FIELD OF THE INVENTION
The present invention relates to novel injectable compositions comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s). The composition may be mixed with an aqueous component and optionally further diluted with a suitable diluting medium prior to administration. The present invention also describes process for preparation of such compositions and method of using such compositions. The compositions preferably comprise a taxoid as active agent(s) and are characterized by providing the active agent(s) to localize in certain tissues, thereby increasing the efficacy of treatment of cancers associated with such tissues.
BACKGROUND OF THE INVENTION
The preferred route of oral administration is limited to those drug molecules that are permeable across the gastric mucosa and are at least sparingly soluble. A large majority of the drugs molecules are poorly soluble, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable drug products. There are numerous methods that may facilitate solubility to further enhance performance of poorly soluble drugs especially which can increase or enhance in vitro dissolution and/or in vivo solubility or absorption. A number of other systems are available for the oral delivery of low solubility drugs, including lipid-based soft-gel systems and self-emulsifying formulations comprising a lipid component and one or more surfactants and Osmotic pumps.
However, the poor solubility of an active agent causes subsequently poor bioavailability after oral administration. The alternative is to develop parenteral compositions especially IV injections or infusions; but for this the active agents need to be "solubilized." There are various approaches to solubilizing drugs such as inclusion complexes with cyclodextrins, formation of mixed micelles, and liposome formulations. However, these approaches have proved to be inefficient, as evidenced by the low number of marketed products. Some of the partly successful formulations possess additional physical stability problems such as aqueous dispersion (eg, AmBisome® - the liposomal product of amphotericin B). AmBisome needs to be lyophilized and reconstituted prior to administration. Thus, the optimal solution to this problem has not yet been developed. Of course, the problem involves not only an innovative formulation approach, but also an exclusive technology that provides the pharmaceutical industry with an automated and industrial-scale production possibility. However, developing a creative formulation concept is alone not enough; the industry also needs to be provided with a simple and an automated production process. One possible formulation approach for IV injectables is the use of parenteral oil/water (o/w) emulsions. Apart from solubilizing drugs to produce

improved bioavailability, often there is also a reduction of side effects. To incorporate poorly active agents in o/w emulsions, the "solvent approach" was developed. This approach involved dissolving the drug and the lecithin in an organic solvent, evaporating the organic solvent, and using the drug-lecithin blend to form the emulsion. However, the solvent approach faced some complications regarding industrial application because of the solvent removal process and the requirement for production of the emulsions under sterile conditions. As an alternative, a new concept called "SolEmuls technology" was developed. The technology uses a solvent-free high-pressure homogenization process to incorporate poorly soluble drugs in a commercial emulsion (e.g. Lipoftmdin).
An 'emulsion' is a system where one liquid is dispersed in another immiscible liquid. In case of the emulsions containing oil and water, they can be classified as o/w (oil-in-water), w/o (water-in-oil), w/o/w types depending on whether the continuous phase is either oil or water. Especially the o/w emulsions have been used as delivery systems of insoluble drugs since they have hydrophobic domains. Since emulsion is a metastable system, stabilizing agent is needed to slow down the destabilization speed of the emulsion and to resist the aggregation phenomena including coalescence to achieve the drug delivery function efficiently. The term "self-emulsifying pharmaceutical composition" refers to a concentrated composition capable of generating emulsions or microemulsions upon mixing with sufficient aqueous media.
Antineoplastic agents, particularly active principles of the taxoid class are injectable, but their solubility in water is especially low. This makes it very difficult to produce a preparation for parenteral administration, which is acceptable from a therapeutic standpoint. The taxoid class includes docetaxel as well as derivatives of this product. Docetaxel is an antineoplastic agent prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. US Patent No. 4,814,470 describes the taxol derivative, Docetaxel, and its use as antitumour agent. Docetaxel (Taxotere®) is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy, locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy, in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer, in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition and in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

US Patent No. 5,403,858 pertains to a composition consisting essentially of a compound, specifically taxol derivative, dissolved in a surfactant selected from the group consisting of polysorbate, polyoxyethylene glycol and hydrogenated castor oil, and essentially free of ethanol. US Patent No. 5,438,072 discloses injectable compositions useful for the preparation of perfusion solutions comprising taxane derivatives, wherein formation of a gelled phase during mixing of the compositions with an aqueous solution is avoided or wherein any gelled phase formed during mixing of the composition with an aqueous solution can be broken, said composition comprising a solution convenient for storage of said taxane derivatives in a surface active agent selected from polysorbates, ethylene oxide esters-ethers and fatty acids glycerides, and a water solution of an effective amount of a dilution additive selected from organic compounds having a hydroxyl group an amine functional group and a molecular weight of less than 200 or sodium chloride. US Patent No. 5,698,582 discloses a composition comprising a taxane derivative dissolved in a surfactant selected from polysorbate or polyethoxylated castor oil, and essentially free or free of ethanol.
PCT Publication No. WO9800128 relates to a pharmaceutical composition for parenteral administration comprising a taxane analog, dimethylacetamide, (DMA), polyethylene glycol (PEG) and an aqueous lipid emulsion. Another PCT Publication No. WO200520962 pertains to a pharmaceutical composition in a form of an anhydrous self-nanoemulsifying oily formulation comprising one or more therapeutic agent(s) which have low solubility in water or are water-insoluble, vitamin E, one co-solvent selected from propylene glycol and ethanol and mixture thereof, one surfactant selected from tyloxapol and from mixture of tyloxapol and TPGS, and optionally, a bioenhancer. US Patent No. 5,616,330 discloses a composition for intravenous administration of taxine in a stable oil-in-water emulsion comprising a taxine, a triglyceride, water; and a surfactant, wherein said taxine is solubilized in said triglyceride in an effective pharmaceutical amount for intravenous administration, said taxine and triglyceride forming a stable dispersed phase in the water, said stable dispersed phase having a mean particle size of about 0.2 to about 0.4 urn upon aging said emulsion over a period of about six weeks at 40°C as a measure of stability.
US Patent No. 6,979,456 discloses a storage-stable, self-emulsifying, and non-aqueous, preconcentrate of a taxane in a microemulsion comprising a taxane dissolved in a carrier system, which carrier system consists essentially of 10 to 80% w/w of a hydrophobic component selected from the group consisting of a triglyceride, a diglyceride, a monoglyceride, a free fatty acid, a fatty acid ester, a fish oil, a vegetable oil, and combinations thereof; 20 to 80% w/w of a

surfactant component consisting of one or more non-ionic surfactants; up to 35% w/w diethylene glycol monoethylether; and up to 40% w/w of a hydrophilic component selected from the group consisting of a hydroxyalkane, a dihydroxyalkane, a polyethylene glycol having an average molecular weight of at most 1000, and combinations thereof; wherein the preconcentrate, when mixed with water or simulated gastric fluid, forms a liquid having an average droplet size, of at most 10 microns, and a dose of the preconcentrate has a taxane bioavailability of 25 to 60% of the taxane in the dose upon oral administration.
There have been several other attempts to provide formulations comprising an antineoplastic agent, the most successful of which has been incorporation of the drug into a liposomal formulation. However, this preparation suffers from the fact that it is difficult to achieve a quantitative incorporation of the drug into the liposomal compartment. Furthermore, the product must be lyophilized and stored as a powder because taxol precipitates from aqueous liposomal formulations within a week of storage. For this reason, the liposomal formulation must be freeze dried and reconstituted prior to use. Attempts to formulate antineoplastic agents in a stable lipid emulsion have been unsuccessful. Taxol, an antineoplastic agent, is reported to be insoluble in lipid emulsions, which contains only oil base such as soybean oil or a mixture of soybean and safflower oils. Heating taxol in either soybean oil or safflower oil, even upon sonication, does not result in the dissolution of appreciable amounts of taxol, and addition of taxol to a lipid emulsion during the homogenization step meets with equally disappointing results. Moreover, emulsions incorporating taxol and formulated with surfactant such as triacetin, L-alpha lecithin, Polysorbate 80, Pluronic F-68, ethyl oleate and glycerol are highly toxic and unstable. Therefore, there is still a clear need for stable, biocompatible, efficacious, safe and easy-to-formulate compositions of an antineoplastic agent such as taxol exhibiting minimal side effects. Hence, the novel pharmaceutical composition of the present invention provides the solution to above said problems by providing an improved composition having a sufficient titer of active principle.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel injectable pharmaceutical composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s).
It is an objective of the present invention to provide novel injectable composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and

optionally other pharmaceutically acceptable excipient(s) wherein the said composition is mixed with an aqueous component prior to administration.
It is also an objective of the present invention to provide novel injectable composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s) mixed with an aqueous component, wherein the said composition is further diluted with a suitable diluting medium prior to administration.
It is also an objective of the present invention to provide novel injectable pharmaceutical composition comprising at least one antineoplastic agent(s), preferably a taxoid, more preferably docetaxel or paclitaxel, or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof as the poorly soluble active agent, either alone or in combination with other active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s).
It is another objective of the present invention to provide process for preparation of such
injectable composition which comprises of the following steps:
i) mixing the active agent(s) with surfactant(s), and oil component,
ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
iii) formulating the mixture into an injectable dosage form.
It is a further objective of the present invention to provide process for the preparation of such
novel injectable composition which comprises of the following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a
homogeneous mixture, ii) mixing of oil component into the above homogeneous mixture and mixing at high sheer to
obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iv) formulating the mixture into a suitable injectable dosage form.
It is a further objective of the present invention to provide process for the preparation of such novel injectable composition which comprises of the following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a homogeneous mixture,
ii) mixing of oil component into the above homogeneous mixture and mixing at high sheer to
obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), iv) preparing the aqueous component by mixing excipient(s), and v) mixing the material of step (iii) and step (iv) to obtain an injectable dosage form.
The novel injectable compositions of the present invention is preferably formulated such that the composition forms an emulsion in vivo upon administration or the compositions are formulated as an emulsion system prior to administration.
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition.
The novel pharmaceutical compositions of the present invention preferably provide the active agent(s) to localize in certain tissues, thereby increasing the efficacy of treatment, particularly of cancers, associated with such tissues.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel injectable pharmaceutical composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s).
In an embodiment of the present invention, the novel injectable composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s) is mixed with an aqueous component prior to administration.
In another embodiment of the present invention, the novel injectable pharmaceutical composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s) mixed with an aqueous component is further diluted with a suitable diluting medium prior to administration.
In another embodiment of the present invention is provided novel injectable composition comprising at least one antineoplastic agent(s), preferably a taxoid, more preferably docetaxel or paclitaxel, or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms,
derivatives or mixtures thereof as the poorly soluble active agent, either alone or in combination with other active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutically acceptable excipient(s).
In an embodiment, the composition of the present invention is a self-emulsifying pharmaceutical composition comprising at least one poorly soluble active agent(s), at least one surfactant(s), at least one oil component, optionally with other pharmaceutically acceptable excipient(s).
In an embodiment, the compositions of the present invention are easy to formulate and are amenable to convenient scale up from bench scale production to industrial scale production. Another advantage of the formulation technology of the present invention is that the compositions comprise the use of common and commercially used excipient(s) particularly oils that makes expensive toxicology studies redundant.
The active agent of the present invention is selected from but not limited to a group comprising poorly soluble active agent(s) such as cardiovascular drug, respiratory drug, sympathomimetic drug, cholinomimetic drug, adrenergic agonist or antagonist, analgesic/antipyretic, anesthetic, antiasthamatic, antibiotic, antidepressant, antidiabetic, antifungal agent, antihypertensive agent, anti-inflammatory, antineoplastic, antianxiety agent, immunosuppressive agent, antimigraine agent, sedatives/hypnotic, antianginal agent, antipsychotic agent, antimanic agent, antiarrhythmic, antiarthritic agent, antigout agent, anticoagulant, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet agent, anticonvulsant, antiparkinson agent, antihistamine/antipruritic, agent useful for calcium regulation, antibacterial agent, antiviral agent, antimicrobial, anti-infective, bronchodialator, hormone, hypoglycemic agent, hypolipidemic agent, protein, nucleic acid, agent useful for erythropoiesis stimulation, antiulcer/antireflux agent, antinauseant/antiemetic, oil-soluble vitamin, mitotane, visadine, halonitrosourea, anthrocycline or ellipticine and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, used either alone or in combination thereof.
Preferably the active agent of the present invention is an antineoplastic agent selected from but not limited to a group comprising antineoplastic drugs, monoclonal antibodies, immunotherapy or radiotherapy or biological response modifiers. Suitable biological response modifiers include lymphokines and cytokines such as interleukins, interferons ([small alpha, Greek], [small beta, Greek] or [small delta, Greek]) and Tumor Necrosis Factor (TNF). Other chemotherapeutic agents which are

useful in the treatment of disorders due to abnormal cell proliferation include alkylating agents, for instance nitrogen mustards such as mechlorethamine, cyclophosphamide, melphalan and chlorambucil; alkyl sulphonates such as busulfan; nitrosoureas such as carmustine, lomustine, semustine and streptozocin; triazenes such as dacarbazine; antimetabolites such as folic acid analogues, for instance methotrexate; pyrimidine analogues such as fluorouracil and cytarabine; purine analogues such as mercaptopurine and thioguanine; taxanes such as Paclitaxel, Docetaxel or PNU-1; natural products, for instance vinca alkaloids such as vinblastine, vincristine and vindesine; epipodophyllotoxins such as etoposide and teniposide; antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin; enzymes such as L-asparaginase; various agents such as coordination complexes of platinum, for instance cisplatin; substituted ureas such as hydroxyurea; methyl-hydrazine derivatives such as procarbazine; adrenocortical suppressants such as mitotane and aminoglutethimide; hormones and antagonists such as adrenocortico-steroids e.g. prednisone; progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate; oestrogens such as diethylstilboestrol and ethynyloestradiol; antioestrogens such as tamoxifen; and androgens such as testosterone propionate and fluoxymesterone or their pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives, used either alone or in combination thereof.
In an embodiment of the present invention, the surfactant is an anionic, cationic, nonionic or zwitterionic surfactant. In a further embodiment, the surfactant is selected from but not limited to group comprising polyoxyethylene sorbitan fatty acid esters e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters; sorbitan fatty acid esters (SPAN®); polysorbates (Tween®), polyoxyethylene fatty acid esters e.g. polyoxyethylene stearic acid esters (Myrj®), polyoxyethylene castor oil derivatives (Cremophor®), particularly suitable are polyoxyl 35 castor oil (Cremophor®EL) and polyoxyl 40 hydrogenated castor oil (Cremophor®RH40); tocopherol; tocopheryl polyethylene glycol succinate (vitamin E TPGS); tocopherol palmitate and tocopherol acetate; PEG glyceryl fatty acid esters such as PEG-8 glyceryl caprylate/caprate (Labrasol®), PEG glyceryl caprylate/caprate (Labrafac®), PEG-32 glyceryl laurate (Gelucire® 44/14), PEG-6 glyceryl mono oleate (Labrafil® M 1944 CS), PEG-6 glyceryl linoleate (Labrafil® M 2125 CS); propylene glycol mono- and di-fatty acid esters, such as propylene glycol laurate, propylene glycol caprylate/caprate; diethyleneglycol-monoethylether (Transcutol®); polyoxyethylene-polyoxypropylene co-polymers (Pluronic® or Poloxamer®); glycerol triacetate; monoglycerides and acetylated monoglycerides e.g. glycerol monodicocoate (Imwitor® 928), glycerol monocaprylate (Imwitor® 308), and mono-and di-acetylated monoglycerides, and the like or mixtures thereof. Preferably the surfactant is a polysorbate, more preferably is Tween®80. Preferably the surfactant is

present in an amount between about 0.5% to about 80% w/w of the composition. Preferably the ratio of the active agent(s) to the surfactant(s) is about 1:90 to about 90:1. It might be emphasized that the choice and the quantity of surfactant or the use of a combination of surfactants or the ratio of active agent(s) and surfactant(s) is governed by the nature of active agent used, the type of dosage form, the intended route of administration, the desired particle size of the composition, the intended use and the duration of use of the composition, and the like.
In an embodiment of the present invention, the oil component is selected from oil or a combination of multiple oils. In certain embodiments, the oil component of the present invention comprises a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof. In certain embodiments, the oil component comprises an ester formed between one or more fatty acids and an alcohol other than glycerol. In a preferred embodiment of the present invention, the oil component is selected from but not limited to group comprising vegetable oils such as almond oil, borage oil, black currant seed oil, corn oil, safflower oil, soybean oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, sunflower oil, sesame oil, etc; medium chain triglycerides such as Miglyol® 812, Crodamol® GTCC-PN or Neobees® M-5 oil; water-immiscible biocompatible oil or modified oils such as alkyl alcohols with an even number of carbons like ethyloleate, propylene glycol dicaprylate, isopropyl myristate, ethyl laurate, butyloleate, oleyl acetate, oleyl propionate, octyl octanoate, octyl decanonate, and oleyl oleate; saturated, partially saturated or unsaturated oils, and the like; or mixtures thereof. Preferably the oil component is vegetable oil or medium chain triglycerides. Preferably the vegetable oil or medium chain triglycerides is present in an amount not less than 0.1% w/w of the composition, most preferably about 2-70% w/w of the composition.
In an embodiment, the oily composition of the present invention additionally comprises excipients selected from but not limited to a group comprising co-surfactants, co-solvents, organic solvents, preservatives, antioxidants, stabilizers, or any other excipient soluble in the oily composition known to the art, or mixtures thereof.
In another embodiment, the composition of the present invention is diluted with an aqueous component. The aqueous component is either incorporated into the oily composition of the present invention or formulated separately and mixed with the oily composition prior to administration. In an embodiment, the aqueous component comprises excipients selected from but not limited to a group comprising co-surfactants, co-solvents, water, hydrophilic solvents, preservatives, antioxidants, stabilizers, buffering agents, pH adjusting agents, osmotic agents,

isotonicity producing agents, or any other excipient soluble in the aqueous component known to the art or mixtures thereof.
In an embodiment, the compositions of the present invention are self-emulsifying systems. In a further embodiment, the self-emulsifying systems of present invention can be in the form of microemulsion or nanoemulsion, more preferably self-microemulsifying drug delivery system (SMEDDS) or self-nanoemulsifying drug delivery system (SNEDDS), most preferably is self-nanoemulsifying drug delivery system (SNEDDS). The SNEDDS generated in the present invention are solutions comprising a hydrophilic phase and a lipophilic phase and are also characterized by their thermodynamic stability, optical transparency and small average droplet size, having the average particle size or average droplet size less than preferably about 500 nm, more preferably less than about 200 nm. However, it might be understood that the particle size of the compositions of the present invention is not limited to as stated hereinbefore but depends on the type of dosage form intended to be manufactured, for instance, when the compositions are formulated for parenteral use, the average particle size is preferably less than about 100 nm but when the composition is formulated for oral use, the average particle size is preferably less than about 2000 nm. Further, the quantity of the various components used particularly the quantity of the surfactant and the oil component and/or alternatively the quantity of the aqueous phase if used, the method of preparation, for instance the process parameters, leads to compositions having varied average particle sizes.
In an embodiment of the present invention, the composition additionally comprises of a solvent/cosolvent and/or a co-surfactant. In an embodiment of the present invention, the co-surfactant is selected from but not limited to group comprising polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers known as "poloxamer"; polyglycerin fatty acid ester such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid ester such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate(TWEEN®); polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; and the like or mixtures thereof. In an embodiment of the present invention, the solvent/cosolvent is selected from but not limited to group comprising alcohols such as propylene glycol, polypropylene glycol, polyethylene glycol (such as PEG300, 400, 600, etc.), glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethyl acetamide, and the like or mixtures thereof. More preferably

the solvent used is ethanol. The choice of the sol vent/cosol vent and its quantity primarily depends on the solubility of the active agent(s).
The pharmaceutically acceptable excipients of the present invention are selected from but not limited to a group comprising stabilizers, tonicity modifier, anti-foaming agent, fillers, anti-oxidants, buffering agents, colorants, organic solvents, preservatives, diluents, viscosifying agents, mucoadhesive agents, fillers, bulking agents, chelating agents, and the like known to the art used either alone or in combination thereof. Suitable anti-foaming agents include for example silicon emulsions or sorbitan sesquoleate. Suitable stabilizers to prevent or reduce the deterioration of the other components in compositions of the present invention include antioxidants such as glycine, alpha-tocopherol or ascorbate, BHA, BHT, and the like or mixtures thereof. Suitable tonicity modifier includes for example glycerol (1-5% by weight) and amino acids (1-5% by weight). It will be appreciated that certain excipients used in the present composition can serve more than one purpose.
In an embodiment, the pharmaceutical composition of present invention is in the form of a parenteral self-nanoemulsifying drug delivery system (SNEDDS). The SNEDDS is further diluted with a solvent/cosolvent to produce a stock solution with decreased viscosity and thereby avoiding the gelling effect. A stock solution possesses still more preferably a concentration of between 1-20% by weight of active agent to the volume of the composition. This solution can be mixed, in particular to provide a final concentration of, for example, about 0.5% by weight with the perfusion fluid, which can be physiological saline or a glucose solution. The perfusion containing the active agent possesses a physical stability of at least about 8 to about 24 hours or more compared to surfactant based true solution having stability upto about 4 hours only. Physical stability is understood to mean that the solution does not exhibit any visible precipitation after 8 to 10 hours of storage at room temperature. The perfusions may be injected into humans at a predetermined flow rate depending on the amount of active principle it is desired to inject. The anaphylactic shock phenomena which were observed with the solutions of the prior can be avoided with these solutions.
In another embodiment of the present invention is provided a process for preparation of such
composition which comprises of the following steps:
i) mixing the active agent(s) with surfactant(s), and oil component,
ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
iii) formulating the mixture into an injectable dosage form.

In another embodiment of the present invention, the process for the preparation of such novel
composition comprises of the following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a
homogeneous mixture, ii) mixing of oil component into the above homogeneous mixture and mixing at high sheer to
obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iv) formulating the mixture into a suitable injectable dosage form.
In another embodiment of the present invention, the process for the preparation of such novel
composition comprises of the following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a
homogeneous mixture, ii) mixing of oil component into the above homogeneous mixture and mixing at high sheer to
obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), iv) preparing the aqueous component by mixing excipient(s), and v) mixing the material of step (iii) and step (iv) to obtain an injectable dosage form.
In another embodiment, the compositions of the present invention after being mixed with an aqueous component may be further diluted with a diluting medium. In a further embodiment, the novel injectable compositions of the present invention is preferably formulated such that the composition forms an emulsion in vivo upon administration or the compositions are formulated as an emulsion system prior to administration.
In an embodiment, besides being used as self-emulsifying pharmaceutical composition, the compositions of the present invention can also be prepared with a suitable solid material to obtain a solid or near solid powder that can be reconstituted at a later date and diluted with suitable solvent to form the emulsion before injection. In another embodiment, before lyophilizing, the self-emulsifying composition of the present invention is converted into the emulsion by the use of the aqueous component. The solid matrix is prepared by freeze-drying (lyophilizing) an oil-in-water emulsion of the present invention, which can reform an emulsion of similar droplet size upon mixing with suitable solvent (reconstitution). Suitable solid material that may be used to make the oily composition of the present invention as a powder or that may be used in the emulsion compositions of this invention include, but are not limited to, polyols,

monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, or mixtures thereof.
In an embodiment, the injectable composition of the present invention can be administered to animals or humans via intravascular, intramuscular, cutaneous and subcutaneous routes. Specifically emulsions according to the invention can be given by any of the following routes among others: intra-abdominal, infra-arterial, intra-articular, intra-capsular, intra-cervical, intra-cranial, intra-ductal, intra-dural, intra-lesional, intra-ocular, intra-locular, intra-lumbar, intramural, intra-operative, intra-parietal, intra-peritoneal, intra-plural, intra-pulmonary, intra-spinal, intrathoracic, intra-tracheal, intra-tyrnpanic, intra-uterine, intra-ventricular, intravenous or transdermal. In a preferred embodiment, the injectable composition of the present invention is preferably administered via intravenous route, more preferably through i.v. infusion.
In yet another embodiment of the present invention is provided a method of using such novel pharmaceutical compositions. The compositions comprising antineoplastic agent(s) as the active agent(s) are useful for treating subjects with locally advanced or metastatic breast cancer after failure of prior chemotherapy, locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
The novel injectable pharmaceutical compositions of the present invention preferably provide the active agent(s) to localize in certain tissues, thereby increasing the efficacy of treatment, particularly of cancers, associated with such tissues.
The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention.
EXAMPLES
Example-1
S. No. Composition (mg/unit dose)
1. Docetaxel 40
2. Polysorbate 80 (Tween® 80) 935
3. Medium chain triglyceride (Crodamol® GTCC) 165
Procedure
i) Docetaxel was dissolved in Polysorbate 80.
ii) Medium chain triglyceride was mixed to the solution of step (i) to get the homogeneous mixture.

iii) The homogeneous mixture or self-emulsifying base of step (ii) was filled into vials and was sealed.
Example-2
S. No. Composition (mg/unit dose)
1. Docetaxel 40
2. Polysorbate 80 (Tween® 80) 935
3. Medium chain triglyceride (Crodamol® GTCC) 165
4. Ethanol 400
5. Polyoxyethylene-polyoxypropylenecopolymers(Poloxamer®188) 5
6. Water for injection 600
Procedure
i) Docetaxel was dissolved in Polysorbate 80 by sonication.
ii) Medium chain triglyceride was mixed to the solution of step (i) to get the homogeneous mixture.
iii) The homogeneous mixture of step (ii) was filled into vials and was sealed.
iv) Ethanol, Polyoxyethylene-polyoxypropylene copolymers and water for injection were mixed
together to form the aqueous component.
v) The homogeneous mixture of step (iv) was filled into vials and was sealed, vi) The material of step (iii) shall be mixed with the material of step (v) prior tip administration.
Example-3
S. No. Composition (mg/unit dose)
1. Docetaxel 40
2. Polysorbate 80 (Tween® 80) 935
3. Medium chain triglyceride (Crodamol® GTCC) 165
4. Ethanol 400
5. Polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188) 5
6. Water for injection 600
Procedure
i) Docetaxel was dissolved in Polysorbate 80 by sonication.
ii) Medium chain triglyceride was mixed to the solution of step (i) to get the homogeneous mixture.
iii) Ethanol, Polyoxyethylene-polyoxypropylene copolymers and Water for injection were
added to the mixture of step (ii) and were mixed to get the homogeneous mixture, iv) The homogeneous mixture of step (iii) was filled into vials and was sealed.

Example-4
S. No. Composition (mg/unit dose)
1. Paclitaxel 6
2. PEG 660 Hydroxy Stearate (Solutol® HS 15) 700
3. PEG 35 Castor Oil (Cremophor® EL) 118
4. Soybean Oil 196
5. Propylene glycol 500
6. Normal Saline q.s.
Procedure
i) PEG 660 Hydroxy Stearate was melted at 60°C and PEG 35 Castor Oil was added to it. ii) Paclitaxel was added to the mixture of step (i) and was sonicated at 50°C to get it dissolved, iii) Soybean oil was added to the mixture of step (ii) and was mixed to get homogeneous mixture. The said mixture was solidified to pasty nature upon standing at room temperature, iv) The mixture of step (iii) was melted and was diluted with Propylene glycol. v) The homogeneous mixture of step (iv) was filled into vials and was sealed, vi) The mixture of step (v) shall be diluted with Normal Saline prior to administration.
Example-5
S. No. Composition (mg/unit dose)
1. Docetaxel 40
2. Polysorbate 80 (Tween® 80) 825
3. PEG 35 Castor Oil (Cremophor® EL) 110
4. Medium chain triglyceride (Crodamol® GTCC) 165
5. Ethanol 400
Procedure
i) Docetaxel was dissolved in a mixture of Polysorbate 80 and PEG 35 Castor Oil by sonication. ii) Medium chain triglyceride was mixed to the solution of step (i) to get the homogeneous mixture, iii) Ethanol was added to the mixture of step (ii) and was mixed to get the homogeneous mixture, iv) The homogeneous mixture of step (iii) was filled into vials and was sealed.
Example-6
S. No. Composition (mg/vial)
1. Delavirdine mesylate 100
2. Tocopheryl polyethylene glycol succinate (Vitamin E TPGS) 505

3. Saffloweroil 135
Procedure
i) Delavirdine mesylate was dissolved in Tocopheryl polyethylene glycol succinate by sonication.
ii) Safflower oil was mixed to the solution of step (i) to get the homogeneous mixture.
iii) The homogeneous mixture or self-emulsifying base of step (ii) was filled into was filled into vial.
ExampIe-7
S. No. Composition (mg/vial)
1. Pioglitazone hydrochloride 50
2. PEG-32 glyceryl laurate (Gelucire® 44/14) 50
3. Medium chain triglyceride (Neobees® M-5 oil) 110
4. Polypropylene glycol 40
5. Water for injection 100
6. Mannitol 400
Procedure
i) PEG-32 glyceryl laurate was melted at 50°C and Pioglitazone hydrochloride was dissolved in it. ii) Medium chain triglyceride was mixed to the solution of step (i) to get the homogeneous mixture, iii) Polypropylene glycol and water for injection were added to the mixture of step (ii) and were
mixed to get the homogeneous mixture, iv) The homogeneous mixture of step (iii) was mixed with Mannitol to obtain a powder, which was
filled into a vial.

We Claim:
1. A novel injcctablc pharmaceutical composition comprising at least one poorly soluble
active agent(s), at least one surfactant(s), at least one oil component, and optionally other pharmaceutical ly acceptable excipient(s).
2. A composition according to claim 1, wherein the said composition is mixed with an
aqueous component prior to administration.
3. A composition according to claim 2, wherein the said composition is further diluted with a
suitable diluting medium prior to administration.
4. A composition according to any of the claims 1-3, wherein the poorly soluble active agent is
selected from a group comprising cardiovascular drug, respiratory drug, sympathomimetic
drug, cholinomimetic drug, adrenergic agonist or antagonist, analgesic/antipyretic,
anesthetic, antiasthamatic, antibiotic, antidepressant, antidiabetic, antifungal agent,
antihypertensive agent, anti-inflammatory, antineoplastic, antianxiety agent,
immunosuppressive agent, antimigraine agent, sedatives/hypnotic, antianginal agent,
antipsychotic agent, antimanic agent, antiarrhythmic, antiarthritic agent, antigout agent,
anticoagulant, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet
agent, anticonvulsant, antiparkinson agent, antihistamine/antipruritic, agent useful for
calcium regulation, antibacterial agent, antiviral agent, antimicrobial, anti-infective,
bronchodialator, hormone, hypoglycemic agent, hypolipidemic agent, protein, nucleic acid,
agent useful for erythropoiesis stimulation, and ulcer/antire flux agent,
antinauseant/antiemetic, oil-soluble vitamin, mitotane, visadine, halonitrosourea,
anthrocycline or ellipticine, and their pharmaceutical ly acceptable salts, esters, amides,
polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures, used
either alone or in combination thereof.
5. A composition according to claim 4, wherein the antineoplastic active agent is selected from
a group comprising antineoplastic drugs, monoclonal antibodies, immunotherapy or
radiotherapy or biological response modifiers, or their pharmaceutical ly acceptable salts,
hydrates, polymorphs, esters, and derivatives, used either alone or in combination thereof.
6. A composition according to claim 5, wherein the antineoplastic drug is a taxoid selected

from a group comprising docetaxel and paclitaxel, or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof.
7. An injectable composition according to claim 1, wherein the said composition is formulated
such that the composition forms an emulsion in vivo upon administration or the composition
is formulated as an emulsion system prior to administration.
8. An injectable composition according to claim 1, wherein the said composition provides the
active agent(s) to localize in certain tissues, thereby increasing the efficacy of treatment
associated with such tissues.
9. An injectable composition according to claim 8, wherein the said composition provides
effective treatment of cancer associated with certain tissues.
10. A process of preparation of the composition according to claim 1, which comprises of the
following steps:
i) mixing the active agent(s) with surfactant(s), and oil component,
ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
iii) formulating the mixture into an injectable dosage form.
11. A process of preparation of the composition according to claim 1, which comprises of the
following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a
homogeneous mixture, ii) mixing of oil component into the above homogeneous mixture and mixing at high
sheer to obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iv) formulating the mixture into a suitable injectable dosage form.
12. A process of preparation of the composition according to claim 1, which comprises of the
following steps:
i) dispersing the active agent(s) in a surfactant and mixing at high sheer to obtain a
homogeneous mixture, ii) mixing of oil component into the above homogeneous mixture and mixing at high
sheer to obtain a homogeneous mixture,
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), iv) preparing the aqueous component by mixing excipient(s), and v) mixing the material of step (iii) and step (iv) to obtain an injectable dosage form.
13. The pharmaceutical composition and process for the preparation substantially as herein described and illustrated by the examples.