WO2001072300A1 - Uses of metal salts to stabilize taxane-based compositions - Google Patents
Uses of metal salts to stabilize taxane-based compositions Download PDFInfo
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- WO2001072300A1 WO2001072300A1 PCT/US2001/009416 US0109416W WO0172300A1 WO 2001072300 A1 WO2001072300 A1 WO 2001072300A1 US 0109416 W US0109416 W US 0109416W WO 0172300 A1 WO0172300 A1 WO 0172300A1
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- 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
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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
- A61K31/28—Compounds containing heavy metals
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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
- A61K31/335—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
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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
- A61K31/335—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
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- 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
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- Taxol (paclitaxel) is a compound extracted from the bark of a western yew, Taxus brevifolia and known for its antineoplastic activity. Since 1977, taxol has been tested and used as an antineoplastic agent because of its unique mechanism of action and good cytotoxic activity against IP implanted D16 melanoma and the human X-l mammary tumor xenograft. Paclitaxel has been widely used in treating ovarian and breast cancer. It has also been shown to be effective against other types of cancer, such as melanoma, lymphoma, and those developed in the lung, head and neck.
- paclitaxel has a bioavailability of 0% upon oral administration (Second NCI Workshop on Taxol and Taxus (Sept. 1992)). Accordingly, efforts have been directed to other modes of administration, such as intravenous injection ("IN").
- taxol exhibits poor solubility in aqueous solution.
- One approach to address the poor solubility of taxanes such as paclitaxel has been to seek excipients which increase the solubility of paclitaxel.
- paclitaxel formulations for IN administration have been developed utilizing a surfactant, such as polyethoxylated castor oil which is commercially available as CREMOPHOR ELTM, as a drug carrier.
- Polyethoxylated castor oils are commonly used as solubilizing and/or dispersing agents for a variety of pharmaceutically active agents that are substantially insoluble in water.
- surfactants in the formulation compromises the stability of paclitaxel. Impurities tend to catalyze the decomposition of the pharmaceutically active agents, particularly antineoplastic agents such as paclitaxel.
- pharmaceutical compositions of paclitaxel in a co-solvent system containing dehydrated ethyl alcohol and commercial grade Cremophor EL® exhibit a loss of potency of greater than 60% after storage for 12 weeks at 50°C, the loss of which is attributable to the decomposition of paclitaxel during storage.
- impurities such as colorants and dopants that are contained in the castor oil solution that is used to prepare the pharmaceutical composition
- other impurities are formed during storage of the ultimate pharmaceutical formulation.
- impurities include fibrous precipitate of unknown composition, and which also cause loss of potency of the active agent.
- Various attempts have been made to increase paclitaxel stability in IN formulations.
- Aluminum oxide and magnesium silicates have been used to eliminate carboxylate anions from Cremophor. See WO 98/30205. Acidifying agents have also been tested for increasing taxol stability. See U.S. Patent 5,977,164. Agharkar, et al, U.S. Patent 5,504,102 discloses treating a polyoxyethylated castor oil with an acid or contacting with alumina to reduce the carboxylate anion content. The low carboxylate anion content of the solvent is believed to provide extended shelf life and lower amounts of degradation by-products.
- International patent publication WO 00023070 is directed to a method of purifying polyethoxylated castor oils using a combination of an activated carbon column and an ion exchange resin column.
- ZA 9903053 to Schein Pharmaceutical, Inc. teaches a polyethoxylated castor oil with low cation content ("lcp-castor oil"), wherein the cation concentrations are no greater than Al (20), K (20), Na (12) and Ca (80), expressed in ppm.
- the lcp-castor oil is purified by contacting an untreated or partially treated polyethoxylated castor oil with an activated cationic exchange resin.
- Patent 5,925,776 also teaches a low cation content polyethoxylated castor oil prepared by contacting the polyethoxylated castor oil with a strong cation exchange resin such as sulfonated divinylbenzene-styrene copolymer.
- Dralle-Nass, et al, U.S. Patent 5,925,776, is directed to a method of purifying alkoxylated fats such as Cremophor with a mixture of alumina and silicate (e.g., Mg, Ca or Al) solids followed by filtration.
- a paclitaxel-containing solution is contacted with a molecular sieve material, preferably porous Al 2 O 3 (or zeolite) having a particle size of 5-200 microns and a pore size of up to about 150 angstroms.
- EP 674510 Bl to Napro Biotherapeutics teaches a composition of taxol and polyethoxylated castor oil having a pH less than 8.1.
- the pH balance reportedly improves stability.
- citric acid is used to adjust the pH value.
- Such IN formulations should be capable of achieving target therapeutic blood levels of taxane and be suitable to maintain the taxane in solution.
- the IN formulations should also be chemically stable over extended periods of time, and possess overall palatability while demonstrating long term stability.
- the present invention provides compositions containing a taxane and a carrier stabilized with at least one metal salt of an acid.
- the acid is gluconic acid, an amino acid, ascorbic acid, palmitic acid, citric acid, an alpha or a beta hydroxy acid, sulfuric acid, alpha-hydroxymethylsulfinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, benzoic acid, or sulfonic acid
- the metal is iron, copper, zinc, calcium, manganese, magnesium, aluminum, tin, lanthanum, platinum, cerium, or titanium.
- the metal salt is zinc methionine, sodium hydroxymethylsulfinate or an iron, copper, zinc, calcium, manganese, magnesium, aluminum, or titanium gluconate or hydroxymethylsulfinate.
- the carrier contains both a polyethoxylated castor oil such as Cremophor and a co-solubilizer such as vitamin E TPGS.
- the stabilized taxane compositions are prepared by contacting the castor oil and the metal salt prior to the addition of the taxane.
- the metal salt and castor oil are mixed together and then heated, or the castor oil is applied to a column containing the metal salt.
- the castor oil is contacted with activated charcoal in a separate step.
- the metal salt stabilizes the taxane by inhibiting or protecting against solvolysis of the ester side chain at C-13, deacetylation at C-10 and/or epimerization at C-7 (compared to solvolysis, deacetylation and epimerization at the same positions of the taxane in a composition comprising the taxane and the castor oil but not the metal salt).
- Taxanes as used herein identifies 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) and purely synthetic taxanes.
- the taxane is selected from the group consisting of paclitaxel, docetaxel, derivatives, metabolites, analogs 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 formulations of the present invention may vary based on the carrier(s), co-solubilizer(s) and/or metal salts and on the desired total dose of taxane to be administered intravenously to a mammal.
- the concentration of taxane in the compositions ranges 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.
- the metals are non-toxic and can be found in Martindale - The Extra Pharmacopeia, James E.F. Reynolds, Ed., The Pharmaceutical Press, London, the content of which is incorporated herein by reference.
- the metals include, but are not limited to copper (Cu ++ ), magnesium (Mg ++ ), zinc (Zn ++ ), calcium (Ca ++ ), iron (Fe ++ and Fe +++ ), aluminum (Al +++ ), cobalt (Co ++ ), titanium (Ti +++ and Ti + ), platinum (Pt**), lanthanum (La +++ ), cerium (Ce ⁇ "" and Ce 4+ ), selenium (Se 4+ ), and manganese (Mn ++ ).
- Suitable acids include amino acids, ascorbic acid, saturated or unsaturated fatty acids such as palmitic acid, alpha and beta hydroxy acids, e.g. gluconic acid and citric acid, sulfuric acid, alpha-hydroxymethylsulfinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, benzoic acid, selenious acid, and sulfonic acid.
- amino acids examples include naturally occurring amino acids such as glycine, alanine, leucine, isoleucine, phenylalanine, tryptophan, aspartic acid, glutamic acid, methionine, threonine, valine, lysine, arginine, serine, histidine, proline, glutamine, methionine and asparagine, and synthetic non-naturally occurring amino acids.
- Methionine is a preferred amino acid
- zinc methionine is a preferred metal salt.
- Synthetic amino acids include derivatives of the naturally occurring amino acids such as N-alkylated or N-hydroxy-alkylated amino acids.
- metal salts include iron, copper, zinc, calcium, manganese, magnesium, aluminum, or titanium gluconate or hydroxymethylsulfinate.
- arsenates, cyanates and other toxic metal salts can not be used in the present taxane formulation.
- amounts of the metal salt effective to provide increased stability of the taxane range from about 0.2% to about 5% of the composition by weight. A preferred range is from about 0.4% to 3% and a more preferred range is from about 0.6% to about 2%.
- 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 which 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.
- Representative 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 - C 18 fatty acids; CREMOPHOR TM 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.
- 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 - C 18 fatty acids
- the castor oil is preferably is a polyethoxylated castor oil, or polyethoxylated castor oil derivatives.
- the pharmaceutical composition further comprises a de
- 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.
- Preferred 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.
- viscosity-reducing co-solubilizers include PHARMASOLVETM (N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ); MIGLYOLTM 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.
- PHARMASOLVETM N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ
- MIGLYOLTM 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 TM polyethylene glycol esters of caprylic and capric acids H ⁇ ls AG
- modified castor oils including polyoxyethylated or hydrogenated castor oils (such as CREMOPHOR TM EL, EP-P or RH 40) (BASF, Mt.
- oils such as olive oil, polyoxyethylated fatty ethers or modified castor oils; certain saturated polyglycolyzed glycerides, including glycerides of C 8 - C 18 fatty acids (such as a LABRASOL ); citrate esters such as tributyl citrate, triethyl citrate and acetyl triethyl citrate, propylene glycol, alone or in combination with PHARMASOLVE , ethanol (including dehydrated ethanol), water, and lower molecular weight polyethylene glycols such as PEG having a molecular weight in the range of 200 to 400 daltons, preferably PEG 200, PEG 300 and/or PEG 400.
- PEG having a molecular weight in the range of 200 to 400 daltons, preferably PEG 200, PEG 300 and/or PEG 400.
- the co-solubilizer is ethanol. In a more particularly preferred embodiment, 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 solubilized 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.
- 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.
- Preferred surfactants include Vitamin E (e.g. alpha-tocopherol) and beta-carotene.
- the carrier is pretreated with the metal salt prior to preparing the final taxane composition.
- the metal salt may or may not be present in the final composition.
- the carrier and the metal salt are added together and the resultant solution (dispersion) is heated, typically at a temperature from about 30°C to about 60°C for a time generally in the range of from about 30 minutes to about 8 hours.
- the carrier is applied to a matrix such as column containing the metal salt. Columns containing metal salts are prepared by filling a suitable column with a metal salt. Columns of any size can be used in the present invention. However, the column is preferably between 10 cm and 2 meters in length and between 1 cm and 30 cm in diameter.
- the metal salt has a particle size of between 0.1 ⁇ m and 3 mm in diameter, preferably between 1 ⁇ m and 1 mm.
- the carrier is treated by passing it through the metal salt column at a rate of between 0.1 ml/min and 500 ml/min, preferably at a rate of between 1.0 ml/min and 200 ml/min.
- 18 g ferrous sulfate is packed into an empty HPLC steel column 250 mm x 4.6 mm, Cremophor EL is pumped through the packed column at a flow rate of approximately 0.2 mlJmin.
- the treated Cremophor EL is then used in the taxane formulation.
- the pretreatment with the metal salt is performed in conjunction with another pretreatment with activated charcoal.
- Activated charcoal is commercially available from several sources e.g., Calgon (Pittsburg, PA) and Spectrum Chemical Manufacturing Corp. (Gardena, CA).
- charcoal may be activated in accordance with standard procedures, notably by chemical treatment, or steam or some other heat source, charcoal can be "activated”.
- Bon Subscribe-Faivre, et al., Life Sci. 6 ' 6Y°):817-827 (2000) discloses pinewood charcoal LSM (CECA-SA, 92 La Defense) and peat charcoal SX4 (Norit 93, Le Blanc Masnil), activated by steam and washed with phosphoric acid.
- the surface absorption for pinewood charcoal is 1,000 m 2 /g and 650 m 2 /g for peat charcoal.
- the activated charcoal has a surface area ranging from about 500 to about 1300 m /g (including sub-ranges thereof), and preferably a median surface area range of about 900 m /g.
- taxane carriers such as castor oils with charcoal is described in International patent publication WO 00023070.
- a predetermined amount of the carrier is added together with activated charcoal to produce a suspension of the charcoal in the carrier.
- the product is thus a free suspension of the activated charcoal.
- the charcoal is present in the suspension in an amount of from 3 to about 20% (w/w), preferably from about 5 to about 10 % (w/w), including sub- ranges thereof.
- the carrier and activated charcoal are allowed to remain in contact under conditions (e.g., time and temperature) to allow removal or capture of impurities by the charcoal.
- the activated charcoal adsorbs the impurities.
- the suspension is heated, generally at a temperature of from about 30°C to about 60°C, and for a period of time from about 1 to about 6 hours, including sub-ranges thereof. It is believed that the heating enhances absorption of impurities and thus facilitates their removal from the carrier. It is also preferred to stir the suspension, at least periodically.
- the activated charcoal is then separated from the carrier. This separation is conveniently performed by at least one filtration step. In the event that two or more filtration steps are used, filters having successively smaller apertures are used.
- the heated suspension is filtered while it is still heated. It is believed that the lesser viscosity of the heated suspension facilitates filtration. In less preferred embodiments, the heated suspension is allowed to cool to about room temperature, optionally with stirring. Other techniques for separating or removing activated charcoal are known in the art.
- the taxane in the formulations of the present invention exhibits reduced solvolysis of an ester side chain at C-13, reduced deacetylation at C-10, and/or reduced epimerization at C- 7 thereof.
- the stabilization of a taxane provided by a metal salt may be determined by the extent of the reduction of one or more known degradation products (e.g., 7- epi-taxol C, 10-decetyl taxol, 7-epi-taxol, 7-epi-10-deacetyl-taxol, baccatin III, 10- deacetylbaccatin III, cephalomannine, nitine, 7-epi-cephalomannine.
- 7- epi-taxol C 10-decetyl taxol
- 7-epi-taxol 7-epi-10-deacetyl-taxol
- baccatin III 10- deacetylbaccatin III
- cephalomannine nitine, 7-ep
- a bioavailability enhancing agent can also be used in conjunction with the formulations of the present invention. See U.S. Patent 5,968,972 to Broder, et al.
- 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.
- 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.
- the present invention is intended for use with any mammal that may benefit from the compositions of the present invention.
- mammals Foremost among such mammals are humans, although the invention is not intended to be so limited, and is applicable to veterinary uses.
- the compositions are useful in the treatment of both malignant and non-malignant diseases.
- Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 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)).
- the following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature.
- EXAMPLE 1 Stability Tests of Paclitaxel in Pretreated Cremophor EL The stabilizing effect of coordinating metal salts, such as zinc, copper and ferrous sulfate or gluconate, on paclitaxel in an EtOH/EL (50:50) formulation (6 mg/mL) was examined. Salt columns were used to treat Cremophor EL before being added to paclitaxel formulations, which was then analyzed after being subjected to stress (24 hours at 80°C).
- coordinating metal salts such as zinc, copper and ferrous sulfate or gluconate
- Paclitaxel formulation (6 mg/mL) in Cremophor EL/EtOH (50:50) was used as the control. It was prepared by (1) adding 60 mg of paclitaxel bulk powder and 3 ml absolute ethanol to a 10 ml volumetric flask, (2) swirling and gently warming the flask until complete dissolution of the paclitaxel powder, (3) adding 5.27 g Cremophor EL to the solution, and (4) diluting the resulting mixture to a final volume of 10 ml with absolute ethanol.
- the metal salt formulations were prepared in a similar manner as the control, except step (3). Instead of adding 5.27 g Cremophor EL to the solution, the Cremophor EL was suspended in about 5 ml of ethanol and the Cremophor EL suspension was stirred over the metal salt, i.e., zinc gluconate, ferrous gluconate, copper gluconate, or ferrous sulfate, for 4 hours at 45°C. The Cremophor EL suspension was then filtered and added to the 10 ml volumetric flask to prepare paclitaxel formulation. The paclitaxel samples and the control were tested for thermal stability by treating the samples at 80°C for 24 hours. The stability tests of these paclitaxel formulations are shown in Table 1 below.
- control is prepared in the same way as in Example 1.
- Paclitaxel composition containing zinc gluconate was prepared by (1) mixing 100 ⁇ L of a zinc gluconate solution (100 mg/mL) in H 2 O with an aliquot (2.0 mL) of a solution (6 mg/mL) of paclitaxel in Cremophor EIJEtOH (50:50), (2) vortexing the resulting suspension for five minutes, and (3) filtering the mixture using a 0.45 ⁇ m filter to obtain a clear, colorless solution.
- Paclitaxel composition containing Cu 2+ Gluconate, Fe 2+ Gluconate, Ca 2+ Ascorbate, FeSO , A.A 6-Palmitate, or HOCH 2 SO 2 Na was prepared in the same way.
- the paclitaxel samples and the control were subjected to 80°C for 24 hours. Then the paclitaxel degradation was tested.
- the paclitaxel stability tests results are shown in Table 2.
- Paclitaxel formulation (6 mg/mL) in Vitamin E TPGS/EtOH (50:50) was used as control. It was prepared by (1) preparing a working placebo of Vitamin E TPGS/EtOH (50:50) by gently warming a mixture of Vitamin E TPGS and absolute ethanol, (2) adding the placebo (7 mL) to a 10 ml volumetric flask containing paclitaxel bulk powder (60 mg), (3) stirring the mixture at room temperature until complete dissolution of the paclitaxel, and (4) diluting the resulting solution to a final volume of 10 ml with the placebo.
- the paclitaxel formulations containing metals salts were prepared by adding various amount of Cu “1"1" Gluconate, Fe ++ Gluconate, Zn ++ Gluconate, or HOCH 2 SO 2 Na to the control formulation.
- the stability test results were listed in Table 3.
- Paclitaxel formulation (6 mg/mL) in Vitamin E TPGS/PG/EtOH (40:40:20) was used as control. It was prepared by (1) preparing a working solution of the placebo by gently warming a mixture of Vitamin E TPGS, propylene glycol and absolute ethanol (ratio 40:40:20), (2) adding the placebo (7 mL) to a 10 ml volumetric flask containing 60 mg paclitaxel, (3) stirring the mixture at room temperature until complete dissolution of the paclitaxel powder, and diluting the resulting solution to final volume of 10 ml with absolute ethanol.
- the paclitaxel formulation containing Ascorbyl 6-Palmitate was prepared by adding Ascorbyl 6-Palmitate to the control formulation.
- the stability test results were listed in Table 4.
- Ascorbyl palmitate (5 mg) added as an ethanol solution to the paclitaxel formulation.
- the data in Table 4 show that in the presence of Ascorbyl 6-Palmitate, paclitaxel degradation is less than 1% after being exposed to a temperature of 80°C for 24 hours. In the absence of Ascorbyl 6-Palmitate, paclitaxel degradation in the formulation is more than 34% after being exposed to the same condition.
- EXAMPLE 5 Paclitaxel Stability Test in the Presence of Zn Methionine
- the sample is prepared by suspending 100 mg of ZnMet and 60 mg of paclitaxel in 10 ml of a mixture of Cremophor EL and Ethanol.
- the control is prepared by suspending 60 mg of paclitaxel in 10 ml of a mixture of Cremophor EL and Ethanol. Both the sample and the control are treated 80°C for 48 hours and then tested for paclitaxel stablilities.
- the stability of paclitaxel in the sample is more than 98% while the stability of paclitaxel in the control is less than 60%.
- 10 mg of ZnMet and 6 mg of paclitaxel were suspended in a mixture of Cremophor EL and Ethanol.
- Cremophor El (-400 mL) was pumped through a steel column containing activated charcoal (34 g) at a flow rate of approximately 0.2 mlVmin. The initial eluate (-20 mL) was discarded and the successive fraction (-45 mL) was collected and subsequently passed through a second steel column containing FeSO (18 g). The initial eluate was discarded (-20 mL) and the remainder of material was used to prepare the Paclitaxel formulation for stability analysis.
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CA002404374A CA2404374A1 (en) | 2000-03-24 | 2001-03-23 | Use of metal salts to stabilize taxane-based compositions |
JP2001570261A JP2003528142A (en) | 2000-03-24 | 2001-03-23 | Use of metal salts to stabilize taxane-based compositions |
EP01920712A EP1408956A1 (en) | 2000-03-24 | 2001-03-23 | Uses of metal salts to stabilize taxane-based compositions |
AU2001247739A AU2001247739A1 (en) | 2000-03-24 | 2001-03-23 | Uses of metal salts to stabilize taxane-based compositions |
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US19180200P | 2000-03-24 | 2000-03-24 | |
US60/191,802 | 2000-03-24 |
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PCT/US2001/009416 WO2001072300A1 (en) | 2000-03-24 | 2001-03-23 | Uses of metal salts to stabilize taxane-based compositions |
PCT/US2001/009382 WO2001072299A1 (en) | 2000-03-24 | 2001-03-23 | Taxane-based compositions and methods of use |
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EP (2) | EP1315484A1 (en) |
JP (2) | JP2003528142A (en) |
KR (2) | KR20030019328A (en) |
AR (2) | AR027714A1 (en) |
AU (2) | AU2001247726A1 (en) |
CA (2) | CA2404370A1 (en) |
WO (2) | WO2001072300A1 (en) |
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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 (en) * | 1998-03-23 | 1999-10-15 | 임성주 | Inclined Plate Culture Tank |
US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
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- 2001-03-23 AR ARP010101394A patent/AR027714A1/en not_active Application Discontinuation
- 2001-03-23 WO PCT/US2001/009416 patent/WO2001072300A1/en not_active Application Discontinuation
- 2001-03-23 EP EP01920699A patent/EP1315484A1/en not_active Withdrawn
- 2001-03-23 JP JP2001570261A patent/JP2003528142A/en active Pending
- 2001-03-23 JP JP2001570260A patent/JP2003528141A/en active Pending
- 2001-03-23 AU AU2001247726A patent/AU2001247726A1/en not_active Abandoned
- 2001-03-23 CA CA002404370A patent/CA2404370A1/en not_active Abandoned
- 2001-03-23 KR KR1020027012469A patent/KR20030019328A/en not_active Application Discontinuation
- 2001-03-23 KR KR1020027012452A patent/KR20030019327A/en not_active Application Discontinuation
- 2001-03-23 AU AU2001247739A patent/AU2001247739A1/en not_active Abandoned
- 2001-03-23 CA CA002404374A patent/CA2404374A1/en not_active Abandoned
- 2001-03-23 WO PCT/US2001/009382 patent/WO2001072299A1/en not_active Application Discontinuation
- 2001-03-23 EP EP01920712A patent/EP1408956A1/en not_active Withdrawn
- 2001-03-23 AR ARP010101395A patent/AR027715A1/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
WO2001072299A1 (en) | 2001-10-04 |
AR027715A1 (en) | 2003-04-09 |
JP2003528142A (en) | 2003-09-24 |
AR027714A1 (en) | 2003-04-09 |
EP1315484A1 (en) | 2003-06-04 |
KR20030019327A (en) | 2003-03-06 |
CA2404374A1 (en) | 2001-10-04 |
KR20030019328A (en) | 2003-03-06 |
AU2001247739A1 (en) | 2001-10-08 |
CA2404370A1 (en) | 2001-10-04 |
AU2001247726A1 (en) | 2001-10-08 |
EP1408956A1 (en) | 2004-04-21 |
JP2003528141A (en) | 2003-09-24 |
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