Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2002-11-26
2004-03-23
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C514S449000
Reexamination Certificate
active
06710195
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the formulation of pharmaceutical compositions. More particularly, the invention relates to the preparation and use of polyoxyethylated castor oil in pharmaceutical compositions.
2. Description of Related Art
Paclitaxel has proven to be a highly sucessful antineoplastic agent. It is currently administered to patients in a formulation that comprises paclitaxel, Cremophor® (polyoxyethylated castor oil), and ethanol.
Paclitaxel is a unique diterpene derived from the bark of the
Taxus brevifolia
(Pacific yew) tree. A crude extract of the bark demonstrated antineoplastic activity in preclinical tumor screening 30 years ago as part of the National Cancer Institute's (NCI's) large-scale screening program. The active component of the extract, paclitaxel, was isolated and described by M. C. Wani et al, Plant antitumor agents. VI: The isolation and structure of Paclitaxel. a novel antileukemic and antitumor agent from
Taxus brevifolia,
J. Am. Chem. Soc. 93:2325-2327 (1971). This document, and all others referred to herein, are incorporated by reference as if reproduced fully below.
Unfortunately, paclitaxel is poorly soluble in water (less than 0.01 mg/mL) and other common vehicles used for the parenteral administration of drugs. Certain organic solvents, however, may at least partially dissolve paclitaxel. However, when a water-miscible organic solvent containing paclitaxel at near its saturation solubility is diluted with aqueous infusion fluid, the drug may precipitate.
Solubilization of paclitaxel with surfactants allows for dilution of saturated or near-saturated formulations of paclitaxel. Specifically, paclitaxel has been formulated using 50% Cremophor® EL 50% dehydrated alcohol (USP, United States Pharmacopoeia), diluted in NS normal saline or D5W (5% dextrose in water) to a final concentration of 5% Cremophor® EL and 5% dehydrated alcohol or less, for the intravenous administration of the drug to humans in early clinical trials. (Cremophor® EL; Badische Anilin und Soda Fabrik AG (BASF), Ludwigshafen, Federal Republic of Germany). A concentrate of paclitaxel for injection is currently available from Bristol-Myers Squibb Co. (New York, N.Y.) in vials where each milliliter of formulation contains approximately 6 mg Paclitaxel, 527 mg of Cremophor® EL, and 49.7% (vol/vol) dehydrated alcohol. This concentrated formulation must be further diluted with NS, D5W, D5NS (normal saline, 5% dextrose in water and 5% dextrose in normal saline) or D5W-R (Ringer's solution with 5% dextrose in water) prior to administration. It has been noted that the Cremophor®/ethanol formulation of paclitaxel precipitates upon dilution with infusion fluid, and fibrous precipitates formed in some compositions during storage for extended periods of time. Additional information regarding Cremophor® formulations of paclitaxel may be found in Agharkar et al., U.S. Pat. No. 5,504,102.
It was discovered that commercial grade Cremophor® EL with ethanol as a co-solvent, although effective in solubilizing pharmaceutical agents, produces injection compositions that exhibit instability over extended periods of time. In particular, concentrated formulations of paclitaxel in a co-solvent of 50:50 by volume of 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 potency is attributed to the decomposition of paclitaxel during storage.
Various methods of stabilizing paclitaxel solubilized in polyoxyethylated castor oil and ethanol during storage have been developed. For example, U.S. Pat. Nos. 5,504,102, 5,733,888, 5,972,992, 5,977,164, 6,071,952, 6,140,359 each teach adding an agent to modify the pH of the concentrated formulation in order to stabilize paclitaxel.
Other concentrated formulations of taxoid compounds have been developed. For example, several U.S. patents assigned to Rhone-Poulenc Rorer (U.S. Pat. Nos. 5,403,858, 5,438,072, 5,670,536, 5,698,582, 5,714,512) provide a formulation composed of a taxane compound dissolved in a surfactant selected from a group consisting of polysorbate, polyoxyethylene glycol, or hydrogenated castor oil, and essentially free of ethanol.
U.S. Pat. No. 6,071,952 to Owens et al discloses a human administration comprising an anti-neoplastic taxol compound, a solubilizing/dispersing agent, and a stabilizing amount of an anti-oxidant.
It is important for concentrated formulations of paclitaxel to have prolonged shelf lives since product instability increases manufacturing costs due to extensive consumption of raw materials and yields a product of inferior quality, both translating into higher patient cost. Additional stabilization strategies for paclitaxel and other pharmaceutically active agents are therefore needed, one of which is provided by the present invention.
SUMMARY OF THE INVENTION
The present invention provides novel methods of preparing pharmaceutical formulations containing polyoxyethylated castor oil as excipient. In particular, methods are provided for preparing pharmaceutical compositions containing paclitaxel formulated with polyoxyethylated castor oil that has been aged to a reduced pH value relative to that of polyoxyethylated castor oil freshly synthesized. Aging can be performed by varying the time and condition of storage, such as by heating, pressurization, air-sparging or combinations thereof, without substantially changing physical and chemical characteristics of polyoxyethylated castor oil except its pH value. Such aged polyoxyethylated castor oil is then mixed with a pharmaceutically active agent such as paclitaxel. Pharmaceutical compositions comprising the aged polyoxyethylated castor oil and a pharmaceutically active agent are also provided. Paclitaxel formulations containing the aged polyoxyethylated castor oil that is acidified without addition of an acidifying chemical are believed to be physically and chemically more stable than those formulated with polyoxyethylated castor oil freshly synthesized or at higher pH.
In one aspect of the invention, a method is provided for preparing a pharmaceutical composition.
In one embodiment, the method comprises:
taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen for a period of time, the exposure to the gas over the period of time causing an acidity of the polyoxyethylated castor oil to increase; and
forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil and a pharmaceutically active agent such as paclitaxel and docetaxel, wherein at least 80% of the potency of the pharmaceutically active agent is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.
In another embodiment, the method comprises:
taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 5.9; and
forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil and a pharmaceutically active agent such as paclitaxel and docetaxel.
Optionally, aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or lower than 5.5, optionally equal to or lower than 5, optionally equal to or lower than 4.8.
Optionally, aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.7 and 5.9, optionally between 3.8 and 5.5, optionally between 3.9 and 5, and optionally between 4 and 4.8.
In yet another embodiment, the method comprises:
taking polyoxyethylated castor oil which if diluted 1:10 in wate
Gore Ashok Y.
Joshi-Hangal Rajashree
Redkar Sanjeev
Rubinfeld Joseph
Carr Deborah D.
Chen Shirley
Goodrich & Rosati
Sonsini Wilson
SuperGen, Inc.
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