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Method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions

a technology of polyoxyethylated castor oil and composition, which is applied in the directions of drug compositions, biocide, plant/algae/fungi/lichens ingredients, etc., can solve the problems of drug precipitation, poor water soluble paclitaxel, and unstable injection compositions

Inactive Publication Date: 2004-08-26
SUPERGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, paclitaxel is poorly soluble in water (less than 0.01 mg / mL) and other common vehicles used for the parenteral administration of drugs.
However, when a watermiscible organic solvent containing paclitaxel at near its saturation solubility is diluted with aqueous infusion fluid, the drug may precipitate.
EL with ethanol as a co-solvent, although effective in solubilizing pharmaceutical agents, produces injection compositions that exhibit instability over extended periods of time.
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.

Method used

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  • Method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions
  • Method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions
  • Method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions

Examples

Experimental program
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Effect test

example 1

[0090] Three different lots of Cremophor.RTM. ELP were stored in original plastic containers under ambient conditions. Samples from these lots were taken at different times. The pH of these samples, after being diluted 1:10 with water, was measured. Table 1 provides the pH measurements for the samples. The pH measurements are also plotted in FIG. 1. As can be seen from both Table 1 and FIG. 1, Cremophor.RTM. ELP becomes more acidic over time. Without being bound by theory, it appears from FIG. 1 that the acidification of the Cremophor.RTM. ELP decelerates over time under ambient conditions such that the resulting pH may plateau around pH 3.6 and 4.0.

1TABLE 1 pH of different lots of Cremophor ELP measured at predetermined time intervals. Lot # 14-3441 42-3489 94-3817 pH on Certificate of Analysis provided by BASF TTime (Months) 6.4 6.1 6.1 Initial 4.1 5.1 6.1 1 4.2 5.3 6.2 2 4.0 4.7 6.0 3 3.6 4.1 5.6 4 3.6 4.0 5.0

example 2

[0091] Twenty (20) mL aliquots obtained from two lots of Cremophor.RTM. ELP were stored in glass vials at 50.degree. C. Samples from these aliquots were taken at different times. The pH of these samples, after being diluted 1:10 with water, was measured. Table 2 provides the pH measurements for the samples. The pH measurements are also plotted in FIG. 2.

[0092] As can be seen from both the table and FIG. 2, increasing the storage temperature from ambient to 50.degree. C. accelerates the rate at which the acidity of the Cremophor increases. For example, the pH of samples from Lot 94-3817 stored at 50.degree. C. dropped from 6.1 to 4.4 in four weeks whereas it took samples from Lot 94-3817 stored at ambient conditions to drop from pH 6.1 to pH 5.0 in four months (see Table 1 for results).

2TABLE 2 pH measurements of different lots of Cremophor .RTM. ELP at predetermined time intervals following storage at 50.degree. C. 42-3489 94-3817 pH on Certificate of Analysis provided by BASF Time ...

example 3

[0093] Twenty (20) mL aliquots obtained from three lots of Cremophor.RTM. ELP were stored in glass vials and in plastic containers at 70.degree. C. Samples from these aliquots were taken at different times. The pH of these samples, after being diluted 1:10 with water, was measured. Table 3 provides the pH measurements for the samples. The pH measurements are also plotted in FIG. 3.

[0094] Increasing the storage temperature from 50.degree. C. to 70 .degree. C. does not greatly accelerate the rate at which the acidity of the Cremophor increases when results for different lots of Cremophor ELP in Table 2 are compared with corresponding results in Table 3.

[0095] The type of container used to age Cremophor.RTM. ELP did not appear to be critical. For example, the pH of samples from Lot 94-3817 stored at 70.degree. C. dropped from pH 6.1 to 4.1 in four weeks in plastic container and pH 4.2 in the same time when stored in glass container. However, the pH data from Lot #37-3442 suggests some ...

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Abstract

A method is provided for preparing a pharmaceutical composition comprising: taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 5 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; 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.

Description

[0001] This application is a continuation of U.S. application Ser. No. 10 / 306,824 filed Nov. 26, 2002, which claims the benefit of U.S. Provisional Application No. 60 / 333,459, filed Nov. 26, 2001, entitled "Method For Preparing And Using Polyoxyethylated Castor Oil In Pharmaceutical Compositions." These applications are incorporated herein by reference.[0002] 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.DESCRIPTION OF RELATED ART[0003] Paclitaxel has proven to be a highly sucessful antineoplastic agent. It is currently administered to patients in a formulation that comprises paclitaxel, Cremophor.RTM. (polyoxyethylated castor oil), and ethanol.[0004] Paclitaxel is a unique diterpene derived from the bark of the Taxus brevifolia (Pacific yew) tree. A crude extract of the bark demonstrated antineoplastic activit...

Claims

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Application Information

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IPC IPC(8): A61K9/08A61K9/00A61K31/337A61K36/47A61K47/10A61K47/22A61K47/34A61K47/44A61K47/46A61P35/00
CPCA61K9/0019A61K47/44A61K31/337A61P35/00
Inventor JOSHI-HANGAL, RAJASHREERUBINFELD, JOSEPHREDKAR, SANJEEVGORE, ASHOK Y.
Owner SUPERGEN
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