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Polyoxypropylene/polyoxyethylene copolymers with improved biological activity

a polyoxyethylene and polyethylene technology, applied in the field of polyoxypropylene/polyoxyethylene copolymer preparation, can solve the problems of toxic to cells, unsatisfactory biological activity of the surface-active copolymer, and low molecular weight molecules with unsaturated polymers in the population, so as to achieve better biological activity and more predictable effects

Inactive Publication Date: 2000-04-18
CYRX CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention comprises novel preparations of polyoxypropylene / polyoxyethylene copolymers which retain the therapeutic activity of the commercial preparations, but are free from the undesirable effects which are inherent in the prior art preparations. Because the polyoxypropylene / polyoxyethylene copolymers which comprise the present invention are a less polydisperse population of molecules than the prior art polyoxypropylene / polyoxyethylene copolymers, the biological activity of the copolymers is better defined and more predictable. In addition, the polyoxypropylene / polyoxyethylene copolymers which comprise the present invention are substantially free of unsaturation.
It is yet another object of the present invention to provide a surface-active copolymer that can be used safely in both humans and animals in treating adult respiratory distress syndrome.

Problems solved by technology

It has been determined that the toxicity exhibited by the commercially available surface-active copolymer poloxamer 188 is primarily due to the small amounts of high and low molecular weight molecules that are present as a result of the manufacturing process.
The low molecular weight molecules (those lower than 5,000 daltons) have detergent-like physical properties which can be toxic to cells in culture.
In addition, the low molecular weight molecules have unsaturated polymers present in the population.

Method used

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  • Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
  • Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
  • Polyoxypropylene/polyoxyethylene copolymers with improved biological activity

Examples

Experimental program
Comparison scheme
Effect test

example i

Poloxamer 188 (BASF Corporation, Parsippany N.J.) is dissolved in tetrahydrofuran at a concentration of 20 mg / mL. A Model 600E Powerline chromatographic system equipped with a column heater module, a Model 410 refractive index detector and Maxima 820 software package (all from Waters, Div. of Millipore, Milford, Mass.) is used to fractionate the commercially prepared poloxamer 188 copolymer. The chromatographic system is equipped with two LiChrogel PS-40 columns and a LiChrogel PS-20 column in series (EM Science, Gibbstown, N.J.). The LiChrogel PS-40 columns are 10 .mu.m particle size and the LiChrogel PS-20 column is 5 .mu.m particle size. All columns are 7 mm by 25 cm in size.

200 .mu.L (4 mg) of the poloxamer 188 in tetrahydrofuran is added to the column and the sample is run with the columns and the detector at 40.degree. C. The resulting chromatogram is shown in FIG. 2.

example ii

The sample that was collected in Example I was fractionated into six fractions and each fraction was run on the column as described in Example I. The chromatograms from the various chromatographic runs are shown in FIGS. 3 through 8. The fraction that demonstrates the least toxicity while retaining the therapeutic activity of the poloxamer 188 is shown in FIG. 5. As can be clearly seen, the shoulders on either side of the peak in FIG. 5 are absent.

The average molecular weight for each fraction is shown in Table II. The chromatogram for each fraction is indicated in FIGS. 3 through 8.

TABLE II ______________________________________ Time off Molecular Polydispersity Fraction FIG. Column (Min) Wt. Value ______________________________________ 1 3 11.5-12.0 17000 1.0400 2 4 12.0-12.5 10270 1.0474 3 5 12.5-13.0 8964 1.0280 4 6 13.0-13.5 8188 1.0332 5 7 13.5-14.0 5418 1.1103 6 8 14.0-14.5 3589 1.0459 ______________________________________

The polydispersity value for the unfractionated polox...

example iii

In a one-liter 3 neck round bottom flask equipped with a mechanical stirrer, reflux condenser, thermometer and propylene oxide feed inlet, there is placed 57 grams (0.75 mol) of propylene glycol and 7.5 grams of anhydrous sodium hydroxide. The flask is purged with nitrogen to remove air and heated to 120.degree. C. with stirring until the sodium hydroxide is dissolved. Sufficient propylene oxide is introduced into the mixture as fast as it reacts until the product possesses a calculated molecular weight of approximately 1750 daltons. The product is cooled under nitrogen and the NaOH catalyst is neutralized with sulfuric acid and the product is then filtered. The final product is a water-insoluble polyoxypropylene glycol.

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Abstract

The present invention comprises novel preparations of polyoxypropylene / polyoxyethylene copolymers which retain the therapeutic activity of the commercial preparations, but are substantially free from the undesirable effects which are inherent in the prior art preparations. Because the preparations of polyoxypropylene / polyoxyethylene copolymers which comprise the present invention are a less polydisperse population of molecules than the prior art polyoxypropylene / polyoxyethylene copolymers, the biological activity of the copolymers is better defined and more predictable.

Description

TECHNICAL FIELDThe present invention relates to a preparation of polyoxypropylene / polyoxyethylene copolymer which has an improved toxicity and efficacy profile. The present invention also includes polyoxypropylene / polyoxyethylene block copolymers with a polydispersity value of less than approximately 1.05.BACKGROUND OF THE INVENTIONCertain polyoxypropylene / polyoxyethylene copolymers have been found to have beneficial biological effects when administered to a human or animal. These beneficial biological effects are summarized as follows:Polyoxypropylene / polyoxyethylene Copolymers as Rheologic AgentsThe copolymers can be used for treating circulatory diseases either alone or in combination with other compounds, including but not limited to, fibrinolytic enzymes, anticoagulants, free radical scavengers, antiinflammatory agents, antibiotics, membrane stabilizers and / or perfusion media. These activities have been described in U.S. Pat. Nos. 4,801,452, 4,873,083, 4,879,109, 4,837,014, 4,8...

Claims

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Application Information

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IPC IPC(8): A61K31/74A61K31/765A61K31/77A61K45/00A61K45/06A61K47/48C08G65/26C08G65/08C08G65/30C08G65/00A61P7/02C07C43/11C08G65/02C08G65/28
CPCA61K31/765A61K31/77A61K45/06A61K47/48169C08G65/30C08G65/08C08G65/2609C08G65/2624A61K47/48215A61K47/60A61K47/56A61P7/02
Inventor EMANUELE, R. MARTINHUNTER, ROBERT L.CULBRETH, PAULA H.
Owner CYRX CORP
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