Biodegradable polypeptide and the use thereof for the gradual release of drugs

• US 4,976,962 A
• Filed: 07/11/1989
• Issued: 12/11/1990
• Est. Priority Date: 10/19/1984
• Status: Expired due to Term

• Current Assignee: Bracco Research SA
• Original Assignee: Bernard Lamy, Daniel Bichon
• Inventors: Bichon, Daniel, Lamy, Bernard
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/378,072
• Time in Patent Office: 518 Days
• Field of Search: 514/2, 514/773, 514/962, 514/963, 514/964, 514/965, 424/451, 424/457, 424/464, 424/486, 424/422, 424/424, 424/425, 424/426
• US Class Current: 424/424
• CPC Class Codes: A61K 9/2045 Polyamides; Polyaminoacids, e.g. polylysine
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08G 69/10 Alpha-amino-carboxylic acids polysuccinimides C08G73/1092
• CPC Class Codes: C08G 73/1092 Polysuccinimides
• CPC Class Codes: C08L 77/04 Polyamides derived from alpha-amino carboxylic acids C08L77/10 takes precedence

Abstract

Biodegradable alkyloxycarbonylmethyl or aryloxycarbonylmethyl polyaspartate and polyglutamate which can be used as a carrier for drugs which are either in the encapsulated state or are incorporated in the polymer matrix. The polypeptide thus loaded degrades enzymatically in the organ where it has been placed and thus gradually releases the drug which it contains.

Claims

1. A pharmaceutical composition comprising an effective amount of a drug carried by a polypeptide comprising a member of the group consisting of (a) polymers corresponding to the formula ##STR15## in which R¹ is a lower alkyl or hydrogen, R being an aliphatic or aromatic radical or R and R¹ are bound to one another to form a hydrocarbon bridge of two or three links which may or may not be substituted;

and (b) polymers corresponding to the formula;

##STR16## wherein the groups R and R¹ have the meanings given above and wherein ##STR17## is an uncarboxylated or carboxylated amino acid moiety of which the --COOH is free or partially or completely esterified;

n is 1 to 2 and x is equal to y+z is selected so that the molecular weight of the polypeptide is not less than 5000 D, the drug being progressively released as a result of the biodegradation of the polypeptide carrier.

2. A composition according to claim 1 wherein the polypeptide is one where R is selected from the methyl, ethyl, isopropyl, isobutyl, tert.butyl, neopentyl, phenyl, benzyl radicals, the C₁₀ to C₂₂ fatty alkyls and methoxylated polyethylene glycol containing from 1 to 100 oxyethylene units.

3. A composition according to claim 1 wherein the polypeptide is one where, when R and R¹ are bound to one another, the link formed by them is selected from the following formulae:

--CH₂ --CH₂ --;

--CH═

CH--;

--CH(CH₃)--CH(CH₃);

--C(CH₃)═

C(CH₃)--;

1,2-phenylene;

cyclohexenylene;

cyclopentenylene, cyclopentadienylene, trimethylene;

--CH═

CH--CH₂ ;

##STR18##

4. A composition according to claim 1 wherein the polypeptide is one where the compound I is selected from alkyloxycarbonylmethyl and aryloxycarbonylmethyl glutamate and aspartate, that compound II is selected from the copolymers of alkyloxycarbonylmethyl and aryloxycarbonylmethyl glutamate or aspartate with one or more other amino acids selected from alanine, leucine, valine and phenylalanine.

5. A composition according to claim 1 wherein the polypeptide is one where the copolymer II is selected from the copolymers of polyglutamate or aspartate I with glutamic acid and/or the lower alkyl glutamates and aspartic acid and/or the lower alkyl aspartates respectively.

6. A composition according to claim 1 wherein the polypeptide is one where the alkyl or aryl groups R are selected from the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, benzyl, phenyl, lauryl, ketyl, oleyl and stearyl groups.

7. A composition according to claim 1 wherein drug and said polymer are mixed homogeneously and shaped into pharmaceutically acceptable form.

8. A composition according to claim 1 including a polyalkylene glycol to plasticize the polymer.

9. A composition according to claim 1 in the form of a capsule, rod, granule or other therapeutically administrable form.

10. In a treatment method requiring the controlled release of a drug in the body, the improvement which comprises using the composition of claim 1.

11. A biodegradable implant or prostheses including a polypeptide comprising a member of the group consisting of (a) polymers corresponding to the formula ##STR19## in which R¹ is a lower alkyl or hydrogen, R being an aliphatic or aromatic radical or R and R¹ are bound to one another to form a hydrocarbon bridge of two or three links which may or may not be substituted;

and (b) polymers corresponding to the formula;

##STR20## wherein the groups R and R¹ have the meanings given above and wherein ##STR21## is an uncarboxylated or carboxylated amino acid moiety of which the --COOH is free or partially or completely esterified;

n is 1 or 2 and x which is equal to y+z is selected so that the molecular weight of the polypeptide is not less than 5000 D, the drug being progressively released as a result of the biodegradation of the polypeptide carrier.

12. A film-forming polymeric composition suitable for use as a dressing comprising, a solution in a water-soluble organic solvent of a polypeptide comprising a member of the group consisting of (a) polymers corresponding to the formula ##STR22## in which R¹ is a lower alkyl or hydrogen, R being an aliphatic or aromatic radical or R and R¹ are bound to one another to form a hydrocarbon bridge of two or three links which may or may not be substituted;

and (b) polymers corresponding to the formula;

##STR23## wherein the groups R and R¹ have the meanings given above and wherein ##STR24## is an uncarboxylated or carboxylated amino acid moiety of which the --COOH is free or partially or completely esterified;

n is 1 or 2 and x which is equal to y+z is selected so that the molecular weight of the polypeptide is not less than 5000 D, the drug being progressively released as a result of the biodegradation of the polypeptide carrier.

13. A film-forming polymeric composition according to claim 12 wherein R is selected from the methyl, ethyl, isopropyl, isobutyl, neopentyl, tert.butyl, phenyl, benzyl, radicals and the C₁₀ to C₂₂ fatty alkyls.

14. A film-forming polymeric composition according to claim 12 wherein when R and R¹ are bound to one another, the bond formed by them is selected from the following formulae:

--CH₂ --CH₂ --;

--CH═

CH--;

--CH(CH₃)--CH(CH₃);

--C(CH₃)═

C(CH₃)--;

1,2-phenylene;

cyclohexenylene;

cyclopentenylene, cyclopentadienylene, --(CH₂)₃ --;

--CH═

CH--CH_2- ;

##STR25##

15. A film-forming polymeric composition according to claim 12 wherein compound (I), is selected from alkyloxycarbonylmethyl and aryloxycarbonylmethyl glutamate and aspartate and compound (II) is selected from the copolymers of alkyloxycarbonylmethyl and aryloxycarbonylmethyl glutamate or aspartate with one or more other amino acids selected from alanine, leucine, valine and phenylalanine.

16. A film-forming polymeric composition according to claim 12 wherein copolymer II is selected from the copolymers of polyglutamate or aspartate I with glutamic acid and/or the lower alkyl glutamates and with aspartic acid and/or the lower alkyl aspartates.

17. A film-forming polymeric composition according to claim 15 wherein the alkyl groups are selected from the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, neopentyl, benzyl, phenyl, lauryl, ketyl, stearyl and oleyl groups.

18. A composition according to claim 12 wherein the solvent is a polyalkylene glycol.

19. A composition according to claim 12 wherein the solvent is at least one of the following solvents:

polyethylene glycol, dimethylformamide, acetone, ethylmethylketone, butanol, ethanol, dioxan or tetrahydrofuran.

20. A composition according to claim 12 wherein said solution also contains a pore-forming agent.

21. A composition according to claim 20 wherein the pore-forming agent is very finely ground salt, dissolution of the grains thereof in water leading to the formation of a porous foam structure.

22. A composition according to claim 20 wherein the pore-forming agent is a volatile organic solvent, the covering layer being freeze-dried so as to form a porous structure in the mass by evaporation of the volatile solvent.

23. A method of using the film-forming polymeric composition according to claim 12 wherein a layer of the solution is applied to a surface to be covered, the thus covered surface is then contacted with water so that the water dissolves and eliminates the water-soluble solvent to leave a film of the film-forming substance.

24. A method of using the composition off claim 12 wherein a drug is included in said solution, the drug being gradually released to its destination as the result of biodegradation of the film of polymer carrier.