Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same

• US 6,403,675 B1
• Filed: 04/30/1998
• Issued: 06/11/2002
• Est. Priority Date: 04/30/1997
• Status: Expired due to Term

• Current Assignee: Eisai Incorporated (Eisai Medical Research Incorporated), Johns Hopkins University
• Original Assignee: Johns Hopkins University, Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Kadiyala, Irina, Zhao, Zhong, Leong, Kam W., English, James P., Dang, Wenbin, Mao, Hai-quan
• Primary Examiner(s): SZEKELY, PETER A
• Application Number:
  US09/070,204
• Time in Patent Office: 1,503 Days
• Field of Search: 523/113, 523/111, 524/610, 528/354, 528/356, 528/400, 424/486, 424/78.08, 623/1
• US Class Current: 523/113
• 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: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: C08G 79/04 Phosphorus linked to oxygen or to oxygen and carbon
• CPC Class Codes: C08L 85/02 containing phosphorus
• CPC Class Codes: Y10S 623/924 Material characteristic

Abstract

Biodegradable, flowable or flexible polymer compositions are described comprising a polymer having the recurring monomeric units shown in formula I:

wherein:

each of R and R′ is independently straight or branched alkylene, either unsubstituted or substituted with one or more non-interfering substituents;

L is a divalent cycloaliphatic group;

R″ is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and

n is 5 to 1,000,

wherein said biodegradable polymer is biocompatible before and upon biodegradation. In one embodiment, one or more of R, R′ or R″ is a biologically active substance. Amorphous compositions containing a biologically active substance, in addition to the polymer, and methods for controllably releasing biologically active substances using the compositions, are also described.

Claims

1. A biodegradable, flowable or flexible polymer composition comprising (a) a polymer having the recurring monomeric units shown in formula I:

wherein;

each of R and R′

is independently straight or branched aliphatic, either unsubstituted or substituted with one or more non-interfering substituents;

L is a divalent cycloaliphatic group, wherein the cyclic portion of said cycloaliphatic group is not aromatic or heterocyclic in nature;

R″

is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and

n is 5 to 1,000; and

(b) at least one biologically active substance,

wherein said biodegradable polymer composition is biocompatible both before and upon biodegradation.

2. The polymer composition of claim 1 wherein each of R and R′

is a branched or straight chain alkylene group having from one to seven carbon atoms.

3. The polymer composition of claim 1 wherein each of R and R′

is a methylene group or an ethylene group.

4. The polymer composition of claim 1 wherein R″

is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group.

5. The polymer composition of claim 1 wherein R″

is an alkoxy group.

6. The polymer composition of claim 1 wherein n is 5 to 500.

7. The polymer composition of claim 1 wherein L is cyclohexylene.

8. The polymer composition of claim 1 wherein said polymer comprises additional biocompatible monomeric units or is blended with other biocompatible polymers.

9. The polymer composition of claim 1 wherein said composition also comprises at least one biologically active substance.

10. The polymer composition of claim 1 wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, antigenic materials, and pro-drugs of these substances.

11. The polymer composition of claim 1 wherein said biologically active substance is a therapeutic drug or pro-drug.

12. The polymer composition of claim 11 wherein said drug is selected from the group consisting of anti-neoplastic agents, local anesthetics, antibiotics, anti-virals, anti-fungals, anti-inflammatories, anticoagulants, antigenic materials suitable for vaccine applications, and pro-drugs of these substances.

13. The polymer composition of claim 1 wherein said polymer composition is non-toxic and results in minimal tissue irritation when injected or is otherwise placed into intimate contact with vasculated tissues.

28. The polymer composition of claim 11 wherein said drug is selected from the group consisting of β

-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, anti-asthmatic agents, anti-allergenic materials, anti-arrhythmics, anti-cholesterolemic and anti-lipid agents, anti-cholinergics and sympathomimetics, anti-convulsants, anti-diarrheals, anti-emetics, anti-hypertensive agents, anti-infective agents, anti-malarials, anti-manic agents, anti-nauseants, anti-obesity agents, anti-parkinsonian agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, benzophenanthridine alkaloids, biologicals, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, estrogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energizers, psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents, tranquilizers, uterine relaxants, vitamins, and pro-drugs of these substances.

30. The polymer composition of claim 1, wherein said biologically active substance is lidocaine.

31. The polymer composition of claim 1, wherein said biologically active substance is paclitaxel.

14. A biodegradable, flowable or flexible polymer composition comprising a polymer having the recurring monomeric units shown in formula I:

wherein;

each of R and R′

is independently straight or branched aliphatic, either unsubstituted or substituted with one or more non-interfering substituents;

L is a divalent cycloaliphatic group, wherein the cyclic portion of said cycloaliphatic group is not aromatic or heterocyclic in nature;

R″

is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and

n is 5 to 1,000,

or alternatively one or more of R, R′ and

R″

is a biologically active substance in a form capable of being released in a physiological environment;

wherein said biodegradable polymer composition is biocompatible both before and upon biodegradation.

15. The polymer composition of claim 14 wherein each of R and R′

is a branched or straight chain alkylene group having from one to seven carbon atoms.

16. The polymer composition of claim 14 wherein each of R and R′

is a methylene group or an ethylene group.

17. The polymer composition of claim 14 wherein R″

is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy group.

18. The polymer composition of claim 14 wherein R″

is an alkoxy group.

19. The polymer composition of claim 14 wherein n is 5 to 500.

20. The polymer composition of claim 14 wherein L is cyclohexylene.

21. The polymer composition of claim 14 wherein said polymer comprises additional biocompatible monomeric units or is blended with other biocompatible polymers.

22. The polymer composition of claim 14 wherein R″

is a biologically active substance.

23. The polymer composition of claim 14 wherein either R or R′

is a biologically active substance.

24. The polymer composition of claim 14 wherein said biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, antigenic materials, and pro-drugs of these substances.

25. The polymer composition of claim 14 wherein said biologically active substance is a therapeutic drug or pro-drug.

26. The polymer composition of claim 25 wherein said drug is selected from the group consisting of anti-neoplastic agents, local anesthetics, antibiotics, anti-virals, anti-fungals, anti-inflammatories, anticoagulants, antigenic materials suitable for vaccine applications, and pro-drugs of these substances.

27. The polymer composition of claim 14 wherein said polymer composition is non-toxic and results in minimal tissue irritation when injected or is otherwise placed into intimate contact with vasculated tissues.

29. The polymer composition of claim 25 wherein said drug is selected from the group consisting of β

-adrenergic blocking agents, anabolic agents, androgenic steroids, antacids, anti-asthmatic agents, anti-allergenic materials, anti-arrhythmics, anti-cholesterolemic and anti-lipid agents, anti-cholinergics and sympathomimetics, anti-convulsants, anti-diarrheals, anti-emetics, anti-hypertensive agents, anti-infective agents, anti-malarials, anti-manic agents, anti-nauseants, anti-obesity agents, anti-parkinsonian agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, benzophenanthridine alkaloids, biologicals, cardioactive agents, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, estrogens, expectorants, gastrointestinal sedatives, humoral agents, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange agents, laxatives, mineral supplements, miotics, mucolytic agents, neuromuscular drugs, nutritional substances, peripheral vasodilators, progestational agents, prostaglandins, psychic energizers, psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents, tranquilizers, uterine relaxants, vitamins, and pro-drugs of these substances.

32. The polymer composition of claim 14, wherein said biologically active substance is lidocaine.

33. The polymer composition of claim 14, wherein said biologically active substance is paclitaxel.