EP1315484A1 - Compositions a base de taxane et procedes d'utilisation - Google Patents

Compositions a base de taxane et procedes d'utilisation

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Publication number
EP1315484A1
EP1315484A1 EP01920699A EP01920699A EP1315484A1 EP 1315484 A1 EP1315484 A1 EP 1315484A1 EP 01920699 A EP01920699 A EP 01920699A EP 01920699 A EP01920699 A EP 01920699A EP 1315484 A1 EP1315484 A1 EP 1315484A1
Authority
EP
European Patent Office
Prior art keywords
composition
taxane
paclitaxel
compositions
ethanol
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.)
Withdrawn
Application number
EP01920699A
Other languages
German (de)
English (en)
Inventor
Kai Zhang
Gregory A. Smith
Jose C. Gutierrez-Roca
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Branded Pharmaceutical Products R&D Inc
Original Assignee
Baker Cummins Pharmaceuticals Inc
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 Baker Cummins Pharmaceuticals Inc filed Critical Baker Cummins Pharmaceuticals Inc
Publication of EP1315484A1 publication Critical patent/EP1315484A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K31/28—Compounds containing heavy metals
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to novel compositions useful to administer aqueous insoluble medicaments, including medicaments known to be poorly absorbed when administered orally.
  • the invention further relates to compositions and methods of using the same, to achieve target blood levels of a taxane in a mammal.
  • the invention relates to methods of treatment employing such compositions.
  • paclitaxel Poorly soluble chemotherapeutic and/or anticancer agents include taxanes, such as paclitaxel, which are not normally bioavailable when administered orally.
  • Wani et al, J. Am. Chem. Soc, 93:2325 (1971) teaches that paclitaxel, a member of the taxane family of terpenes, is a natural diterpene product isolated from the Pacific yew tree (Taxus brevifolia).
  • Taxus brevifolia Pacific yew tree
  • 332(15): 1004- 1014 (1995) attributes paclitaxel anticancer properties to the inhibition of disassembly of microtubules rendering them extraordinarily stable and dysfunctional, thereby causing cell death by disrupting normal dynamics required during cell division and vital interphase processes.
  • Paclitaxel and docetaxel have been approved for clinical use in the treatment of several, unrelated conditions. Markman et al, Yale J. of Bio. & Med., 64:583 (1991), and McGuire, et al, Ann. Intern. Med. 111:273 (1989) disclose the use of paclitaxel for refractory ovarian cancer in the United States; Mavrodius et al, ASCO 78:254a (1999) describes the use of docetaxel for gastric cancer; Holmes et al, J. Nat.
  • Cancer Inst., 83: 1797 (1991) discloses the use of paclitaxel for chemotherapy for several types of neoplasms including breast cancer (see also Taxol (paclitaxel) Mead Johnson Oncology Products package insert); Fencel et al, ASCO 78:283a (1999) teaches the use of paclitaxel and docetaxel for esophageal cancer; Vanhoefer et al, ASCO 78:303a (1999) describes phase II studies using docetaxel in metastatic gastric cancer; Kourossis et al, ASCO 77:266(a) (1998) teaches the use of docetaxel as salvage chemotherapy for advanced gastric cancer; Xiao et al, ASCO 77:306(a) (1998) assessing new paclitaxel treatment regimens in patients with esophageal carcinoma who had been previously treated with paclitaxel; Schultz et al, reporting phase ⁇ trials of docetaxel in patients with
  • prodrug compounds that are more water-soluble than the parent compound and that display the cytotoxic properties upon activation.
  • One important group of such prodrugs includes the 2'-onium salts of paclitaxel and docetaxel (see e.g. Nicolaou, et al, Angew. Chin. Int. Engl. 53:1583-1587 (1994)), particularly the 2'- methylpyridinium mesylate (2'-MPM) salts disclosed in PCT publication no. WO 98/58927. Suffness (ed.) in Taxol Science and Applications CRC Press (1995) states that to date none has progressed to clinical evaluation because of marginal improvements in solubility, stability problems and low regeneration rates.
  • paclitaxel has a bioavailability of 0% upon oral administration, and Suffness et al. reports that oral dosing with paclitaxel did not seem possible. For these reasons, paclitaxel has not been administered orally to human patients.
  • docetaxel N-debenzoyl-N-tert- butoxycarbonyl-10-deacetyl paclitaxel
  • TAXOTERE ® Rhone- Poulenc-Rorer S.A.
  • the poor bioavailability of paclitaxel after oral administration may be ascribed to a membrane-bound P-glycoprotein which functions as an energy-dependent transport, or efflux pump, to decrease intracellular accumulation of drug by extruding xenobiotics from the cell (see e.g., Taxol® Science and Applications, supra). It is hypothesized that, by preventing movement through mucosal cells of the small intestine, the P-glycoprotein prevents systemic absorption. A number of known agents have been shown to inhibit P-glycoprotein (e.g., cyclosporin A, verapamil, tamoxifen, quinidine and phenothiazines).
  • P-glycoprotein e.g., cyclosporin A, verapamil, tamoxifen, quinidine and phenothiazines.
  • MDR multidrug resistance
  • Benet PCT publication WO 95/20980 (published August 10, 1995) purports to teach a method for increasing the bioavailability of orally administered hydrophobic pharmaceutical compounds.
  • This method comprises the concurrent oral administration of a bioenhancer including an inhibitor of a cytochrome P450 3A enzyme or an inhibitor of P- glycoprotein-mediated membrane transport.
  • Benet does not identify which bioavailability enhancing agent(s) improve the availability of specific target pharmaceutical compounds, nor does it teach specific dosage amounts, schedules or regimens for administration of the enhancing or target agents.
  • the only combination disclosed is ketoconazole as the enhancer, and cyclosporin A as the target drug.
  • Benet merely provides that bioenhancers are hydrophobic compounds generally comprising two co-planar aromatic rings, a positively charged nitrogen group or a carbonyl group ⁇ a class that includes an unascertainable number of compounds, including several inoperable embodiments.
  • the classes of active agents disclosed by Benet include the great majority of pharmaceutical agents listed in the Physicians' Desk Reference and thus, are of no value to medical practitioners seeking safe, practical and effective methods of orally administering specific agents.
  • Benet provides no teaching that could be followed by one of skill to identify suitable bioenhancer/active drug combinations or to design therapeutically effective oral modalities.
  • PCT publication no. WO 98/30205 (published July 16, 1998) (hereinafter "Quay") allegedly discloses a method for increasing the bioavailability of poorly soluble drugs.
  • the application discloses an emulsion of alpha-tocopherol including a surfactant.
  • PEGylated Vitamin E PEGylated alpha-tocopherol includes polyethylene glycol subunits attached by a succinic acid diester at the ring hydroxyl of Vitamin E.
  • Alpha-tocopherol allegedly serves as a surfactant, stabilizer and a secondary solvent in emulsions of alpha-tocopherol.
  • this reference is expressly limited to formulations that are (a) emulsions and (b) essentially ethanol-free.
  • compositions should be capable of achieving target therapeutic blood levels of taxane.
  • compositions should be (i) bioavailable, (ii) suitable to maintain the taxane in solution, (iii) chemically stable over extended periods of time and (iv) possess overall palatability while demonstrating long term stability.
  • the present inventors have devised taxane-based compositions and methods of using the same useful to achieve target blood levels of the taxane, in a mammal.
  • the compositions exhibit long-term stability and overall palatability.
  • such approaches provide the means to achieve taxane blood levels comparable to the levels achieved by less convenient methodologies currently available such as, for example, therapeutically effective infusion modalities.
  • the invention thus provides compositions and methods useful to improve the absorption of a taxane from the gastrointestinal tract into the bloodstream and to provide target blood levels, including therapeutically effective blood levels, of such taxane in a mammal.
  • the taxane blood levels achieved exceed those achieved by compositions disclosed in WO97/15269.
  • the methods and compositions according to the invention are useful as analytical tools for biochemical studies as well as therapeutic tools.
  • the invention provides pharmaceutical compositions demonstrating long- term stability and overall palatability.
  • Such compositions comprise a poorly soluble medicament, a carrier, a co-solubilizer, and a stabilizer.
  • the medicament is a taxane.
  • Preferred embodiments of the invention may provide more than one type of taxane, carrier, co-solubilizer, or stabilizer.
  • Some compositions of the invention further include additional components, such as for example surfactants, pharmaceutical excipients, diluents, sweeteners, flavoring agents or coloring agents, as described in more detail herein.
  • the taxane is paclitaxel or docetaxel.
  • the invention provides methods suitable to achieve therapeutically effective taxane blood levels in a mammal by the oral administration of the pharmaceutical compositions described.
  • the methods of the invention including the administration of a bioavailability enhancing agent, result in taxane blood levels which are comparable to those achieved by long term infusion such as 96-hours infusion shown to be therapeutically effective (e.g., for the treatment of advanced metastatic breast cancer as described in Wilson, et al, J. Clin. Oncol. 72:1621-1629 (1994), and Seidman, et al, J. Clin. Oncol. 76:3353-3361 (1998).
  • Pharmaceutical compositions and bioavailability enhancing agents useful according to this aspect are as described for the first aspect of the invention.
  • the invention provides a method to investigate the properties of diterpenoids. More specifically, the invention provides tools to investigate biochemical properties of taxane moieties in novel formulations capable of mediating large increases in solubility. Such studies will lead to a more comprehensive pharmacokinetic and pharmaceutical description of taxanes essential to identify novel applications and possibly to further optimize already existing therapeutic outcomes.
  • a further aspect of the invention pertains to methods of treatment of a mammal suffering from a taxane-responsive disease by the oral administration of pharmaceutical compositions as described herein.
  • the pharmaceutical compositions of the invention are orally administered in conjunction with an oral bioavailability-enhancing agent to provide blood levels of the taxane which are comparable to the levels achieved by intravenous injection of the taxane.
  • Pharmaceutical compositions and bioavailability enhancing agents useful according to this aspect are as described for the first aspect according to the invention.
  • Figure 1 is a graphic representation showing the ability of compositions of the invention (PG/TPGS/ETOH and ascorbyl palmitate (40:40:20) with (•) 12 mg/ml, (V) 15mg/ml, ( ⁇ ) 20 mg/ml, (o) 25 mg/ml, and ( ) 50 mg/ml paclitaxel), to remain in solution for a period of time > 2hours in a reciprocal water-shaking bath.
  • Figure 2 is a graphic representation showing the average plasma concentrations of paclitaxel from (•) 9 patients orally administered a Cremophor EL based formulation, and from (o) 2 orally administered a composition of the present invention (PG/TPGS/ETOH and ascorbyl palmitate (40:40:20).
  • PG/TPGS/ETOH and ascorbyl palmitate 40:40:20.
  • the present inventors have devised novel compositions and methods of using the same to orally administer aqueous insoluble medicaments, including medicaments known to be poorly absorbed when administered orally.
  • the invention further relates to compositions and methods of using the same useful to achieve target blood levels, including therapeutic blood levels, of a taxane in a mammal.
  • the invention relates to treatment regimens employing such compositions.
  • the U.S. patents and other publications identified herein are within the knowledge of those skilled in this field and are hereby incorporated by reference in their entirety.
  • Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th Ed., McGraw Hill Companies Inc., New York (1996). Standard reference works setting forth.the general principles of modern pharmaceutics (Remington's Pharmaceutical Sciences, 18 th Ed., Gennaro, Mack Publishing Co., Easton, PA (1990) and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins (1995)). Any suitable materials and/or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference is made in the following description and examples are obtainable from commercial sources, unless otherwise noted.
  • the present invention is intended for use with any mammal that may experience the benefits of the methods of the invention. Foremost among such mammals are humans, although the invention is not intended to be so limited, and is applicable to veterinary uses.
  • the invention provides pharmaceutical compositions demonstrating long- term stability and overall palatability.
  • Such compositions comprise a taxane, a carrier, a co- solubilizer, and a stabilizer.
  • the term "carrier” is used to denote a moiety that maintains (and in preferred embodiments improves) the aqueous solubility of the taxane in the pharmaceutical composition of the invention.
  • Carriers according to the instant invention include without limitation moieties that may also function as co-solubilizers.
  • the carriers of the invention are characterized by a core structure that may be either a straight chain polyether or a branched glycol (e.g., glycol) coupled with at least one fatty acid ester.
  • Preferred carriers for use in the invention are non-ionic surfactants or emulsifiers having HLB values of at least about 10. It has been found that such non-ionic surfactants or emulsifiers are not only compatible carriers for the lipophilic taxanes (which are poorly soluble in water) but also promote absorption of the active ingredient from the gastrointestinal tract into the bloodstream. Only those members of these surfactant families that have HLB values of about 10 or greater may be used as carriers in the subject compositions.
  • Representative non-limiting examples of carriers according to the invention include
  • Vitamin E TPGS d-alpha-tocopheryl polyethylene glycol 1000 succinate, available from Eastman Chemical Co., Kingsport, TN
  • saturated polyglycolyzed glycerides such as the GELUCIRE and LABRASOL products (Gattefosse Corp., Westwood, NJ) which include glycerides of C 8 - 8 fatty acids
  • CREMOPHOR EL or other modified castor oils including polyoxyethylated or hydrogenated castor oils such as EL-P or RH40 modified castor oils (available from BASF, Mt.
  • compositions of the invention comprise at least 30% by weight of carrier.
  • the carrier is present in an amount of from about 30 to about 90% of the composition by weight.
  • the pharmaceutical composition of the invention comprises about 40% by weight of Vitamin E TPGS.
  • co-solubilizer is used to designate a viscosity-reducing moiety which increases the fluidity of the compositions of the invention at body temperature, as generally required for oral bioavailability, and/or reduce the melting point of the compositions below body temperature.
  • Co-solubilizers according to the invention decrease the viscosity and increase the fluidity of the vehicle at body temperature, and also may increase the amount of the active agent that can be dissolved or dispersed in the vehicle in comparison with the use of a carrier alone.
  • Co-solubilizers according to the invention include moieties capable of functioning as carriers as well.
  • Co-solubilizers according to the instant invention include without limitation moieties that may also provide increased taxane solubility.
  • Representative non-limiting examples of viscosity-reducing co-solubilizers include
  • PHARMASOLVE TM N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ
  • MIGLYOL glycerol or propylene glycol esters of caprylic and capric acids H ⁇ ls AG, Marl, Germany
  • polyoxyethylated hydroxystearates including stearyl or oleyl ethers (e.g., SOLUTOL TM HS 15) (BASF, Mt.
  • TWEEN TM polyoxyethylated sorbitan esters ICI Wilmington, DE
  • SOFTIGEN polyethylene glycol esters of caprylic and capric acids Hiils AG
  • modified castor oils including polyoxyethylated or hydrogenated castor oils (such as CREMOPHOR TM EL, EP-P or RH 40) (BASF, Mt.
  • the co-solubilizer is ethanol.
  • the co- solubilizer comprises propylene glycol and ethanol. Up to 90% of the composition by weight may be co-solubilizer. In some embodiments of the invention, from about 10 to about 70% by weight is co-solubilizer. In preferred embodiments of the invention, the co-solubilizer is present in an amount of from about 20 to about 60% by weight. Accordingly, preferred pharmaceutical compositions may comprise from about 10% to about 70% by weight of propylene glycol, more preferably from about 20 to about 60% by weight of propylene glycol. In a particularly preferred embodiment the pharmaceutical composition of the invention comprises about 40% by weight of propylene glycol.
  • the pharmaceutical composition of the invention comprises from about 5 to about 50% by weight of ethanol, more preferably from about 10 to about 30% weight of ethanol. In most preferred embodiments, the pharmaceutical composition of the invention comprises about 20% by weight of ethanol.
  • Several materials identified as carriers have also been found to be effective co-solubilizers, either alone or in combination with other viscosity-reducing agents, or certain other carriers. In general, any solvent in which paclitaxel or other taxanes are at least moderately soluble at body temperature or with gentle heating can be used as a co-solubilizer in the vehicle of the novel compositions.
  • Preferred co-solubilizers are those in which at least 25 mg/ml of paclitaxel or other taxane can be dissolved at about 20-25°C. Some embodiments of the invention comprise more than one co-solubilizer. In some preferred embodiments, the compositions of the invention include at least two solubilizers.
  • stabilizer denotes a moiety that increases the stability of a taxane.
  • Stabilizers according to the invention may stabilize taxanes by decreasing the rates of solvolysis (e.g., loss of the ester side chain at C-13 or deacetylation at C-10) and/or epimerization of the taxane molecule (e.g., at C-7) as compared to taxane.
  • the stabilization of a taxane by a stabilizer according to the invention is detectable by a reduction of one or more known degradation products (e.g., 7-epi-taxol C, 10-deacetyltaxol, 7-epi-taxol, 7-epi-10-deacetyl-taxol, baccatin III, 10-deacetylbaccatin III, cephalomannine, nitine, 7-epi-cephalomannine (see, for example, Miller et al, J. Org. Chem. 46:1469-1474 (1981) and Volk, et al, J. Chromatography B 696: 99-115 (1997).
  • one or more known degradation products e.g., 7-epi-taxol C, 10-deacetyltaxol, 7-epi-taxol, 7-epi-10-deacetyl-taxol, baccatin III, 10-deacetylbaccatin
  • the stabilizer is ascorbic acid 6-palmitate (i.e., ascorbyl palmitate).
  • Other stabilizers useful in the present invention include metal salts of acids such as alpha-hydroxy or beta-hydroxy acids, metal sulfates (e.g., FeSO 4 , metal alpha-hydroxymethylsulfinates and metal sulfonates.
  • the metal salts are the subject of Applicants' commonly owned U.S. patent application no , entitled "Uses of
  • preferred stabilizers are radical inhibitors. Radical inhibitors are well known in the art (see e.g., Remington's Pharmaceutical Sciences, supra)).
  • Non-limiting representative radical inhibitors according to the invention include Fe 2+ gluconate, Cu 2+ gluconate, Zn 2+ gluconate, Ca 2+ ascorbate, HOCH 2 SO 2 Na, ascorbyl palmitate, beta-carotene, zinc methionine and zinc citrate.
  • Yet other preferred stabilizers contemplated by the inventors may additionally aid in preserving the color of the pharmaceutical compositions.
  • An example of this type of stabilizer is dl-alpha-tocopherol, commercially available from BASF (Mt. Olive, NJ).
  • the preferred range of the amount of stabilizer present in the compositions of the invention is from about 0.2% to about 1.0% by total weight of the composition. In general, the amount ranges from about 0.05% to about 2.0% by weight. Determinations are to whether a given substance functions as a stabilizer for purposes of the present invention, and if so, the optimal amount to add to the compostion, are made by routine experimentation. For example, taxane formulations containing varying amounts of the compound are subjected to stress conditions (e.g., 80 °C for 24 hours) and then analyzed by HPLC. The formulations are compared to a control (not containing the compound) and the percentage of unchanged taxane is calculated from the HPLC profile. Compounds that achieve taxane ratios of 97% are generally considered acceptable; compounds achieving ratios greater than 98.5% are preferred. See also the Miller and Volk publications, above.
  • compositions according to the invention may include more than one type of carrier, co-solubilizer, or stabilizer.
  • the compositions of the invention may optionally be formulated with additional components, such as for example surfactants, pharmaceutical excipients, diluents, sweeteners, flavoring agents or coloring agents, as described in more details herein.
  • additional components such as for example surfactants, pharmaceutical excipients, diluents, sweeteners, flavoring agents or coloring agents, as described in more details herein.
  • Conventional pharmaceutical excipients, diluents, sweeteners, flavoring agents, coloring agents and any other inert ingredients regularly included in dosage forms intended for oral administration are well known in the art (see Remington's Pharmaceutical Sciences, supra).
  • a “surfactant” according to the invention is an amphiphilic moiety having a surface-active group capable of maintaining and/or promoting the dispersion of an hydrophobic compound within an aqueous media.
  • surfactants suitable in the compositions of the invention are well known in the art.
  • Non-limiting representative surfactants include Vitamin E (e.g. alpha-tocopherol) and beta-carotene.
  • Taxanes are used to identify a diterpene moiety that is only slightly soluble in water.
  • Taxanes according to the invention include without limitation moieties isolated from the Pacific yew tree (Taxus brevifolia) as well as derivatives, analogs, metabolites and prodrugs, and other taxanes.
  • the taxane is selected from the group consisting of paclitaxel, docetaxel, derivatives, analogs, metabolites and prodrugs of paclitaxel or docetaxel, and salts, polymorphs and hydrates thereof. More preferably, the taxane comprises paclitaxel. In some embodiments of the invention more than one taxane is included as active ingredient.
  • the taxane concentration in the compositions of the invention may vary based on the carrier(s) co-solubilizer(s) and/or stabilizers selected and on the desired total dose of taxane to be administered orally to the mammal.
  • concentration of taxane in the pharmaceutical compositions according to the invention may range from about 2 to about 100 mg/ml, preferably from about 6 to about 60 mg/ml or more, preferably from about 10 to about 50 mg/ml.
  • a bioavailability-enhancing agent in conjunction with the administration of the compositions according to the invention furthers the achievement of a blood level of the taxane that is comparable to the blood level achieved by intravenous injection of the taxane.
  • a bioavailability-enhancing agent may be administered before, at the same time, or immediately after the administration of the compositions of the invention.
  • the pharmaceutical compositions include a bioavailability- enhancing agent.
  • bioavailability enhancing agent also referred to as “enhancing agent” or “enabling agent” is used to refer to an agent capable of promoting the absorption or bioavailability of another agent.
  • Preferred bioavailability enhancing agents include cyclosporins and related oligopeptides produced by species in the genus Topycladium, ketoconazole, dexverapamil, amiodarone, nifedipine, reserpine, quinidine, nicardipine, ethacrynic acid, propafenone, reserpine, amiloride, ergot alkaloids, cefoperazone, tetracycline, chloroquine, fosfomycin, ivermectin, tamoxifen VX-710, VX-853, genistein and related isoflavonoids, calphostin, ceramides, morphine, morphine congeners, other opioids and opioid antagonists.
  • Cyclosporins are a group of nonpolar cyclic oligopeptides (some of which have immunosuppressant activity) produced by the genus Topycladium, including, e.g., Topycladium inflatum gams (formerly designated as Trichoderma polysporum), Topycladium terricola and other fungi imperfecti.
  • Topycladium inflatum gams formerly designated as Trichoderma polysporum
  • Topycladium terricola Topycladium terricola
  • the major component, cyclosporin A (cyclosporine or CsA)
  • CsA cyclosporine
  • a number of synthetic and semi-synthetic analogs have also been prepared.
  • Cyclosporins particularly cyclosporine (cyclosporin A) are known inhibitors of the P-glycoprotein efflux pump and other transporter pumps as well as of certain P450 degradative enzymes, but to date no effective regimens for applying this property clinically have been developed to the point of clinical and commercial feasibility or regulatory approval.
  • Cyclosporins which may be used in preferred embodiments of the invention include, but are not limited to: cyclosporins A through Z but particularly cyclosporin A (cyclosporine), cyclosporin F, cyclosporin D, dihydro cyclosporin A, dihydro cyclosporin C, acetyl cyclosporin A, PSC-833, SDZ-NIM 811 which is (Me-Ile-4)-cyclosporin, an antiviral, non- immunosuppressive cyclosporin. Characteristic amino acid variations defining cyclosporins A-Z are described in Table 1 below. Table 1: Cyclosporins A-Z
  • the invention provides a long term-stable pharmaceutical composition for oral administration to a mammal including a taxane, Vitamin E TPGS, propylene glycol, ethanol and ascorbyl palmitate.
  • compositions of the invention may be prepared by any conventional method known to individuals of skill in the pharmaceutical arts for preparing liquid or other fluid oral formulations containing surfactant carriers and lipophilic active ingredients. Suitable non-limiting representative methods of preparing the compositions of the invention include for example the protocols described in examples herein. Since the majority of the preferred carriers are very viscous at room temperature, and in some cases retain a relatively high viscosity even upon the addition of a minor proportion of co-solubilizer, it is generally preferred in preparing the compositions to mix the carriers and co-solubilizers to be used, add the taxane active ingredient, and heat the resulting mixture while stirring, for example to about 40° C. This method enables the preparation of clear solutions.
  • Certain co-solubilizers however, particularly PHARMASOLVE TM , lower the carrier viscosity and enhance taxane solubility to such a degree that the composition can be prepared by stirring at room temperature with no heating. It is desirable that the viscosity of the finished composition not be higher than 40,000 cps at body temperature (approximately 37° C).
  • compositions of the invention may be in the form of true solutions, emulsions or suspensions, but solutions of the active taxane ingredient in the carrier or carrier/co-solubilizer system are preferred.
  • the invention also sets for the methods of using the compositions for a variety of purposes including, but not limited to therapeutic applications.
  • the invention provides methods to achieve target blood level of taxane in a mammal by the oral administration of an effective amount of a pharmaceutical composition as described herein. Such methods are suitable to provide a target blood level of the taxane which is comparable to that achieved by intravenous administration of the taxane.
  • a preferred method of the invention is to administer the oral pharmaceutical compositions concomitantly with the administration of at least one dose of an oral bioavailability enhancing agent because the levels of taxane that are subsequently achieved are in fact associated with pharmacological activity of the taxane.
  • compositions and bioavailability enhancing agents useful according to this aspect are as described for the first aspect of the invention.
  • “Target blood levels” are blood concentrations of a taxane at or above the threshold concentrations necessary to observe the particular activities associated with taxanes that are sought.
  • Non-limiting representative examples include the inhibition of tubulin disassembly, which occurs at blood levels of about 0.1 ⁇ M or about 85 ng/ml and the inhibition of protein isoprenylation (which occurs at blood levels of about 0.03 ⁇ M or about 25 ng/ml).
  • taxanes such as paclitaxel have been shown to inhibit angiogenesis and to inhibit the phosphorlation of intracellular Bcl-2. Some of these activities (such as the direct inhibition of oncogene functions or the inhibition of a transducing element) are directly related to taxane antitumorigenic properties.
  • target blood levels are therapeutic blood levels at which a particular pharmacological activity is observed.
  • Target blood levels may vary considerably due to a number of variables such as for example, use of concomitant medications, hepatitic status, albumin levels in the mammal being treated and variations between different pharmaceutical formulations.
  • Target blood levels may be easily ascertained by routine methodologies such as the administration of the compositions of the invention in step-wise increments while monitoring paclitaxel concentration in the mammal.
  • target blood levels are at least about 0.1 ⁇ M or about 85 ng/ml for a period of time (e.g., several hours). In some embodiments of the invention wherein the mammal is a human in need of a regimen to inhibit protein isoprenylation, target blood levels are at least about 0.03 ⁇ M or about 25 ng/ml. Such target blood levels include without limitation, blood levels from about 25ng/ml to about 85ng/ml.
  • the invention provides a method to investigate the physical properties of diterpenoids. More specifically, the invention provides tools useful to investigate the biochemical properties of taxane moieties in novel formulations capable of mediating larger increases in tissue distribution in vivo, without an increase in toxicity. Such tools, capable of expanding taxane volume of distribution, will allow investigators to elucidate a variety of biochemical properties in vivo, such as for example the effects of paclitaxel on the level of tubulin and/or microtubule- associated proteins (MAPs) overexpression, cell cycle progression, and nucleation of microtubule assembly in various tissues. Such studies promise to lead to a more comprehensive pharmacokinetic and pharmacological description of taxanes essential to identify novel applications and possibly to further optimize already existing therapeutic outcomes.
  • MAPs microtubule-associated proteins
  • taxane-responsive disease is used to refer to any condition including a disease condition, which is ameliorated by the oral administration of effective amounts of the pharmaceutical compositions described herein.
  • a taxane responsive disease is characterized by uncontrolled cellular proliferation including, but not limited to the heterogeneous diseases of cancer, tumors, angiogenesis, psoriasis and polycystic kidney disease.
  • non-limiting representative examples of taxane-responsive diseases include cancers, tumors, Kaposi's sarcoma, malignancies, uncontrolled tissue and cellular proliferation secondary to tissue injury.
  • Non-cancerous diseases that may be effectively treated in accordance with the present invention are uncontrolled tissue or cellular proliferation secondary to tissue injury, polycystic kidney disease, inflammatory diseases (e.g., arthritis) and malaria, including chloroquine- and pyrimethamine-resistant malaria parasites (Pouvelle, et al, supra).
  • treatment or “treating” as used herein with reference to a taxane responsive disease refer to prophylaxis and to the amelioration of symptoms already present in an individual by altering the taxane blood levels. It will be appreciated by a person of skill that a treatment need not be completely effective in preventing the onset of a disease or eliminating the symptoms associated with a disease, nor does a treatment need to cure a disease in order to be effective. Any reduction in the severity of the symptoms, delay in the onset of symptoms, or delay in the rate of progression of severity of symptoms is contemplated. Persons at risk of developing a taxane- responsive disease may be treated prophylactically based on any variety of factors suggesting the possible onset of the disease, e.g., family history, environmental exposure, genetic markers, early symptoms, and the like.
  • the preferred method of the invention for treating a mammal suffering from taxane-responsive disease is to administer the oral compositions containing a taxane such as paclitaxel concomitantly with the administration of an oral bioavailability enhancing agent.
  • a preferred embodiment of the method of the invention comprises the oral administration an enhancing agent simultaneously with, or prior to, or both simultaneously with and prior to the oral administration to increase the quantity of absorption of the taxane into the bloodstream.
  • Pharmaceutical compositions and bioavailability enhancing agents useful according to this aspect of the invention are as described for the first aspect of the invention.
  • the dosage range of the bioavailability enhancing agent to be co-administered with the taxane in accordance with the invention is from about 0.1 to about 20 mg/kg of patient body weight, preferably from about 3 to about 15mg/kg of patient body weight, and more preferably from 5-10 mg/kg.
  • "Co-administration" of the enhancing agent comprehends administration substantially simultaneously with the taxane (either less than 0.5 hr. before, less than 0.5 hr. after or together), from about 0.5 to about 72 hr. before the administration of the taxane, or both, i.e., with one or more doses of the same or different enhancing agents given at least 0.5 hr.
  • the dosage range of the orally administered taxane in the compositions of the invention will vary in accordance with a number of factors, including the particular taxane, on its therapeutic index, the requirements of the disease being treated, the age and condition of the mammal, the nature of the disease(s) being treated the stage of the disease, other medications and being taken by the mammal, and the like.
  • the pharmacology and pharmacokinetics of taxanes, especially paclitaxel and docetaxel, are well known. This pharmacological information can be used in conjunction with the exigencies of the mammal being treated to optimize dosing and scheduling regimens.
  • paclitaxel or other taxane dosage forms may contain sufficient quantities of the target agent to provide a daily dosage of about 20-200 mg/m 2 (based on the mammal/patient body surface area) or about 0.5-30 mg/kg (based on mammal/patient body weight) as single or divided (2-3) daily doses.
  • Preferred dosage amounts are about 50-200 mg/m 2 or about 2-6 mg/kg to maintain blood levels of taxane in the range of 50-500 ng/ml for extended periods of time (e.g., 8-12 hours) after each oral dose.
  • Preferred dosing schedules for administration of oral paclitaxel are (a) the daily administration to a patient in need thereof of 1-3 equally divided doses providing about 20-1000 mg/m 2 (based on body surface area), and preferably about 50-200 mg/m 2 , with daily administration being continued for 1-4 consecutive days each 2-3 weeks, (b) administration for about one day each week, and (c) daily administration for two or three weeks, followed by a one week rest period.
  • the former schedule is comparable to use of a 96-hour paclitaxel infusion every 2-3 weeks, which is considered by some a preferred IV treatment regimen.
  • the pharmaceutical composition administered comprises about 60mg/m 2 paclitaxel by weight. In another particularly preferred embodiment, the pharmaceutical composition comprises about 180 mg/m 2 by weight.
  • Two or more different enhancing agents and/or two or more different taxane target agents may be administered together, alternately or intermittently in all of the various aspects of the method of the invention.
  • oral paclitaxel administered alone e.g., in a solid dosage form or even in a liquid vehicle not containing an oral absorption promoting carrier
  • the amount of the taxane absorbed into the bloodstream is at least about 15% of the amount absorbed when the same dose of paclitaxel is administered to intravenously in a standard intravenous vehicle e.g., example a CREMOPHOR EIJethanol vehicle.
  • the relative percentage of absorption is determined by standard methodologies in the field such as by comparing the respective AUC (is the area under the plasma concentration-time curve, commonly used in pharmacokinetics to quantify the percentage of drug absorption and elimination determined after oral/intravenous administration of the drug.
  • a high AUC is an indication that the drug tested is more likely to be available to reach the target tissue or organ.
  • the novel pharmaceutical compositions may be administered in any known pharmaceutical dosage form.
  • the compositions may be encapsulated in a soft or hard gelatin capsule or may be administered in the form of a liquid preparation.
  • Oral administration of taxanes in accordance with the invention may actually decrease toxic side effects in many cases as compared with currently utilized IV therapy. Rather than producing a sudden and rapid high concentration in blood level as is usually the case with an IV infusion, absorption of the active agent through the gut wall (promoted by the enhancing agents), provides a more gradual appearance in the blood levels. A stable, steady-state maintenance of those levels at or close to the ideal range for a long period of time can be more easily achieved with oral administration than with the inconvenience and risk of infection in an already immuno- compromised host.
  • the oral compositions of the invention may be administered in a two-part medicament system (e.g., to accommodate the use of carriers which are chemically or physically incompatible with desired adjunctive ingredients such as flavoring or coloring agents).
  • the taxane may be administered to the patient as the first part of the medicament in a solubilizing vehicle, which may be sweetened, flavored or colored as desired.
  • the administration of the taxane may be followed by administration of a larger volume of fluid, for example 1 to 8 fluid ounces (30 - 240 ml), containing at least one carrier or a carrier/co-solubilizer system in accordance with the invention.
  • Illustrative examples of "chaser" formulations that may be used in a two-part oral taxane medicament include: a) 2 - 20% (by weight) Vitamin E TPGS + water q.s.; b) 2 - 25% Vitamin E TPGS + 2 - 25% PHARMASOLVE + water q.s.; and c) 2 - 20% Vitamin E TPGS + 2 - 25% propylene glycol + water q.s.
  • the oral compositions of the invention contain not only one or more taxane but also one or more bioavailability enhancing agents in a combination dosage form.
  • such combination dosage form may contain from about 0.1 to about 20 mg/kg (based on average patient body weight) of one or more of cyclosporins A, D, C, F and G, dihydro CsA, dihydro CsC and acetyl CsA together with about 20 to about 1000 mg/m 2 (based on average patient body surface area), and preferably about 50-200 mg/m 2 of paclitaxel, docetaxel, other taxanes or paclitaxel or docetaxel derivatives.
  • compositions and methods of the present invention provide many advantages in comparison with prior art and intravenous regimens (e.g., added stability, overall palatability, decreased toxicity due to lower peak levels, patient convenience and comfort, ease of administration and lowered expense).
  • compositions and methods of the invention greatly reduce the likelihood of allergic hypersensitivity reactions common with IV administration, thereby reducing or overcoming the need for pre-medication regimens (such as H- 1 and H-2 blockers plus steroids).
  • pre-medication regimens such as H- 1 and H-2 blockers plus steroids.
  • the latter is of particular relevance in the treatment of diabetic cancer patients since it is known that steroids may cause diabetes mellitus.
  • the present invention provides for the administration of taxanes, e.g., paclitaxel, in comparatively infrequent daily doses (e.g., about twice/day) and/or according to schedules that would otherwise not be possible or practical with the intravenous route.
  • a bioavailability enhancer e.g., cyclosporin A
  • paclitaxel could be given intermittently as single dose on a fixed schedule (weekly, biweekly, etc.) or chronically, over a period of consecutive days (e.g., 4 days) every 2-4 weeks with the goal of keeping the levels within a safe and effective "window".
  • Paclitaxel NaPro BioTherapeutics, Inc., Boulder, CO
  • Ascorbyl Palmitate NF Aldrich Chemical Co., Milwaukee WI
  • dl-alpha-tocopherol USP Roche Vitamins, Nutiey, NJ
  • compositions of the invention are their stability.
  • the following experiment illustrates the stability of the compositions according to the invention.
  • the representative compositions prepared as described in Example 1 were assayed in compliance with ICH guidelines.
  • 10.2 - 10.5 ml of solution was delivered into individual 15cc amber glass bottles using a 28/400 Black Phenolic Cap with Poly Seal Liner. Gross, tare and net weight of each bottle were recorded.
  • the bottles were then placed upright at 40° C and 75% humidity. Subsets of bottles were removed and tested according to methodology well known in the field (i.e., presence of known degradation products by HPLC after each time point as shown below (2 weeks, and 1-6 months).
  • compositions were found to be stable showing minimal levels (expressed as a % of total impurities) of compounds considered hallmarks of paclitaxel degradation such as 7-epi- Taxol C, 10-deacetyltaxol, or baccatin III as compared to negative control formulations based on CREMOPHORE ELTM (data not shown).
  • impurities were less than 3.5% after as long as six months of incubation (data not shown).
  • paclitaxel solubility in representative compositions of the invention, formulations prepared as in Example 1 and having final paclitaxel concentrations of 12, 15, 25, and 50 mg/ml were diluted with water to a 1 to 11 ratio (1 ml paclitaxel formulation and 10 ml water). The solutions were then assayed by HPLC analytical method. As shown in Figure 1, paclitaxel remained in solution for at least two hours (thus showing solubility for an adequate period of time) in all preparations with the exception of the 50 mg/ml preparation. Notably, preparations containing between 12 to 20 mg/ml remained in solution for the entire duration of the study.
  • compositions and methods of the invention are used to achieve target blood levels, including therapeutic blood levels, of taxane in a mammal.
  • Serial blood samples were taken frequently over 30-48 hours and assayed for paclitaxel. Individual and mean pharmacokinetic parameters of paclitaxel are shown in Table 3.
  • compositions of the invention may provide sufficient levels of paclitaxel in plasma with ingestion of less ethanol than the CREMOPHOR ELTM based formulations.
  • Table 4 shows a comparison of the pharmacokinetic parameters for a CREMOPHOR
  • compositions of the invention Another property of the compositions of the invention is their palatability as compared with their counte ⁇ art CREMOPHORTM EL (a polyethoxylated castor oil)/EtOH based formulations.
  • Formulations prepared with traditional stabilizers have an unpleasant bitter taste probably due to the castor oil.
  • For this pu ⁇ ose 5 ml aliquots of Formula One (40% Vitamin E. TPGS + 40% propylene glycol + 20% ethanol, see Example 1) and 75% CREMOPHORTM EL + 25% Ethanol were placed in 17 glass vials (an additional vial without formulations was used as a negative control).
  • Various flavors commercially available from international flavor & Fragrances, Inc., Dayton, NJ; Crompton & Knowles, Charlotte, N.C.
  • the pu ⁇ ose of the following experiment was to illustrate the ability of representative compositions and methods of the invention to yield abso ⁇ tion values greater than those observed with prior art IV methodologies.
  • Each group of animals received one oral dose of cyclosporin A (5 mg/kg) prior to dosing with a representative pharmaceutical composition according to the invention including paclitaxel.
  • One hour subsequent to cyclosporin dosing each group received approximately 9 mg/kg of paclitaxel orally in a composition according to the invention.
  • Blood samples were collected from each animal at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose of paclitaxel.
  • the blood samples were combusted and assayed for total radioactivity.
  • the total blood radioactivity levels (corresponding to concentration in the blood of 3 H-paclitaxel) were plotted on a graph vs. time post-dose.
  • Data for each group of rats were compiled in the form of mean AUC, Cmax and Tmax.
  • the percentage of abso ⁇ tion of H-paclitaxel for each group of animals was calculated by comparing the mean AUC value for the group to the corresponding mean AUC of a reference group of rats administered 3 H-paclitaxel (9 mg/kg) intravenously in the form of PAXENE TM (Baker Norton Pharmaceuticals, Miami FL) which includes CREMOPHORTM EL, ethanol and citric acid.
  • PAXENE TM Boker Norton Pharmaceuticals, Miami FL
  • CREMOPHORTM EL CREMOPHORTM EL
  • citric acid citric acid
  • the table sets forth the total dose of paclitaxel inco ⁇ orated into each vehicle as actually administered to the experimental animals, the concentration of paclitaxel in the composition, the HLB value of the carrier, the mean AUC value for the group of rats receiving the formulation and the percentage of paclitaxel abso ⁇ tion in comparison with rats receiving IV administration.
  • Table 7 Absorption Results of Polyoxyethylated (POE) Sorbitan
  • Table 8 summarizes data for formulations containing POE alkyl ethers as carriers. The data correspond to the data described in the preceding table.
  • Table 10 summarizes data for formulations containing ethoxylated-modified triglycerides as carriers. The data set forth correspond to the data described in Example 7.
  • Table 11 summarizes data for formulations containing POE 660 hydroxystearates as carriers. The data set forth correspond to the data described in Example 7.
  • Table 12 summarizes data for formulations containing saturated polyglycolized glycerides as carriers. The data set forth correspond to the data described in Example 7.
  • Mygliols Neutral oils (saturated coconut and palm kernel fatty acids) mainly C8 - n CIO fatty acids
  • Cremophor EL Polyoxyl 35 castor oil (HLB 12 - 14)
  • Cremophor RH 40 Polyoxyl 40 Hydrogenated castor oil (HLB 14 - 16) Vitamin E TPGS Systems as Carriers
  • Table 13 summarizes data for formulations containing Vitamin E TPGS systems as carriers. The data set forth correspond to the data described in Example 7.
  • Table 14 summarizes data for formulations containing POE and hydrogenated castor oil derivatives as carriers. The data set forth correspond to the data described in Example 7.
  • Polysorbate 80 Carriers Table 15 summarizes data for formulations containing polysorbate 80 as at least one of the carriers. The data set forth correspond to the data described in Example 7.
  • TBC Tributyl citrate (citrate ester)
  • ATEC Acetyl triethyl citrate (citrate ester)
  • the present invention is useful in clinical medicine, and particularly in the treatment of malignant and non-malignant diseases.

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Abstract

L'invention concerne des compositions à base de taxane et des procédés permettant d'utiliser ces compositions pour atteindre des concentrations sanguines cibles de taxane chez un mammifère, par exemple, pour traiter des maladies malignes et des maladies bénignes. Les compositions décrites dans cette invention présentent une stabilité à long terme et une sapidité globale. L'invention concerne également des procédés permettant d'utiliser ces compositions comme outils d'analyse dans des études pharmacocinétiques.
EP01920699A 2000-03-24 2001-03-23 Compositions a base de taxane et procedes d'utilisation Withdrawn EP1315484A1 (fr)

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Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2466851C (fr) * 2001-11-26 2012-09-11 Supergen, Inc. Procede de preparation et d'utilisation d'huile de ricin polyoxyethylee dans des compositions pharmaceutiques
CA2471572A1 (fr) * 2001-12-28 2003-07-17 Ivax Research, Inc. Compositions a base de taxane et procedes d'utilisation
KR100533458B1 (ko) * 2002-07-20 2005-12-07 대화제약 주식회사 파클리탁셀의 가용화용 조성물 및 그의 제조 방법
AU2002950713A0 (en) 2002-08-09 2002-09-12 Vital Health Sciences Pty Ltd Carrier
US7989490B2 (en) * 2004-06-02 2011-08-02 Cordis Corporation Injectable formulations of taxanes for cad treatment
EP2269650A3 (fr) * 2004-08-03 2012-05-16 Vital Health Sciences Pty Ltd. Support pour l'administration entérale
KR100866728B1 (ko) * 2004-11-12 2008-11-03 주식회사종근당 타크로리무스를 함유하는 주사제
EP1690551A3 (fr) 2005-02-10 2006-10-18 Sindan Pharma Srl Purification d'un tenside par ultrafiltration
WO2006084902A2 (fr) * 2005-02-10 2006-08-17 Sindan Pharma Srl Procede de purification d'un agent de surface
CA2611831C (fr) 2005-06-17 2014-09-16 Vital Health Sciences Pty Ltd. Charge comprenant un ou plusieurs derives de di- et/ou monophosphate d'agent de transfert d'electrons ou des complexes de ceux-ci
JP2008543789A (ja) * 2005-06-17 2008-12-04 ホスピラ オーストラリア ピーティーワイ エルティーディー ドセタキセルの液体薬学的処方物
CA2620585C (fr) 2005-08-31 2015-04-28 Abraxis Bioscience, Llc Compositions comprenant des agents pharmaceutiques peu solubles dans l'eau et des agents antimicrobiens
US8512761B2 (en) * 2006-01-27 2013-08-20 Yale University Fast acting inhibitor of gastric acid secretion
BRPI0600194A (pt) * 2006-01-30 2007-10-23 Quiral Quimica Do Brasil S A composições farmacêuticas contendo docetaxel e um inibidor de degradação e processo de obtenção das mesmas
ES2344674B1 (es) 2008-08-07 2011-06-29 Gp Pharm, S.A. Composicion farmaceutica inyectable de taxanos.
JO3434B1 (ar) * 2009-07-31 2019-10-20 Millennium Pharm Inc مركبات صيدلانية لمعالجة السرطان وامراض واضطرابات اخري
US7772274B1 (en) 2009-10-19 2010-08-10 Scidose, Llc Docetaxel formulations with lipoic acid
US8912228B2 (en) 2009-10-19 2014-12-16 Scidose Llc Docetaxel formulations with lipoic acid
US8541465B2 (en) 2009-10-19 2013-09-24 Scidose, Llc Docetaxel formulations with lipoic acid and/or dihydrolipoic acid
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
ES2829386T3 (es) 2010-03-30 2021-05-31 Phosphagenics Ltd Parche de administración transdérmica
CN109745287A (zh) 2010-05-03 2019-05-14 帝国制药美国公司 非水性紫杉烷前-乳剂制剂以及制备和使用该制剂的方法
AU2011327824B2 (en) * 2010-11-08 2016-06-02 Cadila Pharmaceuticals Limited Pharmaceutical composition of taxoids
EP2685992A4 (fr) 2011-03-15 2014-09-10 Phosphagenics Ltd Amino-quinoléines en tant qu'inhibiteurs de kinase
JO3685B1 (ar) 2012-10-01 2020-08-27 Teikoku Pharma Usa Inc صيغ التشتيت الجسيمي للتاكسين غير المائي وطرق استخدامها
CN105209042B (zh) 2013-03-22 2019-03-08 米伦纽姆医药公司 催化性mtorc 1/2抑制剂与选择性极光a激酶抑制剂的组合
AU2016367708B2 (en) 2015-12-09 2022-07-14 Phosphagenics Limited Pharmaceutical formulation
MX2019006845A (es) 2016-12-21 2019-10-15 Avecho Biotechnology Ltd Proceso.
CN110585189B (zh) * 2019-09-05 2022-12-30 广东艾时代生物科技有限责任公司 三尖杉宁碱在制备治疗疟疾药物中的应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW406020B (en) * 1993-09-29 2000-09-21 Bristol Myers Squibb Co Stabilized pharmaceutical composition and its method for preparation and stabilizing solvent
US5919815A (en) * 1996-05-22 1999-07-06 Neuromedica, Inc. Taxane compounds and compositions
KR19990075621A (ko) * 1998-03-23 1999-10-15 임성주 경사 평판형 배양조
CN1225262A (zh) * 1998-12-09 1999-08-11 延边香料研究所 一种含有紫杉醇的抗癌药物
US6136846A (en) * 1999-10-25 2000-10-24 Supergen, Inc. Formulation for paclitaxel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0172299A1 *

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