CA2221444A1 - A method of making pharmaceutically active taxanes orally bioavailable - Google Patents
A method of making pharmaceutically active taxanes orally bioavailable Download PDFInfo
- Publication number
- CA2221444A1 CA2221444A1 CA002221444A CA2221444A CA2221444A1 CA 2221444 A1 CA2221444 A1 CA 2221444A1 CA 002221444 A CA002221444 A CA 002221444A CA 2221444 A CA2221444 A CA 2221444A CA 2221444 A1 CA2221444 A1 CA 2221444A1
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- CA
- Canada
- Prior art keywords
- taxane
- cinchonine
- paclitaxel
- orally bioavailable
- orally
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention concerns a method of making pharmacologically active taxane compounds orally bioavailable. More particularly, the invention provides enhancing the oral absorption of pharmacologically active taxane compounds by co-administering a taxane with cinchonine.
Description
A METHOO O~ MAKING PHARMACEUTICALLY ACTIVE
TAXANES ORALLY BIOAVAILABLE
5 Field of the Invention The present invention concerns a method of making pharmacologically active taxane compounds orally bioavailable. More particularly, the invention provides enhancing the oral absorption of 10 pharmacologically active taxane compounds by co-administering a taxane with cinchonine.
Background Art Taxol(~) (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated *s unique mode of action, which involves abnormal polym~ri7~tion of tubulin and disruption of mitosis. It has 20 recently been approved for the treatment of refractory advanced ovarian cancer and breast cancer; and studies involving other cancers have shown promising results. The results of paclitaxel clinical studies are reviewed by numerous authors, such as by Rowinsky and Donehower in "The Clinical Pharmacology and Use of 25 Antimicrotubule Agents in Cancer Chemotherapeutics," Pharmac.
Ther.~ 52:35-84, 1991; by Spencer and Faulds in "Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer," Drugs, 48 (5) 794-847, 1994; and by K.C. Nicolaou et al. in "Chemistry and Biology of Taxol," Angew.
30 Chem. Int. Ed. Engl. 33: 15-44, 1994, and also in the re~r~.lces cited therein.
A semi-synthetic analog of paclitaxel named Taxotere(~) (docetaxel) has also been found to have good antitumor activity. The structures of paclitaxel and docetaxel are shown below.
.~
SUBSl ITUTE S~tEET (RULE 26) WO 97/27855 PCT/US97/004~)5 . 2 - R'O~ ~ OH
- RCONH O \
Ph~ o~
HO - AcO
PhC(O)O
Taxol(g) (paclitaxel): R = Ph; R' = acetyl Taxotere(~ (docetaxel): R = t-butoxy; R' = hydrogen ~
Oral bioavailability of paclitaxel or docetaxel is extremely low;
thus, they are essentially orally inactive. (For example see Figure 2 which gives rat plasma concentration of paclitaxel given orally.) The drugs are administered intravenously. In a typical patient previously 10 treated with chemotherapy for ovarian cancer, the recomm~n~led regimen for paclitaxel is 135 mg/m2 or 17~ mg/m2 administered intravenously over three hours every three weeks. For a patient with carcinoma of the breast, the recomm~nded dose for paclitaxel is 175 mg/m2 administered intravenously over 3 hours every three weeks.
15- (Physicians' Desk Reference, 49th Edition, 1995) Such intravenous infusion of paclitaxel (or any ph~macologically active taxanes) makes the administration of the anticancer drug very inconvenient and expensive. Thus a method of m~king taxane more orally bioavailable would allow patient self-medication and thus increase convenience 20 and reduce overall medical costs.
There have been attempts to enhance the oral activity of taxanes by first converting taxanes into prodrugs with the intent to enhance the oral absorption and thereafter delivering the free taxanes 25 ~y~L~ ically. One such approach is described in European Patent Application No. 639577 published February 22, 1995. Without resorting to the prodrug method, we have now surprisingly discovered that orally administered paclitaxel co-administered with cinchonine signific~ntly increases the oral bioavailability of paclitaxel. The 30 merh~nism of this action is not entirely understood.
..
WO 97127855 PCT/US97/0(~405 SUMMARY O~ THE INVENTION
The present invention concerns a method of making p~rm~-~ologically active taxane compounds orally bioavailable. More particularly, the invention provides ms~king ph~rmAcologically active taxane compounds orally bioavailable by co-a~mini~tering a taxane with cinchonine. Another aspect of invention concerns a pharmacelltic~l formulation comprising a taxane and cinchonine. Yet another aspect of this invention relates to a method of orally ~mini~tering a taxane with cinchor~ine to a p~ nt in need of taxane.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Rat plasma paclitaxel concentration (ng/ml) after p.o. co-administration of p~l litAxel (50mg/kg) and cinchonine (250 mg/kg3.
Figure 2. Rat plasma paclitaxel concentration (ng/ml) after p.o. co-adminstration of paclitaxel (50mg/kg) and cinchonine (250 mg/kg), and paclitaxel (5Qmg/kg) p.o. admir~istration alone.
DETAILED DESCRIPTION
The term pharmacologically active taxane compounds (or simply taxanes) which are co-administered with cinchonine refer to compounds with a diterpene framework of the structure:
H
~ - o WO 97/2785~; PCT/US97/00405 . 4 They have inherent inhibitory effect with regard to abnormal cell proliferation, and have inherent therapeutic properties that make it possible to treat patients who have pathological conditions associated with abnormal cell proliferation. The pathological conditions include the abnormal cellular proliferation of malignant or non-m~lign~nt cells in various tissues and/or organs, including, non-limitatively, muscle, bone and/or conjunctive tissues; the skin, brain, lungs and sexual organs; the lymphatic and/or renal ~yslem; m~mm~ry cells and/or blood ce~ls; the liver, digestive system, and pancreas; and the thyroid and/or adrenal ~ n-l.s These pathological con~itions can also include psoriasis; solid tllmors; ovarian, breast, brain, prostate, colon, stomach, kidney, and/or testicular cancer, Kaposi's sarcoma;
cholangiocarcinoma; choriocar~inom~; neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granulocytic lymphomas.
The taxanes in accordance with the invention are particularly useful in the treatment of non-Hodgkin's lymphoma, multiple myeloma, melanoma, and ovarian, urothelial, oesophageal, lung, and breast nc~r.s. The taxanes can be ll~ili7efi to yr~vellt or delay the appearance or reappearance, or to treat these pathological con~iition~. Tn ~ ition~
the taxanes are useful in treating and/or preventing polycystic kidney diseases (PKD~ and rheumatoid arthritis. Naturally, pharmacologically active taxanes encompass species such as paclitaxel or docetaxel.
Specific Fmbodiment In one specific embodiment, paclitaxel and cinchonine, a cinchona alkaloid, were co~lmini.stered orally at 50 and 250 mg/kg, respectively. These two drugs were solubilized in the same dosing solution (10% EtOH, 10% Cremophor EL, and 80% water) yielding concentrations of 8 and 40 mg/ml ~or paclitaxel and cinchonine, respectively. The resultant paclitaxel plasma AUC's (area-under-the-curve) were 20-40 times higher (Fig. 1) in three rats when cinchonine was co-administered compared to historical data when paclitaxel was a-lmini.stered alone. These results have since been confirmed in a head-to-head comparison with paclitaxel dosing alone (Fig. 2). The . 5 mechAni~m of this enhancement by cinchonine is not entirely understood.
The present invention concerns a method of increasing oral 5 absorption of pharmacologically active taxane compounds, i.e.
increasing the orally bioavailability, in m~mmAl~ including humans.
More particularly, the invention provides making ph~ cologically active taxane compounds orally bioavailable by co-a-lmini~tering a taxane with cinchonine. ~y co-a~lmini~tering a taxane with 10 cinchonine, it is intended that cinchonine be a-lmini.~tered orally or parenterally, either simultaneously or non-simlllt~neouly with oral taxane ~lmini~tration. ~or example, this invention also ~n~ompasses a method of increasing bioavailability of taxanes by intravenous administration of cinchonine before or after the oral ~mini.~tration of 15 a taxane compound. However, the preferred method is simultaneous oral a~lminictration of a taxane and cinchonine to a m~mm~l, such as a hllm~n patient, in need of such taxane.
When taxane and ~;nrhonine is co-administered, they can be in 20 separate formulations or in the same formulation. Thus another aspect of invention concerns a pharmaceutical formulation (composition) comprising a taxane, cinchonine and one or more pharmaceutically acceptable exipients designed for the purpose of enhancing the oral absorption (and hence, the bioavailability.) Typical 25 of pharmaceutically acceptable exipients are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium 30 carbonate, silicic acid. The pharmaceutical formulation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
The doses of cinchonine and pharmacologically active taxane utilized to implement the methods in accordance with the invention WO 97t27855 PCT/US97/00405 .. 6 are the ones that make it possible to administer prophylactic treatrnent or to evoke a maximal therapeutic response. The doses vary, depending on the type of administration, the particular product s~le~te~, and the personal characteristics o~ the subject to be treated. In 5 general, the doses are the ones that are therapelltl~ ~lly effective for the tr.o~tm~nt of disorders caused by abnormal cell proliferation. The actual dose used will vary according to the particular composition formulated, the route of a-1mini~tration, and the particular site, host and type of disease being treated. Many factors that modify the action 10 of the drug will be taken into account in deterrnining the dosage including age, weight, sex, diet and the physical condition of the patient. In general the preferred dose of cinchonine and ph~rm~ ologically active taxane is indepl~n~1~ntly 1 to 500 mg/kg per administration to a mammal, including a human patient, in need of 15 such taxane.
TAXANES ORALLY BIOAVAILABLE
5 Field of the Invention The present invention concerns a method of making pharmacologically active taxane compounds orally bioavailable. More particularly, the invention provides enhancing the oral absorption of 10 pharmacologically active taxane compounds by co-administering a taxane with cinchonine.
Background Art Taxol(~) (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated *s unique mode of action, which involves abnormal polym~ri7~tion of tubulin and disruption of mitosis. It has 20 recently been approved for the treatment of refractory advanced ovarian cancer and breast cancer; and studies involving other cancers have shown promising results. The results of paclitaxel clinical studies are reviewed by numerous authors, such as by Rowinsky and Donehower in "The Clinical Pharmacology and Use of 25 Antimicrotubule Agents in Cancer Chemotherapeutics," Pharmac.
Ther.~ 52:35-84, 1991; by Spencer and Faulds in "Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer," Drugs, 48 (5) 794-847, 1994; and by K.C. Nicolaou et al. in "Chemistry and Biology of Taxol," Angew.
30 Chem. Int. Ed. Engl. 33: 15-44, 1994, and also in the re~r~.lces cited therein.
A semi-synthetic analog of paclitaxel named Taxotere(~) (docetaxel) has also been found to have good antitumor activity. The structures of paclitaxel and docetaxel are shown below.
.~
SUBSl ITUTE S~tEET (RULE 26) WO 97/27855 PCT/US97/004~)5 . 2 - R'O~ ~ OH
- RCONH O \
Ph~ o~
HO - AcO
PhC(O)O
Taxol(g) (paclitaxel): R = Ph; R' = acetyl Taxotere(~ (docetaxel): R = t-butoxy; R' = hydrogen ~
Oral bioavailability of paclitaxel or docetaxel is extremely low;
thus, they are essentially orally inactive. (For example see Figure 2 which gives rat plasma concentration of paclitaxel given orally.) The drugs are administered intravenously. In a typical patient previously 10 treated with chemotherapy for ovarian cancer, the recomm~n~led regimen for paclitaxel is 135 mg/m2 or 17~ mg/m2 administered intravenously over three hours every three weeks. For a patient with carcinoma of the breast, the recomm~nded dose for paclitaxel is 175 mg/m2 administered intravenously over 3 hours every three weeks.
15- (Physicians' Desk Reference, 49th Edition, 1995) Such intravenous infusion of paclitaxel (or any ph~macologically active taxanes) makes the administration of the anticancer drug very inconvenient and expensive. Thus a method of m~king taxane more orally bioavailable would allow patient self-medication and thus increase convenience 20 and reduce overall medical costs.
There have been attempts to enhance the oral activity of taxanes by first converting taxanes into prodrugs with the intent to enhance the oral absorption and thereafter delivering the free taxanes 25 ~y~L~ ically. One such approach is described in European Patent Application No. 639577 published February 22, 1995. Without resorting to the prodrug method, we have now surprisingly discovered that orally administered paclitaxel co-administered with cinchonine signific~ntly increases the oral bioavailability of paclitaxel. The 30 merh~nism of this action is not entirely understood.
..
WO 97127855 PCT/US97/0(~405 SUMMARY O~ THE INVENTION
The present invention concerns a method of making p~rm~-~ologically active taxane compounds orally bioavailable. More particularly, the invention provides ms~king ph~rmAcologically active taxane compounds orally bioavailable by co-a~mini~tering a taxane with cinchonine. Another aspect of invention concerns a pharmacelltic~l formulation comprising a taxane and cinchonine. Yet another aspect of this invention relates to a method of orally ~mini~tering a taxane with cinchor~ine to a p~ nt in need of taxane.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Rat plasma paclitaxel concentration (ng/ml) after p.o. co-administration of p~l litAxel (50mg/kg) and cinchonine (250 mg/kg3.
Figure 2. Rat plasma paclitaxel concentration (ng/ml) after p.o. co-adminstration of paclitaxel (50mg/kg) and cinchonine (250 mg/kg), and paclitaxel (5Qmg/kg) p.o. admir~istration alone.
DETAILED DESCRIPTION
The term pharmacologically active taxane compounds (or simply taxanes) which are co-administered with cinchonine refer to compounds with a diterpene framework of the structure:
H
~ - o WO 97/2785~; PCT/US97/00405 . 4 They have inherent inhibitory effect with regard to abnormal cell proliferation, and have inherent therapeutic properties that make it possible to treat patients who have pathological conditions associated with abnormal cell proliferation. The pathological conditions include the abnormal cellular proliferation of malignant or non-m~lign~nt cells in various tissues and/or organs, including, non-limitatively, muscle, bone and/or conjunctive tissues; the skin, brain, lungs and sexual organs; the lymphatic and/or renal ~yslem; m~mm~ry cells and/or blood ce~ls; the liver, digestive system, and pancreas; and the thyroid and/or adrenal ~ n-l.s These pathological con~itions can also include psoriasis; solid tllmors; ovarian, breast, brain, prostate, colon, stomach, kidney, and/or testicular cancer, Kaposi's sarcoma;
cholangiocarcinoma; choriocar~inom~; neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granulocytic lymphomas.
The taxanes in accordance with the invention are particularly useful in the treatment of non-Hodgkin's lymphoma, multiple myeloma, melanoma, and ovarian, urothelial, oesophageal, lung, and breast nc~r.s. The taxanes can be ll~ili7efi to yr~vellt or delay the appearance or reappearance, or to treat these pathological con~iition~. Tn ~ ition~
the taxanes are useful in treating and/or preventing polycystic kidney diseases (PKD~ and rheumatoid arthritis. Naturally, pharmacologically active taxanes encompass species such as paclitaxel or docetaxel.
Specific Fmbodiment In one specific embodiment, paclitaxel and cinchonine, a cinchona alkaloid, were co~lmini.stered orally at 50 and 250 mg/kg, respectively. These two drugs were solubilized in the same dosing solution (10% EtOH, 10% Cremophor EL, and 80% water) yielding concentrations of 8 and 40 mg/ml ~or paclitaxel and cinchonine, respectively. The resultant paclitaxel plasma AUC's (area-under-the-curve) were 20-40 times higher (Fig. 1) in three rats when cinchonine was co-administered compared to historical data when paclitaxel was a-lmini.stered alone. These results have since been confirmed in a head-to-head comparison with paclitaxel dosing alone (Fig. 2). The . 5 mechAni~m of this enhancement by cinchonine is not entirely understood.
The present invention concerns a method of increasing oral 5 absorption of pharmacologically active taxane compounds, i.e.
increasing the orally bioavailability, in m~mmAl~ including humans.
More particularly, the invention provides making ph~ cologically active taxane compounds orally bioavailable by co-a-lmini~tering a taxane with cinchonine. ~y co-a~lmini~tering a taxane with 10 cinchonine, it is intended that cinchonine be a-lmini.~tered orally or parenterally, either simultaneously or non-simlllt~neouly with oral taxane ~lmini~tration. ~or example, this invention also ~n~ompasses a method of increasing bioavailability of taxanes by intravenous administration of cinchonine before or after the oral ~mini.~tration of 15 a taxane compound. However, the preferred method is simultaneous oral a~lminictration of a taxane and cinchonine to a m~mm~l, such as a hllm~n patient, in need of such taxane.
When taxane and ~;nrhonine is co-administered, they can be in 20 separate formulations or in the same formulation. Thus another aspect of invention concerns a pharmaceutical formulation (composition) comprising a taxane, cinchonine and one or more pharmaceutically acceptable exipients designed for the purpose of enhancing the oral absorption (and hence, the bioavailability.) Typical 25 of pharmaceutically acceptable exipients are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium 30 carbonate, silicic acid. The pharmaceutical formulation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
The doses of cinchonine and pharmacologically active taxane utilized to implement the methods in accordance with the invention WO 97t27855 PCT/US97/00405 .. 6 are the ones that make it possible to administer prophylactic treatrnent or to evoke a maximal therapeutic response. The doses vary, depending on the type of administration, the particular product s~le~te~, and the personal characteristics o~ the subject to be treated. In 5 general, the doses are the ones that are therapelltl~ ~lly effective for the tr.o~tm~nt of disorders caused by abnormal cell proliferation. The actual dose used will vary according to the particular composition formulated, the route of a-1mini~tration, and the particular site, host and type of disease being treated. Many factors that modify the action 10 of the drug will be taken into account in deterrnining the dosage including age, weight, sex, diet and the physical condition of the patient. In general the preferred dose of cinchonine and ph~rm~ ologically active taxane is indepl~n~1~ntly 1 to 500 mg/kg per administration to a mammal, including a human patient, in need of 15 such taxane.
Claims (8)
1. A method of enhancing oral absorption of a pharmacologically active taxane to a human in need of such taxane whereby the taxane is co-administered with cinchonine.
2. A method as claimed in 1 in which cinchonine is co-administered orally.
3. A method as claimed in claim 2 in which cinchonine is co-administered orally and simultaneously with the taxane.
4. A method as claimed in claims 1-3 in which the taxane is paclitaxel.
5. A method as claimed in claims 1-3 in which the taxane is docetaxel.
6. A method as claimed in claim 3 in which the taxane is paclitaxel.
7. A method as claimed in claim 6 in which paclitaxel is given 50 mg/kg, and cinchonine is orally administered at 250 mg/kg.
8. A pharmaceutical formulation (composition) comprising a taxane, cinchonine, and one or more pharmaceutically acceptable exipients.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1091696P | 1996-01-31 | 1996-01-31 | |
US60/010,916 | 1996-01-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2221444A1 true CA2221444A1 (en) | 1997-08-07 |
Family
ID=21748017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002221444A Abandoned CA2221444A1 (en) | 1996-01-31 | 1997-01-15 | A method of making pharmaceutically active taxanes orally bioavailable |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0822815A4 (en) |
CA (1) | CA2221444A1 (en) |
WO (1) | WO1997027855A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6245805B1 (en) | 1995-10-26 | 2001-06-12 | Baker Norton Pharmaceuticals, Inc. | Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents |
US6395770B1 (en) | 1995-10-26 | 2002-05-28 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
PL337064A1 (en) * | 1997-05-27 | 2000-07-31 | Baker Norton Pharma | Method of and compositions for orally administering taxanes to human beings |
BR0015149A (en) * | 1999-10-27 | 2002-10-29 | Baker Norton Pharma | Method and compositions for administering taxanes orally to human patients |
KR20020013174A (en) * | 2000-08-11 | 2002-02-20 | 민경윤 | Oral composition for enhancing absorbability of a drug of which absorption rate in oral administration is low |
DE60220519T2 (en) | 2001-04-20 | 2007-09-27 | The University Of British Columbia, Vancouver | MICELLAR DRUG DISPERSION SYSTEM FOR HYDROPHOBIC DRUGS |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69215999T2 (en) * | 1991-02-25 | 1997-07-03 | Debiopharm S.A., Lausanne | Therapeutic agents for the treatment of drug resistance to cancer |
CA2129288C (en) * | 1993-08-17 | 2000-05-16 | Jerzy Golik | Phosphonooxymethyl esters of taxane derivatives |
-
1997
- 1997-01-15 CA CA002221444A patent/CA2221444A1/en not_active Abandoned
- 1997-01-15 WO PCT/US1997/000405 patent/WO1997027855A1/en not_active Application Discontinuation
- 1997-01-15 EP EP97901977A patent/EP0822815A4/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
AU1575897A (en) | 1997-08-22 |
EP0822815A1 (en) | 1998-02-11 |
WO1997027855A1 (en) | 1997-08-07 |
EP0822815A4 (en) | 1998-04-01 |
AU701607B2 (en) | 1999-02-04 |
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