WO1997027855A1 - Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale - Google Patents

Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale Download PDF

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Publication number
WO1997027855A1
WO1997027855A1 PCT/US1997/000405 US9700405W WO9727855A1 WO 1997027855 A1 WO1997027855 A1 WO 1997027855A1 US 9700405 W US9700405 W US 9700405W WO 9727855 A1 WO9727855 A1 WO 9727855A1
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WO
WIPO (PCT)
Prior art keywords
taxane
cinchonine
paclitaxel
orally bioavailable
pharmacologically active
Prior art date
Application number
PCT/US1997/000405
Other languages
English (en)
Inventor
Steven B. Hansel
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to EP97901977A priority Critical patent/EP0822815A4/fr
Priority to AU15758/97A priority patent/AU701607C/en
Publication of WO1997027855A1 publication Critical patent/WO1997027855A1/fr
Priority to JP10005248A priority patent/JPH10203975A/ja

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Classifications

    • 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

Definitions

  • 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.
  • 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 its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has 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 Antimicrotubule Agents in Cancer Chemotherapeutics," Pharmac. Ther..
  • Taxotere® docetaxel
  • the structures of paclitaxel and docetaxel are shown below.
  • Oral bioavailability of paclitaxel or docetaxel is extremely low; thus, they are essentially orally inactive.
  • the drugs are administered intravenously.
  • the recommended regimen for paclitaxel is 135 mg/m 2 or 175 mg/m 2 administered intravenously over three hours every three weeks.
  • the recommended dose for paclitaxel is 175 mg/m 2 administered intravenously over 3 hours every three weeks.
  • the present invention concerns a method of making pharmacologically active taxane compounds orally bioavailable. More particularly, the invention provides making pharmacologically active taxane compounds orally bioavailable by co-administering a taxane with cinchonine. Another aspect of invention concerns a pharmaceutical formulation comprising a taxane and cinchonine. Yet another aspect of this invention relates to a method of orally administering a taxane with cinchonine to a patient in need of taxane.
  • Figure 1 Rat plasma paclitaxel concentration (ng/ml) after p.o. co- administration of paclitaxel (50mg/kg) and cinchonine (250 mg/kg).
  • Figure 2 Rat plasma paclitaxel concentration (ng/ml) after p.o. co- adminstration of paclitaxel (50mg/kg) and cinchonine (250 mg/kg), and paclitaxel (50mg/kg) p.o. administration alone.
  • pharmacologically active taxane compounds which are co-administered with cinchonine refer to compounds with a diterpene framework of the structure:
  • the pathological conditions include the abnormal cellular proliferation of malignant or non-malignant 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 system; mammary cells and /or blood cells; the liver, digestive system, and pancreas; and the thyroid and/or adrenal glands.
  • pathological conditions can also include psoriasis; solid tumors; ovarian, breast, brain, prostate, colon, stomach, kidney, and/or testicular cancer, Kaposi's sarcoma; cholangiocarcinoma; choriocarcinoma; neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granuiocytic 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 cancers.
  • the taxanes can be utilized to prevent or delay the appearance or reappearance, or to treat these pathological conditions.
  • the taxanes are useful in treating and /or preventing poly cys tic kidney diseases (PKD) and rheumatoid arthritis.
  • PPD poly cys tic kidney diseases
  • pharmacologically active taxanes encompass species such as paclitaxel or docetaxel.
  • paclitaxel and cinchonine, a cinchona alkaloid were coadministered 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 for 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 administered alone.
  • the present invention concerns a method of increasing oral absorption of pharmacologically active taxane compounds, i.e. increasing the orally bioavailability, in mammals including humans. More particularly, the invention provides making pharmacologically active taxane compounds orally bioavailable by co-administering a taxane with cinchonine. By co-administering a taxane with cinchonine, it is intended that cinchonine be administered orally or parenterally, either simultaneously or non-simultaneouly with oral taxane administration.
  • this invention also encompasses a method of increasing bioavailability of taxanes by intravenous administration of cinchonine before or after the oral administration of a taxane compound.
  • the preferred method is simultaneous oral administration of a taxane and cinchonine to a mammal, such as a human patient, in need of such taxane.
  • compositions comprising a taxane, cinchonine and one or more pharmaceutically acceptable exipients designed for the purpose of enhancing the oral abso ⁇ tion (and hence, the bioavailability.
  • 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 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.
  • 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 are the ones that make it possible to administer prophylactic treatment or to evoke a maximal therapeutic response.
  • the doses vary, depending on the type of administration, the particular product selected, and the personal characteristics of the subject to be treated. In general, the doses are the ones that are therapeutically effective for the treatment of disorders caused by abnormal cell proliferation.
  • the actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of disease being treated. Many factors that modify the action of the drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.
  • the preferred dose of cinchonine and pharmacologically active taxane is independently 1 to 500 mg/kg per administration to a mammal, including a human patient, in need of such taxane.

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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

L'invention a trait à un procédé permettant de rendre actifs du point de vue pharmaceutique des composés à base de taxane assimilables par voie orale. Elle concerne plus particulièrement le renforcement de l'efficacité de l'absorption par voie orale de composés à base de taxane, actifs du point de vue pharmaceutique, par une administration conjointe de taxane et de cinchonine.
PCT/US1997/000405 1996-01-31 1997-01-15 Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale WO1997027855A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97901977A EP0822815A4 (fr) 1996-01-31 1997-01-15 Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale
AU15758/97A AU701607C (en) 1996-01-31 1997-01-15 A method of making pharmaceutically active taxanes orally bioavailable
JP10005248A JPH10203975A (ja) 1997-01-15 1998-01-14 タクサンの経口吸収を増大させる医薬組成物

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
WO1997027855A1 true WO1997027855A1 (fr) 1997-08-07

Family

ID=21748017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/000405 WO1997027855A1 (fr) 1996-01-31 1997-01-15 Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale

Country Status (3)

Country Link
EP (1) EP0822815A4 (fr)
CA (1) CA2221444A1 (fr)
WO (1) WO1997027855A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0994706A1 (fr) * 1997-05-27 2000-04-26 Baker Norton Pharmaceuticals, Inc. Methodes et compositions d'administration de taxanes par voie orale a des humains
WO2001030448A1 (fr) * 1999-10-27 2001-05-03 Baker Norton Pharmaceuticals, Inc. Methode et compositions pour administration orale de taxanes a des patients humains
WO2002013815A1 (fr) * 2000-08-11 2002-02-21 Hanmi Pharm. Co., Ltd. Composition medicamenteuse orale contenant un derive de verapamil en tant que promoteur de l'absorption de medicament
US6610735B2 (en) 1995-10-26 2003-08-26 Baker Norton Pharmaceuticals, Inc. Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents
US6730698B2 (en) 1995-10-26 2004-05-04 Baker Norton Pharmaceuticals, Inc. Method and compositions for administering taxanes orally to human patients
US7875677B2 (en) 2001-04-20 2011-01-25 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0639577A1 (fr) * 1993-08-17 1995-02-22 Bristol-Myers Squibb Company Ethers phosphonooxyméthyliques ou méthylthiométhyliques de dérivés ou taxane comme agents antitumoraux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69215999T2 (de) * 1991-02-25 1997-07-03 Debiopharm S.A., Lausanne Therapeutische Mittel für die Behandlungder Resistenz gegen Arzneimittel bei Krebs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0639577A1 (fr) * 1993-08-17 1995-02-22 Bristol-Myers Squibb Company Ethers phosphonooxyméthyliques ou méthylthiométhyliques de dérivés ou taxane comme agents antitumoraux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
M. WINDHOLZ et al., "The Merck Index", Published 1983, by MERCK & CO. INC., (RAHWAY, NJ, USA), page 324, Abstract No. 2262. *
See also references of EP0822815A1 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610735B2 (en) 1995-10-26 2003-08-26 Baker Norton Pharmaceuticals, Inc. Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents
US6730698B2 (en) 1995-10-26 2004-05-04 Baker Norton Pharmaceuticals, Inc. Method and compositions for administering taxanes orally to human patients
US6818615B2 (en) 1995-10-26 2004-11-16 Baker Norton Pharmaceuticals, Inc. Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents
US6936583B2 (en) 1995-10-26 2005-08-30 Baker Norton Pharmaceuticals, Inc. Method and compositions for administering taxanes orally to human patients
US7041640B2 (en) 1995-10-26 2006-05-09 Baker Norton Pharmaceuticals, Inc. Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents
EP0994706A1 (fr) * 1997-05-27 2000-04-26 Baker Norton Pharmaceuticals, Inc. Methodes et compositions d'administration de taxanes par voie orale a des humains
EP0994706A4 (fr) * 1997-05-27 2001-05-16 Baker Norton Pharma Methodes et compositions d'administration de taxanes par voie orale a des humains
WO2001030448A1 (fr) * 1999-10-27 2001-05-03 Baker Norton Pharmaceuticals, Inc. Methode et compositions pour administration orale de taxanes a des patients humains
WO2002013815A1 (fr) * 2000-08-11 2002-02-21 Hanmi Pharm. Co., Ltd. Composition medicamenteuse orale contenant un derive de verapamil en tant que promoteur de l'absorption de medicament
US7875677B2 (en) 2001-04-20 2011-01-25 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs

Also Published As

Publication number Publication date
AU1575897A (en) 1997-08-22
EP0822815A1 (fr) 1998-02-11
CA2221444A1 (fr) 1997-08-07
EP0822815A4 (fr) 1998-04-01
AU701607B2 (en) 1999-02-04

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