Title of Invention

PHARMACEUTICAL FORMULATION FOR INCREASING SOLUBILITY OF 1-HYDROXYCAMPTOTHECIN COMPOUNDS IN NON-AQUEOUS POLAR SOLVENTS

Abstract The present invention relates to a pharmaceutical formulation for increasing the solubility of a 10-hydroxycamptothecin compound in non-aqueous polar solvent, comprising a 10-hydroxycamptothecin compound and an amine compound whose pKa value is 74 or more By using the formulation according to the present invention, the solubility of the 10-hydroxycamptothecin compound for non-aqueous polar solvent is increased, while maintaining the active lactone form of 10-hydroxycamptothecin.
Full Text

PHARMACEUTICAL FORMULATION FOR INCREASING SOLUBILITY OF 10-HYDROXYCAMPTOTHECIN COMPOUNDS IN NON-AQUEOUS POLAR
SOLVENTS
TECHNICAL FIELD
The present invention relates to a pharmaceutical formulation comprising of a 10-hydroxycamptothecin compound and an amine compound whose pKa value is 7.4 or more for increasing the solubility of the 10-hydroxycamptothecin compound in non-aqueous polar solvent.
BACKGROUND ART
Camptothecin; (S)-4-Ethyl-4-hydroxy-lH-pyrano[3'r4':6,7]indolizino[l,2-b]quinol ine-3,14(4H,12H)-dione) is prototype DNA topoisomerase 1 inhibitor, and is known as strong anti-cancer medicine. Camptothecin has such standard structure that hydroxyl and ethyl are substituted at a position of C20 in the central structure containing five connected rings A to E, as shown in the following formula 1:


Camptothecin compound has very low solubility in water as well as in organic solvents, such as ethanol, dichloromethane, acetone, acetonitrile, ethylacetate, etc. which are generally used for formulation. Also, camptothecin is activated in acidic conditions since the E ring thereof exists in the form of a lactone, whereas it is inactive in alkaline aqueous solution since the E ring exists in the inactive form of a carboxy anion. The solubility of the inactive form of the carboxy anion in water is 4 nig/m or more, but that
of the active form of lactone form is not more than 10 μg/ml.
Particularly, 10-hydroxycamptothecin (compound of formula la) having a phenolic hydroxyl group at 10 position of A ring is ionized in basic solution whose pH is 8 to 12, and thus the solubility of the camptothecin compound in polar solvent can be increased. However, if the above basic solution is an aqueous solution, a hydroxyl ion attacks the lactone ring of the camptothecin compound, thereby forming camptothecin compound of formula 2 in the form of carboxy anion, and being converted to the inactive form (see Reaction equation 1):

As shown above, camptothecin compound has highly potent anti-cancer activity, but its use for anti-cancer therapy is limited since the active form of camptothecin

compound has very low solubility in water. Thus, in order to use camptothecin compound as a medicine for treating diseases, it is needed to increase the solubility of the camptothecin compound in solvent with maintaining the lactone structure, i.e., active form. For example, 7-ethyl-l0-hydroxycamptothecin (compound of formula lb) is known as SN-38, and is an active metabolite of Irinotecan (CPT-11) which is an anti-cancer agent on the market.

SN-38 is known lo kill cells by combining with topoisomerase I , an enzyme participating in the process of cell division, and by inhibiting synthesis of DNA during cell division. However, the solubility of SN-38 in water is not more than 10 fig/mi, and as
such it is difficult to develop SN-38 as a clinic product. Thus, CPT-11 which increases the solubility of SN-38 in water by making it as a prodrug has been developed and commercialized. After administration into the human body, CPT-11 is metabolized by carboxyestcrasc in the liver or cancer cell, and converted into SN-38 having physiological activity to show anti-cancer effects. However, the conversion ratio of CPT-11 into SN-38 having such activity in the human body is only about 2 to 8%.
On the other hand, it has been found that the activity of SN-38 for inhibiting topoisomerase I is higher than that of CPT-11 by about 1,000 times, and the in vitro

cytotoxicity of SN-38 is higher than that of CPT-11 by 2,000 times. Also, it is known that the effect of SN-38 for inhibiting acetylcholine which causes diarrhea is much lower than that of CPT-11, and thus the possibility to cause diarrhea that is one of the main side effects of CPT-I1 is very low.
SN-38 exists in the active form of a lactone in acidic conditions, and exists in the inactive form of a carboxy anion in alkaline condition, depending on pH in aqueous solution. It is known that the solubility in water of SN-38 in the form of the carboxy anion is 4 or more nig/roE, but that of SN-38 in the active form of lactone is not more than
10 μg/ml. Thus, if camptothecin compounds can be solubilized at a more than clinically
significant concentration while maintaining the active form of a lactone, they can be developed as a very superior anti-cancer agent. Therefore, there have been extensive studies to solubilize camptothecin compounds. For example, U.S. Patent Nos. 5,447,936, 5,859,023, 5,674,874, 5,958,937, and 5,900,419 disclosed compositions to solubilize camptothecin compounds comprising SN-38 in polar organic solvents such as dimethylaceteamide, N-methyl-2-pyrrolidone, dimethylisosorbide, etc. However, the injection of such polar organic solvent into blood vessels is extremely limited due to some drawbacks thai the amount of solvent usable for the human body is limited and the drug is extracted at the time of mixing with water. Also, U.S. published patent No. 2003-215492 disclosed a liposome-formulated composition by complexing SN-38 with lipid. The method used therein is to form SN-38 in the form of a lactone under the pH of acidic conditions, after forming SN-38 in the form of a carboxy anion in an aqueous solution at
pF-f 8 ' 10 and formulating it into liposome. Also, Zhang, et al. [International Journal of

Pharmaceutics, 270 (2004), pp. 93-107] disclosed a LE-SN-38 liposome formulation containing SN-38, and Williams, et al. [Journal of Controlled Release, 91 (2003), pp. 167-172] disclosed a nanoparticle formulation containing SN-38.
However, the need remains to develop a method of soluhilizing 10-hydroxycamptothecin at a more than clinically significant concentration while maintaining the active form.
DISCLOSURE OF THE INVENTION
TECHNICAL SUBJECT
The present inventors have conducted continuous studies to develop a method for solubilizing a 10-hydroxycamptothecin compound at a more clinically significant concentration while maintaining the active form. As a result, they confirmed that if an amine compound having a pKa value of 7.4 or more is added to a 10-hydroxycamptothecin, the base's nucleophilic attack to the lactone group of the camptothecin compound does not happen, and thus the lactone group is conserved, maintaining the drug's activity, and also the hydroxyl group at the 10-position is ionized to a phenolic anion, and so the solubility in polar organic solvent can be increased. Therefore, the present inventors completed the present invention.
The object of the present invention is to provide a formulation for increasing the solubility of a 10-hydroxycamptothecin compound comprising the 10-hydroxycamptothecin compound and an amine compound whose pK.a value is 7.4 and

more, for non-aqueous polar solvent.
BEST MODE FOR CARRYING OUT THE INVENTION
First, the present invention relates to a formulation for increasing the solubility of a 10-hydroxycamptothecin compound in non-aqueous polar solvent comprising the 10-hydroxycamptothecin compound and an amine compound whose pK» value is 7.4 or more, for non-aqueous polar solvent.
In the present invention, a 10-hydroxycamptothecin compound means all camptothecin compounds having a phenolic hydroxy group at 10 position of A ring of the camptothecin as shown in the following formula la:

A 10-hydroxycamptothecin compound according to the present invention can be additionally substituted with lower alkyl, alkoxy, acyloxy, hydroxy, acyl, halo, amido, cyano group, etc. at 9 or 11 position of A ring, or 7 position of B ring. The 10-hydroxycamptothecin compound of the present invention comprises, but is not limited to, 10-hydroxycamptothecin and 7-ethyl-10-hydroxy camptothecin(SN-38). In the present invention, 10-hydroxycamptothecin is preferably SN-38.
According to the present invention, if a 10-hydroxycarnptothecin compound, for

example SN-38, is added to non-aqueous polar solvent together with an amine compound that has a particularly low nucleophilic and high basic property, that is, the pKa value of the compound is 7.4 or more, among basic compounds, the base's nucleophilic attack to the lactone group of the camptothecin compound does not happen, as shown in the following Reaction equation 1, and so the lactone group is conserved. Then, while the activity of a drug is maintained, the hydroxyl group at the 10-position is ionized to a phenolic anion, to increase the solubility in non-aqueous polar solvent (see Reaction equation 2).

An amine compound of the present invention can anionize the hydroxy group at the 10 position, and can be any of primary, secondary, or tertiary amine compound whose pKa value is 7.4 or more, preferably 9 or more. Preferably, the amine compound is selected from the group consisting of hydroxy alkylamines of C1 to C20, alkylamines of C\ to C2o, and mixture thereof. Such amine compounds include hydroxyalkylamines such as mono-, di-, or triethanolamine, mono-, di-, or trisopropanoiamine, tromethamine(tris(hydroxymethyl) aminoethane), etc.; tertiary alkylamines such as triethylamine, tripropylamine, tributylamine, etc.; secondary alkylamines such as diethylamine. dipropylamine, dibutylamine, etc.; or mixtures thereof, preferably,

hydroxyalkylamines such as diethanolamine, triethanolamiiie, tromethamine, etc.
Amine compounds can be used in an amount of more ihan 1 equivalent to 1 equivalent of camptothecin compound, preferably 1 to 100 equivalents, more preferably 1 to 50 equivalents, most preferably 5 to 20 equivalents.
The non-aqueous polar solvent of the present invention includes organic solvents approved for use in the human body, preferably ethanol, propyleneglycol, liquid polyethyleneglycol having a molecular weight of 200 to 1,000 daltons, glycerine, N,N-dimethy!acetamide, N-methylpyrrolidone, dimethylisosorbide, or mixtures thereof. The above non-aqueous polar solvent is used in an amount enough to make the concentration of 10-hydroxycamptothecin, preferably 0.1 to 5 mg/m£, and more preferably
0.5 to 2 mg/mP..
The formulation composition of the present invention may contain surfactant in order to prevent the precipitation of drug when the composition is diluted or reconstituted with aqueous solution such as water for injection, physiological saline, or 5% dextrose solution, and to delay the conversion of the lactone group to the carboxy anion by postponing the exposure of the lactone group of camptothecin compound to aqueous solution.
As a surfactant of the present invention, any surfactant can be used regardless of property and appearance thereof, when the present formulation composition is solubilized in organic solvent. The examples of" such surfactant include block copolymer surfactants such as polyoxyethylenesorbitan fatty acid ester like twecn 20, tween 40, tween 80, etc.; polyoxyethylene castor oil derivatives such as cremophore EL, cremophore RH40,

gremophare RH604 etc.; polyoxyelhylene alkyl ethers suck as polyoxyl 20 cetosteryl ether, polyoxyl 20 cetyl ether, polyoxy] 20 oleyl ether, polyoxyl 2 celyl ether, polyoxyl 2 oleyl ether, polyoxyl 2 stearyl ether, polyoxyl 4 lauryl ether, polyoxy] 100 stearyl ether, etc.; d-a-tocopheryl polyethyleneglycol 1000 succinate (vitamiue E TPGS), solutol HS 15 (polyethyleneglycol 660 12-hydroxystearate); poloxamcrs such as poloxamer 124, poloxamer 188, poloxamer 407, etc., preferably polyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oil derivative, d-a-tocopheryl polyethyleneglycol 1000 succinate, solutol HS 15, etc.
On the other hand, when the present formulation composition is prepared in
lyophilized form, the present invention may use polymer surfactants which are solid at
room temperature, block copolymers of poloxamer such as poloxamer 124, poloxamer 188,
poloxamer 407, etc., or amphiphilic block copolymers prepared by connecting hydrophilic
polymer block (A) and hydrophobic polymer block (B) in form of A-B, A-B-A, B-A-B, etc.
In amphihilic block copolymers, hydrophilic polymer block (A) is an aqueous soluble
polymer, for example, poiyalkyleneglycol or derivatives thereof, polyvinylalcohol,
polyvinylpyrrolidone or polyacrylamide, etc., preferably, one of polyethyleneglycol,
polyvinylpyrrolidone, and polyethylene-co-propylcncglycol. Hydrophobic polymer
block (B) is an insoluble, superiorly biocompatible, and bio-degradable polymer, and its
examples include polyester, polyanhydride, polyamino acid, polyorthoester or
polyphosphazene, etc.; preferably polylactidc, polyglycolide, polycaprolactone,
polydioxane-2-one, potylaclic-co-glycolide, polylactic-co-dioxane-2-one,
polylactic-co-caprolactone, polyglycolic-co-caprolactone, etc. As the above polymer, it is

preferable to use a compound having the average number molecular weight of 200 to 60,000.
Surfactants may be used in 1,000 or less weight ratio to a 10-hydroxycamptothecin, preferably 1 to 500 weight ratio, and more preferably 10 to 250 weight ratio.
When the present formulation composition is prepared as a lyophilized formulation, a caking agent for lyophilization, such as mannitol, sorbitol or lactose, can be added thereto.
The present formulation composition may further contain pharmaceutically acceptable excipient, and hydrophobic oil such as tocopherol, benzylbenzoate, sesame seed oil, castor oil, soybean oil, cotton seed oil, triglyceride, etc. can be added thereto in order to delay exposure of the present composition to an aqueous solution when the composition is diluted with water for injection.
One embodiment of the method for preparing the present formulation composition as a solution or lyophilized formulation is as follows.
1 to 10 mg of a 10-hydroxycamptothecin and an amine compound are added to
non-aqueous solvent by 1 to 100 equivalents to a camptothecin compound, and solubilized, and then surfactant is added thereto to prepare a solution. This solution is filtered with a filter having a pore size of 200 iini to remove insoluble substance, and then is sealed. As
a specific example, 1 mg of SN-38 and 10 rag of tromethamine may be added to 1 inf. of
anhydrous ethanol to prepare a pure solution of orange color. Then, 500 nig of

cremophore EL is added thereto to prepare a pure solution. This solution is diluted with acetonitrile, and then analyzed by HPLC to confirm that 100% of SN-38 exists in the form of a lactone, and the solubility of SN-38 is 98 weight% or more. Also, the prepared solution is kept in a refrigerator for 1 week, and then diluted with 0.9% of physiological saline to prepare 5 ml of solution. Thereafter, SN-38 is determined by HPLC to confirm
that the concentration of SN-38 was 220 £g/nv, 95% or more of SN-38 existed in the form
of the lactone, and the pH of the solution diluted with saline was 8.7.
Alternatively, a 10-hydroxycamptothecin compound and an amine compound are solubilized in non-aqueous polar solvent, and polymer surfactant is added thereto to prepare a solution. Next, a caking agent for lyophilization is added thereto to prepare a lyophilized formulation. As a specific example, 250 mg of copolymer (mPEG-PLA) of
polyethyleneglycol (molecular weight: 2,000 daltons) and polylactic acid (molecular weight: 1,800 daltons) may be added to a solution in which SN-38 and tromethamine are solubilized in anhydrous ethanol as above, to prepare a pure solution, and then 4 \nt of
aqueous mannitol solution (100 mg/rofc) as a caking agent for lyophilization is added
thereto, which is filtered with a filter having a pore size of 200 nm, and lyophilized. This
lyophilized formulation is reconstituted with 4 ml of water for injection, and then analyzed
by HPLC to confirm that the concentration of SN-38 was 205 ug/ml, 92% or more of
SN-38 existed in the form of a lactone, and the pH of the aqueous solution was 8.4.
In the present formulation composition, camptothecin compounds can maintain the active lactone form and the solubility of the compounds in non-aqueous polar solvent is

increased. As a specific example, the solubility of SN-38 determined after suspending SN-38 in anhydrous ethanol without adding an amine compound was within the range of a few μg/mL However, when determined after adding 10 equivalents of triethanolamine to
anhydrous ethanol, the solubility of SN-38 was about 1 mg/ml, which is increased by about
500 or more times. Also, from HPLC analysis, SN-38 was in the form of a lactone, and no carboxy anion form was observed.
The pharmaceutical formulation according to the present invention can be used as an anti-cancer agent, and can comprise 1 to 40 nig of camptothecin compound in 1 ml of solution. Solution or lyophilized formulations having such concentration may be orally administered or injected to treat cancer patients. At the time of orally administering the present formulation as a capsule or a tablet, it is preferable to use a concentrated solution, and so the formulation may be used in an undiluted original solution or lyophilized form. In the case of injection, it is preferable that the concentration of the camptothecin compound in a diluted solution is about 0.001 to about 1.0 ing/n£, more preferably 0.1 to
0.5 mg/inf, by diluting or reconstituting the present formulatiom composition with aqueous
solution such as water for injection, physiological saline, or 5% dextrose solution, etc., and
the pH is 3 to 12.
Below, the present invention is specifically described by examples, but the scope of the present invention is not limited by them in any manner.

Example 1: Improvement of the solubility of SN-38 in polar organic solvent in the presence of an amine compound
1 rag of SN-38 (manufacturer: Abatra Co., China) was put into each of six
containers, and suspended in 1 ml of anhydrous ethanol. Diethanolamine was added to
each of the containers by 0, 1, 5, 10, 20 and 100 equivalents to 1 equivalent of SN-38, and heated to 60 "C, and then kept at room temperature for 12 hours. After 12 hours, this solution was filtered with a filter having a pore size of 200 nm. The addition of 1 or more
equivalents of diethanolamine provided a solution that was orange in color. The filtrate was analyzed by HPLC to determine the solubility of SN-38, under the following condition:


sulfoxide (DMSO) solvent, from which the BUndttxf curve was obtained, and then SN-38 was quantified. The solubility results for SN-38 in the presence of diethanolamine are shown in Table 2.

As shown in Table 2, the solubility of SN-38 in ethanol was 0.008 mg/i Example 2: Solubility of SN-38 in ethanol according to the kind of amine compound
As described in Example 1,1 ing of SN-38 was suspended in 1 m£ of anhydrous ethanol. Several kinds of amine compounds as shown in the following Table 3 were

added to SN-38 by 10 equivalents, which was heated to 60 *C and then kept at room temperature for 12 hours. After 12 hours, the solution was filtered with a filter having a pore size of 200 run, and then the solubility of SN-3S was determined by HPLC. The results are shown in Table 3.

As shown in Table 3, when the amine compound was added to SN-38 by 10 equivalents, 1 iiig/inf. or more of SN-38 was dissolved, and 100 % of SN-38 existed in the form of a lactone, irrespective of the kind of amine added.
Example 3: Solubility of SN-38 in polar organic solvent
As described in Example 1,1 mg of SN-38 was suspended in 1ml of several kinds

of organic solvents as shown in Table 4. Tromethamine was added thereto by 10 equivalents to SN-38, heated to 60 "C, and then kept at room temperature for 12 hours. After 12 hours, the solution was filtered with a filter having a pore size of 200 nm, and then the solubility of SN-38 was determined by HPLC. The results are shown in Table 4.

As shown in Table 4, when tromethamine was added to SN-38 by 10 equivalents, 1 nig/mf. or more of SN-38 was dissolved in all the kinds of organic solvents, and 100 % of SN-38 existed in the form of lactone.
Example 4: Preparation of SN-38 formulation composition comprising surfactant

Several kinds of surfactants as shown in Table 5 were added to Component 7 of Example 2, by 200 times of weight of SN-38 to prepare a solution, and the component was shown in Table 5.
[Table 5]

Example 5: Solubility of SN-38 formulation composition in water according to the content of surfactant
Cremophore EL was added to Component 7 of Example 2, at 10 to 500 times by weight of SN-38, and then diluted with injectable water, to make the total volume of 5 ml. This solution was filtered with a filter having a pore size of 200 nm, and the content of SN-38, the ratio of lactone to carboxy anion, and the change in hydrogen ion content were determined with time, while keeping the solution at room temperature. The components of the above formulation composition are shown in Table 6, and the result determined therefrom are shown in Table 7.



with time. In addition, the time to change from the lactone form to the carboxy anion form was delayed as the content of surfactant was increased.
Example 6: Preparation of SN-38 soluble composition
According to the components shown in Table 8, SN-38 was suspended in organic solvent, and then an amine compound was added thereto to prepare a pure solution of orange color. Subsequently, surfactant was added thereto, and the solution was filtered with a filter of 200 run, and stored in a glass vial.


n\l of cremophore EL was added thereto to prepare a pure mixing solution. To this solution, 100 rag of SN-38 was added and heated to 60 XI to obtain a pure solution of orange color. The solution was kept at room temperature for 1 hour, and filtered with a filter having a pore size of 200 nmi, and filled in glass vial by 2 inf. of solution to prepare a
formulation containing 2 mg of SN-38 in the concentration of 1 mg/ml per vial.
Example 8; Preparation of lyophilized SN-38 soluble composition
12 mg oftromethamine was dissolved in 1 ml of anhydrous ethanol, and 3 rag of
SN-38 was added thereto and heated to 60 "C to prepare a pure solution of orange color. Subsequently, the block copolymer of methoxypolyethyleneglycol and polylactic acid, and 200 mg of mPEG-PLA (mPEG molecular weight: 2,000 daltons, PLA molecular weight:
1,800 daltons) were added thereto to prepare a pure solution. Then, 5 inf, of aqueous mannitol solution (50 nig/m$) was added thereto, mixed, filtered with a filter having a pore size of 200 nm, and lyophilized to prepare a lyophilized formulation.
Injectable water of 4 inf. was added to the lyophilized vial to reconstitute the lyophilized formulation. Here, the pH of the aqueous solution was 8.4, the drug content was 242 #g/inP. by HPLC analysis, and the lactone form of SN-38 was 97%.
INDUSTRIAL APPLICABILITY

The formulation of the present invention can be used to increase the solubility of a 10-hydroxycamptothecin in non-aqueous polar solvent, with most of 10-hydroxycamptothccin existing in the active lactone form. Also, by using the present formulation additionally containing surfactant, ihe conversion into the inactive form was delayed when diluted or reconstituted with aqueous solution such as water for injection or physiological saline.





WHAT IS CLAIMED IS
1. A formulation for increasing the solubility of a 10-hydroxycainptothecin compound in non-aqueous polar solvent, comprising the 10-hydroxycamptothecin compound and an amine compound whose pK* value is 7.4 or more.
2. The formulation according to claim 1, wherein the 10-hydroxycamptothecin compound is 10-hydroxycamptothecin or 7-ethyl-l O-hydroxycamptothecin (SN-38).
3. The formulation according to claim 1, wherein the amine compound is selected from the group consisting of hydroxy alkylamines of Ci to C2o* alkylamines of Ct to C2o.and mixtures thereof.
4. The formulation according to claim 3, wherein the amine compound is selected from the group consisting of mono-, di-, or triethanolamine, mono-, di-, or triisopropanolamine, tromethamine, triethylamine, tripropylamine, tributylamine, diethylamine, dipropylamine, dibutylamine, and mixtures thereof.
5. The formulation according to claim 1, comprising 1 to 100 equivalents of the amine compound to 1 equivalent of 1 O-hydroxycamptothecin.
6. The formulation according to claim 1, additionally comprising a non-aqueous polar solvent.
7. The formulation according to claim 6, wherein the non-aqueous polar solvent is selected from the group consisting of ethanol, propyleneglycol, liquid polyethyleneglycol having a molecular weight of 200 to 1.000 daltons, glycerine,

N,N-dimethylacetamide, N-methylpyrrolidone, dimethylisosorbide, and mixtures thereof.
8. The formulation according to claim 7, wherein the concentration of the 10-hydroxycamptothecin compound is 0.1 to 5 nig/rod.
9. The formulation according to claim 1. additionally comprising a surfactant.
10. The formulation according to claim 9, wherein the content of surfactant is 1 to 1,000 weight ratio to the 10-hydroxycarnptothecin.
11. The formulation according to claim 9, wherein the surfactant is selected from the group consisting of polyoxyethylenesorbitane fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, d-a-tocopheryl polyethyleneglycol succinate, polyethyleneglycol 12-hydroxystearate, poloxamer, amphiphilic block copolymer consisting of hydrophilic polymer block (A) the hydrophobic polymer block (B), and mixture thereof, and wherein, the hydrophilic polymer block (A) is polyalkyleneglycol or derivatives thereof, polyvinylalcohol, polyvinylpyrrolidone, or polyacrylamide, and the hydrophobic polymer block (B) is polyester, polyanhydride, polyamino acid, polyorthoester, or polyphosphazene.
12. The formulation of lyophilized form according to claim 11, comprising poloxamer or amphiphilic block copolymer consisting of hydrophilic polymer block (A) and hydrophobic polymer block (B) as a surfactant, and additionally comprising a caking 3gent for lyophilization.
13. The formulation according to claim 1, additionally comprising hydrophobic oil.

14. The formulation according to claim 13, wherein hydrophobic oil is
selected from the group consisting of tocopherol, benzylbenzoate, sesame seed oil, castor
oil, soybean oil, cotton seed oil, triglyceride, and mixtures thereof.
15. The formulation according to any one of claims 1 to 14, wherein the
formulation is used as an anti-cancer agent.
16. The formulation in the form of a tablet, capsule, or injection according to
any one of claims 1 to 14.
17. The formulation in the form of injection according to claim 16, wherein
the formulation is diluted or reconstituted with aqueous solution so that the concentration
of the 10-hydroxycamptothecin compound is in the range of 0.1 to 0.5 mg/mt, and the pH
is in the range of 3 to 12.
Dated this 7 day of May 2007





Documents:

1927-chenp-2007 amended pages of specification 24-03-2011.pdf

1927-chenp-2007 amended claims 24-03-2011.pdf

1927-chenp-2007 correspondence others 24-03-2011.pdf

1927-chenp-2007 power of attorney 24-03-2011.pdf

1927-chenp-2007 amended claims 15-04-2011.pdf

1927-chenp-2007 correspondence others 18-03-2011.pdf

1927-CHENP-2007 AMENDED CLAIMS 01-07-2010.pdf

1927-CHENP-2007 AMENDED PAGES OF SPECIFICATION 01-07-2010.pdf

1927-CHENP-2007 CORRESPONDENCE OTHERS 01-07-2010.pdf

1927-CHENP-2007 CORRESPONDENCE OTHERS 15-04-2011.pdf

1927-chenp-2007 form-3 01-07-2010.pdf

1927-CHENP-2007 OTHER PATENT DOCUMENT 01-07-2010.pdf

1927-CHENP-2007 POWER OF ATTORNEY 01-07-2010.pdf

1927-CHENP-2007 CORRESPONDENCE-OTHERS 10-11-2009.pdf

1927-CHENP-2007 PCT SEARCH REPORT 10-11-2009.pdf

1927-chenp-2007-abstract.pdf

1927-chenp-2007-claims.pdf

1927-chenp-2007-correspondnece-others.pdf

1927-chenp-2007-description(complete).pdf

1927-chenp-2007-form 1.pdf

1927-chenp-2007-form 26.pdf

1927-chenp-2007-form 3.pdf

1927-chenp-2007-form 5.pdf

1927-chenp-2007-pct.pdf


Patent Number 248398
Indian Patent Application Number 1927/CHENP/2007
PG Journal Number 28/2011
Publication Date 15-Jul-2011
Grant Date 12-Jul-2011
Date of Filing 07-May-2007
Name of Patentee SAMYANG CORPORATION
Applicant Address 263, YEONJI-DONG, JONGRO-GU, SEOUL 110-725 KOREA
Inventors:
# Inventor's Name Inventor's Address
1 SEO, MIN-HYO SOOJEONG TOWN APT. #2-1008, DOONSAN 2-DONG, SEO-GU, DAEJEON 302-775
2 KANG, HYE-WON 63-2, HWAAM-DONG, YUSEONG-GU, DAEJEON 305-348, KOREA
PCT International Classification Number A61K 31/475
PCT International Application Number PCT/KR05/03706
PCT International Filing date 2005-11-04
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10-2004-0089876 2004-11-05 Republic of Korea