Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2002-07-15
2003-07-15
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C528S271000, C528S272000, C528S302000, C528S354000, C528S361000, C525S437000, C525S444000, C424S426000, C424S460000, C424S461000, C424S468000
Reexamination Certificate
active
06592895
ABSTRACT:
TECHNICAL FIELD
This invention is directed at biodegradable polyhydric alcohol esters where the acyl moieties originate from aliphatic homopolymer or copolymer polyesters.
BACKGROUND OF THE INVENTION
In recent years there has been an increased interest in star-shaped polymers, a kind of branched polymer having three or more polymeric arms attached to a center core.
This kind of polymer has not heretofore been used for biomedical application.
SUMMARY OF THE INVENTION
It has been discovered here that biodegradable star-shaped polymers useful inter alia for biomedical application can be made based on esterifying polyhydric alcohols to provide acyl moieties originating from aliphatic homopolymer or copolymer polyesters.
One embodiment of the invention herein, denoted the first embodiment, is directed to biodegradable polyhydric alcohol esters where the acyl moieties of the esters originate from aliphatic homopolymer or copolymer polyesters and contain free hydroxyl at their terminal ends and the weight average molecular weight of the esters ranges from 1,000 to 80,000, for example, from 2,000 to 50,000. These compounds are precursors for double bond functionalized biodegradable polyhydric alcohol esters where some or each of the acyl moieties are functionalized to incorporate an unsaturated group, which is another aspect of the invention herein. The functionalizing to incorporate unsaturated group can be effected, e.g., by reacting free hydroxyls with maleic anhydride to provide unsaturated terminal moieties which are 2-carboxy ethenyl groups.
Another embodiment of the invention herein, denoted the second embodiment, is directed to biodegradable polyester-polysaccharide hydrogels formed by photocrosslinking esters of polysaccharide formed by reaction of polysaccharide with hydroxy function pendant groups, for example, unsaturated esters of polysaccharide formed by reaction of polysaccharide with unsaturated group providing compound, with 2-carboxy ethenyl terminated polyhydric alcohol esters of the first embodiment. These hydrogels are useful, for example, as drug delivery systems.
The weight average molecular weights herein are determined by gel permeation chromatography using polystyrene standards.
The term “photocrosslinking” is used herein to mean causing vinyl bonds to break and form cross-links by the application of radiant energy.
The term “biodegradable” is used herein to mean capable of being broken down by various enzymes such as trypsins, lipases and lysosomes in the normal functioning of the human body and living organisms (e.g., bacteria) and/or water environment.
DETAILED DESCRIPTION
We turn now to the compounds of the first embodiment which are biodegradable polyhydric alcohol esters where the acyl moieties of the esters originate from aliphatic homopolymer or copolymer polyesters and contain free hydroxyl at their terminal ends and the weight average molecular weight of the esters ranges from 1,000 to 80,000, for example, from 2,000 to 50,000.
The polyhydric alcohol moiety portion of the polyhydric alcohol esters is obtained by action of the acid group of aliphatic homopolymer or copolymer polyester on a polyhydric alcohol having, for example, from 3 to 6 hydroxyl groups. The aliphatic homopolymer or copolymer polyesters include, for example, poly(&egr;-caprolactone) which can be formed in situ during the esterification reaction and which is preferred herein, poly(lactide-co-&egr;-caprolactone) which can be formed in situ during the esterification reaction, poly(glycolide-co-&egr;-caprolactone) which can be formed in situ during the esterification reaction, poly(&bgr;-valerolactone-co-&egr;-caprolactone) which can be formed in situ during the esterification reaction, poly(&bgr;-hydroxybutyrate-co-&egr;-caprolactone) which can be formed in situ during the esterification reaction, and poly(1,4-dioxan-2-one-co-&egr;-caprolactone) which can be formed in situ during the esterification reaction. The polyhydric alcohols include, for example, glycerol, glycerol derivatives, pentaerythritol, sugars, e.g., glucose and glucono-&dgr;-lactone; 1,3-propanediol-2-ethyl-2-(hydroxymethyl); butanediols, D-+-arabitol, perseitol ribitol, xylitol, D-threitol, dulcitol L-fucitol sorbitol, erythritol, dextran and other polysaccbarides, and polyvinyl alcohol.
The maximum number of polymeric arms obtained in the polyhydric alcohol esters of the first embodiment corresponds to the number of hydroxyl groups on the polyhydric alcohol.
We turn now to the case where the acyl moieties originate from poly(&egr;-caprolactone) which is formed in situ during the esterification reaction. The polyhydric alcohol esters are obtained by a ring opening polymerization of &egr;-caprolactone in the presence of the polyhydric alcohol. The mole ratio of &egr;-caprolactone to hydroxyl of polyhydric alcohol ranges from 1:1 to 150:1. Thus, for example, in the case of glycerol as the polyhydric alcohol, the mole ratio is calculated from three times the moles of &egr;-caprolactone per mole of glycerol; and in the case of pentaerythritol, the mole ratio is calculated from four times the moles of &egr;-caprolactone per mole of pentaerythritol.
The esterification reaction is preferably carried out in the presence of a ring opening catalyst, e.g., stannous octoate, present in an amount ranging from 0.01% by weight to 1% by weight of &egr;-caprolactone. Ring opening catalysts that can be used in place of stannous octoate include, for example, aluminum triisopropoxide, [(n-C
4
H
9
O)
2
AlO]
2
Zn, dibutyltin dimethoxide, Zn L-lactate, aluminum thiolates and triethyl aluminum.
The esterification reaction is carried out, for example, at 20 to 150° C. for 10 minutes to 72 hours in a polymerization tube containing dry inert gas (e.g., argon or nitrogen) sealed in vacuum. The inclusion of the dry inert gas prevents hydrolysis and oxidation of the catalyst.
The structure of a three-arm polyhydric alcohol ester obtained from ring opening polymerization of &egr;-caprolactone in the presence of glycerol is depicted below:
In the above structure, n ranges, for example, from 1 to 150.
The structure of a four-arm polyhydric alcohol ester obtained from ring opening polymerization of &egr;-caprolactone in the presence of pentaerythritol is depicted below:
In the above structure, n ranges, for example, from 1 to 150.
As indicated above, the polyhydric alcohol esters containing free hydroxyl at terminal ends of the acyl moieties are precursors for double bond functionalized biodegradable polyhydric alcohol esters where some or each of the acyl moieties are functionalized to incorporate an unsaturated group. In a preferred case, the functionalizing is obtained by reaction of free hydroxyls of the precursor compounds with maleic anhydride. Other reactants besides maleic anhydride to incorporate unsaturated group include, for example, acryloyl chloride which is CH
2
═CHCOCl, methacryloyl chloride which is CH
2
═CH(CH
3
)COCl and allyl isocyanate which is CH
2
═CHCH
2
NCO. In the case where maleic anhydride is utilized, unsaturated terminal moieties are obtained which are 2-carboxy ethenyl groups.
For the reaction of maleic anhydride with free hydroxyl at terminal end of acyl moiety of precursor free hydroxyl containing polyhydric alcohol ester, the mole ratio of hydroxyl functionality to moles of maleic anhydride can range, for example, from 1:1 to 1:10, and the reaction can be carried out at 100 to 180° C. over a time period of 1 hour to 72 hours and preferably is carried out under inert gas such as nitrogen to prevent hydrolysis of maleic anhydride and of the precursor esters. The reaction with maleic anhydride produces 2-carboxy ethenyl functionalized maximum number of arms corresponding to number of free hydroxyls on polyhydric alcohol starting material, hereinafter referred to as 2-carboxy ethenyl functionalized polyhydric alcohol esters.
A structure of a 2-carboxy ethenyl functionalized polyhydric alcohol ester obtained from precursor obtained from glycerol is depicted below:
In the above structure, n
Chu Chih-Chang
Lang Meidong
Acquah Samuel A.
Cornell Research Foundation Inc.
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