Crosslinked, porous polymers for controlled drug delivery

• US 4,548,990 A
• Filed: 08/15/1983
• Issued: 10/22/1985
• Est. Priority Date: 08/15/1983
• Status: Expired due to Fees

• Current Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Mueller, Karl F., Heiber, Sonia J.
• Primary Examiner(s): Moyer, Donald B.
• Assistant Examiner(s): Faraci, C. Joseph
• Application Number:
  US06/523,236
• Time in Patent Office: 799 Days
• Field of Search: 424/80, 424/81, 424/19, 525/123
• US Class Current: 525/123
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

A controlled-release, drug-delivery composition which comprises (A) a crosslinked copolymer, capable of swelling in ethanol to give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer containing no more than 20% by weight of water, where the swelling ratio (% ethanol: % water) is 2:1 to 22:1, which comprises the copolymerization product of (a) 50 to 99% by weight of said copolymer of a water-insoluble monoolefinic monomer or (a) with 0 to 45% by weight of total monomers of a water-soluble monoolefinic monomer, with (b) 50 to 1% by weight, but not more than 20 mol % of a divinyl or polyvinyl crosslinking agent; and (B) an effective amount of a pharmaceutical medicament is useful for the controlled and prolonged release of drugs when taken orally.

Claims

1. A controlled-release, drug-delivery carrier composition which comprises

a crosslinked copolymer, capable of swelling in ethanol to give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer containing no more than 20% by weight of water, where the % ethanol:

% water is 2;

1 to 22;

1 respectively, which copolymer is the copolymerization product of

(a) 50 to 99% by weight of said copolymer of (aa) a water-insoluble monoolefinic monomer, or mixture of said monomers, or mixture of said monomers with 0 to 45% by weight of total monomers of (bb) a water-soluble monolefinic monomer, or mixture of said water-soluble monomers, with

(b) 50 to 1% by weight of said copolymer of a divinyl or polyvinyl crosslinking agent having a molecular weight of 100 to 10,000, but where (b) is not more than 20 mol% of component (a).

2. A composition according to claim 1 wherein the swollen copolymer the % ethanol:

% water is 3;

1 to 15;

1 respectively.

3. A composition according to claim 2 wherein the swollen copolymer the % ethanol:

% water is 4;

1 to 8;

1 respectively.

4. A composition according to claim 1 where in the copolymer at least a third by weight of the water-insoluble monomer of component (a) is a monomer with an alkyl group of 4 to 21 carbon atoms.

5. A composition according to claim 1 wherein the copolymer is the copolymerization product of 75-98% by weight of component (a) and 25-2% by weight of component (b).

6. A composition according to claim 1 wherein component (a) comprises 70-95% by weight of water-insoluble monomer (aa) and 30-5% by weight of water-soluble monomer (bb).

7. A composition according to claim 1 wherein component (a) is 75-0% by weight of methyl acrylate, methyl methacrylate or mixture thereof, and 25-100% by weight of a C₄ -C₁₀ alkyl acrylate or methacrylate or mixture thereof.

8. A composition according to claim 1 wherein the water-insoluble monomer of component (a) is methyl methacrylate, n-butyl acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate, n-octyl acrylate, n-octyl methacrylate, glycidyl methacrylate, vinyl acetate or mixtures thereof.

9. A composition according to claim 1 wherein 10-60% by weight of component (a) is n-butyl acrylate or 2-ethylhexyl acrylate.

10. A composition according to claim 1 wherein the water-soluble monomer of component (a) is N-vinyl-2-pyrrolidone, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, acrylic acid, methacrylic acid, N,N-dimethylacrylamide, 2-dimethylaminoethyl methacrylate or mixtures thereof.

11. A composition according to claim 1 where the crosslinking agent of component (b) is a terminal diolefinic hydrophobic macromer having a molecular weight from about 400 to about 8000, said macromer having the formula ##STR2## wherein R₁ is a chain having a molecular weight from about 200 to about 8000, which is the residue of a poly(propylene oxide) or poly(tetramethylene oxide) glycol having ether linkages;

R₂ is hydrogen, methyl or --CH₂ COOR₄, wherein R₄ is hydrogen or an alkyl group with up to 10 carbon atoms;

R₃ is hydrogen or COOR₄, with the proviso that at least one of R₂ and R₃ is hydrogen;

X is oxa, --COO--, or --CONR₅ -- is hydrogen or alkyl with up to 5 carbon atoms and Y is a direct bond or the radical --R₆ --Z₁ --CO--NH--R₇ --NH--CO--Z₂ --, wherein R₆ is linked to X and represents branched or linear alkylene with up to 7 carbon atoms;

Z₁ and Z₂ is oxa or NR₅ and R₇ is the diradical of an aliphatic or aromatic diisocyanate, with the proviso that in case X is oxa, Y is different from a direct bond, and R₂ and R₃ are hydrogen.

12. A composition according to claim 11 wherein R₁ is polypropylene oxide or polytetramethyleneoxide chain with a molecular weight of about 600 to about 4000.

13. A composition according to claim 11 wherein said macromer is a polytetramethyleneoxide glycol with a molecular weight of about 600 to about 4000, endcapped with toluene or isophorone diisocyanate and reacted with 2 moles of a hydroxyalkyl acrylate or methacrylate, wherein alkyl has 2 to 4 carbon atoms.

14. A composition according to claim 1 wherein the crosslinking agent (b) is a C₂ -C₆ alkylene diacrylate, a C₂ -C₆ alkylene dimethacrylate, 3-oxapentamethylene diacrylate, 3-oxapentamethylene dimethacrylate, trimethylolpropane triacrylate or mixtures thereof.

15. A composition according to claim 1 where the copolymer is the copolymerization product of 85-99% of component (a) and 15-1% of component (b), where (a) is 15-50% by weight of methyl methacrylate, 15-70% by weight of 2-ethylhexyl acrylate, n-butyl acrylate or n-octyl acrylate, 5-15% by weight of N-vinyl-2-pyrrolidone and 0-25% by weight of 2-hydroxyethyl methacrylate.