Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-02
2003-10-28
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06638973
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to various formulations of taxane derivatives having improved solubility as compared to paclitaxel, particularly formulations of such taxane derivatives for parenteral administration to a patient.
Paclitaxel has shown remarkable antineoplastic effect in a wide range of human cancers. Initially approved in 1992 for the treatment of refractory ovarian cancer, paclitaxel is now the first-line therapy for metastatic breast cancer and advanced ovarian cancer. Paclitaxel's effectiveness has also been demonstrated against non-small cell lung cancer, head and neck cancers, melanoma, colon cancer and Kaposi's sarcoma. In addition to its cytotoxic effects, paclitaxel has also been shown to be a potent inhibitor of angiogenesis. Despite its broad clinical utility, there has been difficulty formulating paclitaxel because of its insolubility in water. The aqueous solubility of paclitaxel is only 0.25 g per ml. Paclitaxel is also insoluble in most pharmaceutically-acceptable solvents, and lacks a suitable chemical functionality for formation of a more soluble salt. Consequently, special formulations are required for parenteral administration of paclitaxel. Paclitaxel is very poorly absorbed when administered orally (less than 1%). No oral formulation of paclitaxel has obtained regulatory approval for administration to patients.
Paclitaxel is currently formulated as Taxol®, which is a concentrated nonaqueous solution containing 6 mg paclitaxel per ml in a vehicle composed of 527 mg of polyoxyethylated castor oil (Cremophor® EL) and 49.7% (v/v) dehydrated ethyl alcohol, USP, per milliliter (available from Bristol-Myers Squibb Co., Princeton, N.J.). Cremophor® EL improves the physical stability of the solution, and ethyl alcohol solubilizes paclitaxel. The solution is stored under refrigeration and diluted just before use in 5% dextrose or 0.9% saline. Intravenous infusions of paclitaxel are generally prepared for patient administration within the concentration range of 0.3 to 1.2 mg/ml. In addition to paclitaxel, the diluted solution for administration consists of up to 10% ethanol, up to 10% Cremophor® EL and up to 80% aqueous solution. However, dilution to certain concentrations may produce a supersaturated solution that could precipitate. An inline 0.22 micron filter is used during Taxol® administration to guard against the potentially life-threatening infusion of particulates.
Several toxic side effects have resulted from the administration of paclitaxel in a Cremophor®/ethanol-based formulation including anaphylactic reactions, hypotension, angioedema, urticaria, peripheral neuropathy, arthralgia, mucositis, nausea, vomiting, alopecia, alcohol poisoning, respiratory distress such as dyspnea, cardiovascular irregularities, flu-like symptoms such as myalgia, gastrointestinal distress, hematologic complications such as neutropenia, genitourinary effects, and skin rashes. Some of these undesirable adverse effects were encountered in clinical trials, and in at least one case, the reaction was fatal. To reduce the incidence and severity of these reactions, patients are premedicated with corticosteroids, diphenhydramine, H
2
-antagonists, antihistamines, or granulocyte colony-stimulating factor (G-CSF), and the duration of the infusion has been prolonged. Although such premedication has reduced the incidence of serious hypersensitivity reactions to less than 5%, milder reactions are still reported in approximately 30% of patients.
There is an additional drawback to the Cremophor®-based formulation. Cremophor® EL can leach phthalate plasticizers from polyvinyl chloride infusion bags and intravenous administration set tubing. This has led to the use of glass bottles or polyolefin containers for storing Taxol® solution and polyethylene-lined administration tubing or tubing made with tris (2-ethylhexyl) trimellitate plasticizer for Taxol® administration.
The physiological problems associated with paclitaxel administration have limited the dosage of paclitaxel that a patient can receive and prolonged the time of administration. Paclitaxel is typically given in a dose ranging from about 110 mg/m
2
to 300 mg/m
2
over a 3-24 hour period every 21 days or more, often with premedication. At dosages above 300 mg/m
2
, peripheral neuropathy has been observed. Infusion times do not generally exceed 24 hours because the paclitaxel is physically stable for only 27 hours.
In instances where a patient receives a multi-day continuous infusion, the patient must have a new bag of Taxol® solution each day. In addition to the inconvenience for patients and staff and increased therapy cost, the bag exchange increases the risk of intravenous catheter microbial colonization. It would be advantageous to have a taxane product that remains stable for the entire period of the multi-day administration.
There is a strong need for reformulating taxane compositions using a safer and better-tolerated vehicle than Cremophor®. Alternative formulations of paclitaxel that avoid the use of Cremophor® have been proposed. One approach is incorporation of the drug into a liposomal formulation. However, it has been reported that there is difficulty in achieving a quantitative incorporation of the drug into the liposomal compartment, and that low loading capability and nonspecific uptake by the reticuloendothelial system have limited the clinical usefulness of such liposomes. This formulation is also not storage stable and must be freeze dried and reconstituted before use.
Another approach is to formulate paclitaxel as a lipid emulsion. Most of the efforts to create a paclitaxel formulation as a stable lipid emulsion have been unsuccessful. It has been widely reported in the literature that paclitaxel is insoluble in lipid emulsions containing soybean oil, such as Intralipid®, or lipid emulsions that are a mixture of soybean and safflower oils, such as Liposyn®. See, for example, L. C. Collins-Gold et al., “Parenteral Emulsions for Drug Delivery,” Advanced Drug Delivery Reviews, 5, 189-208 (1990); B. D. Tarr, “A New Parenteral Emulsion for the Administration of Taxol,” Pharmaceutical Research, 4(2), 163 (1987); Dolatrai M. Vyas, Paclitaxel (Taxol) Formulation And Prodrugs, The Chemistry and Pharmacology of Taxol and its Derivatives, Elsevier Science B. V., 107 (1995); J. M. Meerum Terwogt et al., “Alternative Formulations of Paclitaxel” Cancer Treatment Reviews, 23, 89 (1997). Paclitaxel's solubility in soybean oil is only 0.3 mg/ml. Vyas, supra. Physical methods for solubilizing paclitaxel in either soybean oil or safflower oil, such as heating or heating with sonication do not solubilize appreciable amounts of paclitaxel. Thus, the lipid emulsion formulations have significant drawbacks in that additives are still needed to solubilize paclitaxel and to prevent it from precipitating out of solution.
Tarr et al., supra, developed a parenteral triacetin emulsion formulation of paclitaxel. The emulsion contained 50% triacetin, 2.0% ethyl oleate, 1.5% Pluronic® F68, 1.5% purified soybean oil and 10 mg paclitaxel. Glycerol was added up to 10% to prevent creaming. This emulsion was reported to be adequately stable for parenteral administration. However, triacetin (glyceryl triacetate) itself proved to be toxic to mice when administered intravenously in concentrations required to deliver therapeutic doses of paclitaxel. Furthermore, no antitumor activity was observed with this formulation.
Andersson, U.S. Pat. No. 5,877,205, discloses a pharmaceutical composition for parenteral administration containing a taxane analog, dimethylacetamide, polyethylene glycol and an aqueous lipid emulsion. The aqueous lipid emulsion is preferably a soybean oil emulsion. Andersson solubilizes paclitaxel by dissolving it in an organic solvent of dimethylacetamide as the primary vehicle and adding a secondary polyethylene glycol solvent to stabilize the drug in solution for subsequent final dilution in an aqueous solvent, such as an aqueous lipid emulsion (e.g., emulsified soybean oil (I
FSU Research Foundation, Inc.
Jones Dwayne C.
Senniger Powers Leavitt & Roedel
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