DRUG DELIVERY

FIELD OF THE INVENTION

[0001] The present invention relates to a targeted drug delivery system comprising nanoparticles having a core comprising one or more polymer(s) and one or more lipid(s) wherein the nanoparticles comprise a therapeutically effective amount of an anticancer drug or its pharmaceutically acceptable salts, one or more biodegradable polymer(s), one or more lipid(s), one or more of surfactant(s) and optionally one or more targeting ligands. The present invention also relates to a pharmaceutical composition comprising this delivery system and a process for the preparation of such composition thereof.

BACKGROUND OF THE INVENTION

[0002] Paclitaxel is one of the most effective chemotherapeutic agents effective against all forms of cancer. A number of pharmacological tests show that Paclitaxel has a significant effect on advanced ovarian cancer, metastatic breast cancer and melanoma and has high curative rate on refractory ovarian cancer and metastatic breast cancer, also has good prospects on the treatment of prostate cancer, gastrointestinal cancer, small cell lung cancer and non-small cell lung cancer. So it is one of the anti-cancer drugs with highest anti-cancer effect discovered at present and has a unique acting mechanism of inhibiting growth and isolation of cancer cells.

[0003] However, the main problem of Paclitaxel is that it requires addition of adjuvants, such as Cremophor EL (polyethoxylated castor oil derivative), to a drug formulation due to its insolubility in water, and it causes side effects which includes allergic hypersensitivity, hyperlipidemia and abnormal protein pattern synthesis due to ethanol toxicity in chemotherapeutic treatment. The unpleasant and unwanted systemic side effects of the drug restrict its large dose administration. Therefore, there is a need for systematic administration of paclitaxel by nanop articulate encapsulation of the drug thereby forming a less toxic formulation and administering the dose by targeting the drug toa target site with minimal dose in blood stream. [0004] Decreasing the dose of Paclitaxel has been a challenging problem since early stages of work. A less toxic formulation of Paclitaxel can be achieved by targeting the drug to the target site with a minimal dose in blood stream.

[0005] Target delivery of mediated therapeutic agents for vascular diseases, or other local disorders such as cancer or infection, is a strategy to enhance delivery of therapeutic agents, thereby minimizing the undesired side effects of the drug. Nanoparticle technology has emerged to be a physiologically advantageous to enhance delivery of therapeutic agents to tumors, thereby increasing the potential for diagnosis at an earlier stage or for therapeutic success or both.

[0006] Controlled or Sustained or Timed or Extended drug delivery systems, by nanoparticle technology is a modern form of therapy where a drug is transported to a place of action, with influence on vital tissues and also minimizing undesirable side effects. Accumulation of therapeutic compound in the target site increases and, consequently the required doses of drugs are lower. This is especially important when there is a discrepancy between dose or concentration of a drug and its therapeutic results or toxic effects. Cell- specific targeting can be accomplished by attaching drugs to specially designed carriers. Various nanostructures, including liposomes, polymers, dendrimers, silicon or carbon materials, and magnetic nanoparticles, have been tested as carriers in drug delivery systems.

[0007] A recent study by Maeda and Matsumura illustrates that the tumors posses a fenestrated vasculature, having pores size ranging from 200 to 800 nm in dimension and a lack of lymphatic drainage, together termed to enhance permeability and retention effect. There is therefore, a need for colloidal carriers in the nanometer size range which could target tumors passively, by specific extravasations through these fenestrations, and are retained at the site for prolonged time because of lack of lymphatic drainage. Nanoparticle allows encapsulating larger dose therapeutic agents which need to be administrated in higher doses like Paclitaxel and also decrease the systemic side effects of the drug.

[0008] Parenteral administration of nanoparticles provides controlled systemic release that is suitable for drugs with low oral bioavailability, short biological plasma half-life and limited stability. Another significant advantage of parenteral nanoparticles is the possibility of concentrating drug in a certain organ. However, nanoparticles are quickly recognized, uptaken and eliminated from the blood circulation by macrophages of the mononuclear phagocyte system (MPS) after their intravenous administration. This phenomenon limits their function in controlled release as well as the possibility of concentrating the drug in tissues other then MPS.

[0009] In recent years biodegradable polymeric nanoparticles have been proposed as new drug administration systems for anti-cancer agents. One of the most important features that offered is controlled release of the incorporated drug. This leads to greater therapeutic efficacy, provides a more comfortable administration for the patient and allows preventing overdose. Furthermore, drugs with different physicochemical features can be included, enabling improving their stability in biological fluids. This fact is very important in the case of antigens, proteins and macromolecules in general. Furthermore due to their small size, nanoparticles are suitable for the administration of drugs through various routes, such as orally, parenterally and ocularly (Kreuter, Adv. Drug Del. Rev., 7 (1991) 71-86; Gref et al., Science, 263 (1994) 1600-1603; Zimmer and Kreuter, Adv. Drug Del. Rev., 16 (1995) 61- 73).

[00010] Commonly used polymer for targeted nanoparticle drug delivery is polyester polylactic-polyglycolic acid copolymer (PLGA). While PLGA is biocompatible, it degrades relatively rapidly. Thus the use of PLGA for long-term sustained release drug delivery systems has been limited. In addition, due to the limited number of hydroxyl groups on PLGA, it has been difficult to chemically link a significant amount of bioactive agent to the polymer chain. Therefore, there is a need for providing PLGA and other non-reactive polymers with more reactive functional groups for subsequent chemical modification and/or linking with therapeutic agents of interest. There is also a need in the art for biocompatible polymers which have long term biodegradable characteristics.

[00011] The existing art in general describes use of polymers as surfactants in forming biocomapatible and biostable nanoparticle, for example, European patent EP 1795185, provides formulation comprising biocompatible and biodegradable nanoparticles and /or microparticles loaded with the pharmacologically active agent and d-alpha tocopheryl polyethylene glycol 1000 succinate and European patent EP 2309990 ('990) discloses the nanoparticles having biocompatible polymer such as diblock poly(lactic) acid-poly(ethylene) glycol. D-alpha tocopheryl polyethylene glycol 1000 polymer increases the encapsulation efficiency of nanoparticle up to 100% with better controlled release kinetics and enhanced cellular uptake with decrease in drug cytotoxicity. However the patent does not describe the method of implementating the target ligands to the nanoparticle formulation for its application in drug target therapy. [00012] Polycaprolactone, another biodegradable polymer used in the medical field, has long-term sustained release potential. In fact, polycaprolactones have been used for contraceptive systems incorporating hydrophobic agents, such as steroids. Unfortunately, polycaprolactones are not useful for hydrophilic agents, or for rapid release applications. Polycaprolactone also lacks reactive functional groups that can be used to derivatize, or chemically modify, the polymer. It would be advantageous to form a new biodegradable polymer, containing the hydrophobic polycaprolactone block, but with more desirable hydrophilic characteristics, rapid biodegradation kinetics, and the potential for further derivatization (e.g., through the addition of reactive epoxy groups).

[00013] To prevent the nanoparticles from opsonization and removal by reticuloendothelial system, conjugation of polymer such as polyethlene glycol (PEG) to a hydrophobic polymer like poly lactic-coglycolic acid (PLGA) or any other polymer can create a di-block copolymer with a natural tendency for partitioning at the hydrophilic/hydrophobic interface, thereby enhancing the retention of nanoparticle in the blood stream.

[00014] Increased plasma circulatory half-life of systemic particle-based drug delivery, however, remains a challenge and is a prerequisite for site-specific targeting. Functional modification of the nanoparticle surface with hydrophilic polymers such as polyethylene glycol (PEG) is a strategy to reduce blood clearance mediated by the mononuclear phagocytic system (MPS). There are in general many prior arts which discuss the implementation of PLGA in regard of target cancer therapy such as Jin C, et al (2008) Cancer Biol Ther 7: 911-916, Danhier F., et al.(2009) Jounal of Control Release 133 : 11-17., Fonseca C, et al. (2002). Journal of Control Release 83 : 273-286. Hence there is a need of modification of nanoparticle core and its surface fictionalization.

[00015] European Patent EP 22622537 describes a pharmaceutical composition comprising a polymer PGGA-conjugate with nanoparticle of Paclitaxel. The pharmaceutical composition is used to treat a variety of cancers, such as lung cancer, skin cancer, kidney cancer, liver cancer and spleen cancer. However it does not disclose the application to tumors targeted to breast cancer. Furthermore it does not disclose or teach the method to minimize the dosage of Pacilaxtel which reduces the toxic effects of the drug.

[00016] European Patent EP 2136788 provides polymers and macromolecules, in particular, to polymers useful in nanoparticles. One aspect of the invention is directed to a method of developing nanoparticles with desired properties. In one set of embodiments, the method includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing together two or more macromolecules in different ratios. One or more of the macromolecule may be a polymeric conjugates of a moiety to a biocompatible polymer. In some cases the nanoparticles may contain a drug. Other aspects of the invention are directed to methods using nanoparticles libraries. However the patent does not discuss target delivery of the formulations.

[00017] Passive targeting relies on the properties of the delivery system and the disease pathology in order to preferentially accumulate the drug at the site of interest and avoid nonspecific distribution. For instance, Poly ethylene glycol (PEG)- or Poly ethylene oxide (PEO)-modified nanocarrier systems can preferentially accumulate in the vicinity of tumor mass upon intravenous administration based on hyperpermeability of newly-formed blood vessels by a process known as enhanced permeability and retention (EPR) effect. Maeda et al. first described the EPR effect in murine solid tumor models. When polymer-drug conjugates are administered, 10-100 fold higher concentrations can be achieved in the tumor (due to EPR effect) than when free drug is administered. Some investigators have also suggested that the EPR effect is present in inflammatory areas and in myocardial infarction. However the patent does not discuss target delivery of the formulations.

[00018] Various drug delivery strategies devised for passive targeting involve use of specific stimuli-sensitive delivery system that can release the encapsulated payload only when such a stimuli is present. For instance, the pH around tumor and other hypoxic disease tissues in the body tend to be more acidic (i.e., 5.5-6.5), relative to physiological pH (i.e., 7.4). The significant enhancement in drug delivery and accumulation in the tumor mass when pH-sensitive PEO-modified poly (beta-amino ester) (PbAE) nanoparticles were used; in contrast drug delivery using non-pH sensitive polyethylene oxide-polycaprolactone (PEO- PCL) nanoparticles in aqueous solution was not as effective. Other approaches for passive targeting involve optimization of nanocarrier size and surface charge modulation. Nanoparticles of 200 to 400 nm in diameter and those with positive surface charge are known to preferentially accumulate and reside in the tumor mass for longer duration than do either neutral or negatively charged nanoparticles.

[00019] There is thus a need to develop new drug delivery systems which can provide good entrapment efficiency of PLGA and other non-reactive polymers with more reactive functional groups for subsequent chemical modification and/or linking with therapeutic agents of interest like Paclitaxel. With good entrapment efficiency there is further requirement to form nanoparticles of the drug which release drug in a desired level over a certain period of time. There is also a need to substantially reduce the cost of such delivery systems owing to use of polymers such as PLGA in such systems.

[00020] To overcome the cons of the available system, in the present invention the inventors have disclosed a core of nanoparticle comprising both PLGA and lipid.

[00021] Additionally there is a need for surface modifications of nanocarrier systems for targeted delivery to the tumor cells or to the endothelial cells of the tumor blood vessels. However the patent does not discuss on surface modification.

[00022] Thus the present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

OBJECTS OF THE INVENTION

[00023] The main object of the present invention is to provide a targeted drug delivery system comprising nanoparticles with a core comprising polymer and lipid wherein the nanoparticles comprise a therapeutically effective amount of an anticancer drug or its pharmaceutically acceptable salts, one or more biodegradable polymer(s), one or more lipid(s), and one or more of surfactant(s).

[00024] Another object of the present invention is to provide a process for preparing the targeted drug delivery system and the pharmaceutical composition thereof.

[00025] A further object of the present invention is to provide a pharmaceutical composition comprising drug delivery system of the present invention for the treatment and/or prevention of cancer.

[00026] Another object of the present invention is to provide a drug delivery system capable of being target specific.

[00027] Another object of the present invention is to provide a drug delivery system capable of being modulated to entrap maximum drug.

[00028] Another object of the present invention is to provide a drug delivery system capable of releasing the therapeutic drug in a controlled manner.

[00029] Another object of the present invention is to provide a drug delivery system capable of longer retention of nanoparticles in blood stream and at the target site.

[00030] Another object of the present invention is to provide a drug delivery system that can deliver therapeutic levels of drugs to treat diseases such as cancer, while reducing the patient side effects. [00031] Still another object of the present invention is to provide a drug delivery system which obviates the disadvantages associated with the known arts.

[00032] Yet another object of the present invention is to provide a process that is technically and commercially feasible.

SUMMARY OF THE INVENTION

[00033] The present invention relates to a targeted drug delivery system comprising nanoparticles having a core comprising one or more polymer(s) and one or more lipid(s), wherein the nanoparticles comprise a therapeutically effective amount of an anticancer drug or its pharmaceutically acceptable salts, one or more biodegradable polymer(s), one or more lipid(s), and one or more of surfactant(s).

[00034] In an embodiment, the drug delivery system of the present invention can also comprise one or more stealth agent(s), one or more of targeting ligand(s) and one or more anti opsonization agent(s), along with one or more pharmaceutically acceptable excipient(s).

[00035] In an embodiment, the anticancer drug loaded in the delivery system of the present invention is selected from the group comprising Taxol derivatives, more preferably Paclitaxel or its pharmaceutically acceptable salts thereof.

[00036] The present invention further provides a process for the preparing the drug delivery system and the pharmaceutical composition thereof.

[00037] The present invention further relates to a pharmaceutical composition comprising drug delivery system of the present invention for the treatment and/or prevention of cancer.

[00038] According to the present invention, concentration of therapeutic drug Paclitaxel ranges from 0% to 40% w/v of the pharmaceutical composition, one or more of biodegradable polymer(s) ranges from 0.01% to 99.99 %> w/v, one or more of lipid (s) ranges from 0.01%) to 99.99 %> w/v. The proportions in the pharmaceutical composition may be with or without the drug. The composition also may comprise of one or more targeting ligand(s) ranging from 0.001%) to 20%> w/v of the pharmaceutical composition; and concentration of one or more surfactant(s) ranges from 0.0001%) to 40%> w/v of the pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[00039] Figures 1 and 2 depict the particle size results of the composition of Example 1 of the present invention.

[00040] Figure 3 depict the zeta potential of the composition of Example 1 of the present invention.

[00041] Figures 4 to 6 depict the transmission electron microscopy results for the composition of Example 1.

[00042] Figure 7 depicts the XRD spectrum of Paclitaxel.

[00043] Figure 8 depicts the XRD-Spectrum of PLGA polymer.

[00044] Figure 9 depicts the XRD-Spectrum of the composition of Example 1.

DETAILED DESCRIPTION OF THE INVENTION

[00045] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying figures and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein.

[00046] The present invention relates to a targeted or without target drug delivery system comprising nanoparticles having a core comprising one or more polymer(s) and one or more lipid(s), wherein the nanoparticles comprise a therapeutically effective amount of an anticancer drug or its pharmaceutically acceptable salts, one or more biodegradable polymer(s), one or more lipid(s), and one or more of surfactant(s).

[00047] In an embodiment, the drug delivery system of the present invention can also comprise one or more stealth agent(s), one or more of targeting ligand(s) and one or more anti opsonization agent(s), along with one or more pharmaceutically acceptable excipient(s).

[00048] In one embodiment, the drug delivery system of the present invention comprises one or more polymer(s) in combination with one or more lipid(s) wherein this combination forms a core of the nanoparticles. This combination of one or more polymer(s) with one or more lipid(s) forming core of the nanoparticles can significantly reduce the high costs involved in using very expensive polymers such as PLGA in formulations.

[00049] A further embodiment of the present invention is to provide a process for preparing drug delivery system and the pharmaceutical composition thereof. [00050] As used herein, the term "active ingredient" or "active pharmaceutical ingredient" or "drug" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect.

[00051] The term "subject" as used herein refers to a mammal, preferably a human.

[00052] The term "nanoparticles" as used herein refers to designate spheres or similar shapes with a size less than 1.0 micrometer, preferably in the range of 1 to 999 nanometers."

[00053] The term "tumour" and/or "cancer" is to be understood as referring to all forms of neoplastic cell growth, including tumours of the lung, liver, blood cells, skin, pancreas, stomach, colon, prostate, uterus, breast, lymph glands and bladder. Breast cancer may especially suitable for treatment according to the present invention.

[00054] The term "biocompatible and biodegradable polymer" as used herein refers to polymers that do not induce any adverse response when inserted or injected into a living subject, for example, without significant inflammation and/or acute rejection of the polymer by the immune system. Furthermore, such polymers when introduced into cells are broken down by the cellular machinery (biologically degradable) and/or by a chemical process, such as hydrolysis, (chemically degradable) into components that the cells can either reuse or dispose of without significant toxic effect on the cells. Non-limiting examples of biocompatible and biodegradable polymers that may be useful in various embodiments of the present invention include polyesters, including copolymers comprising lactic acid and glycolic acid units, such as poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide), collectively referred to herein as "PLGA"; and homopolymers comprising glycolic acid units, referred to herein as "PGA," and lactic acid units, such as poly-L-lactic acid,poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide, collectively referred to herein as "PLApoly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, polyorthoesters, poly(dioxanone)s, polycaprolactones, biodegradable polyurethane, polycyanoacrylates blends thereof,

copolymers and cationic polysaccharide type polymers such as chitosan and its derivatives such as CM-chitosan, carboxyethyl-chitosan, methyl-chitosan, ethyl-chitosan hydroxyethyl- chitosan, hydroxypropyl-chitosan, oxidized chitosan, acetyl-chitosan, aminoalkyl-chitosan, allyl-chitosan and the like thereof.

[00055] In one preferred embodiment, the polymer is PLGA.

[00056] The term "lipid" as used herein refers at least one selected from the group consisting of glyceryl behenate (Compritol 888ATO), tricaprin, trilaurin, trimyristin, tripalmitin, tristearin, 1 ,2-dioctanoyl-SA7-glycerol, 1 ,2- didecanoyl-s/7-glycerol, 1 ,2- dilauroyl-sn-glycerol, 1 ,2-dimyristoyl-sn-glycerol, 1 ,2- dipalmitoyl-sn-glycerol, 1 - palmitoyl-2-oleoyl-sn-glycerol, 1 -stearoyl-2-linoleoyl-SA7- glycerol, 1 -stearoyl-2- arachidonoyl-sn-glycerol, 1 -stearoyl-2-docosahexaenoyl- sn-glycerol, l-oleoyl-2-acetyl- snglycerol, 1 ,2-di-O-phytanyl-sn -glycerol, 1 ,2- dipalmitoyl ethylene glycol, 1-2-di oleoyl ethylene glycol, glycerylmonostearate, behenoyl polyoxyl-8 glycerides, glyceryl palmitostearate, 1-O-hexadecyl-sn- glycerol, l-0-hexadecyl-2-acetyl-s/?- glycerol, 1 -O- hexadecyl-2-O-methyl-sn- glycerol, 1 ,2-diacyl-3-0-(a-D-glucopyranosyl)- SA7-glycerol, stearoyl macrogol-32 glycerides, stearoyl polyoxyl-32 glycerides, lauroyl macrogol-32 glycerides, lauroyl polyoxyl-32 glycerides, lauroyl macrogol-6 glycerides, lauroyl polyoxyl-6 glycerides, oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6 glycerides, linoleoyl macrogol-6 glycerides, polyglyceryl-3 dioleate, glycerol monolinoleate, glyceryl monolinoleate, glycerol monooleates, diethylene glycol monoethyl ether, glyceryl dibehenate, glycerol distearate, glyceryl distearate, glyceryl dipalmitostearate and linoleoyl polyoxyl-6 glyceride, more preferably, glyceryl behenate.

[00057] The term "polyethylene glycol" as used herein refers to any hydrophilic polymer soluble in water containing ether groups linked by 2 or 3 carbon atom, optionally branched alkylene groups. Therefore this definition includes branched or non-branched polyethylene glycols, polypropylene glycols, and also block or random copolymers including the two types of units. The term also includes derivatives of the terminal hydroxyl groups, which can be modified (1 or both ends) so as to introduce alkoxy, acrylate, methacrylate, alkyl, amino, phosphate, isothiocyanate, sulfhydryl, mercapto and sulfate groups. The polyethylene glycol or polypropylene glycol can have substituents in the alkylene groups.

[00058] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed agents wherein the parent agent is modified by making acid or base salts of the agent. For example, acid salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral— H group) using conventional means known in the art, involving reaction with a suitable acid. Suitable acids for preparing acid salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Conversely, preparation of basic salts of acid moieties which may be present on a drug are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.

[00059] The anticancer drug loaded in the delivery system of the present invention is selected, without restriction, from the group comprising mTor inhibitors (e.g., sirolimus, temsirolimus, or everolimus), doxorubicin (adriamycin), gemcitabine (gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, venorelbine, 5-fluorouracil (5- FU), vinca alkaloids such as vinblastine or vincristine; bleomycin, paclitaxel (taxol), docetaxel (taxotere), aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-11, 10-hydroxy-7-ethylcamptothecin (SN38), dacarbazine, S-I capecitabine, ftorafur, 5'deoxyfluorouridine, UFT, eniluracil, deoxycytidine, 5-azacytosine, 5-azadeoxycytosine, allopurinol, 2-chloroadenosine, trimetrexate, aminopterin, methylene- 10-deazaminopterin (MDAM), oxaplatin, picoplatin, tetraplatin, satraplatin, platinum -DACH, ormaplatin, CI-973, JM-216, and analogs thereof, epirubicin, etoposide phosphate, 9- aminocamptothecin, 10,11 -methyl enedioxycamptothecin, karenitecin, 9-nitrocamptothecin, TAS 103, vindesine, L-phenylalanine mustard, ifosphamide, mefosphamide, perfosfamide, trophosphamide carmustine, semustine, epothilones A-E, tomudex, 6-mercaptopurine, 6- thioguanine, amsacrine, etoposide phosphate, karenitecin, acyclovir, valacyclovir, ganciclovir, amantadine, rimantadine, lamivudine, zidovudine, bevacizumab, trastuzumab, rituximab, 5-Fluorouracil, monoclonal antibodies such as Rituximab, Trastuzumab, Cetuximab, Bevacizumab, Erlotinib, Imatinib, Sunitinib, of any molecular weights or of any models, Pegabtanib and/or the combinations thereof.

[00060] In a preferred embodiment, the anticancer drug loaded in the delivery system of the present invention is Paclitaxel or any analogue or derivative of paclitaxel, which exhibits either a pharmacological or a therapeutical activity, which is at least equivalent to that of Paclitaxel. Within the scope of the present invention is Paclitaxel in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes thereof etc.). Included is also any analogue, derivative or active metabolite of Paclitaxel, pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof.

[00061] In one embodiment, the surfactant is selected from the group comprising nonionic surfactants, amphoteric surfactants, anionic surfactants, cationic surfactants and/or mixtures thereof. The nonionic surfactant and/or amphoteric surfactant is selected, without restriction, from the group formed by lecithins, alkyl glycosides with an alkyl group that has from 6 to 24 carbon atoms, saturated and unsaturated fatty alcohols with an alkyl group that has from 8 to 24 carbon atoms, Poloxamers such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or mixtures of two or more thereof, such as 407 and 124, polysorbates such as group consisting of Tween ^® 20, Tween ^® 60, Tween ^® 80, Triton ^® X-100, Span ^® 20, Span ^® 60 and Span ^® 80, fatty acid esters with sugars, sorbitane esters, polyethylene glycol fatty acid esters such as Solutol HS, castor oil, fatty alcohol and polyoxyethylene ethers, fatty acid alkanolamides, amine oxides, glycine derivatives, digitonin, inulin lauryl carbamate and/or mixtures thereof. More preferably, the nonionic surfactant and/or amphoteric surfactant is selected from the group formed by octyl glucoside, decyl glucoside, lauryl glucoside, octyl fructoside, dodecyl maltoside, and/or mixtures thereof. The cationic surfactant is selected, without restriction, from the group formed by quaternary ammonium salts, such as cetyl trimethyl ammonium bromide, lauryl trimethyl ammonium chloride, benzyl dimethyl hexadecyl ammonium chloride, distearyl dimethyl ammonium chloride, dilauryl dimethyl ammonium chloride, dimyristyl, dimethyl ammonium chloride, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, methyl benzetonium chloride, tocopherol polyethylene glycol succinate or its analog such as, but not limited to, tocopherol polyethylene glycol sebacate (PTS), tocopherol polyethylene glycol dodecanodioate(PTD), tocopherol polyethylene glycol suberate(PTSr) and tocopherol polyethylene glycol azelaate (PTAz), tocopherol polyethylene glycol succinate (TPGS) and/or mixtures thereof.

[00062] In one preferred embodiment, the surfactant is selected from polysorbates such as Tween ^® 20, Tween ^® 60, Tween ^® 80, Triton ^® X- 100, Span ^® 20, Span ^® 60 and Span ^® 80.

[00063] In an embodiment, the composition of the present invention further comprises an amphiphilic stabilizing agent wherein the stabilizing agent is selected from a group comprising a polyol, polyvinyl alcohol, polyethylene glycol, polypropylene glycol, polypropylenediol, polytetrahydrofuran, poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers, and combinations thereof.

[00064] The term "targeting ligands" as used herein refers to cell interactive compounds which enhance the interaction between the nanoparticles and the target cells. Suitable targeting ligands for the present invention include but not limited to antibodies, nucleic acids, folate, thiamine, riboflavin, sugar residues such as galactose, peptides such as argenine-glycine-aspartic acid (RGD), proteins such as transferrin, and the like thereof.

[00065] In an embodiment, the nanoparticles can be prepared by any of the prior art methods including but not limited to, for example, High pressure homogenization, Ultrasonication/high speed homogenization, Solvent evaporation method, Supercritical fluid method, Spray drying method, Double emulsion method and the like. Preferably, the method used for the preparation of the nanoparticles of the present invention is Homogenization method.

[00066] In a preferred embodiment of the present invention, the nanoparticles can be prepared by high pressure homogenization process.

[00067] In an embodiment of the present invention, surface coating of nanoparticles can be done during or after the preparation of nanoparticles. In a further embodiment, the surface coating is done by any of the prior art methods including but not limited to, for example covalent conjugation and passive adsorption of shielding polymers to the particle surface.

[00068] In an embodiment of the present invention, the polymers which are encapsulated in nanoparticles enhance the retention of nanoparticles in the blood stream by preventing it from opsonization and reticuloendothelial system.

[00069] In a further embodiment of the present invention, surface functionalisation of PLGA nanoparticles with PEG using hydrophobic polymer anchorage with either phospholipids (l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)] (PE-b-PEG) or PLGA polymer (PLGA-block-PEG) or any other related methods.

[00070] In an embodiment of the present invention, the targeting ligands adhere on the surface of nanoparticles so that the nanoparticles can be targeted at the desired site of the subject. A targeting ligand present on the surface of the particle may allow the particle to become localized at a particular targeting site, for instance, a tumor, a disease site, a tissue, an organ, a type of cell, etc. As such, the nanoparticle may then be "target specific." The drug or other payload may then, in some cases, be released from the particle and allowed to interact locally with the particular targeting site.

[00071] In a further embodiment of the present invention, the targeting ligands can be, for example, further substituted with a functional group that can be reacted with a polymer of the present invention (e.g., PEG) in order to produce a polymer conjugated to a targeting moiety. The functional groups include any moiety that can be used to create a covalent bond with a polymer (e.g., PEG), such as amino, hydroxy, and thio. In a particular embodiment, the small molecules can be substituted with H ₂ , SH or OH, which are either bound directly to the small molecule, or bound to the small molecule via an additional group, e.g., alkyl or phenyl.

[00072] In another embodiment of the present invention, cationization of nanoparticle is done to enhance the residual time of the nanoparticles at the tumour site. The cationization provides nanoparticles a positive charge which increases the availability of the nanoparticles around the blood stream for a longer time period. Cationization particles include but are not limited to for example, chitosan, dodecyl ammonium bromide, poly sulfones, Dotap and the like.

[00073] In one preferred embodiment of the present invention, the cationization particle chitosan can also be conjugated with other polymers such as PLGA, PGA, PEG, PLA in combination with one or more lipid(s), to modify the release profile of active drug from nanoparticles.

[00074] In a particular embodiment of the present invention, size of the nanoparticles ranges from 1 and 1000 nm, preferably from 10 and 500 nm, and more preferably from 50 to 450 nm.

[00075] In a particular embodiment of the present invention, drug entrapment efficiency in nanoparticles of the present invention ranges from 80- 100%, preferably from 85-100%, more preferably from 90-100%.

[00076] One embodiment of the present invention provides a pharmaceutical composition comprising the drug delivery system of the present invention.

[00077] In an embodiment, the pharmaceutical composition can be substantially free of other components, for example, as in the case where the pharmaceutical composition comprises nanoparticles in the form of a dry powder (e.g., a lyophilized free-flowing powder). Alternatively, the pharmaceutical composition can further include other components (i.e., in addition to the nanoparticles discussed above), such as commonly employed pharmaceutically acceptable excipients and the like selected with regard to the desired dosage form.

[00078] In an embodiment of the present invention, the pharmaceutical composition can be administered by a number of routes including, for example, orally, sublingual, parenterally (eg, by injection intramuscularly, intravenously or subcutaneously), topically, nasally or via slow releasing microcarriers, more preferably topically.

[00079] In an embodiment of the present invention, the pharmaceutical composition comprising the nanoparticles of the present invention optionally comprises at least one carrier selected from the group comprising preservatives, solubilizers, antioxidants, humectants, permeation enhancers and the like. There may be one or more carriers used in the preparation of the composition of the present invention. The carrier may be solid or liquid. See, for example, Remington: The Science and Practice of Pharmacy, 1995, Gennaro ed. The pharmaceutical composition comprising the nanoparticles of the present invention can be formulated into a particular dosage form by using any common technique available in the art.

[00080] The exact dose of the composition of the present invention required to be administered, may vary from subject to subject, depending on the age, weight, general condition of the subject, the mode of administration, and the like. An appropriate dose is readily determined by one of ordinary skills in the art.

[00081] Nanoparticles of PLGA has a low entrapment and drug loading capacity, but in the composition of the present invention, the invention have used both polymer and lipid in the core which makes the invention to entrap drug to its highest capacity.

[00082] The composition of the present invention should have very less burst release compared to known formulations of PLGA. The formulation of the present invention has polymer on the surface, which can be modified easily for targeting. The formulation of the present invention will release the lipid on attraction into the cells which will release more drug and can kill the cells quickly compared to any nanoparticle, and then will slowly release the drug from the polymer.

[00083] While certain embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the disclosure. Therefore, it is to be understood that the present disclosure has been described by way of illustration and not limitations. ADVANTAGES OF THE INVENTION

[00084] The present invention provides a targeted drug delivery system comprising nanoparticles having polymer and lipid core wherein the nanoparticles comprise a therapeutically effective amount of an anticancer drug or its pharmaceutically acceptable salts, one or more biodegradable polymer(s), one or more lipid(s), and one or more of surfactant(s).

[00085] The present invention further provides a process for preparing the targeted drug delivery system and the pharmaceutical composition thereof.

[00086] The present invention provides a pharmaceutical composition comprising drug delivery system of the present invention for the treatment, diagnosis and/or prevention of cancer.

[00087] The present invention provides a drug delivery system capable of being target specific.

[00088] The present invention provides a drug delivery system capable of being modulated to entrap maximum drug.

[00089] The present invention provides a drug delivery system capable of release the therapeutic ingredient in a controlled manner.

[00090] The present invention provides a drug delivery system capable of longer retention of nanoparticles in blood stream and target site.

[00091] The present invention provides a drug delivery system that can deliver therapeutic levels of drugs to treat diseases such as cancer, while reducing the patient side effects.

[00092] The present invention provides a drug delivery system which obviates the disadvantages associated with the known arts.

EXAMPLES

[0053] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention. Example 1: Composition of the present invention for 150 ml

Ingredients Quantity

PLGA Ester or Acid Terminated 400 mg to 1 Gram

(polymer)

Glyceryl behenate (lipid) 400 mg to 1 Gram

Paclitaxel Less than 25 % of the

lipid +polymer total

weight

Tween® 80 (surfactant) Less than 10% of

aqueous phase

Example 2: Method of Preparation of the composition of the present invention

The composition was prepared by taking the organic phase in a beaker and with heating at 35 to 70°C, required quantity of Lipid was dissolved in it. The desired quantity of polymer was dissolved in a separate organic phase and after observed that completely dissolved. Drug was dissolved in the organic phase. This was transferred to the organic phase having polymer. The total organic phase was transferred into an aqueous phase containing the surfactant, with stirring of 6000 to 18000 RPM for 0.5 to 7 min. This formed emulsion is transferred into the High Pressure Homogenizer at required pressure and for required number of cycles.

Example 3: Particle Size

Figures 1 and 2 depict the particle size results of the composition of the present invention. The particle size results of the developed composition of Example 1 resulted to be 278 nm for a 60 ml batch and 269 nm for 120 ml batch.

Example 4: Zeta potential

Figure 3 depict the zeta potential of the composition of present invention. The Zeta potential of the composition of Example 1 without cationic agent is -6.54.

Example 5: Transmission electron Microscopy Figures 4 to 6 depict the transmission electron microscopy results for the composition of Example 1. In Figure 4, focused particles have a size more than 500 nm, but in the image one can clearly observe the black spots inside the nanoparticle.

As one can observe in Figure 5, the black spots are out of the nanoparticle. It is confirmed in no nanoparticle drug is visible. The inference is that the lipid is forming a nanostructure within the formulated polymer nanoparticle, but this can only be proved by the release study, if it releases in this pattern, free drug first followed by drug from lipid and then drug from polymer. Further Figure 5 shows the lipid nanoparticles are of 5 to 15 nm in size

Figure 6 shows the free lipid nanoparticle lying outside the polymer nanoparticle and size range is at 150 nm for polymeric and 10 nm for lipidic. This study was performed after keeping the nanoparticle for 5 days in aqueous phase and after confirming the polymeric nanoparticle has started degrading.

Example 6: XRD Spectrum of Paclitaxel

Figure 7 depicts the XRD spectrum of Paclitaxel. The Measurement conditions are as below: Dataset Name Paclitaxel (Drug)

2Theta:0.001; Minimum step size Omega:0.001

Raw Data Origin XRD measurement (* XRDML)

Scan Axis Gonio

Start Position [°2Th.] 5.0084

End Position [°2Th.] 49.9904

Step Size [°2Th.] 0.0170

Scan Step Time [s] 25.1954

Scan Type Continuous

PSD Mode Scanning

PSD Length [°2Th.] 2.12

Offset [°2Th.] 0.0000

Divergence Slit Type Fixed Divergence Slit Size [°] 0.8709

Specimen Length [mm] 10.00

Measurement Temperature

Anode Material Cu K-Alphal [A] 1.54060 K-Alpha2 [A] 1.54443 K-Beta [A] 1.39225 K-A2 / K-Al Ratio 0.50000 Generator Settings 40 mA, 45 kV Diffractometer Type 0000000011023505 Diffractometer Number

Goniometer Radius [mm] 240.00

Dist. Focus-Diverg. Slit [mm] 100.00

Incident Beam Monochromator No

Spinning No

The peak list is as below:

__

d-spacing Rel. Int. [%] Area

[°2Th.] [A] [cts*°2Th.]

5.6589 0.1338 15.61753 55.07 531.16 5.9742 0.2175 14.79421 100.00 1567.47 6.5385 0.1338 13.51859 9.69 93.43 9.1717 0.1673 9.64239 42.22 509.08 9.2989 0.2007 9.51083 51.19 740.68 10.0098 0.2007 8.83684 8.99 130.01

10.4529 0.1338 8.46325 12.86 124.02

11.4804 0.0836 7.70797 21.39 128.95

11.6474 0.0836 7.59787 17.73 106.90

12.7519 0.1506 6.94214 50.63 549.43

12.8918 0.1171 6.86713 44.01 371.46

13.8686 0.2007 6.38557 10.87 157.24

14.2763 0.1506 6.20412 15.11 163.99

14.8442 0.2676 5.96802 9.98 192.58

16.1317 0.1506 5.49450 10.10 109.62

17.3502 0.6022 5.11125 17.71 768.57

18.3312 0.3346 4.83988 14.39 347.05

19.1094 0.3680 4.64449 15.45 409.83

19.8329 0.2007 4.47668 12.50 180.90

20.3797 0.3346 4.35779 14.47 349.04

21.5184 0.2676 4.12968 14.36 277.03

22.3392 0.1673 3.97978 17.91 215.93

23.1248 0.1338 3.84632 12.12 116.95

23.7678 0.2676 3.74370 7.69 148.34

24.3698 0.2676 3.65257 6.02 116.22

25.5545 0.4015 3.48586 11.82 342.06

26.5722 0.2676 3.35462 4.69 90.50 27.4482 0.3011 3.24951 7.34 159.31

29.0041 0.3011 3.07864 6.97 151.34

30.2968 0.2342 2.95017 5.99 101.18

31.4425 0.4015 2.84524 2.77 80.14

32.2281 0.3346 2.77765 3.00 72.33

33.1403 0.4684 2.70325 2.35 79.41

34.5491 0.2676 2.59618 2.49 48.13

35.7305 0.2007 2.51300 2.19 31.67

37.4915 0.4015 2.39891 1.06 30.71

39.6036 0.2676 2.27571 0.70 13.50

40.5348 0.4684 2.22556 1.96 66.32

41.6933 0.2007 2.16636 1.16 16.84

42.6890 0.5353 2.11811 0.80 30.99

46.1508 0.6691 1.96697 0.33 15.98

47.8908 0.4896 1.89792 0.45 21.63

Example 7: XRD-Spectrum of PLGA polymer

Figure 8 depicts the XRD-Spectrum of PLGA polymer. The measurement conditions below:

Dataset Name POLYMER (PLGA)

Raw Data Origin XRD measurement (* XRDML)

Scan Axis Gonio

Start Position [°2Th.] 5.0084 End Position [°2Th.] 49.9904

Step Size [°2Th.] 0.0170

Scan Step Time [s] 25.1954

Scan Type Continuous PSD Mode Scanning

PSD Length [°2Th.] 2.12

Offset [°2Th.] 0.0000

Divergence Slit Type Fixed

Divergence Slit Size [°] 0.8709

Specimen Length [mm] 10.00

Measurement Temperature [°C] 25.00 Anode Material Cu

K-Alphal [A] 1.54060

K-Alpha2 [A] 1.54443

K-Beta [A] 1.39225

K-A2 / K-Al Ratio 0.50000

Generator Settings 40 mA, 45 kV

Diffractometer Type 0000000011023505

Diffractometer Number 0

Goniometer Radius [mm] 240.00

Dist. Focus-Diverg. Slit [mm] 100.00

Incident Beam Monochromator No

Spinning No Example 8: XRD-Spectrum of the composition of Example 1

Figure 9 depicts the XRD-Spectrum of the composition of Example 1. The measurement conditions are as below:

Dataset Name NANOPAC (Formulation)

Raw Data Origin XRD measurement (*.XRDML)

Scan Axis Gonio

Start Position [°2Th.] 5.0084

End Position [°2Th.] 49.9904

Step Size [°2Th.] 0.0170

Scan Step Time [s] 25.1954

Scan Type Continuous

PSD Mode Scanning

PSD Length [°2Th.] 2.12

Offset [°2Th.] 0.0000

Divergence Slit Type Fixed

Divergence Slit Size [°] 0.8709

Specimen Length [mm] 10.00

Measurement Temperature

Anode Material Cu K-Alphal [A] 1.54060 K-Alpha2 [A] 1.54443 K-Beta [A] 1.39225 K-A2 / K-Al Ratio 0.50000

Generator Settings 40 mA 45 kV Diffractometer Type 0000000011023505

Diffractometer Number 0

Goniometer Radius [mm] 240.00

Dist. Focus-Diverg. Slit [mm] 100.00

Incident Beam Monochromator No

Spinning No

The peak list is as below:

Pos. [°2Th.] FWHM d-spacing Rel. Int. [%] Area

[°2Th.] [A] [cts*°2Th.]

21.4657 0.4896 4.13627 100.00 233.58