Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2001-04-06
2002-05-14
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...
C514S552000
Reexamination Certificate
active
06388112
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a process for purifying a solvent suitable for use with a pharmaceutical agent and to the purified solvent and pharmaceutical compositions prepared therewith.
BACKGROUND OF THE INVENTION
Administration of pharmaceutical compounds, and in particular administration by injection, requires a solvent or carrier that is suitable for administration to the patient. The solvent used in conjunction with the pharmaceutical agent must, when combined with the pharmaceutical agent, produce an effective composition for injection, ideally having good shelf life. The solvent should be non-toxic to the patient and compatible with the particular pharmaceutical agent to be injected. Many solvents are not especially efficient for solubilizing the pharmaceutical agent to enable an effective composition for administration, while simultaneously possessing these advantageous qualities.
Compositions containing polyethoxylated castor oil and similar solvents are frequently used in combination with a pharmaceutical agent to produce a mixture suitable for administration by injection. The solvents acceptable for pharmaceutical use are set forth in a United States Pharmacopoeia (USP) with the acceptable limits for various parameters of these solvents in a National Formulary (NF). A potential problem associated with such solvents is that acids, salts or other ionic impurities, as well as residual water in the solvent or solvent system, even if within the acceptable limits, can catalyze the degradation of the pharmaceutical agent. For example, it is believed that carboxylate anions present in polyethoxylated castor oil can catalyze the decomposition of paciltaxel, even at levels within the defined limits set forth in the National Formulary. See, for example, U.S. Pat. No. 5,504,102, incorporated herein by reference. The U.S. Pat. No. 5,504,201 patent discloses removing the carboxylate anions from polyethoxylated castor oils by acid addition or alumina adsorption. A solvent with sufficiently low levels of particular deleterious impurities will yield a more stable pharmaceutical agent containing compositions.
Because such solvents and solvent systems are combined with pharmaceuticals used in the treatment of, among other things, cancer, the importance of developing a method for removing impurities that deleteriously effect the stability of the pharmaceutical agent is apparent. There is a need for the development of a solvent or cosolvent system that does not negatively impact the potency or purity of the pharmaceutical agent and which provides for good shelf life. The present invention addresses the problems of loss of effectiveness of the pharmaceutical agent due to decomposition during storage. Moreover, the present invention does not affect the pH during purification of the solvent
SUMMARY OF THE INVENTION
The present invention provides a process for purifying a solvent for use in the formulation of a pharmaceutical agent composition. The invention also provides purified solvent produced by this process and a pharmaceutical composition comprising the purified solvent and a pharmaceutical agent, which composition has extended shelf-life. More particularly, the present invention is directed to an improved process for purifying a solvent which results in advantageously low quantities of salts, acids and various other ionic impurities, as well as low residual water content and enhanced clarity. In a preferred aspect of the invention, the process involves the purification of polyethoxylated castor oils, sometimes called polyoxyethylated castor oils, by forming a solution of the solvent in alcohol and contacting the solution with an activated carbon column, followed by contacting the solution with an ion exchange resin column and then evaporating the residual water and alcohol. The resin column follows the charcoal column in the preferred embodiment so that, in the event any charcoal particulates remain after the charcoal column, they will be eliminated by the resin column. While not wanting to be bound by theory, it is believed that contact with the activated carbon removes water and unsaturated aliphatic and aromatic compounds by an adsorption mechanism. The ion exchange resin is believed to exchange cations and anions from the solvent with OH− and H+.
The solvents that are purified are non-ionic surfactants. The solvent is preferably a condensation product of an alkylene oxide and an oil or fatty acid. The preferred solvent is a polyethoxylated castor oil, such as polyoxyl 35 castor oil, Cremophor RH60, or a similar solvent such as polysorbate 80. Still more preferably, the solvent is a polyoxyl 35 castor oil. Commercially available polyethoxylated castor oils to which the present process is particularly suited are sold under the trade name Cremophor, such as Cremophor EL and Cremophor RH60. In the present invention, the polyethoxylated castor oils such as Cremophor EL and Cremophor RH60 are treated to enhance clarity and reduce potassium, salt, acid, water content and other deleterious impurities.
It is another aspect of the present invention to provide purified polyethoxylated castor oils that, when employed to solubilize pharmaceutical agents, produce a pharmaceutical composition having an advantageously long shelf life.
In one embodiment, such as for purifying polyoxyl 35, the resulting, purified polyethoxylated castor oil has a specific gravity between 1.05 and 1.06 g/ml, a viscosity between 650 and 850 cps at 25° C. an acid value (NF) of not more than 2.0, a hydroxyl value (NF) between 65 and 80, a potassium content less than or-equal to 15 ppm, a water percentage less than about 3.0%, and preferably less than or equal to 0.5%, a saponification of between 60 and 75 and an iodine value (NF) of 25 to 35.
In another embodiment, such as for purifying polysorbate 80, the resulting, purified solvent has a specific gravity between 1.06 and 1.09 g/ml, a viscosity between 300 and 500 cps., an acid value (NF) of not more than 2.2, a hydroxyl value (NF) between 65 and 80, a water percentage less than about 3.0%, and preferably less than or equal to 0.5%, and a saponification of between 45 and 55. Polysorbate 80 is a non-ionic surfactant and can be generally classified as a polyol with a similar chemical structure to the polyethoxylated castor oils and is hereinafter generally referred to as a polyethoxylated castor oil.
In another embodiment, such as for purifying Cremophor RH60, the resulting, purified polyethoxylated castor oil has a specific gravity of about 1.1 g/ml, a viscosity of about 211 cps. at 60° C., an acid value (NF) less than 0.2, a hydroxyl value (NF) of about 69, an iodine value less than about 2, a water percentage of about 0.4%, a potassium value less than about 7 ppm, and a saponification of about 44.
The invention is also directed towards stabilized pharmaceutical compositions prepared from the solvent according to the invention. Preferred pharmaceutical compounds that may be combined with the solvent after purification include antineoplastic compounds such as teniposide, paclitaxel and camptothecin, immunosuppressive agents such as cyclosporin and tacrolimus, oil soluble vitamins, mixtures thereof and the like. A purified polyethoxylated castor oil having the preferred characteristics will produce a pharmaceutical composition having a good shelf life. In the preferred embodiment, the pharmaceutical agent is paclitaxel and the process is carried out so as to produce a polyethoxylated castor oil that, when combined with the paclitaxel in a pharmaceutical composition, will provide at least about 90% of the initial amount of paclitaxel after being stored at 40° C. for ninety days. Still more preferably, the composition will provide at least about 97%±5% paclitaxel after being stored at 40° C. for ninety days.
To obtain this product, the process employs respective amounts of activated carbon and ion exchange resin, and passes the polyethoxylated castor oil through the respective columns at rates suitable to produce a purif
Ben Venue Laboratories, Inc.
Carr Deborah D.
Watts Hoffman Fisher & Heinke
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