force-time profiles of films were generated as shown in Fig. 2. Though force of elongation at break is slightly lowered in presence of paclitaxel in film (10.3 vs. 9.8 N), the area under the profile has been increased (31.3 vs. 45.9 Ns). For convenience of interpretation, each profile is further described in terms of ascending and descending portions. The time to plateau of the ascending portion of paclitaxel chitosan film was greater in comparison to control film. As brittleness is reflected in the time to plateau, greater time is indicative of lack of brittleness of film. In addition, the descending segment of the profile of control film was uniform, while that of paclitaxel film was irregular and protracted. The discontinuities in internal structure and variation in strength of film matrix may be the reason of the irregular descending portion of profile.
Films exhibited sufficient mechanical strength when assessed in terms of force of breaking point and percent elongation at beak. Generally, stiff and brittle materials display a steep rise in stress strain curve (undergoing little or no cold flow) which extends only over narrow areas indicating that work required to beak them is small and have low impact resistance. The long elongated fibrous structures in paclitaxel chitosan film form an entangled network with chitosan polymer chains during film formation (see below) and, thereby alter the film property, namely the elongation at break. It was also observed that paclitaxel film ruptures gradually rather than abruptly (an extended profile), on application of force leading to increased area under stress curve imparting toughness to the film. These observations indicate that, chitosan films are not brittle in nature but tough and flexible, and discontinuities in film are caused by interruptions in film matrix by fibrous paclitaxel structures,

EXAMPLE 4
Solid state characterization of paclitaxel impregnated with the biodegradable film matrix
METHODS:
Differential scanning calorimetry
DSC studies were performed with a Mettler Toledo 82 le thermal analyzer (Switzerland) calibrated with indium as standard. For thermogram acquisition, sample sizes of 1-5 mg were scanned with a heating rate of 5°C/min over a temperature range of 25-300°C. In order to check the reversibility of transition, samples were heated to a point just above the corresponding transition temperature, cooled to room temperature and reheated up to 300°C.
Scanning electron microscopy
Paclitaxel samples and chitosan films were viewed using Jeol scanning electron microscope, JSM 1600 (Japan) for morphological examination. Powder samples of paclitaxel and films were mounted onto aluminum stubs using double sided adhesive tape and sputter coated with a thin layer of gold at 10 torr vacuum before examination (Jeol Fine coat, Ion sputter, JFC-1100). The specimens were scanned with an electron beam of acceleration potential of 1.2 kV and images were collected in secondary electron mode.
X-ray diffraction studies
Molecular arrangement of paclitaxel and chitosan in powder as well as in films was compared by powder X-ray diffraction patterns acquired at room temperature on a Philips PW 1729 diffractometer (Holland) using Cu Ko. radiation. The data was collected over an angular range from 3-50° 26 in continuous mode using a step size of 0.02° 26 and step time of 5 s.
Results:
Thermal studies of flints
The DSC thermograms of paclitaxel, recrystallized paclitaxel, blank and paclitaxel chitosan films are shown in Fig. 3 and the observed thermal events are summarized in

Table 2. Thermogram of paclitaxel showed an initial broad peak at 64.5"C due to removal of absorbed moisture or nonstructural water followed by a single endotherm at 223.6°C just prior to an exotherm of degradation peak (Fig. 3a). Another minor broad peak at 168.9°C was observed which may be due to the presence of small amounts of micro crystalline/amorphous form in the sample (since this peak was absent from second heating phase on DSC run when the sample was initially heated to 200°C, cooled back to 25°C and reheated, results not shown). In addition, DSC studies were also performed on dry powder (recrystallized paclitaxel) obtained by evaporation of paclitaxel poloxamer mixtures dispersed in aqueous acetic acid-ETOH solvent system (with same proportions as mentioned in Table 1) with the only difference being that chitosan was omitted. In DSC thermograms of recrystallized paclitaxel, a single endotherm of transition of poloxamer at 49.7°C along with two minor transitions were observed, however the melting peak of paclitaxel was found to shift to 197.4°C as against 223.6°C. On the other hand, the degradation peak of paclitaxel appeared at 219.6°C(Table2).
Both blank and paclitaxel chitosan films exhibited four endothermic peaks in DSC thermograms. The transition of poloxamer in these films occurred at 48°C with no appreciable shift (Fig. 3c). Other peaks in the region of 85-88°C have resulted from loss of moisture on heating. In blank film, a small endotherm was present at 139.9°C, while in paclitaxel film an asymmetric peak representing thermal event of micro crystalline/amorphous form of paclitaxel was seen. This event was followed by a broad endothermic peak at 230.5°C in both the films which may be attributed to glycerol component (boiling point of glycerol = 182°C). However, thermal events of paclitaxel, namely melting and decomposition, which were previously noted in the region of 190-225°C were not observable in film (Fig. 3d). Further, decomposition of chitosan was observed as a broad exotherm in films at 274-280°C while the same was at 294.5°C for chitosan powder under identical experimental DSC conditions (Fig. 3b).
Film morphology scanning electron microscopy studies
SEM photomicrographs revealed that commercial sample of paclitaxel has plate like appearance while recrystallized sample appeared fibrous and elongated as shown in Fig. 4A and B. In addition, SEM photographs of control and paclitaxel films were also

acquin : ind compared with that of paclitaxel samples. The morphology of control film
was p! and the picture was dark indicating that it has a smooth surface (Fig. 4C). In
contra > control film, features of paclitaxel chitosan film resembled to that of fibrous
recrys :ed paclitaxel morphology (Fig.4D). This typical surface appearance suggests
that p; ixel is not only dispersed in the film matrix but projected onto to surface of
film. Edition, some irregular masses were also identified in the pictures of
recrys: ed paclitaxel and film loaded with paclitaxel.
X-ray . action studies
X-ray -action is an authentic tool to study crystal lattice arrangements and yields
very u: information on degree of crystallinity of samples. X-ray diffraction pattern
of pac el, blank and paclitaxel film and were obtained and compared which
revealc larked differences in the molecular state of paclitaxel (Fig. 5). The
diffract un of blank chitosan film has shown two low intensity peaks at 19.1 and
23.3° 2 ith a characteristic broad hump in the range of 7° to 45° 29. This halo
diffract pattern (broad hump) is an indication of predominantly amorphous form of
chitosa films (Fig. 5a). In case of paclitaxel, diffractogram exhibited peaks at the
follow; 8 values: 4.1,5.4, 5.8, 9.1, 10.2, 11.3, 12.3, 12.5° (Fig. 5b). Amongst these,
the peal highest intensity was located at 5.8° 29 and the peaks at 11.3 and 12.5° 29
were br When diffraction pattern of paclitaxel in chitosan film was compared with
thai of utaxel, the pattern differed to a large extent. A number of high angle
diffracti -eaks were observed in paclitaxel chitosan film at the following 29 values:
4.1, 5.2, 10.8, 12.1, 12.6, 13.8, 14.6, 18.6, 20, 20.7, 21.6, 23.6° (Fig. 5c). The 12.6°
29 peak the highest intensity and hump in the baseline occurred from 7 to 45° 29 as
observer chitosan film. It is probable that the new sharp diffraction peaks are result
of new t\ of paclitaxel.
As DSC useful tool to monitor the effects of additives on the thermal behavior of
materials s technique was employed to derive qualitative information about the
physicoci cat status of drug in films. The recrystallized paclitaxel showed two
peaks, a 1 •ndotherm peak representative of transition temperature of poloxamer, and
an exothi : peak for degradation of paclitaxel. The lack of a second endothermic

pea*, in me L/oC run above 100°C suggests that paclitaxel was present as amorphous form (Table 2).
Amorphous paclitaxel prepared by quench cool method was reported to have a glass transition temperature of 152.4°C. However, it appears that the reported form is not present in the film since a new peak at 172.5°C (which was not present in control films) was observed in paclitaxel chitosan films (Fig. 3). The melting/transition point of this peak was different from that of reported value suggesting that the peak arises due to melting/transition of a new solid-state form of paclitaxel. Further, the sample was subjected to a heat-cool cycle (25-190-25-300°C) in order to ascertain the nature of this thermal event. On the second heating phase of a heat-cool cycle, all peaks were absent from the recrystallized sample suggesting that these events are irrereversible and the peak at 172.5°C is representative of transition and not melting process. In addition, decomposition peak shifted to lower temperatures in film which may be indicative of loss of interpolymer chain interactions as chitosan films were reported to undergo thermal decomposition at 290-300°C.
As observed from SEM photomicrographs, the crystals of paclitaxel (plate like) have a different appearance to that of recrystallized paclitaxel (elongated and fibrous) (Fig. 4). This dissimilarity suggests that the crystal habit and/or lattice of paclitaxel was modified during film casting. In addition, the micrographs of recrystallized paclitaxel and paclitaxel loaded film also showed scattered irregular masses. Since, the proportion of poloxamer was not sufficient to form dispersion with the total amount of paclitaxel, excess of paclitaxel was observed to precipitate in a different form (irregular masses). This implies that paclitaxel is present in film both as amorphous form (fibrous form) and non-amorphous form (irregular masses) which is further substantiated by DSC and X-ray diffraction studies.
X-ray diffraction is an authentic tool to study the degree of crystallinity of pharmaceutical drugs and excipients. A lower °26 value indicates larger d-spacings while an increase in the number of high angle reflections indicate higher molecular state order. In addition, broadness of reflections, high noise and low peak intensities are characteristic of a poorly crystalline material. A broad hump in the diffraction pattern

of chitosan extending over a large range of °20 suggests that chitosan is present in amorphous state in the film (Fig. 5a). The two broad peaks superimposed on hump were also observed in other studies which were attributed to hydrated and anhydrous crystals of chitosan in film. Film of paclitaxel has exhibited a greater number of peaks than observed for paclitaxel, and further, shifts were observed for majority of peaks, with the most intense peak located at higher °26 value in film (Fig. 5c). The dissimilarity in diffraction pattern is indicative of different crystalline form of paclitaxel in film while the more intense and several new diffraction peaks provide evidence on increased crystallinity of paclitaxel. It was previously reported that dehydration of paclitaxel resulted in the increased degree of crystallinity compared with hydrated form and similarly, the polymorphic change is expected during drying process of film formation. Hence, X-ray diffraction studies confirm film casting methodology resulted in conversion of paclitaxel into a new form (dehydrated/crystalline form) with a different crystal lattice arrangement compared with commercial sample (paclitaxel).
EXAMPLE 5 Histology studies
Method: Histology studies were done in order to examine the acute toxicity of film at the implantation site. After a two-month implantation period, mice were sacrificed by cervical dislocation and an incision was made in the implantation area. Then, the tissue in which film was imbibed was removed and stored in 50% formalin until processing. Subsequently, tissue processing involved dehydration through graded series of alcohols (70, 80, 95 and 100%) followed by xylene and then infiltration with paraffin. For, obtaining thin sections (3-5 urn), tissues were embedded on edge of paraffin blocks and were cut on a rotary microtome. These sections were deparafinized, rehydrated with graded alcohols (100, 95, 80, 75%) and stained with hemotoxylin/eosin for microscopic examination. Similarly, sections of paclitaxel chitosan film and tissue of healthy mouse were obtained to serve as control.
Results: The tissue responses to implanted film were studied by microscopic examination of tissues in the implanted area (Fig.6). Lack of increase in number of macrophages at the site of implantation suggests that inflammatory responses were either minimal or absent. It has been previously reported that, the degree of

deacetylation of chitosan was key factor in determining not only release rate but also inflammatory responses.
Typically, gels composed from grades of low degrees of deacetylation had short residence times and higher inflammatory response while those with higher degree have longer residence time and minimal or no inflammation. In the present study, the grade of chitosan used for fabrication of film was >85% deacetylated, and hence, the high degree of deacetylation of chitosan may be the reason for reducing local inflammatory responses.
Though under in vitro conditions, chitosan film retained integrity in the presence of lysozyme, it has demonstrated susceptibility to biodegradation under in vivo conditions in mice. Moreover, tissue examined at the site of implantation appeared normal (absence of significant infiltration of macrophages) signifying that film had not imposed any unfavorable influences to create hostile environment. Hence, these studies turned out to be very significant in understanding film host tissue responses with the result that normal physiological processes remain unaffected after implantation
These data show that paclitaxel can be effectively utilized by local delivery with the controlled release polymer chitosan. Further, the data show that local controlled drug delivery allow the clinical use of this highly effective drug that could not be utilized systemically because of its toxicity and narrow therapeutic window.
Modifications and variations of the compositions of the present invention and methods for use will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to fall within the scope of the appended claims.
The drug delivery system can be used for known anticancer agents including an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), mercaptopurine, fludarabine, cytarabine, asparaginase, pentostatin, procarbazine, thiotepa, streptozocin, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel), etc.), an alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.),

platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative).
The delivery system allows 1 % to 70 % incorporation of the drug into the polymer matrix, preferably between 10 %v to 50 %. Further, the polymer retains 90% of the drug payload due to its high molecular weight and therefore the drug release is streamlined. The lysozyme, which acts as excipient enhances the further diffusion of the drug. The non-obvious factor contributes to the unexpected results from the properties of the composition, which is surprising to the person skilled in the art. The spectrum of non-obviousness is enhanced since the efficacy achieved is not the sum of the properties of the two compounds but the path these compounds follow by overcoming the blood-brain barrier and systemic toxicity to deliver the desired anticancer response without any unusual affects is unexpected by the person skilled in the art. The combination of polymer chitosan and the anticancer chemotherapeutic agent forms a constructive network, which is well identified and readily accepted by the carrier system i.e the blood and subsequently by the body.
The inventiveness is a synergistic mutual association between the delivery mechanism and the subject, so as the subject receives a consistent dosage of the drug for about eight hours, without any systemic toxicity or loss in the efficacy.The drug delivery system also works in synchronization with other anticancer chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. Since cancer chemotherapy is often a combination therapy, one or more drugs from appropriate class from the above mentioned substances and any possible route may administer group/category of drugs and the treatment can continue for any desirable length of time, and it can be repeated, as appropriate to achieve the desired end results. Such results can include the attenuation of the progression of the cancer, shrinkage of such tumors, or, desirably, remission of all symptoms.

The combination is therefore a non-obvious combination. Infact, the present combination provide unexpected result and the properties of the combination is surprising to the person skilled in the art.
ADVANTAGES:
1. The polymer chitosan is biodegradable and biocompatible and retains its
integrity for longer period.
2. The composition includes anticancer chemotherapeutic agents of both high and
low molecular weights, exhibit non-renal and show non-toxic systemic
clearence.
3. The drug delivery dosage is upto eight hours.
4. The drug delivery system overcomes the blood-brain barrier and is non-
cytotoxic.
5. The packing of the drug is by micellar entrapment during film casting which
incorporates the drug thereby increasing its delivery efficacy.
6. The synergistic network of drug delivery system allows its easy and non-toxic
acceptance within the body.
7. The drug delivery system performs synergistically with other anticancer
chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting
compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic
agents, anti-edema agents, radiosensitizers, and combinations thereof.
8. The chemotherapeutic agent is released from the natural polymer by
degradation or diffusion.
(Table Remove)

WHAT IS CLAIMED
1. A pharmaceutical composition for preventing and/or treating solid tumors said
composition comprising natural polymeric matrix, poloxamer and anticancer
chemotherapeutic agent/s, optionally along with additives selected from the
group consisting of surfactant/s, and plasticizers.
2. A pharmaceutical composition as claimed in claim 1, wherein the natural
polymer matrix is biocompatible and biodegradable.
3. A pharmaceutical composition as claimed in claim 1, wherein the natural
polymer matrix is hydrophilic, soluble in water, retains integrity for suitable
time period, strong but flexible and does not crumble or fragment during use.
4. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent is impregnated within, throughout and/or on the surface
of the natural polymeric matrix.
5. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent is released by diffusion, degradation of the polymer or
in combination thereof.
6. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent is hydrophobic, high molecular weight, exhibit rapid
non-renal clearance in vivo and have functional equivalent derivatives.
7. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent/s includes an antimetabolite (e.g., 5-flourouricil (5-FU),
methotrexate (MIX), mercaptopurine, fludarabine, cytarabine, asparaginase,
pentostatin, procarbazine, thiotepa, streptozocin, etc.), an anti-microtubule agent
(e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel, etc.), an
alkylating agent (e.g., carmustine, busulfan, chlorambucil, cyclophosphamide,
melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g.,
cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.),
anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g.,

mitomycin-C, Dactinomycin etc.), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone, vitamin D (or a derivative).
8. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent/s include paclitaxel and its functionally effective
derivatives like hydrophobic hydroxy esters of paclitaxel where one or more of
the three hydroxyls of paclitaxel are modified with long chain alkyl or aromatic
pendant groups.
9. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent is present in the polymeric matrix in one or more solid
state forms such as amorphorus, semicrystalline, crystalline, hydrated and
hydrated forms.
10. A pharmaceutical composition as claimed in claim 1, wherein the natural
polymeric matrix used is polymeric chitosan matrix.
11. A pharmaceutical composition as claimed in claim 1, wherein the dosage of
anticancer chemotherapeutic agent/s is 10-25 mg.
12. A pharmaceutical composition as claimed in claim 1, wherein the polymer
chitosan is 20-250 mg.
13. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and
chitosan ratio is 0.00001 to 1: 1
14. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and
surfactant ratio is 0.00001 to 0.2: 1.
15. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and
lipids ratio is 0.00001 to 0.1: 1
16. A pharmaceutical composition as claimed in claim 1, wherein the Paclitaxel and
plasticizers ratio is 0.00001 to 1: 1

17. A pharmaceutical composition as claimed in claim 1, wherein the preferred
weight percent range of anticancer chemotherapeutic agent is 1% to 90 %
18. A pharmaceutical composition as claimed in claim 1, wherein the time duration
for the treatment varies from one month to six months depending upon the size
of implant, location and size of the tumor to be treated.
19. A pharmaceutical composition as claimed in claim 1, wherein the anticancer
chemotherapeutic agent is released by diffusion or degradation over a period of
eight hours.
20. A method of preparing a biocompatible and biodegradable composition, said
method comprising, incorporating an anticancer chemotherapeutic agent/s in a
natural polymeric chitosan matrix in presence of poloxamer carrier and
optionally along with additives selected from the group consisting of
surfactant/s, and plasticizers
21. A method as claimed in claim 20, wherein anticancer chemotherapeutic agent/s
is implanted in the polymer matrix chitosan by using micellar entrapment
during film casting while adjusting the polarity of the medium with ethanol.
22. A method as claimed in claim 20, wherein anticancer chemotherapeutic agent/s
is prepared by either by mixing the polymer with chemotherapeutic agent or
mixing the chemotherapeutic agent in polymer with solvent by casting and then
evaporating the solvent.
23. A method to treat and/or prevent cancer using composition comprising natural
polymeric chitosan matrix and anticancer chemotherapeutic agent/s, optionally
along with additives selected from the group consisting of surfactant/s, lipids
and plasticizers and other chemotherapeutics, said method comprising steps of
administering a pharmaceutically effective dosage of the composition to a
subject, preferably humans.

24. The method as claimed in claim 23, wherein the chemotherapeutic agent is
released with linear or first order kinetics.
25. A method as claimed in claim 23, wherein chemotherapeutic agent can be
administered alone or in combination with, either before, simultaneously, or
subsequent to, treatment using chemotherapeutic or radiation therapy or
surgery.
26. A method as claimed in claim 23, wherein effective dosage of the
chemotherapeutic agents be delivered with additional chemotherapeutics,
antibiotics, antiviral, antinflammatories, targeting compounds, cytokines,
immunotoxins, antitumor antibodies, anti-angiogenic agents, anti-edema,
radiosensitizers, and combinations thereof.

Documents:

777-del-2003-abstract-(19-02-2008).pdf

777-DEL-2003-Abstract-(29-01-2008).pdf

777-DEL-2003-Abstract.pdf

777-del-2003-claims-(19-02-2008).pdf

777-DEL-2003-Claims-(29-01-2008).pdf

777-DEL-2003-Claims.pdf

777-DEL-2003-Correspondence-Others-(29-01-2008).pdf

777-DEL-2003-Correspondence-Others.pdf

777-del-2003-correspondence-po.pdf

777-DEL-2003-Description (Complete).pdf

777-DEL-2003-Description-(Complete)-(29-01-2008).pdf

777-DEL-2003-Drawings-(29-01-2008).pdf

777-DEL-2003-Drawings.pdf

777-DEL-2003-Form-1-(29-01-2008).pdf

777-DEL-2003-Form-1.pdf

777-DEL-2003-Form-18.pdf

777-DEL-2003-Form-2-(29-01-2008).pdf

777-DEL-2003-Form-2.pdf

777-DEL-2003-Form-26.pdf

777-DEL-2003-Form-3.pdf

777-del-2003-form-5.pdf

777-DEL-2003-GPA-(29-01-2008).pdf

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Patent Number

215478

Indian Patent Application Number

777/DEL/2003

PG Journal Number

11/2008

Publication Date

14-Mar-2008

Grant Date

27-Feb-2008

Date of Filing

04-Jun-2003

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)

Applicant Address

SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAMESH PANCHAGNULA	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA.
2	ANANDBABU DHANIKULA	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA.

PCT International Classification Number

A61K 31/722

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA