High molecular weight polymers and copolymers of BHMDO for biomedical application

• US 6,300,458 B1
• Filed: 09/02/1999
• Issued: 10/09/2001
• Est. Priority Date: 09/02/1998
• Status: Expired due to Fees

• Current Assignee: David J. Vandenberg, Jean E. Vandenberg
• Original Assignee: Edwin J. Vandenberg
• Inventors: Vandenberg, Edwin J.
• Primary Examiner(s): Boykin, Terressa M.
• Application Number:
  US09/388,704
• Time in Patent Office: 768 Days
• Field of Search: 528/196
• US Class Current: 528/196
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: C08G 63/64 Polyesters containing both carboxylic ester groups and carbonate groups
• CPC Class Codes: C08G 64/0208 saturated

Abstract

Hydroxypolycarbonates (HPC) offer to the biomedical area hydroxyl functional polymers not now readily available to bind drugs, proteins, or carbohydrate polymers chemically or via hydrogen bonding to facilitate drug delivery and utility with subsequent biodegradability to acceptable byproducts. The cyclic carbonate (CC) from the monoketal diol of pentaerythritol polymerized in CHCl₃ at 60° C. with Et₂Zn catalyst in CHCl₃ at 60° C. in 4 hours to a quantitative yield of high molecular weight, crystalline polymer (PCC), melt peak 199° C. and Tg of 99° C. PCC is readily hydrolyzed with 80% acetic acid to the water-insoluble but water-swollen HPC, poly[5,5-bis(hydroxymethyl)-1,3-dioxan-2-one], with M_w=3.1×10⁴. HPC degrades completely in vitro in <16 hours in PBS-1X buffer (Ph 7.4, 37° C.) to pentaerythritol and presumably CO₂. This rapid degradation rate is decreased with random copolymers of HPC with CC, ε-caprolactone, or _L-lactide. HPC and PCC may have important biomaterial applications as is and as the copolymers noted above or with ethylene oxide or other desirable comonomers. PCC and CC copolymers have properties attractive to the biomedical area as is or by conversion to the HPC product provided by hydrolysis or by in vivo enzymatic attack.

Claims

1. A hydroxy-protected carbonate monomer having the structure:

in which R₁ is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl and H; and

R₂ is selected from the group consisting of alkyl, cycloalkyl, aryl, alkyaryl, arylalkyl and H.

6. A hydroxy-protected cyclic carbonate monomer according to claim 1 copolymerized with a monomer selected from the group consisting of oxetane, lactide, caprolactone, alkyleneoxide, trimethylene carbonated, and glycolide.

7. A hydroxy-protected cyclic carbonate monomer according to claim 1 in which R₁ is CH₃ and R₂ is CH₃.

8. A hydroxy-protected cyclic monomer according to claim 1.

10. A hydroxy-protected cyclic—

carbonate copolymer produced according to claim 6.

11. A hydroxypolycarbonate containing ethylene oxide units prepared by removing the protecting group by hydrolysis from the product of claim 8.

2. Hydroxypolycarbonates for chemically bonding drugs, nucleic acids, proteins and carbohydrate polymers to facilitate their delivery in mammalian systems, said hydroxypolycarbonates having the structure:

4. A hydroxypolycarbonate according to claim 2 derived from 5,5-bis(hydroxymethyl) 1,3,-dioxan-2-one.

3. A cyclic carbonate polymer having protected hydroxyl groups wherein H of the hydroxy group is replaced with an acetal, ketal, formal or trimethylsilyl group, said carbonate polymer having the structure:

wherein

R₁ is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl and H;

R₂ is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl and H n=1-30.

5. A protected cyclic carbonate polmer according to claim 3 in which R₁ is CH₃ and R₂ is CH₃.

9. The method of synthesizing poly[5,5-bis(hydroxymethyl)-1,3dioxan-2one] comprising reacting pentaerythritol with a compound selected from the group consisting of an acetal, a ketal, a formal and a trimethylsilyl source to replace the hydrogen from each of two hydroxyl groups in said pentaerythritol with a hydroxy protecting group;

admixing another compound therewith to convert the remaining two hydroxyls of said pentaerythritol to a cyclic carbonate;

purifying and polymerizing said resulting cyclic carbonate; and

removing the hydroxy protecting groups to form poly[5,5-bis-(hydroxymethyl)-1-3-dioxan-2-one].