Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-09-01
2002-10-08
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C514S449000, C514S510000
Reexamination Certificate
active
06461637
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method of administering a liposomal encapsulated taxane.
BACKGROUND OF THE INVENTION
The use of taxanes, such as paclitaxel, as antitumor agents for patients suffering from diseases such as ovarian and breast cancer, is known. In addition, paclitaxel has been shown to be clinically potent as a synergistic agent when used in conjunction with radiation treatment. Paclitaxel has a unique mechanism of action and a broad spectrum of anticancer activity because paclitaxel shows stabilization of microtubules rather than disassembly of microtubules.
However, paclitaxel has extremely low solubility in water, which makes it difficult to provide a suitable dosage form. Currently, paclitaxel is prepared and administered in a vehicle containing Cremophor EL (a polyethoxylated castor oil) and ethanol in a 50:50 (vol/vol) ratio. This solution is diluted 1:10 in saline before being administered to humans. The stability of paclitaxel once diluted in saline solution is quite low. The drug degrades within 24 hours and, thus, handling of dosage for the patients becomes very difficult. Since, the drug precipitates from dilution, an on-line filter is utilized for the infusion of the drug to the patients.
In clinical trials, a consistent problem of anaphylactoid reaction, dyspnea, hypertension, and flushing have been encountered. The dose-limiting toxicity is myelosuppression and due to the cardiac toxicity of the present paclitaxel the patient must be hospitalized for continuous infusion of the drug.
Attempts to prevent paclitaxel cardiotoxicity and anaphylactoid reaction have included reliance on pretreatment of patients with antihistamine and corticosteroids, and by prolonging the infusion time from six to twenty four hours. U.S. Pat. No. 5,621,001 (Canetta et al.) discloses a prolonged infusion time in a method for reducing peripheral neurotoxicity symptoms while maintaining an anti-tumor effect in patients suffering from ovarian cancer and undergoing paclitaxel therapy. This method involves administering about 135 mg/m
2
of paclitaxel over a period of about 24 hours. The administration of paclitaxel is repeated at least once, about 21 days after the preceding administration.
U.S. Pat. No. 5,665,761 (Canetta et al.) discloses a pretreatment stage before administration of paclitaxel. The '761 patent provides for paclitaxel infusions over a duration of less than six hours, preferably about three hours, utilizing dosages of between about 135 mg/m
2
and about 275 mg/m
2
, preferably between about 135 mg/m
2
and about 175 mg/m
2
, after patients had been pretreated to alleviate or minimize hypersensitivity responses. For example, the patients are pre-medicated with steroids, antihistamines, and H
2
-antagonists sufficient to at least prevent an anaphylactoid shock capable of causing acute hypersensitivity reactions and patient death. U.S. Pat. No. 5,670,537 (Canetta et al.) also discloses this method of administration for a patient suffering from a paclitaxel-sensitive tumor, such as an ovarian tumor.
U.S. Pat. No. 5,641,803, discloses the administration of paclitaxel to a patient, wherein about 135-175 mg/m
2
of paclitaxel is administered over a period of about three hours. Such a period purportedly was used to overcome, in part, some of the aforementioned problems associated with short infusion times, such as one hour, which had been employed with the conventional paclitaxel formulations containing polyethoxylated castor oil.
In yet another attempt to address the toxicity concerns of the conventional paclitaxel formulation, U.S. Pat. No. 5,696,153 suggests the use of an administration regimen wherein 45 to 120 mg/M
2
of paclitaxel is administered over a period of 60 to 180 minutes, a plurality of times during a 21 day period, with each infusion being separated by an interval of between 4 to 5 days.
However, even with these manipulations of prolonged infusion time and pretreatment of patients with antihistamines and corticosteroids, the patients suffer from serious toxicities which are often fatal. Different agent delivery systems are being utilized to enhance tumor cell-fighting effects of the drug and/or reduce systemic toxicity. Liposomes are one of many carriers that have been developed to help anti-tumor agents become more efficient and less toxic. A “liposome” is a closed structure composed of lipid bi-layers surrounding an internal aqueous space.
U.S. Pat. No. 5,648,090 (Rahman et al.) and U.S. Pat. No. 5,424,073 (Rahman et al.) provide a liposomal encapsulated paclitaxel for a method for treating cancer in mammals using such a liposomal-encapsulated paclitaxel, or anti-neoplastic derivative thereof. The '090 and '073 patents disclose a method of modulating multidrug resistance in cancer cells in a mammalian host by administering to the host a pharmaceutical composition of a therapeutically effective number of liposomes which include a liposome-forming material, cardiolipin, and an agent such as paclitaxel, or an antineoplastic derivative of paclitaxel, or a mixture thereof; and a pharmaceutically acceptable excipient.
Up until the present invention the fastest administration time tolerated by most patients was optimally a three hour time period. However, there is still a need for a more rapid and less toxic method of administration of paclitaxel. The present invention provides such a method.
SUMMARY OF THE INVENTION
The present invention provides a method of administering a taxane to a patient by administering taxane over a period of less than an hour in an amount from about 75 to 300 mg/m
2
wherein the taxane is a liposomal encapsulated taxane or an antineoplastic derivative thereof. The method does not require premedication, as with anti-hypersensitivity agents.
The present invention provides a method of administering a liposomal encapsulated taxane or an antineoplastic derivative thereof, which minimizes the duration of administration and minimizes the accompanying side effects. It is also an object of the present invention to provide a method for treating cancer.
These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The invention may best be understood with reference to the following detailed description of the preferred embodiments.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a method of administering a taxane to a patient in need of treatment with a taxane. In part, the present invention provides a delivery system for a taxane to a host which is characterized by the avoidance of solubility problems of a taxane; the improved taxane stability; the avoidance of anaphylactoid reactions and cardiotoxicity; the ability to administer a taxane as a bolus or short infusion, rather than an extended (24-hour) infusion of free taxane; the increased therapeutic efficacy of taxane; and the modulation of multidrug resistance in cancer cells.
The taxane is delivered in the form of a liposomal encapsulated taxane or antineoplastic derivative thereof. Preferably, the taxane is paclitaxel. A suitable derivative of paclitaxel is taxasm. Other suitable taxanes are 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, taxotere, and mixtures thereof.
The pharmaceutical composition may also include a cardiolipin. The cardiolipin may be obtained from either a natural or synthetic source. The taxane, such as paclitaxel, is encapsulated in liposomes using the cardiolipin. In addition to cardiolipin, the taxane may be encapsulated in liposomes using phosphatidylcholine and cholesterol. Such a composition of lipids provides over 90% encapsulation of the drug in liposomes.
The liposomal encapsulated taxane is prepared by various processes. For example, the taxane or a derivative thereof is dissolved in a solvent. Any non-polar or slightly pol
Kishore Gollamudi S.
Leydig , Voit & Mayer, Ltd.
NeoPharm, Inc.
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