DESC:“ORAL FORMULATIONS OF PACLITAXEL AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to oral capsule as well as suspension formulation of Paclitaxel and pharmaceutically acceptable salt thereof. This present invention discloses suspension and/or soft-gelatin capsule as well as hard-gelatin capsule formulation of Paclitaxel and pharmaceutically acceptable salt thereof. Further, the present invention relates to providing an economical and technically advanced dosage form over existing dosage forms.
BACKGROUND OF THE INVENTION:
Paclitaxel (CAS: 33069-62-4) is a member of the class of tetracyclic di-terpenoid derivative that is a small molecule microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing de-polymerization for the treatment of metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line treatment in combination with carboplatin. Further, in metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine.
Paclitaxel is a white to off-white crystalline powder with an empirical formula of C47H51NO14 and a molecular weight of 853.91 g per mol. Paclitaxel is chemically known as 5ß,20-Epoxy-1,2a,4,7ß,10ß,13a-hexahydroxytax-11-en-9-one-4,10-diacetate-2-benzoate-13-ester with (2R,3S)-N-benzoyl-3¬ phenylisoserine and is represented structurally as below:

PACLITAXEL
Paclitaxel was first isolated in 1971 from the Pacific yew and approved for medical use in 1993. It is now manufactured by cell culture. Paclitaxel was first disclosed in EP Patent EP0118316 which is a patent assigned to Lipid Specialties, Inc.
Paclitaxel is the presently marketed in the formulation having brand name ABRAXANE® which is developed by ABRAXIS BIOSCIENCE LLC, available in multiple strengths for suspension administration by way of intravenous (infusion), which was first approved by the USFDA on Jan 7, 2005. In the US, primarily, it was approved by the USFDA for the treatment of Metastatic breast cancer, after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. Locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine. In the EU marketing authorization holder is Celgene Europe B.V. from the effective date of 15 Jan 2008 for the same treatment which was disclosed in USFDA label like metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer.
ABRAXANE® is available in strength(s) of 100 mg/vial. The recommended dosage of Paclitaxel is 260 mg/m2 intravenously over 30 minutes every 3 weeks for the treatment in metastatic Breast Cancer (MBC) patients. Further, ABRAXANE is 100 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 of each 21-day cycle; administer carboplatin on Day 1 of each 21-day cycle immediately after ABRAXANE for the treatment in Non-Small Cell Lung Cancer (NSCLC) patients, Moreover, ABRAXANE is 125 mg/m2 intravenously over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle; administer gemcitabine on Days 1, 8, and 15 of each 28-day cycle immediately after ABRAXANE for the treatment in Adenocarcinoma of the Pancreas related cancer patients. Therefore, dose recommended according to USFDA label is reduced or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities.
It is well recognized that many drugs for parenteral use, especially those administered intravenously, cause undesirable side effects such as venous irritation, phlebitis, burning and pain on injection, venous thrombosis, extravasation, and other administration related side effects. Many of these drugs are insoluble in water, and are thus formulated with solubilizing agents, surfactants, solvents, and/or emulsifiers that are irritating, allergenic, or toxic when administered to patients (see, e.g., Briggs et al., Anesthesis 37, 1099 (1982), and Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991)). Often, the free drug present in the formulation induces pain or irritation upon administration. For example, phlebitis was observed in 50% of patients who received peripheral vein administration of ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma. (See, e.g., Vallejo et al., Am. J. Clin. Oncol. 19(6), 584-8 (1996)). Moreover, vancomycin has been shown to induce side effects such as phlebitis (see, e.g., Lopes Rocha et al., Braz. J. Infect. Dis., 6(4), 196-200 (2002)). The use of cisplatin, gemcitabine, and SU5416 in patients with solid tumors has resulted in adverse events such as deep venous thromboses and phlebitis (see, e.g., Kuenen et al., J. Clin. Oncol. 20(6), 1657-67 (2002)). In addition, propofol, an anesthetic agent, can induce pain on injection, burning and vein irritation, particularly when administered as a lecithin-stabilized fat emulsion (see, e.g, Tan et al., Anathesia, 53, 468-76, (1998)). Other drugs that exhibit administration-associated side effects include, for example, Taxol (paclitaxel) (see, e.g., package insert for Taxol I.V.), codarone (amiodarone hydrochloride) (see, e.g., package insert for Codarone I.V.), the thyroid hormone T3 or liothyronine (commercially available as Triostat), thiotepa, bleomycin, and diagnostic radiocontrast agents.
The commercially-available paclitaxel formulation (Bristol-Myers Squibb) comprises 6 mg/ml of paclitaxel dissolved in Cremophor® EL (castor oil, polyoxyethylated castor oil) and dehydrated ethanol (50% v/v). Similar formulations are sold by other manufacturers, for example, IVAX Co. Before intravenous injection, the commercial dose must be diluted to a final concentration of 0.3 to 1.2 mg/ml prior to injection. Recommended diluents are 0.9% aqueous sodium chloride, 5% aqueous dextrose, or 0.9% sodium chloride 5% dextrose aqueous solution, or 5% dextrose in Ringer's injection (The Physician's Desk Reference, 54th edition, 881-887, Medical Economics Company (2000); Goldspiel 1994 Ann. Pharmacotherapy 28:S23-26, both of which are incorporated herein by reference). In addition in general, the toxicity of Cremophor® EL, which is a required component of the intravenous formulation, is believed to be unacceptable.
The formulations, e.g. 6 mg/mL of paclitaxel in Ethanol and Cremophor®EL, are further disadvantageous because of the large dosage volumes required due to the low concentration of paclitaxel. Furthermore, recent studies have suggested that Cremophor®EL binds to paclitaxel, entrapping it in micelles, and decreasing absorption from the gut. (Bardelmeijer et al. Cancer Chemother. Pharmacol. 2002, 49:119-125; Malingré et. al. British Journal of Cancer 2001, 85(10), 1472-1477.) Thus, the bioavailability of paclitaxel is quite low when administered orally. There is a need, therefor, for formulations comprising paclitaxel, derivatives and pharmaceutically acceptable salts thereof which have an increased dissolution rate and uptake in the gastrointestinal system and hence a greater bioavailability for oral administration.
US6319943 discloses a composition suitable for orally administering Paclitaxel comprising Paclitaxel, and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures R1COOR2, R1CONR2, and RCOR2, wherein R1 is a derivative of d-C.-tocopherol and R2 is a hydrophilic moiety and method of preparation thereof. Unfortunately, Paclitaxel is poorly soluble in water (less than 0.01 mg/mL) and other common vehicles used for the 45 parenteral administration of drugs. Certain organic solvents, however, may at least partially dissolve Paclitaxel. However, when a water-miscible organic solvent containing Paclitaxel at near its saturation solubility is diluted with aqueous infusion fluid, the drug may precipitate. The said prior art overcome the stability problem but not overcome the problem of solubility and does not provide any solubility data of Paclitaxel formulation with existing prior art. There are so many several approaches are reported after above-mentioned innovator composition.
EP1585548 discloses pharmaceutical composition a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin, wherein the ratio (w/w) of albumin, to the pharmaceutical agent is 1:1 to 9:1, and wherein the pharmaceutical composition comprises particles or droplets having a size less than 200 nm, wherein the pharmaceutical agent is selected from taxane, camptothecin, propofol, amiodarone, cyclosporine, amphotericin, levothyroxine, epothilone, colchicine, thyroid hormone, corticosteroid, melatonin, tacrolimus, mycophenolic acid, and derivatives thereof or wherein the pharmaceutical agent is Paclitaxel, docetaxel or rapamycin. Another problem associated with the manufacture of drugs for injection, particularly water insoluble drugs, is the assurance of sterility. Sterile manufacturing of drug emulsions/dispersions can be accomplished by absolute sterilization of all the components before manufacture, followed by absolutely aseptic technique in all stages of manufacture. However, such methods are time consuming and expensive. In addition, the oxidation of drug formulations by exposure to air during manufacture or storage can lead to, for example, reduced pH, drug degradation, and discoloration, thereby destabilizing the drug formulation and/or reducing shelf life. Hence, it is need to develop a new suspension as well as soft-gelatin type of capsule composition without albumin and also need to develop a suspension which is resolved prior art problem without using iodized oil, vegetable oil and animal oil and it will be administered orally.
Korean Patent Publication Nos. KR20040009015 and KR20070058776 disclose method of preparing composition of oral solubilizing of conventional Paclitaxel is refrigerated in semi-solid form. In case of use, the solution is converted to solution form and administered orally. However, the composition refrigerated in semi-solid form does not convert into a solution at room temperature and still exists in semi-solid form even after long standing. Therefore, there is a problem in that additional treatment through heating is required to switch to a solution state that can be administered to a patient.
There is a need, therefore, for formulations comprising paclitaxel, derivatives and pharmaceutically acceptable salts thereof that can deliver therapeutically effective amounts of paclitaxel and derivatives thereof that overcome the disadvantages caused by paclitaxel's insolubility and the disadvantages of intravenous delivery.
Although the prior arts disclose different types of compositions which address the solubility, stability, patients’ compliance issues of Paclitaxel. It was facing that in clinical trial timing patients’ compliance. In addition, many of these physical property like solubility enhancing techniques involve critical and tedious manufacturing process, make use of many excipients or are modified according to the specific physicochemical characteristics of Paclitaxel.
Hence, the inventors of the present invention felt that still there is an unmet need to develop a dosage form of Oral Paclitaxel, which overcome the drawbacks of prior available formulations, has good physical , increase stability and get the clear solution in comparison with oral liquid Solution, solubility, is cost effective, is eliminate side effects, can be produced by simple manufacturing techniques and can maximize the its physical property, which is like e.g. solubility of Paclitaxel from such oral liquid dosage form and thereby improve its bioavailability.

OBJECTIVES OF THE INVENTION:
The primary object of the present invention is to provide improved oral dosage formulations of Paclitaxel with pharmaceutical acceptable excipients and method of preparation.
Another object of the present invention is to provide economical and advanced dosage forms over existing dosage form and prior-arts.
Yet another object of the present invention is to provide formulation of Paclitaxel and pharmaceutical acceptable excipients thereof, which may contain penetration enhancer or emulsifier agents, or with solubilizer agents.
One more objective of the present invention is to provide Paclitaxel and method of preparation thereof oral dosage form with enhanced its physical property profile like e.g., faster dissolution profile.
Another object of the present invention is to provide improved oral dosage formulations of Paclitaxel with pharmaceutical acceptable excipients wherein oral dosage form may be tablet, capsule, pellets for capsule, granules for the tablet, suspension, emulsion, solution and/or syrup.

SUMMARY OF THE INVENTION:
Despite of extensive research on Paclitaxel as reported in prior-art publications, there is an unmet need to develop a patient compliant oral composition for Paclitaxel with technical advancement which provide good physical property like good solubility, stability, as well as biological activity for immediate action with good bioavailability for long-term storage.
Accordingly, the present invention provides an oral composition of Paclitaxel preferably as homogenous composition, mixture and/or dispersion dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
The prime embodiment of the present invention is that the pharmaceutical composition establishes a very fast release during initial dissolution owing to kind of solubilizing agents as well as vehicle used in the formulation and thereby producing an immediate burst release which in turn immediate absorption of the drug into the blood stream. This action will help to increase bioavailability of Paclitaxel and pharmaceutically acceptable excipients thereof in very short time.
In one general embodiment of the present invention, a pharmaceutical composition per the present invention is in the form of suspension or capsule formulation. Preferably, this suspension and/or capsule formulation is soft-gelatin or hard-gelatin capsule formulation and optionally suspension without using or excluding iodized oil, vegetable oil, and animal oil.
In yet another embodiment of the present invention, a pharmaceutical composition as per the present invention comprises Paclitaxel and one or more pharmaceutically acceptable excipients, surfactants, emulsifier, solubilizers, vehicles, wherein the composition is in the form of a homogenous solution, suspension, and capsule.
In another general embodiment of the present invention, a pharmaceutical composition as per the present invention comprises Paclitaxel or pharmaceutically acceptable excipients like surfactants, emulsifiers, vehicles and/or solubilizers thereof.
In one embodiment of the present invention, wherein the active ingredient incorporated in the pharmaceutical composition is Paclitaxel which may be present in base form, amorphous form, crystalline form, solvate form, hydrate form or ester form.
The embodiments of the pharmaceutical composition may include Paclitaxel as an active ingredient with one or more selected from pharmaceutically acceptable excipients like surfactants, emulsifying agents, diluent, vehicles / solubility enhancing agents, stabilizers / anti-oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents, sweetener agents and the like.
In another embodiment of the present invention, pharmaceutical composition is in the form of an oral suspension and/or capsule composition comprising:
a) Active ingredient is Paclitaxel;
b) Emulsifier, or Vehicle or solubilizer are Glyceryl Monooleate, Glyceryl Trioctanoate (Tricaprylin) homogeneous composition and/ or mixture;
c) Surfactants are Polysorbate 80, Kolliphor ® HS 15, preferably Polysorbate 80 and method of preparation in step-2, was then get suspension.
In yet another embodiment of the present invention, pharmaceutical composition is in the form of an oral suspension composition comprising:
a) Active ingredient is a paclitaxel about 0.01% w/w to 7.00% w/w
b) Surfactant comprising ionic and/or non-ionic surfactant, preferably non-ionic surfactant is a Polysorbate 80 about 0.010%w/w to 25.00%w/w
c) Emulsifier agent is a Glyceryl Monooleate about10%w/w to 19.00%w/w,
d) Vehicle or solubilizer is a Glyceryl Trioctanoate (Tricaprylin) about 15.00%w/w to 25.00%w/w in homogeneous composition and/ or mixture.
The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:
The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, logical, and electrical changes may be made without departing from the scope of the present subject matter.
References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.
Paclitaxel, chemically known as, 5ß,20¬ Epoxy-1,2a,4,7ß,10ß,13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3¬ phenylisoserine, is a small molecule microtubule inhibitor having molecular weight of 853.91 g per mol. Paclitaxel is considered a member of the class of tetracyclic di-terpenoid derivative drug substance due to low aqueous solubility at neutral pH. The mean Paclitaxel is a drug with very much low solubility.
Oral Bioavailability:
In general, an oral formulation is preferred because of the distinct advantages over other methods of administration, in particular intravenous administration. In addition to the flexibility of treatment, the higher rate of compliance and the convenience and ease of administration associated with the elimination of hospital and physician supervision, oral formulations often create a substantial cost savings. However, many pharmaceutical formulations cannot be effectively administered orally because of the poor bioavailability of the active compounds as a result of low absorption from the gastrointestinal tract. Consequently, these active ingredients tend to be administered intravenously or intramuscularly. One such active ingredient that is not administered orally due to its poor bioavailability is paclitaxel.
Further, bioavailability is affected by cell surface proteins present in the gastrointestinal system, such as P-glycoproteins which can reduce gastrointestinal absorption of compounds in the gastrointestinal system. More specifically, they can prevent certain pharmaceutical active ingredients from being passed through the mucosal cells of the small intestines. As a result, the active ingredient is prevented from entering the bloodstream and is thus unable to be utilized. There is a need, therefore, for formulations that can orally deliver compounds, such as paclitaxel, despite its poor solubility, stability and bioavailability and despite the activity of P-glycoproteins.
Further evidence suggests that particle size plays a significant role in the absorption of a pharmaceutical ingredient into the gastrointestinal tract. As such, there is a need for a paclitaxel formulation which upon dilution into the gastric fluid remains dissolved or maintains a sufficiently small particle size.
There is currently no commercially available oral formulation with good bioavailability of paclitaxel in India. To solve this problem existed in the prior-art the inventors of the present invention have developed novel oral formulation of Paclitaxel. The invention of the present application solves problem like patient compliance owing to better physical property like solubility and with good bioavailability in comparison with the existing marketed formulations as well as prior-arts.
In accordance with the present invention, a pharmaceutical composition of Paclitaxel comprising of Paclitaxel as an active ingredient with pharmaceutically acceptable excipients, surfactants, emulsifiers, solubilizers and vehicles.
In accordance with the present invention, the active ingredient incorporated in the pharmaceutical composition is in crystalline form, amorphous form, hydrate form, solvate form and or ester form, active ingredient is present optionally in base form.
The term “drug” or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to Paclitaxel or a pharmaceutical acceptable salt thereof.
The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise of diluent, vehicles / solubility enhancing agents, stabilizers / anti-oxidants, suspending agents, emulsifying agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents and DHP107. DHP 107 is a lipid-based oral solution, which forms a mucoadhesive sponge phase in the presence of water and therefore can adhere to mucosal cells. A paclitaxel-free vehicle formulation (F109) of DHP107 was prepared by mixing monoolein, tricaprylin, and polysorbate 80 in the ratio of 1:0.5:0.3 (v/v/v) at approximately 40 °C. The DHP107 formulation is a semi-solid wax at room temperature and a liquid above 30 °C.
Suitable Emulsifying agents may include one or more Acacia; Carbomer Copolymer Carbomer Interpolymer Cholesterol; Coconut Oil Diethylene Glycol Stearates; Ethylene Glycol Stearates Glyceryl Di-stearate; Glyceryl Monolinoleate; Glyceryl Monooleate; Glyceryl Monostearate Lanolin Alcohols; Lecithin Mono- and Di-glycerides; Poloxamer Polyoxyethylene 50 Stearate; Polyoxyl 10 Oleyl Ether Polyoxyl 20 Cetostearyl Ether; Polyoxyl 35 Castor Oil Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate Polyoxyl Lauryl Ether; Polyoxyl Stearyl Ether Polysorbate 20; Polysorbate 40 Polysorbate 60; Polysorbate 80 Propylene Glycol Monostearate; Sodium Cetostearyl Sulfate Sodium Lauryl Sulfate; Sodium Stearate Sorbitan Monolaurate; Sorbitan Monooleate Sorbitan Monopalmitate; Sorbitan Monostearate Sorbitan Sesquioleate; Sorbitan Trioleate Stearic Acid; Wax, and the like.
Suitable vehicles or solubilizers may include one or more from Soybean Oil, Olive Oil, Sesame Oil, Labrafac® Lipophile WL 1349, Labrafac® CC, Geloil™, Peceol®, Lauroglycol™ 90, Lauroglycol™ FCC, Capryol™ 90, Capryol™ PGMC, Plurol® Oleique CC497, Labrasol®, Labrasol® ALF, Glyceryl Monooleate, Glycerin fatty acid ester (Tricaprylin), Transcutol, PEG 300 caprylic/capric glycerides (Softigen 767) PEG 400 caprylic/capric glycerides (Labrasol) PEG 300 oleic glycerides (Labrafil M-1944CS) PEG 300 linoleic glycerides (Labrafil M-2125CS), Poly ethylene glycol having molecular weight (M.W) of PEG- 200 to 8000, Propylene glycol and the like.
Suitable surfactants may include one or more from anionic, cationic, non-ionic or amphoteric surfactants. Non-limiting examples of surfactants may include polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, ethoxylated cholesterins, vitamin derivatives, e.g. vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS), sodium dodecyl sulfate or sodium lauryl sulfate; a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt; Kolliphor ® HS 15 and Polysorbate 80 and like.
Suitable stabilizers or anti-oxidants may include one or more from citric acid, butylated hydroxytoluene, butylated hydroxy anisole, sodium bisulphite, ascorbic acid, L-cysteine, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, ß-carotenes, uric acid, lipoic acid, propyl gallate, thiourea, glutathione and the like.
Suitable preservative may include one or more from propylene glycol, disodium EDTA, benzalkonium chloride, benzoic acid, butyl paraben, methyl paraben, propyl paraben, sodium benzoate and the like.
In accordance with the present invention, a pharmaceutical composition as per the present invention comprises Paclitaxel and one or more pharmaceutically acceptable excipients wherein the composition is in the form of a homogenous composition, mixture and/or dispersion.
The prime aspect of the present invention is that the pharmaceutical composition establishes a fast release pattern owing to kind of solubilizes, vehicles, surfactant agents, emulsifying agents used in the formulation and thereby producing an immediate burst release that will in turn to increase in bioavailability at initial release.
One aspect of the present invention may include a pharmaceutical composition comprising about 0.01%w/w to 110%w/w of Paclitaxel with pharmaceutically acceptable excipients, surfactants, emulsifiers, vehicles, solubilizers.
In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured is homogenous composition, mixture and/or dispersions, which results in to enhanced bioavailability, as well as physical property profile like stability and solubility profile.
In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process including mixing and homogenization.
Additional aspect according to the present invention is that the formulated product is a stabilized and clear composition, mixture and/or dispersion.
In one aspect process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) Take a Polysorbate 80 in container;
b) Add active pharmaceutical ingredient as a Paclitaxel;
c) Add Glyceryl Trioctanoate (Tricaprylin) in above container or step- a to b
d) Then make up volume with Glyceryl monooleate, along with Paclitaxel obtained in step- a to c and stirred continuously until it became homogeneous composition, and /or suspension and/or mixture.

The invention will be further described with respect to the following example(s); however, the scope of the invention is not limited thereby. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
Following section now will describe formulation examples as well as test examples by which the formulation example were evaluated.

EXAMPLE-1:
Sr. No. Ingredients Qty. per Capsule (mg)
1. Paclitaxel 10.00
2. Glyceryl Monooleate 560.00
3. Glycerin Fatty acid ester (Trycaprylin) 280.00
4. Polysorbate 80 160.00

Process for preparation:
1. Polysorbate 80 were taken in manufacturing vessel and mix then at 40°C temperature.
2. Paclitaxel (1% w/v) was added in the above mixture obtained in step-1 and it was stirred and sonicated to dissolve it completely;
3. Glyceryl monooleate, and Glycerin fatty acid (Tricaprylin) was added in the above mixture obtained in step-2 and it was stirred to dissolve it completely;
4. The homogeneous mixture prepared in step- 3 was filled in soft-gelatine capsule and/ or hard-gelatine capsule.

EXAMPLE-2:
Sr. No. Ingredients Qty. per Capsule (mg)
1. Paclitaxel 10.00
2. Glyceryl Monooleate 560.00
3. Glycerin Fatty acid ester (Trycaprylin) 280.00
4. Kolliphor ® HS 15 160.00

Process for preparation:
1. Kolliphor ® HS 15 were taken in manufacturing vessel and mix then at 40°C temperature.
2. Paclitaxel (1% w/v) was added in the above mixture obtained in step-1 and it was stirred and sonicated to dissolve it completely;
3. Glyceryl monooleate, and Glycerin fatty acid (Tricaprylin) was added in the above mixture obtained in step-2 and it was stirred to dissolve it completely;
4. The homogeneous mixture prepared in step- 3 was filled in soft-gelatine capsule and/ or hard-gelatine capsule.

EXAMPLE-3:
Sr. No. Ingredients Qty. per Capsule (mg)
1. Paclitaxel 10.00
2. Glyceryl Monooleate 390.00
3. Glycerin Fatty acid ester (Trycaprylin) 190.00
4. Polysorbate 80 110.00
5. Gelucire® 44/14 300.00

Process for preparation:
1. Paclitaxel (1% w/v) , Polysorbate 80 and Gelucire® 44/14 were taken in manufacturing vessel, mixed it and dissloved then at 40°C temperature.
2. Glyceryl monooleate, and Glycerin fatty acid (Tricaprylin) was added in the above mixture obtained in step-1 and it was stirred and sonicated to dissolve it completely;
3. The homogeneous mixture prepared in step- 2 was filled in soft-gelatine capsule and/ or hard-gelatine capsule.

EXAMPLE-4:
Sr. No. Ingredients %w/w mg/ml
1. Paclitaxel 1.00 10.00
2. Polysorbate 80 20.20 202.00
3. Glyceryl Trioctanoate 26.60 266.00
4. Glycerol Monooleate 53.20 532.00
Total Weight 101.00 1010.00

Process for preparation:
1. Take Polysorbate 80 in container. Apply nitrogen purging for at least 30 min. Maintain 40°C temperature of bulk before addition of API.
2. Add Paclitaxel in above container and stir till it get completely dissolved.
3. Add Glyceryl Trioctanoate in above container and stir to get uniform mixture.
4. Makeup the volume with Glycerol Monooleate and stir to get uniform solution.

Storage: Store at 2-8 °C temperature in airtight container, Protect from light.
Description: White or pale yellow semi-solid in refrigeration, colourless or pale-yellow transparent liquid above 30 °C.

EXAMPLE-5:
Sr. No. Ingredients %w/w mg/ml
1. Paclitaxel 1.000 10.000
2. Polysorbate 80 0.010 0.075
3. Glyceryl Trioctanoate 26.600 266.000
4. Glycerol Monooleate 73.390 733.925
Total Weight 101.000 1010.000

Process for preparation:
1. Take Polysorbate 80 in container.
2. Add Paclitaxel in above container and stir till it get completely dissolved.
3. Add Glyceryl Trioctanoate in above container and stir to get uniform mixture.
4. Makeup the volume with Glycerol Monooleate and stir to get uniform solution.

Storage: Store at 2-8 °C temperature in airtight container, Protect from light.
Description: White or pale yellow semi-solid in refrigeration, slight transparent liquid above 30°C temperature.
Major Changes
1. The concentration of Polysorbate 80 is decreased and the concentration of Glyceryl Monooleate is increased in compare to the concentration of innovator.
2. Solution is prepared without applying temperature and nitrogen purging to the system.
EXAMPLE-6:
Sr. No. Ingredients %w/w mg/ml
1. Paclitaxel 1.000 10.000
2. Polysorbate 80 0.010 0.075
3. Glyceryl Trioctanoate 50.000 499.963
4. Glycerol Monooleate 50.000 499.963
Total Weight 101.000 1010.001

Process for preparation:
1. Take Polysorbate 80 in container.
2. Add Paclitaxel in above container and stir till it get completely dissolved.
3. Add Glyceryl Trioctanoate in above container and stir to get uniform mixture.
4. Makeup the volume with Glycerol Monooleate and stir to get uniform solution.

Storage: Store at 2-8 °C temperature in airtight container, Protect from light.
Description: White or pale yellow semi-solid in refrigeration, turbid liquid at above 30°C temperature.
Major Changes
1. The concentration of Polysorbate 80 is decreased in compare to the concentration of innovator.
2. 50% concentration of Glyceryl Trioctanoate and 50% concentration of Glyceryl Monooleate taken in compare to the concentration of innovator.
3. Solution is prepared without applying temperature and nitrogen purging to the system.

EXAMPLE-7:
Sr. No. Ingredients %w/w mg/ml
1. Paclitaxel 1.000 10.000
2. Polysorbate 80 7.500 75.000
3. Glyceryl Trioctanoate 30.830 308.330
4. Glycerol Monooleate 60.670 606.670
Total Weight 100.000 1000.000

Process for preparation:
1. Take Polysorbate 80 in container.
2. Add Paclitaxel in above container and stir till it get completely dissolved.
3. Add Glyceryl Trioctanoate in above container and stir to get uniform mixture.
4. Makeup the volume with Glycerol Monooleate and stir to get uniform solution.

Storage: Store at 2-8 °C temperature in airtight container, Protect from light.
Description: White or pale yellow semi-solid in refrigeration, turbid liquid at above 30°C temperature.

Major Changes
1. The concentration of Polysorbate 80 is decreased in compare to the concentration of innovator.
2. Solution is prepared without applying temperature and nitrogen purging to the system.

As per the above example’s result(s) demonstrate that the present novel invention surprisingly produces better result(s) once again and proves its inventiveness by technical advancement against the nearest prior-art publications.
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
The above-mentioned example(s) is/are provided for illustrative purpose only and these example(s) is/are in no way limitative on the present invention.
,CLAIMS:We Claims:

1. An oral pharmaceutical composition of API comprising an active pharmaceutical ingredient and pharmaceutical acceptable excipients where in pharmaceutically excipients may comprise of surfactants, suspending agents, emulsifying agents, solubilizing agents, vehicle agents, solvents.

2. An oral pharmaceutical composition comprising
a. About 0.01%w/w to 7.00%w/w is an active pharmaceutical ingredient;
b. About 0.010%w/w to 25.00%w/w are surfactants comprising ionic surfactants and non-ionic surfactants, preferably one or more non-ionic surfactant.
c. About 15.00%w/w to 55.00%w/w are solubilizing agents and/or solvents, preferably one or more solubilizing agent and/or solvent;
d. About 10.00%w/w to 19.00%w/w are emulsifying agents, preferably one or more emulsifying agent.

3. An oral pharmaceutical composition composition comprising
a. Paclitaxel as an active pharmaceutical ingredient;
b. surfactants are ionic and non-ionic surfactants are selected from sepitrap 80 (Polysorbate 80 and Magnesium aluminometasilicate), polysorbate 80, castor oil, polyoxymethylene lauryl ether, polyoxyethylene and the like.
c. Solubilizing agents and/or solvents are selected from Soybean Oil, Olive Oil, Sesame Oil, Labrafac® Lipophile WL 1349, Labrafac® CC, Geloil™, Peceol®, Lauroglycol™ 90, Lauroglycol™ FCC, Capryol™ 90, Capryol™ PGMC, Plurol® Oleique CC497, Labrasol®, Labrasol® ALF, Glyceryl Monooleate, Glycerin fatty acid ester (Tricaprylin), Transcutol, PEG 300 caprylic/capric glycerides (Softigen 767) PEG 400 caprylic/capric glycerides (Labrasol) PEG 300 oleic glycerides (Labrafil M-1944CS) PEG 300 linoleic glycerides (Labrafil M-2125CS), Poly ethylene glycol having molecular weight (M.W) of PEG- 200 to 8000, Propylene glycol and the like.
d. Emulsifying agents are selected from Acacia; Carbomer Copolymer Carbomer Interpolymer Cholesterol; Coconut Oil Diethylene Glycol Stearates; Ethylene Glycol Stearates Glyceryl Di-stearate; Glyceryl Monolinoleate; Glyceryl Monooleate; Glyceryl Monostearate Lanolin Alcohols; Lecithin Mono- and Di-glycerides; Poloxamer Polyoxyethylene 50 Stearate; Polyoxyl 10 Oleyl Ether Polyoxyl 20 Cetostearyl Ether; Polyoxyl 35 Castor Oil Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate Polyoxyl Lauryl Ether; Polyoxyl Stearyl Ether Polysorbate 20; Polysorbate 40 Polysorbate 60; Polysorbate 80 Propylene Glycol Monostearate; Sodium Cetostearyl Sulfate Sodium Lauryl Sulfate; Sodium Stearate Sorbitan Monolaurate; Sorbitan Monooleate Sorbitan Monopalmitate; Sorbitan Monostearate Sorbitan Sesquioleate; Sorbitan Trioleate Stearic Acid; Wax, and the like.

4. The oral pharmaceutical composition of Paclitaxel as claimed in claims- 2 and 3, where in composition comprising
a. Paclitaxel as an active pharmaceutical ingredient;
b. Surfactants are ionic and non-ionic, preferably non-ionic surfactant is Polysorbate 80;
c. Solubilizing agent and/or solvent is Glyceryl Trioctanoate;
d. Emulsifying agent is Glyceryl Monooleate.

5. Process for the preparation of an oral pharmaceutical composition of Paclitaxel as claimed in claims- 2 and 3 comprising the following steps:
a) Take a Polysorbate 80 in container;
b) Add active pharmaceutical ingredient as a Paclitaxel;
c) Add Glyceryl Trioctanoate (Tricaprylin) in above container or step- a to b;
d) Then make up volume with Glyceryl monooleate, along with Paclitaxel obtained in step- a to c and stirred continuously until it became homogeneous composition, and /or suspension and/or mixture.