Title of Invention

"COMPOSITION FOR STABILIZATION OF PACLITAXEL AND PREPARATION METHOD THEREOF"

Abstract The present invention relates to a paclitaxel composition and the preparation methods thereof to solubilize paclitaxel wherein said composition comprises 4—90% by weight of at least one selected from the monoglycerides, 0.01—90% by weight of at least one oil and 0.01—20% by weight of paclitaxel. Also the present invention relates to a paclitaxel composition including emulsifiers and the preparation methods thereof to solubilize paclitaxel wherein said composition comprises 4—90% by weight of at least one selected from the monoglycerides, 0.01-90% by weight of at least one emulsifier and 0.01-20% by weight of paclitaxel. The composition of the present invention is an effective paclitaxel delivery system since the composition solubilizes paclitaxel, does not from aggregates after being dispersed in water, adsorbs well on the intestinal wall, and therefore has high bioavailability.
Full Text TECHNICAL FIELD
The present invention relates to a composition for solubilization of paclitaxel and method of preparation thereof.
BACKGROUND ART
Paclitaxel, an anticancer agent, shows excellent cytotoxicity to various kinds of cancers such as ovarian cancer, breast cancer, esophagus cancer, melanoma and leukemia. Paclitaxel formulation currently used in clinical remedies has been commercialized in the form of emulsion preconcentrate (self-emulsifying system) because its water solubility is very low even compared with an anti-cancer medicine of Bristol-Myers Squibb Company. Taxol is a commercially available injection agent, in the form of solution, in which paclitaxel is mixed with solubilizing agent, that is, Cremophor EL (polyoxyethylene 35 castor oil, polyoxylethylaed castor oil and polyoxyethoxylated castor oil) in dehydrated alcohol (US patent 5438072). It is known, however, that this agent has a limitation in directions and dosage because solubilizing agent in Taxon@ causes toxic side effects.
Therefore, many studies have been performed to develop new paclitaxel formulations with high stability and low toxic effects. There are many patents describing lipid emulsion, polymeric micelles and liposom. In
emulsion formulation, not only emulsion using conventional oils and emulsifiers but also solid lipid nanoparticles, emulsion concentrate and so on have been patented. Also other solubilization techniques by utilizing liposome, polymeric nanoparticles and polymeric micelles have been developed. These formulations solubilizing paciitaxel took advantage of the accumulated technological advancement already developed for other insoluble drugs.
Also, even though paciitaxel is currently used to treat metastatic ovarian cancer and breast cancer, it is expected to be prescribed for various cancers, especially the metastatic solid tumors (e.g., lung cancer and hepatoma) in the near future. Therefore, market forecast is promising for paciitaxel.
From the pharmaceutical point of view, Taxol®, the most frequently prescribed paciitaxel formulation has a problem of forming precipitation when diluted inside the infusion bag due to the low solubility. In-line filter is used to prevent the precipitation from entering the blood stream of the patient. The exact dose of paciitaxel, therefore, is unknown and varies from time to time. Also, the plasticizer is known to leak out from the infusion bag made of PVC causing potential health problem. From the pharmacological point of view, Cremophor EL, the excipient can cause severe side-effects such as hypersensitivity, vasodilation, dyspnea, enervation and high blood pressure. From the pharmaceutical and pharmacological points of view, the stability and the safety of the drug must be improved by developing other administration routes and formulations.
The most promising and convenient administration route is considered to be the oral route. There is a big hurdle to overcome,
however, since paclitaxel is not absorbed into the body due to the efflux mechanism by p-giycoprotein which exists in the epithelial cell of gastrointestinal tract. Many p-glycoprotein inhibitors are known up to date including cinchonin, calcium channel blockers such as verapamil and dihydropyhdines (for instance nifedipine, nicardipine and nitrendipine), calmodulin antagonist such as trifluoroperazine, antihypertensive such as reserpine, Vinca alkaloids such as vincristine and vinblastine, steroids such as progesterone, antiarrythmics such as amiodarone and quinidine, anthelmintic such as quinacrine and quinine, and immunosuppressants such as cyclosporine A, staurosporine and tacrolimus.
In addition to the increased oral bioavailability of paclitaxel, the p-glycoprotein inhibitors can help overcome multi-drug resistance by inhibiting p-glycoprotein existing in the cancer cells. On the other hand, paclitaxel is known to be metabolized by hepatic microsomal enzyme. Paclitaxel converts to 6-a-hydroxypaclitaxel and 3'-ß-hydroxypaclitaxel by CYP2C8 and CYP3A4, respectively.
Cyclosporin A inhibits the formation of 6-α-hydroxypaclitaxel. Doxorubicin, etoposide (VP-16) and cisplatin inhibit the formation of 3'-p-hydroxypaclitaxel. And verapamil and tamoxifen inhibit the metabolism of paclitaxel to 6-a-hydroxypaclitaxel , and 3-ß-hydroxypaclitaxel. Therefore, co-administration of paclitaxel with the above mentioned metabolism inhibitors could also increase the bioavailability of paclitaxel.
Many formulations have been developed to solubilize paclitaxel. One of the most widely used and successful formulations is Taxol®. Lipid emulsion (US6391832 Medical emulsion for lubrication and delivery of drugs;
US6348491 . Oi!-in-water emulsion for encapsulating paclitaxel) or pre-concentrate which forms transparent colloidal system in water (US6267985 Clear oil-containing pharmaceutical compositions; US62941S2 Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents) are also well known. In case of pre-concentrate, clear oi! composition forms dispersion of very smai! particles whose absorbance at 400 nm is less than 0.3.
The above formulation is distinctly different from the composition for solubilization of paclitaxel in the present invention. The composition in the present invention is coarsely dispersed in water, and the absorbance at 400 nm is above 0.38 in all cases and between 1 and 4 in most cases. In other words, efforts have been made to prepare nano-sized particles or its pre-concentrate to solubilize paclitaxel in the existing inventions whereas the current invention discloses the composition that does not disperse well and does disperse to form particles of a few micrometers in size if it does. The merits of the composition of the present invention include that paclitaxel does not precipitate out in the dispersion while it is a high mucoadhesive in the intestine.
One of the main obstacles in commercializing oral paclitaxel formulations is the problem of forming paclitaxel precipitation upon dilution with body fluid. Even if the formulation is stable before dilution, precipitation forms with time in the dispersion. Paclitaxel precipitation cannot be absorbed into the body in the intestine at all. Once the problem of precipitation formation is solved, however, another obstacle, efflux system of p-glycoprotein in the gastrointestinal tract, awaits lowering bioavailability of paclitaxel.
in the present invention, a mucoadhesive lipid, monoolem was usea as a mam component for oral delivery of paclitaxel. Even though paclitaxel is solubilized in monoolem it forms precipitation in the cubic phase of the monoolein/water system. Therefore, we prepared an oily composition that does not form paclitaxel precipitation with time even after the composition is mixed with water The cubic phase of the monoolein/water system is composed of ca 60 % (v/vj of water On the other hand, when more than 10 % of oil is added to monoolem, the mixture does not form cubic phase, but forms an amorphous composition that contains ca 5 ~ 10 % of water It is worthwhile to note that this composition does not form paclitaxel precipitation Also, this composition is very mucoadhesive to intestinal wall
To date, oral paclitaxel formulation that does not require p-glycoprotein inhibitor has not been developed Also the bioavailability of the oral paclitaxel formulations was very low even when it is co-administered with p-glycoprotein inhibitor o-ally
To overcome the problem of forming paclitaxel precipitation in contact with water and of low oral bioavailability as mentioned above, the present invention provides mucoadhesive compositions for solubilization of paclitaxel that have high bioavailability when administered alone or with p-glycoprotein inhibitor and the preparation method thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions for solubilization of paclitaxel that is stable for a prolonged period, mucoadhesive, and hignly bioavailable and the preparation method thereof
More specifically, the present invention provides compositions for solubilization of paclitaxel including at least one monogiyceride. at least one oil and paclitaxel and the preparation method thereof.
Also, the present invention provides compositions for solubilization of paclitaxel including at least one monogiyceride, at least one oil, at least one emulsifier and paclitaxel and the preparation method thereof.
In what follows, the present invention will be described in detail.
The present invention provides compositions for solubilization of paclitaxel.
Specifically, the above composition is composed of 4 - 90 % by weight of at least one selected from the monoglycerides, 0.01 - 90 % by weight of at least one oil ad 0.01 ~ 20 % by weight of paclitaxel (with respect to the total weight of the composition).
The above composition can be prepared by mixing at least one monogiyceride, at least one oil and paclitaxel at room or elevated temperature.
The above monoglycerides are selected from a group consisting of one or more saturated or unsaturated monoglycerides having 10-22 carbon atoms in the hydrocarbon chain. Monogiyceride is selected preferably from a group consisting of monoolein, monopalmitolein, monomyristolein, monoelaidin and monoerucin, and from a group consisting of the mixture of monoglycerides semi-synthesized from triglycerides of vegetable or animal oil, and more-preferably monoolein
The above oil is selected preferably from a group consisting of triglycerides, iodinated oil and vegetable or animal oil that can solubilize
paclitaxel.
The above triglycerides are selected from a group consisting of one or more saturated or unsaturated triglycerides having 2-20 carbon atoms in the hydrocarbon chain. For instance, triacetin, tributyrin, tricaproin, tricapryiin, tricaprin or triolein can be used.
The above iodized oils include iodized poppy seed oil such as Lipiodol, Ethiodol and iodized soybean oil.
The above vegetable oils include soybean oil, cottonseed oil, olive oil, poppyseed oil, linseed oil or sesame oil.
The above animal oils include squalane or squalene.
Also, the above composition can additionally include other additives up to 5 % by weight. For instance, the composition can further comprise alcohol, polyol or Cremophor to improve the solubility of paclitaxel, tocopherol or tocopherol acetate to prevent oxidation, fatty acid, fatty acid ester or fatty acid alcohol to increase drug absorption, and other insoluble drugs to achieve synergistic effect.
The above insoluble - drugs include other anticancer drugs, p-g!ycoprotein inhibitors or hepatic metabolism blockers.
The above other anticancer drugs include doxorubicin, cisplatin, carboplatin, carmustin (BCNU), dacarbazine, etoposide, 5-fluorouracil or paclitaxel derivatives. The above paclitaxel derivatives include docetaxel, bromotaxel and taxotere.
The above p-glycoprotein inhibitors include cinchonin, calcium
channel blocker, calmodulin antagonist, Vinca alkaloid, antiarrhythmic,
steroid, antihypertension drug, anthelmintic or immunosuppressant. The
above calcium channel blockers include dihydropyridmes such as verapamil
nifedipine, nicardipine or nitrendipine The above calmodulin antagonists
include trifluoroperazine The above antihypertension drugs include
reserpine The above Vinca alkaloids include vincristine or vinblastine The
above steroids include progesterone The above antiarrhythmics include
amiodarone and quinidine The above anthelmintics include quinacrine and
quinine The above immunosuppressants include cyclosporins,
staurosponn and tacrolimus
The above hepatic metabolism blockers include anticancer drugs such as cyclosporin A, doxorubicin, etoposide (VP-16), cisplatin, verapamil and tamoxifen
The compositions for solubilization of paclitaxel according to the present invention can be administered via various routes including oral administration, buccal administration, mucosal administration, nasal administration, intraperitoneal administration, subcutaneous injection, intramuscular injection, transdermal administration, intratumoral administration, and more preferably an oral administration
The method of preparing the above composition for solubilization of paclitaxel comprises the steps of,
1) preparing the viscous liquid by solubilizing 4 - 90% by weight of at least one monoglycende compound in 0.01 ~ 90 % by weight of at least one oil by heating to below 50 °C (step 1), ana
2) preparing homogeneous mixture by solubilizing completely 0.01 ~ 20 % by weight of paclitaxel in said mixture in step (1) (step 2).
The mixture can be heated to 50 °C and sonicated in a bath type
sonicator in step (2) to speed up the solubilization process.
Also, the method of preparing the above composition for solubilization of paclitaxel comprises the steps of;
1) mixing 4 ~ 90% by weight of at least one monoglyceride compound , 0.01 ~ 90 % by weight of at least one oil and 0.01 ~ 20 % by weight of paclitaxel (step 1); and
2) preparing homogeneous mixture by solubilizing completely the said mixture in step (1) (step 2).
The above mixture can be heated to 50 °C and sonicated in a bath type sonicator or stirred in step (2) to speed up the solubilization process.
The preparation methods described above are only two of many possible methods, and other preparation methods can also be used to obtain the above composition for solubilization of paclitaxel.
Also, the present invention provides the compositions for solubilization of paclitaxel including emulsifiers.
More particularly, the above composition is composed of 4-90% by weight of at least one selected from the monoglycerides, 0.01-90 % by
weight of at least one oil, 0.01-90 % by weight of at least one emulsifier and 0.01 - 20 % by weight of paclitaxel (with respect to the total weight of the composition).
The above composition can be prepared by adding at least one monoglyceride, at least one oil, at least one emulsifier and paclitaxel at room or elevated temperature.
The above monoglycendes are selected from a group consisting of one or more saturated or unsaturated monoglycerides rsving 10 ~ 22 carbon atoms in the hydrocarbon chain Monoglyceride is selected preferably from a group of consisting of monoolein. monopalmitolen, monomyristolein. monoelaidin, and monoerucin, or from a group consistrg of monoglycerides semi-synthesized from triglycerides of vegetable or animal oils or their mixture, and more preferably monoolein.
The above oil is selected preferably from a group consisting of triglycerides, iodinated oil and vegetable or animal that can solubilize paclitaxel.
The above triglycerides are selected from a group consisting of one or more saturated or unsaturated triglycerices having 2-20 carbon atoms in the hydrocarbon chain. For instance, triacetin, routyrin, tricaproin, tricaprylin, tricaprin or triolein car be used.
The above iodized oils include icdized popp.. seed oil such as Lipiodol, Ethiodol and iodized soybean oil.
The above vegetable oils include so/bean oil connseed oil, olive oil, poppyseed oil, linseed oil or sesame oil.
The above animal oils include scualane or square.
The above emulsifier is preferred to se'ect from the group consisting of a phospholipid, a non-ionic surfactant, an anior constant a caticnic surfactant, and bile acid.
The phospholipid is preferred to selected from the group consist of a phosphatidylcholine (PC) and its derivative a phoshpandy ethance amine
(PE) and its derivative, a phosphatidyiserine (PS) and its derivative, and a polymeric lipid wherein a hydrophilic polymer is conjugated to the lipid headgroup;
The non-ionic surfactant is selected from the group consisting of a • poloxamer (also known as Pluronic: poiyoxyethylene-polyoxypropylene copolymer), a sorbitan ester (Span), a polyoxyethylene sorbitan (Tween) and a polyoxyethylene ether (Brij).
The anionic surfactant is selected from the group consisting of a phosphatidyiserine (PS) and its derivative, a phosphatide acid (PA) and its derivative and sodium dodecyl sulfate (SDS).
The cationic surfactant is selected from the group consisting of 1,2-
dioleyl-3-trimethylammonium propane (DOTAP),
dimethyldioctadecylammonium bromide (DDAB),
N-[1-(1,2-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA),
1,2-dioleyl-3-ethylphosphocholine (DOEPC) and
33-[N-[(N',N'-dimethylamino)ethan]carbamoyl]cholesterol (DC-Choi).
The bile acid is selected from the group consisting of cholic acid, its salt and derivatives; deoxycholic acid, its salt and derivatives; chenocholic acid, its salt and derivatives; and lithocholic add, its salt and derivatives.
Other additives can be added to the above to be within 5% by weight. For instance, the composition can further comprise alcohol, polyol or Cremophor to improve the solubility of paclitaxel, tocopherol or tocopherol acetate to prevent oxidation, and fatty acid, fatty acid ester or fatty acid alcohol to increase drug absorption. Depending on the symptom, other insoluble drug can also be added in the composition including emulsifier
according to the present invention.
The above insoluble drugs include other anticancer drugs, p-glycoprotein inhibitors or hepatic metabolism blocker.
The above other anticancer drugs include doxorubicin, cisplatin, carboplatin, carmustin (BCNU), dacarbazine, etoposide, 5-fluorouracil or paclitaxel derivatives. The above paclitaxel derivatives include docetaxel, bromotaxel and taxotere.
The above p-glycoprotein inhibitors include cinchonin, calcium
channel blocker, calmodulin antagonist, Vinca alkaloid, antiarrhythmic,
steroid, antihypertension drug, anthelmintic or immunosuppressant. The
above calcium channel blockers include dihydropyridines such as verapamil,
nifedipine, nicardipine or nitrendipine. The above calmodulin antagonists
include trifluoroperazine. The above antihypertension drugs include
reserpine. The above Vinca alkaloids include vincristine or vinblastine. The
above steroids include progesterone. The above antiarrhythmics include
amiodarone and quinidine. The above anthelmintics include quinacnne and
quinine. The above immunosuppressants include cyclosporins,
staurosporin and tacrolimus
The above hepatic metabolism blockers include anticancer drugs such as cyclosporin A, doxorubicin, etoposide (VP-16), cisplatin, verapamil and tamoxifen.
The compositions for solubilization of paclitaxel including emulsifiers according to the present invention can be administered via various routes including oral administration, buccal administration, mucosal administration, nasal administration, intraperitoneal administration, subcutaneous injection, intramuscular injection, transdermal administration, intratumoral
administration, and more preferably an oral administration.
The method of preparing the above composition for solubilization of paclitaxel including emulsifiers comprises the steps of;
1) preparing the viscous liquid by mixing 4 ~ 90% by weight of at least one monoglyceride compound, 0.01 ~ 90 % by weight of at least one oil and 0.01 ~ 90 % by weight of ai least one emulsifier by heating to below 50 °C (step 1); and
2) preparing homogeneous mixture by solubilizing completely 0.01 ~ 20 % by weight of paclitaxel in said mixture in step (1) (step 2).
One of the examples in preparing the composition for solubilization of paclitaxel including emulsifiers is as follows. In homogeneous viscous liquid obtained by mixing monoglyceride, oil and emulsifier by heating to below 50 °C, paclitaxel is added. The mixture was stirred or sonicated for 3 ~ 5 minutes at or below 50 °C to obtain homogeneous composition.
The method of preparing the above composition for solubilization of paclitaxel including emulsifiers can also comprise the steps of;
1) preparing the paclitaxel solution by solubilizing 0.01 ~ 20% by weight of paclitaxel in 0.01 ~ 90 % by weight of at least one oil by sonicating in a bath type sonicator (step 1); and
2) preparing homogeneous mixture by mixing the paclitaxel solution in step (1) and 0.01 ~ 90 % by weight of at least one emulsifier and 4 ~ 90 % by weight of monoglyceride (step 2).
The preparation methods described above are oniy two of many possible methods, and other preparation method can also be used to obtain
the above composition for solubilization of paclitaxel including emulsifier.
The formulations of the present invention in viscous liquid, gel or semi-solid form are stable for a long period of time since the physical property of the composition does not change and the components including paclitaxel do not degrade with time. Also the compositions for solubilization of paclitaxel of the present invention is an efficient solubilization system since they can be easily dispersed in water or in aqueous solutions to become particles bigger than 400 nm in diameter, and the dispersion does not form aggregates with time. Also the absorbance of the dispersion ranges 1 and 4 at the wavelength of 400 nm indicating that the average particle size is relatively big.
In other words, the composition of the present invention does not form fine dispersion with nano-sized particles, but form coarse dispersion with the particles of several hundred nanometers to several micrometers in size. The dispersion of the composition of the present invention does not form paclitaxel aggregate with time. When administered into the body, the composition is highly mucoadhesive and adheres onto a wide area of intestinal wall. Paclitaxel in the composition is absorbed through the mucosal membrane in the intestine since mucoadhesive monoolein can be absorbed without further metabolization process.
Statement of Invention:-
The present invention relates to a composition for solubilization of paclitaxel including emulsifier comprising 40-65% by weight of monoolein, 20-45 % by weight of oil selected from a group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, Lipiodol, iodized poppy seed oil, Ethiodol, iodized soybean oil, soybean oil, cottonseed oil, olive oil, poppyseed oil, linseed oil, sesame oil, squalane and squalene, 10-20% by weight of emulsifier selected from a group consisting of a phospholipid, a non-ionic surfactant, an anionic surfactant, a cationic surfactant and bile acid and 0.3 - 5% by weight of paclitaxel.
The present invention also relates to a method of preparing the composition for solubilization of paclitaxel including emulsifier as claimed in any one of claims 1 to 6 wherein said method comprises the steps of: 1) preparing the viscous liquid by mixing 40-64.7 % by weight of monoolein, 25-49.7 % by weight of oil selected from a group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, Lipiodol, iodized poppy seed oil, Ethodol iodized soybean oil soybean oil, cottonseed oil, olive oil, poppyseed oil, linseed oil, sesame oil, squalane and squalene, 10-20% by weight of emulsifier selected from a group consisting of a phospholipids, a non-ionic surfactant, an anionic surfactant, a cationic surfactant and bile acid by heating up to 50° C and 2) preparing homogeneous mixture by solubilizing completely 0.3-4 % by weight of paclitaxel in said mixture of step 1) by stirring or sonification.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the total concentration of paclitaxel and its metabolites in blood after oral administration of the liquid formulation
solubilizing paditaxel in Examples 1 and 2 of the present invention. The quantitative analysis of total concentration of paclitaxel and its metabolites was performed by ELISA. Taxol® of Bristol-Myers Squibb Company was administered via intravenous route as a control group.
- • - ; a group orally administered with liquid formulation for
solubilization of paclitaxel of the present invention (1 mg
paclitaxel, weight ratio of the composition is monoolein :
tricaprylin : paclitaxel = 66:33:1, the composition in Example 1),
and
- O -; a group orally administered with liquid formulation for
solubilization of paclitaxel of the present invention (2 mg paclitaxel, weight ratio of the composition is monoolein : tricaprylin : paclitaxel = 65:33:2, the composition in Example 2)
- A - ; a group intravenously administered with Taxol® of
Bristol-Myers Squibb Company (10 jag paclitaxel).
Figure 2 is a graph showing the total concentration of paclitaxel and its metabolites in blood after oral administration of the liquid formulation containing emulsifier with different ratios of paclitaxel. The quantitative analysis of total concentration of paclitaxel and its metabolites was performed by ELISA. Taxol® of Bristol-Myers Squibb Company was administered orally as a control group.
- • -; a group orally administered with liquid formulation containing
emulsifier for solubilization of paclitaxel of the present invention (1
mg paclitaxel, weight ratio of the composition is monoolein :
tricaprylin : Tween 80 : paclitaxel = 55:28:16:1, the composition in
Example 3),
- O -; a group orally administered with liquid formulation containing
emulsifier for solubilization of paclitaxel of the present invention (1 mg. paclitaxel, weight ratio of the composition is monoolein tricaprylin : Tween 80 ; paclitaxel = 54:27:16:2, the composition in Example 9),
- A. - a group orally administered with liquid formulation containing
emulsifier for solubilization of paclitaxel of the present invention (1 mg paclitaxel, weight ratio of the composition is monoolein : tricaprylin : Tween 80 : paclitaxel = 55:27:16:3, the composition in Example 10), and
- 0 - ; a group orally administered with Taxol® of Bristol-Myers
Squibb Company (1 mg paclitaxel).
Figure 3 is a graph showing the total concentration of paclitaxel and its metabolites in blood after oral administration of the liquid formulation containing emulsifier in Example 11 of the present invention. The quantitative analysis of total concentration of paclitaxel and its metabolites was performed by ELISA. Taxol® of Bristol-Myers Squibb Company was administered intravenously as a control group.
- • -; a group orally administered with liquid formulation containing
emulsifier for solubilization of paclitaxel of the present invention (1
mg paclitaxel, weight ratio of the composition is
monoolein :tricaprylin : Pluronic F68 : paclitaxel = 55:28:16:1. the
composition in Example 11), and
- O -; a group intravenously administered with TaxolS of
Bristol-Myers Squibb company (10 ug paclitaxel).
Figure 4 is a graph showing the total concentration of paclitaxel and its metabolites in blood after oral administration of the liquid formulation • containing emulsifier in Example 4 of the present invention with or without 1 mg of verapamil. The quantitative analysis of total concentration of paclitaxel and its metabolites was performed by ELISA.
- • -; a group orally administered with liquid formulation containing emulsifier for solubilization of paclitaxel of the preseni invention (1 mg paclitaxel, weight ratio of the composition is monoolein : tricaprylin : Pluronic F-68 : paclitaxel = 55:28:16:1, the composition in Example 4), and - O -; a group orally administered with veracamil and liquid formulation containing emulsifier for solubilization of paclitaxel of the present invention (1 mg paclitaxel, weight ratio of the composition is monoolein : tricaprylin : Pluronic F68 : paclitaxel = 55:28:16:1, the composition in Example 4 + 1 mg verapamil).
Figure 5 is a graph showing the concentration of paclitaxel in blood after oral administration of the oily composition containing emulsifier (weight ratio of the composition is monoolein : tricaprylin : Tween SO : paclitaxel = 55:28:16:1). The quantitative analysis of total concentration of paclitaxel was performed by HPLC. Taxol® of Bristol-Myers Squibb Company was administered intravenously as a control group.
- • -; a group orally administered with liquid formuia:ion containing
emulsifier for solubilization of paclitaxel of the present invention (1
mg paclitaxel), and
- O -; a group intravenously administered with Taxol® of
Bristol-Myers Squibb company (40 µg paciitaxel).
Figure 6 is a graph showing the total concentration of paciitaxel and its metabolites in blood after intraperitoneal or intramuscular administration of the liquid formulation containing emulsifier in the composition of Example 3. The quantitative analysis of total concentration of paciitaxel and its metabolites was performed by ELISA.
- • -; a group intraperitoneally administered with liquid formulation containing emulsifier for solubilization of paciitaxel of the present invention (1 mg paciitaxel, weight ratio of the composition is monoolein : tricaprylin : Tween 80 : paciitaxel = 55:28:16:1, the composition in Example 3),
- O - ; a group intramuscularly administered with liquid formulation containing emulsifier for solubilization of paciitaxel of the present invention (1 mg paciitaxel, weight ratio of the composition is monoolein : tricaprylin : Tween 80 : paciitaxel = 55:28:16:1, the composition in Example 3),
[Best Mode for Carrying Out the Invention] This invention is explained in more detail based on the following
Examples but they should not be construed as limiting the scope of this
invention.
Buffer solutions used in the present invention are as follows:
Plate Well Coating Buffer: 50 mM Sodium Phosphate, C.15 M NaCI
and 0.02% sodium azide, pH 7.0 (PBS),
Plate Well Blocking Buffer: PBS containing 1% (w/v) Bcvine Serum
Albumin (BSA),
Sample Diluting Buffer: PBS containing 0.25% (w/v) BSA, 0.05% (v/v) Tween-20, 20% (v/v) Methanol and 0.02% sodium azide (PBSTM),
Antibody Diluting Buffer: PBS containing 0.25% (w/v) BSA, 0.05% (v/v) Tween-20 and 0.02% sodium azide (PBST),
Wash Buffer: 50 mM Tris HCI, pH 7.0, 0.15 M NaCI, containing 0.05% (v/v) Tween 20 and 0.02% sodium azide (TBST),
Enzyme Substrate Buffer: 25 mM Tris, pH 9.5. 0.15 M NaCI containing 5 mM MgCI2 and 0.02% (w/v) sodium azide.
Example 1. Composition for solubilization of paclitaxel according to the change in the composition ratio (1)
(1) Manufacturing composition for solubilization of paclitaxel Viscous oily solution was prepared by mixing 1g monoolein and 0.5 g tricaprylin and warmed at 40 °C. Fifteen milligrams of paclitaxel was added into the oily solution and sonicated in a bath type sonicator for complete solubilization to obtain a liquid formulation.
(2) Property Analysis of thus prepared composition for solubilization of paclitaxel
The size of the emulsion particles were measured by ..sing Malvern Zetasizer (Malvern Instruments Limited, England) after diluting :ne emulsion by adding 3 mL of distilled water with 2 ul of thus obtained liquid formulation. An average particle size and polydispersity was obtained by measuring a given formulation three times (Orr, Encyclopedia of emulsion technology, 1, 369-404, 1985). The polydispersity was obtained as the variance indicated by the logarithmic scale in the logarithmic normal distribution function. This
method was used in measuring the particle size and the polydispersity throughout the following Examples.
The above composition exists as semi-solid or sold at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either. Unstable dispersion with the average partcle size of 1230 nm was obtained when the above composition was vortexed for 10 s in water. Paclitaxel precipitation was not observed under polarized light microscope 24 hour after preoanng the dispersion.
Example 2. Composition for solubilization of paclitaxel according to the change in the composition ratio (2)
Viscous oily solution was prepared by mixing 1g monoolein and 0.5 g tricaprylin and warmed at 40 °C. Thirty milligrams of paclitaxel was added into the oily solution and sonicated in a bath type sonicator for complete solubilization. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either. Unstable dispersion with the average particle size of 2080 nm was obtained when the above composition was vortexed for 10 s in water. Paclitaxel precipitation was not observed under polarized light microscope 24 hour after prepanng the dispersion.
The results of the Examples 1 and 2 are summarized in the following Table 1.

Table 1

(Table Removed)
Example 3. Composition for solubilization of paclitaxel including emulsifiers according to the change in the composition ratio
(1)
Viscous oily solution was prepared by mixing completely 1g
monoolein, 0.5 g tricaprylin and 0.3 g of Tween 80, and warmed at 40 °C. Eighteen milligrams of paclitaxel was added into the oily solution and sonicated in a bath type sonicator for complete solubilization. Dispersion with the average particle size of 600 nm was obtained when the above composition was vortexed for 10s in water. Paclitaxel precipitation was not observed under polarized light microscope 24 hour after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
Example 4. Composition for solubilization of paclitaxel including emulsifiers according to the change in the composition ratio
(2)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 1 g tricaprylin, 0.4 g of Tween 80 and 10 mg of paclitaxel were used, and their particle size
and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 530 nm was obtained. Paditaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
The results of the Examples 3 and 4 are summarized in the following Table 2.
Table 2
(Table Removed)
Comparative Example 1. Composition including emulsifier for solubilization of paditaxel without oil (1)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1 g monoolein, 0.2 g of Tween 80 and 12 mg of paditaxel were used, and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 700 nm was obtained. Paditaxel precipitation was observed under polarized light microscope, and the dispersion became unstable 1 hour after preparation.
Comparative Example 2. Composition including emulsifier for solubilization of paditaxel without oil (2)
The compositior and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 0.24 g of Pluronic-F-68 and 12.4 mg of paclitaxel were used, and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 640 nm was obtained. Paclitaxel precipitation was observed under polarized light microscope, and the dispersion became unstable 1 hour after preparation.
Comparative Example 3. Composition including emulsifier for solubilization of paclitaxel without monoolein (1)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g tricaprylin, 0.2 g of Tween 80 and 12 mg of paclitaxel were used, and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 560 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either.
Example 5. Composition for solubilization of paclitaxel including emulsifiers according to the change in the oil (1)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 0.5 g tributyrin, 0.3 g of Tween 80 and 18 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 950 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase
separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 &C.
Example 6. Composition for solubilization of paclitaxel including emulsifiers according to the change in the oil (2)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monooleh, 0.5 g lipiodol (Lipiodol Ultra-fluid, Laboratoire Guerbet, France, Iodine content: 38 % by weight), 0.3 g of Tween 80 and 18 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 680 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
Example 7. Composition for solubilization of paclitaxel including emulsifiers according to the change in the oil (3)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 0.5 g squalane (Sigma Chemical Company), 0.3 g of Tween 80 and 18 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 598 nm was obtained. Paclitaxel precipitation was not observed under polarized
light microscope, and phase separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
Example 8. Composition for solubilization of paclitaxel including emulsifiers according to the change in the oil (4)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 0.5 g safflower seed oil (Sigma Chemical Company), 0.3 g of Tween 80 and 18 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 1040 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as iiquid at or above 40 CC.
The results of the Examples 5-8 are summarized in the following Table 3.
Table 3'
(Table Removed)
Example 9. Composition for solubilization of paclitaxel including emulsifiers according to the change in the paclitaxel content
(1)
The composition and dispersed liquid were prepared the same as
those of the Example 1 with the exception that 1g monoolein, 0.5 g tricaprylin, 0.3 g of Tween 80 and 38 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 1450 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
Example 10. Composition for solubilization of paclitaxel including emulsifiers according to the change in the paclitaxel content
(2)
The composition and dispersed liquid were prepared the same as those of the Example 1 with the exception that 1g monoolein, 0.5 g tricaprylin, 0.3 g of Tween 80 and 54 mg of paclitaxel were used and their particle size and polydispersity were measured by the same methods in the Example 1. Dispersion with the average particle size of 1630 nm was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed , 24 hours after preparing the dispersion. Unlike other compositions in Examples 1-7, the above composition exists as liquid or solid at room temperature and in the

refrigerator, respectively.
The results of the Examples S and 10 are summarized in the following Table 4.
Table 4 (Table Removed)
Example 11. Composition for solubilization of paclitaxel including emulsifiers according to the change in the emulsifier
The composition and dispersed liquid were prepared the same as those of the Example 3 with the exception that Pluronic F68 (BASF Company) was used instead of Tween 80. Dispersion with the average particle size of 420 nm (polydispersity 0.284) was obtained. Paclitaxel precipitation was not observed under polarized light microscope, and phase separation was not observed either, 24 hours after preparing the dispersion. The above composition exists as semi-solid or solid at room temperature and in the refrigerator, respectively, but as liquid at or above 40 °C.
Example 12. In vivo oral administration of composition for solubilization of paclitaxel (1)
Animal experiments were performed by using the composition for the solubilization of paclitaxel prepared in the above Example 1.
© Oral administration of composition for the solubilization of paclitaxel
One hundred microliters of the mucoadhesive formulation containing 1 mg paclitaxel was administered into Balb/C mouse (6-7 weeks old, female) fasted for 4 hours previously by using a gastric sonde. As a control group, 167 µl of Taxol® of Bristol-Myers Squibb Company dispersed in 0.5 ml of water (corresponding to 1 mg of paclitaxel) was administered orally. One hundred microliters of tricaprylin/Tween 80 composition without monoolein (containing 1 mg paclitaxel) prepared in Comparative Example 3 was used as another control group and administered orally. One, 2, 3 and 4 h after the oral administration of the compositions, the concentration of paclitaxel in the blood collected from the eye was determined.
As a control for oral administration, Taxol® of Bristol-Myers Squibb Company was administered intravenously into Balb/C mouse (6 ~ 7 weeks old, female), and the concentration of paclitaxel in blood was determined for 4 hours after intravenous injection. After dispersing 0.1 ml of Taxol® in 5.9 ml water, 0.1 ml of the dispersion (corresponding to 10 ug of paclitaxel) was administered by bolus injection into the tail vein of Balb/C mouse fasted for 4 hours. Blood was collected 0.5, 1, 2 and 4 h after the administration of the compositions, and the concentration of paclitaxel in the blood collected from the eye was determined.
(2) Determination of total concentration of oaclitaxei and its metabolites in blood (ELISA method)
The total concentration of paclitaxel and its metabcites in blood was determined by using Anti-taxane monoclonal kit (Model number 8A10) from Hawaii Biotech Company. Paclitaxel is known to be converted to 6-ot-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel by CYP2C8 and CYP3A4,
respectively. Various metabolites including the primary metabolites of paclitaxel exist in the blood. Anti-taxane monoclonal kit enables us to determine the concentration of paclitaxel and all of the metabolites containing taxane ring (Grothaus, G.P., Bignami, G.S., O'Malley, S., Harada, K.E., Byrnes, J.B., Waller, D.F., Raybould, T.J.G., Mcguire, M.T. and Alvaro, B., Taxane-specific monoclonal antibodies: measurement of Taxol, baccatin III, and 'total taxanes' in Taxus brevifolia extracts by enzyme immunoassay. J. Nat. Prod. 58, pp. 1003-1014, 1995).
The blood sample was serially diluted 4 times. Taxol-protein coating antigen (blue label) was diluted 100 times by phosphate buffered saline (PBS). After 100 yd of the diluted antigen solution was put into each well of the 96-well plate, the plate was incubated for 1 hour. After the plate was washed 4 times with TBST, it was blocked by adding PBS containing 1 % bovine serum albumin for 1 hour. After each well was washed continuously four times with TBST, 50 p.! of the serially diluted samples were put into each well. After diluting HBC Taxol Standard (RED label) serially with PBST, 50 [i\ of the diluted standard solution was put into each well. Fifty microliters of the antibody solution prepared by mixing 4.5 ml PBST and 50 u.l of anti-taxane rabbit antibody (green label) was added in each well. After the wells were washed four times with TBST, 100 |il of secondary antibody solution diluted 1000 times with PBST was added and incubated for one hour. After washing the wells four times with TBST, 200 ui of pNPP solution at 1 mg/ml was added in each well. After incubating the plate for 1 hour at room temperature, the absorbance was measured at 4"4 nm by ELISA reader and compared with that at 690 nm for quantitative analysis.
© Results of oral administration of composition for the solubilization of paditaxel
The changes in the paditaxel concentration in blood with time are shown in Figure 1. When the bioavailability of paditaxel upon bolus injection was set to 100 %, the relative bioavailability upon oral administration of composition for the solubilization of paditaxel was calculated by the following formula.
(Formula Removed)
Wherein, AUCoral and AUCiv represent area under the curve after oral and intravenous administration, respectively, and DOSEiv and DOSEoral represent the paditaxel dose for the oral and intravenous administration, respectively. The bioavailability upon oral administration of composition for the solubilization of paditaxel when compared to the bolus injection was 19.5 %.
Example 13. In vivo oral administration of composition for solubilization of paditaxel (2)
Fifty microliters of the composition for solubilizing paditaxel including emulsifier prepared in Example 2 containing 1 re paditaxel was administered into Balb/C mouse as in Example 12. As a control for oral administration, Taxol® of Bristol-Myers Squibb Company was administered intravenously (corresponding to 10 ^g of paclitaxel/riouse). The total concentrations of paditaxel and its metabolites in blood with time are
determined by ELISA. Figure 1 shows the result in comparison to that of Example 12. The bioavailability upon oral administration of composition for the solubilization of paclitaxel when compared to the bolus injection was 9.5 ± 5 %.
Example 14. In vivo oral administration of composition for solubilization of paclitaxel including emulsifier - Effect of paclitaxel content
The compositions for solubilizing paclitaxel including emulsifier prepared in Examples 3, 9 and 10 containing 1 mg paclitaxel were administered into Balb/C mouse by using identical method as in Example 12. As control groups, Taxol® of Bristol-Myers Squibb Company was administered orally (corresponding to 1 mg of paclitaxel) as well as intravenously (corresponding to 10 u.g/mouse) as in Example 11. The total concentrations of paclitaxel and its metabolites in blood with time are determined by ELISA as shown in Figure 2. The bioavailability calculated by setting that of Taxol® upon bolus injection in Example 12 to 100 % is listed in Table 5. The bioavailability upon oral administration of composition for the solubilization of paclitaxel including emulsifier when compared to the bolus injection was approximately 10 ~ 30 %. On the other hand, the bioavailability of orally administered Taxol® was 1.7 ± 3 %.
Table 5
(Table Removed)
Example 15. In vivo oral administration of composition for solubilization of paclitaxel including emulsifier - Effect of emulsifier
The compositions for solubilizing paclitaxel including emulsifier prepared in Example 11 containing 1 mg paclitaxel were administered into Balb/C mouse by using identical method as in Example 12. As a control group, Taxol® of Bristol-Myers Squibb Company was administered intravenously (corresponding to 10 |j.g/mouse). The total concentrations of paclitaxel and its metabolites in blood with time are determined by ELISA as shown in Figure 3. The bioavailability upon oral administration of composition for the solubilization of paclitaxel including emulsifier when compared to the bolus injection was approximately 13.4 ± 4 %.
Example 16. In vivo oral administration of composition for solubilization of paclitaxel including emulsifier - Coadministration of verapamil
The composition for solubilizing paclitaxel including emulsifier prepared in Example 4 containing 1 mg paclitaxel were administered into Balb/C mouse by using identical method as in Example 12. Another group of mice were administered with the composition for solubilizing paclitaxel including emulsifier prepared in Example 4 containing 1 mg paclitaxel and 1
mg of verapamil The total concentrations of paciitaxel and its metabolites n blood with time are determined by ELISA as shown in Figure 4 The bioavailability upon oral administration of composition for the solubilization of paciitaxel including emulsifier when compared to the bolus injection of Taxol© in Eyample 12 was approximately 2 7 %. When verapamil was co-administered, however, the oral bioavailability increased to 17.6 %
Example 17. In vivo oral administration of composition for solubilization of paciitaxel including emulsifier - Determination of paciitaxel concentration by HPLC
The composition for solubilizing paciitaxel including emulsifier prepared in Example 3 containing 1 mg paciitaxel were administered into Balb/C mouse by using identical method as in Example 12. Paciitaxel concentration was determined by HPLC When the above ELISA method was used, total concentration of paciitaxel as well as its metabolites is determined. HPLC analysis, however, detects intact paciitaxel molecule only in the sample.
® Determination of paciitaxel concentration in blood (HPLC method) Plasma was obtained by'centrifuging collected blood for 10 min at 3000 rpm and stored at -20 °C until being analyzed. Into 200 ^| of plasma, 10 |il of butyl-p-hydroxybenzoic acid solution dissolved in ecetonitrii at 100 ug/ml was added as an internal standard The sample was extracted by adding 1 ml tert-butylmethylether and vortexed for 3C seconds. To separate the organic layer, the above solution was centrifuged for 5 min at 3000 rpm, and 0.8 ml of the organic layer was taken out and dried under the
stream of nitrogen atmosphere. The residue was dissolved in 80 \x\ of 60 % acetonitril. Thirty microliters of the above sample was injected into HPLC to analyze the concentration of paclitaxel. HPLC system consists of Shisheido Nanospace Semimicro Column HPLC, SI-1/2001 pump, SI-1/2002 UV-VIS detector, SI-1/2004 column oven, Sl-1/2003 autosampler, SI-1/2009 degassing unit, SI-1/2011, 2012 rotary high pressure 6-way valve and Shisheido-MicroChrom software. CAPCELPAK MF Ph-2 cartridge (4.6 x 20 mm) was used as pre-treatment column, and separation of compounds was achieved using a CAPCELL PAK C18 UG120 (2.0 x 250 mm) concentrating column. Mobile phase was 50 % phosphate buffer solution (0.1 %, pH = 6.86) (pump A) and 50 % acetonitril (pump B), and column temperature was maintained at 30 °C. Paclitaxel concentration in blood was analyzed by column switching method. In case of pre-treatment column and analytical column, the flow rates of the mobile phase, 0.1 % phosphate buffer/acetonitril solution (84 : 16 by weight) were 0.5 ml/min and 0.1 ml/min, respectively.
The switching valve was set to A position to dispose of the eluent of the pre-treatment column, and the eluent of the analytical column was allowed to go through the UV detector. Since the internal standard and pactitaxel were detected at 4.1 ~ 7.2 min and 6.4 ~ 9.3 min, respectively, after going through the pre-treatment column, switching valve was set to B position at 4.0 min to allow the eluent of the pre-treatment column to go through the concentrating column. At 10 min, the switching valve was set to A position again, to change the flow from the concentrating column to analytical column. The chromatograms were collected at 227 nm and analyzed by using Syscon software (Shisheido).
(2) Oral administration of composition for the solubilization of paclitaxel including emulsrfier
The composition for solubilizing paclitaxel including emulsifier prepared in Example 3 containing 1 mg paclitaxel were administered into Balb/C mouse by using identical method as in Example 12. As a control for oral administration, Taxol© of Bristol-Myers Squibb Company was administered intravenously into Balb/C mouse (6-7 weeks old. female), and the concentration of paclitaxel in blood was determined for 4 hours. After dispersing 0.4 ml of Taxol® in 5.6 ml water, 0.1 ml of the dispersion (corresponding to 40 ^g of paclitaxel) was administered by bolus injection into the tail vein of Balb/C mouse fasted for 4 hours. Blood was collected from the eye up to 4 h after the administration of the compositions, the concentration of paclitaxel in the collected blood was determined Paclitaxel concentration was determined by HPLC as shown in Figure 5. The bioavailability upon oral administration of composition for the solubilization cf paclitaxel including emulsifier when compared to the bolus injection was approximately 30.3 %.
Example 18. In vivo intraperitoneal administration of composition for solubilization of paclitaxel including emulsifier
Fifty microliters of the composition for solubilizing pacl'taxel including emulsifier prepared in Examp'e 3 containing 1 mg paclitaxel was administered into Balb/C mouse via intraperitoneal administration. The tota concentrations of paclitaxel and its metabolites in blood with time are
determined by ELISA as shown in Figure 6.
Example 19. In vivo intramuscular administration of composition for solubilization of paciitaxel including emulsifier
Fifty microliters of the composition for solubilizing paciitaxel including emulsifier prepared in Example 3 containing 1 mg paciitaxel were administered into Balb/C mouse via intramuscular administration. The total concentrations of paciitaxel and its metabolites in blood with time are determined by ELISA as shown in Figure 6.
[Industrial Applicability]
As -described above, the composition for solubilizing paciitaxel according to the present invention can solubilize paciitaxel stably and also does not form precipitates of paciitaxel when dispersed in water. Also in aqueous environment, the composition forms unstable dispersion of particles of 30 nm - 5 µm. Paciitaxel concentratiop in blood can be maintained for more than 4 hours when the composition for solubilizing paciitaxel according to the present invention is delivered via oral, intraperitoneal and intramuscular administration.






V/e claim :
1. A composition for solubilization of paclitaxel including emulsifier comprising 40-65% by weight of monoolein, 20-45 % by weight of oil selected from a group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, Lipiodol, iodized poppy seed oil, Ethiodol, iodized soybean oil, soybean oil, cottonseed oil, olive oil, poppyseed oil, linseed oil, sesame oil, squalane and squalene, 10-20% by weight of emulsifier selected from a group consisting of a phospholipid, a non-ionic surfactant, an anionic surfactant, a cationic surfactant and bile acid and 0.3 - 5% by weight of paclitaxel.
2. The composition for solubilization of paclitaxel including emulsifier as claimed in claim 1 wherein said phospholipids is selected from the group consisting of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylserine.
3. The composition for solubilization of paclitaxel including emulsifier as claimed in claim 1, wherein said non-ionic surfactant is selected from the group consisting of a poloxamer a sorbitan ester a polyoxyethylene sorbitan and a popyoxyethylene ether.
4. The composition for solubilization of paclitaxel including emulsifier as claimed in claim 1 wherein said anionic surfactant is selected from the group consisting of a phosphatidylserine a phospahtidie acid and sodium dodecyl sulfate.
5. The composition for solubilization of paclitaxel including emulsifier as claimed in claim 1 wherein said cationic surfactant is selected from the group consisting of a 1,2-dioleyl-3-trimethylammonium propane, dimethyldioctadecylammonium bromide, N-[1-(1,2- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride 1,2-dioleyl-3-ethylphosphocholic acid 3p-N-[(N, N'- dimethylamino) ethanlcarbamoyl] cholesterol.
6. The composition for solubilization of paclitaxel including emulsifier as claimed in claim 1 wherein said bile acid is selected from the group consisting of cholic acid and its salts: deoxycholic acid and its salts; chenocholic acid and its salts; and lithocholic acid and its salts.
7. A method of preparing the composition for solubilization of paclitaxel including emulsifier as claimed in any one of claims 1 to 6 wherein said method comprises the steps of: 1) preparing the viscous liquid by mixing 40-64.7 % by weight of monoolein, 25-49.7 % by weight of oil selected from a
group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, Lipiodol, iodized poppy seed oil, Ethodol iodized soybean oil soybean oil, cottonseed oil, olive oil, poppyseed oil, linseed oil, sesame oil, squalane and squalene, 10-20% by weight of emulsifier selected from a group consisting of a phospholipids, a non-ionic surfactant, an anionic surfactant, a cationic surfactant and bile acid by heating up to 50° C and 2) preparing homogeneous mixture by solubilizing completely 0.3-4 % by weight of paclitaxel in said mixture of step 1) by stirring or sonification.
8. A composition for solubilization of paclitaxel substantially as herein described with reference to the foregoing description examples and the accompanying drawings.
9. A method of preparing the composition for solubiliztion of paclitaxel substantially as herein with reference to the foregoing description examples and the accompanying drawings.


Documents:


Patent Number 240871
Indian Patent Application Number 640/DELNP/2005
PG Journal Number 24/2010
Publication Date 11-Jun-2010
Grant Date 07-Jun-2010
Date of Filing 18-Feb-2005
Name of Patentee DAEHWA PHARM. CO., LTD.
Applicant Address 308, MASAN-RI, HOENGSEONG-CUP, HOENGSEONG-GUM, GANGWON-DO, SOUTH KOREA
Inventors:
# Inventor's Name Inventor's Address
1 CHUNG, HESON SSANGYONG APT., 3-507, GWANGYO-DONG, NAM-GU, INCHEON 402-715, REPUBLIC OF KOREA
2 KWON, ICK-CHAN SIYOUNG APT. 706-704, HAGYE-DONG, NOWON-GU, SEOUL 139-230, REPUBLIC OF KOREA
3 PARK, YEONG-TAEK TAEYOUNG APT., 203-602, BONO 3-DONG, ANSAN, GYEONGGI-DO, 425-735 REPUBLIC OF KOREA
4 CHOI, YOUNG-WOOK JUGONG, APT. 76-501, BANPOBON-DONG, SEOCHO-GU, SEOUL 137-813, REPUBLIC OF KOREA
5 YUK, SOON-HONG HANBIT APT., 133-1105, OEUN-DONG, YUSEONG-GU, DAEJEON 305-755, REPUBLIC OF KOREA
6 PARK, JAE-HYUNG 551-6, BANPO-DONG, SEOCHO-GU, SEOUL 137-040, REPUBLIC OF KOREA
7 CHUNG, JIN-WOOK SAMPUNG APT., 19-1101,SEOCHO 4-DONG, SEOCHO-GU, SEOUL 137-779, REPUBLIC OF KOREA
8 JEONG, SEO-YOUNG MUNCHOLMAEUL LIFE APT.205-501 JUYEOP 2-DONG ILSAN-GU, GOYANGGI-DO 411-747 REPUBLIC OF KOREA,
9 LEE, IN- HYUN 600-99 SINDAEBANG 1,-DONG, DONGJAK-KU, SEOUL 156-011 REPUBLIC OF KOREA
PCT International Classification Number A61K 31/337
PCT International Application Number PCT/KR2003/001427
PCT International Filing date 2003-07-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10-2002-0042791 2002-07-20 Republic of Korea