Biodegradable, anionic polymers derived from the amino acid l-tyrosine

a technology of anionic polymers and amino acids, applied in the field of biodegradable anionic polycarbonates and polyarylates having pendent carboxylic acid groups, can solve the problems of limited application of polymer with protected carboxylic acid groups, difficult selective removal of any carboxylic acid protecting groups, and inability to prepare polycarbonates, polyarylates and poly (alkylene oxide) block copolymers thereof, etc., to achieve the effect of preventing the formation of adh

Inactive Publication Date: 2008-06-26
RUTGERS THE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0035]Another aspect of the present invention provides a method for site-specific or systemic drug delivery by implanting in the body of a patient in need thereof an implantable drug delivery device containing atherapeutically effective amount of a biologically or pharmaceutically active compound in combination with a polymer of the present invention. Yet another aspect of the present invention provides a method for preventing the formation of adhesions between injured tissues by inserting as a barrier between the injured tissues a sheet or a coating of a polymer of the present invention.
[0036]As noted above, derivatives of biologically and pharmaceutically active compounds, including drugs, can be attached to the polymer backbone by covalent bonds linked to the carboxylic acid pendent chain. This provides for the sustained release of the biologically or pharmaceutically active compound by means of hydrolysis of the covalent bond between the drug and the polymer backbone.
[0037]In addition, the pendent carboxylic acid groups of the polymers in the present invention provide the polymers with a pH dependent dissolution rate. This further enables the polymers to be used as coatings in gastrointestinal drug release carriers to protect some biologically and pharmaceutically active compounds such as drugs from degrading in the acidic environment of the stomach. The copolymers of the present invention having a relative high concentration of pendent carboxylic acid groups are stable and water insoluble in acidic environments but dissolve/degrade rapidly when exposed to neutral or basic environments. By contrast, copolymers of low acid to ester ratios are more hydrophobic and will not degrade/resorb rapidly in either basic or acidic environments. Therefore, anot

Problems solved by technology

The polycarbonates, polyarylates and poly (alkylene oxide) block copolymers thereof cannot be prepared by conventional solution processes from monomers having free carboxylic acid groups.
The resulting polymers with protected carboxylic acid groups are limited in application because of their slow rate of degradation and significant hydrophobicity.
Thus, the selective removal of any carboxylic acid protecting groups is a challenge.
For polyarylates and poly (alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional hydrolysis techniques without complete degradation of the polymer backbone.
For polycarbonates and poly (alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional

Method used

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  • Biodegradable, anionic polymers derived from the amino acid l-tyrosine
  • Biodegradable, anionic polymers derived from the amino acid l-tyrosine
  • Biodegradable, anionic polymers derived from the amino acid l-tyrosine

Examples

Experimental program
Comparison scheme
Effect test

example 1

Hydrogenolysis of Poly(DTBn5o-DTEsO Carbonate) Preparation

[0094]In a 500 mL round-bottomed flask was placed 15 g of poly (DTBn-DTE carbonate) which contained DTBn and DTE in a 1:1 ratio. To the flask was then added 150 mL of dry DMF and the mixture was stirred until a clear solution was obtained. To this solution were added 3.5 g of 5 percent Pd on BaSO4 catalyst and 7 mL of 1,4-cyclohexadiene (hydrogen donor). The mixture was stirred at room temperature. A rubber balloon filled with hydrogen gas was attached to the mouth of the flask using a gas inlet adapter. The balloon was replenished with hydrogen as needed. After about 40 h of stirring a 0.5 mL sample was withdrawn, centrifuged, and then precipitated by adding to water with stirring. The precipitate was dried and analyzed by 1H NMR, which showed complete conversion of the benzyl groups to free acid. The reaction was stopped and the reaction mixture was centrifuged. The supernatant was filtered using 0.45 tM syringe filter in s...

example 2

Hydrogenolysis of Poly(DTBn0.05-DTE0.95 Carbonate)

Preparation

[0098]The hydrogenolysis of a 15 gram sample of poly (DTBn-DTE carbonate), which contained DTBn and DTE in a 1:19 ratio and had a Mw of 286 Kda and Mn of 116 Kda was performed as in Example 1.

Structure Proof

[0099]The 1H NMR spectrum of the product in DMSO-d6 showed the following resonances (δ, ppm relative to TMS): 8.40 (br s, 0.95H, NH of DTE), 8.25 (br s, 0.05H, NH of DT), 7.15-7.35 (m, 8H, aromatic H's), 4.71 (m, 1H, CH of tyrosine), 4.03 (q, 1.9H, CH2—CH3), 2.1-3.3 (m, 6H, CH2's of DAT and Tyrosine), 1.11 (t, 2.85H, CH2—CH3). Also a multiplet that is found in poly (DTBn-DTE carbonate) at 5.1 ppm due to benzyl H's was completely absent indicating complete removal of the benzyl protecting groups. The 1:19 ratio of the DT-NH peak to the DTE-NH peak indicates that the polymer is made of 5% DT and 95% DTE. The ratio of CH group to the ethyl ester group shows that there are nineteen ethyl ester groups for every twenty monome...

example 3

Hydrogenolysis of Poly(DTBn0.025-DTE0.90 Carbonate)

Preparation

[0101]Hydrogenolysis of a 15 g sample of poly (DTBn-DTE carbonate) which contained DTBn and DTE in a 1:9 ratio and had a Mw of 183 Kda and Mn of 84 Kda was performed as in Example 1.

Structure Proof

[0102]The 1H NMR spectrum of the product in DMSO-d6 showed the following resonances (δ, ppm relative to TMS): 8.40 (br s, 0.9H, NH of DTE), 8.25 (br, s, 0.1H, NH of DT), 7.15-7.35 (m, 8H, aromatic H's), 4.50 (m, 1H, CH of tyrosine), 4.03 (q, 1.8H, CH2, CH3), 2.1-3.3 (m, 6H, CH2's of DAT and Tyrosine), 1.11 (t, 2.7H, CH2, —CH3). Also a multiplet that is found in poly (DTBn-DTE carbonate) at 5.1 ppm due to benzyl H's was completely absent indicating complete removal of the benzyl protecting groups. The 1:9 ratio of the DT-NH peak to the DTE-NH peak ester group shows that there are nine ethyl ester groups for every ten monomer subunits. These spectral data indicate that the polymer contains DT and DTE in 1:9 ratio and the benzyl pr...

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Abstract

Polymers with a hydrolytically labile polymer backbones with non-toxic biocompatible diphenolic repeating units having the structure:
    • wherein R9 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid group or the benzyl ester thereof; and
    • non-toxic biocompatible diphenolic repeating units having the structure:
    • wherein R12 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid ester group selected from straight and branched alkyl and alkylaryl esters containing up to 18 carbon atoms and ester derivatives of biologically and pharmaceutically active compounds covalently bonded to the polymer, provided that said ester group is not a benzyl group or a group that is removed by hydrogenolysis. Implantable medical devices and treatment methods using the polymers are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a Continuation of U.S. patent application Ser. No. 09 / 350,423 filed Jul. 8, 1999, which, in turn, is a Continuation of U.S. patent application Ser. No. 09 / 056,050 filed Apr. 7, 1998, now U.S. Pat. No. 6,120,491, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 064,656 filed on Nov. 7, 1997. The disclosures of all three applications are incorporated herein by reference.GOVERNMENT LICENSE RIGHTS[0002]The U.S. government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as required by the terms of Grant Nos. GM-39455 and GM-49849 awarded by the National Institutes of Health.BACKGROUND OF THE INVENTION[0003]The present invention relates to biodegradable anionic polycarbonates and polyarylates having pendent carboxylic acid groups, and to block copolymers thereof with poly (alkylene oxides). The present i...

Claims

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Application Information

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IPC IPC(8): A61F2/02C08G65/38C08G8/02A61K9/70A61P41/00A61K9/14C08G63/06C08F12/24C08G64/06A61K9/20A61K38/00A61L17/10A61L27/18A61L27/58A61L31/06A61L31/14C07K14/00C08G63/672C08G63/685C08G64/04C08G64/12C08G64/16C08G64/18C08G64/42C08G69/10C08G69/44C08L101/16
CPCA61K9/204A61K38/00C08G69/44C08G69/10C08G64/183A61L17/10A61L27/18A61L27/58A61L31/06A61L31/148C07K14/001C08G63/672C08G63/6856C08G63/6858C08G64/045C08G64/12C08G64/1641C08L69/00A61P41/00
Inventor KOHN, JOACHIM B.BOLIKAL, DURGADASGUAN, SHUIYUM
Owner RUTGERS THE STATE UNIV
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