Polymer formulations for delivery of bioactive materials

• US 8,114,883 B2
• Filed: 10/10/2008
• Issued: 02/14/2012
• Est. Priority Date: 12/04/2007
• Status: Expired due to Fees

• Current Assignee: Landec Corporation
• Original Assignee: Landec Corporation
• Inventors: Taft, David, Tzannis, Stelios, Dai, Wei-Guo, Ottensmann, Sandra, Bitler, Steven, Zheng, Qiang, Bell, Adam
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Craigo, William
• Application Number:
  US12/287,520
• Publication Number:
  US 20090209558A1
• Time in Patent Office: 1,222 Days
• Field of Search: None
• US Class Current: 514/259.41
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• 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 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Delivery of drugs in association with PLGA polymers which have crystallinity resulting from the presence of long chain alkyl groups in terminal units.

Claims

1. A pharmaceutical formulation comprising a drug and a polymer, wherein

(1) the polymer comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b—

Cy 

 

(2)

wherein

Cy consists of an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

wherein each terminal unit having formula (2) is a moiety selected from the group consisting of

(2A) moieties (i) in which b is a bond, (ii) which have the formula —

Cy and (iii) which are directly linked to the terminal —

CO—

O—

moiety of one of the repeating units having formula (1),

(2B) moieties (i) in which b is a moiety having the formula —

O—

CO—

, (ii) which have the formula

—

O—

CO—

Cy

and (iii) which are directly linked to the terminal —

CF¹F²—

moiety of one of the repeating units having formula (1), and

(2C) moieties (i) in which b is a moiety having the formula

-R_pbalc—

CO—

, (ii) which have the formula

-R_pbalc—

CO—

Cy, where R_pbalc is the residue of a polyol, and (iii) which are directly linked to the terminal —

CO—

O—

moiety of one of the repeating units having formula (1);

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g, and

(3) the polymer has a number average molecular weight, Mn, of less than 10,000.

2. A formulation according to claim 1 wherein the drug is RISPERIDONE.

3. A formulation according to claim 1 wherein the drug is diclofenac sodium.

4. A formulation according to claim 1 wherein Cy consists of an n-alkyl moiety containing 22 carbon atoms.

5. A formulation according to claim 1 wherein at least some of the polymeric molecules contain at least three Cy moieties, and the polymer has a heat of fusion of at least 10 J/g.

7. A formulation according claim 1 wherein the formulation, when tested by a release test in which the formulation is exposed to a buffer solution which is maintained at a pH of 5.5, releases the drug according to at least one of paragraphs (a)-(c) below

(a) at a substantially constant rate over a period of at least 10 days in the first days, and in a total amount less than 30%,

(b) in a total amount less than 30% over the first 10 days, and

(c) at a substantially constant rate over the first 10 days, and in a total amount less than 20% over the first 10 days.

8. A formulation according to claim 1 wherein the formulation, when tested by a release test in which the formulation is exposed to a buffer solution which is maintained at a pH of 7.4, releases the drug

(a) at a substantially constant rate over a period of at least 10 days in the first 20 days, and in a total amount less than 30% over the first 20 days, and

(b) in a total amount less than 30%, preferably less than 20%, over the first 10 days, preferably over the first 20 days, particularly over the first 30 days.

17. A formulation according to claim 1 wherein the drug is selected from the group consisting of proteins, polypeptides and small molecule drugs.

6. A pharmaceutical formulation comprising a drug and a polymer, wherein

(1) the polymer comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b—

Cy 

 

(2)

wherein

Cy consists of an n-alkyl moiety containing 18-24 carbon atoms and a polyoxyalkylene unit, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

wherein each terminal unit having formula (2) is a moiety selected from the group consisting of

(2A) moieties (i) in which b is a bond, (ii) which have the formula —

Cy and (iii) which are directly linked to the terminal —

CO—

O—

moiety of one of the repeating units having formula (1),

(2B) moieties (i) in which b is a moiety having the formula —

O—

CO—

, (ii) which have the formula

—

O—

CO—

Cy

and (iii) which are directly linked to the terminal —

CF¹F²—

moiety of one of the repeating units having formula (1), and

(2C) moieties (i) in which b is a moiety having the formula

-R_pbalc—

CO—

, (ii) which have the formula

-R_pubic—

CO—

Cy, where R_pbalc is the residue of a polyol, and (iii) which are directly linked to the terminal —

CO—

O—

moiety of one of the repeating units having formula (1);

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g, and

(3) the polymer has a number average molecular weight, Mn, of less than 10,000.

9. A pharmaceutical formulation comprising a drug and a polymer, wherein

(1) the polymer consists essentially of a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which consists essentially of a plurality of repeating units having the formula

—

CH₂—

CO—

O—

 

 

(1A)

and a plurality of repeating units having the formula

—

CH(CH₃)—

CO—

O—

 

 

(1B)

and

(ii) a plurality of terminal units each of which has the formula

-b—

Cy 

 

(2)

wherein

Cy consists of an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

wherein each terminal unit having formula (2) is a moiety selected from the group consisting of

(2A) moieties (i) in which b is a bond, (ii) which have the formula —

Cy and (iii) which are directly linked to the terminal —

CO—

—

O—

moiety of one of the repeating units having formula (1),

(2B) moieties (i) in which b is a moiety having the formula —

O—

CO—

, (ii) which have the formula

—

O—

CO—

Cy

and (iii) which are directly linked to the terminal —

CF¹F²—

moiety of one of the repeating units having formula (1), and

(2C) moieties (i) in which b is a moiety having the formula -R_pbalc—

CO—

, (ii) which have the formula -R_pbalc—

CO—

Cy, where R_pbalc is the residue of a polyol, and (iii) which are directly linked to the terminal -0CO—

O—

moiety of one of the repeating units having formula (1);

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than 10°

C., and a heat of fusion of at least 5 J/g; and

(3) the polymer has a number average molecular weight, Mn, of less than 8,000.

10. A formulation according to claim 9 wherein the polymer has molecular weight less than 5000.

11. A formulation according to claim 9 wherein the polymer contains 2-30 molar percent of the terminal units.

12. A formulation according to claim 9 wherein the polymer contains 10-40% by weight of Cy moieties.

13. A formulation according to claim 9 wherein Cy consists of an n-alkyl moiety containing 22 carbon atoms.

14. A formulation according to claim 9 wherein at least one of the terminal units of formula (2) has a formula selected from the group consisting of

—

CH₂—

CH(OH)—

CH₂—

O—

CO-Cy

and

—

CH₂—

CH(O—

CO—

Cy)—

CH₂—

O—

CO—

Cy

wherein the Cy moiety consists of an n-alkyl moiety containing 18-24 carbon atoms.

15. A formulation according to claim 9 wherein at least some of the polymeric molecules contain at least three Cy moieties.

16. A formulation according to claim 9 wherein the polymer contains less than 170 repeating units of the formulas (1A) and (1B).

18. A formulation according to claim 9 wherein the drug is a protein or a polypeptide.

19. A formulation according to claim 9 wherein the drug is a small molecule drug.

20. A pharmaceutical formulation comprising a drug and a polymer, wherein

(1) the polymer comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

wherein

Cy consists of an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7 , and a heat of fusion of at least 5 J/g;

(3) the polymer has a number average molecular weight, Mn, of less than 10,000; and

(4) the polymer is the reaction product of starting materials consisting of

(i) a preformed polymer which comprises a plurality of repeating units having the formula (1) and which has a terminal carboxyl group, and

(ii) an alcohol containing said Cy moiety.

21. A formulation according to claim 20 wherein the preformed polymer has the formula

HO—

(—

CF¹F²—

CO—

O—

)_n—

H

where n is an integer less than 170.

22. A formulation according to claim 20 wherein the preformed polymer was prepared by the polymerization of lactide and glycolide.

23. A formulation according to claim 20 wherein the preformed polymer was prepared by the polymerization of lactic and glycolic acids.

24. A formulation according to claim 20 wherein the reaction product has a number average molecular weight less than 5000.

25. A formulation according to claim 20 wherein the Cy moiety consists of an n-alkyl moiety containing 22 carbon atoms.

26. A formulation according to claim 20 wherein the drug is a protein, polypeptide, or a small molecule drug.

27. A pharmaceutical formulation comprising a drug and a polymer wherein which

(1) the polymer comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b—

Cy 

 

(2)

wherein

Cy consists of an n-alkyl moiety containing 18-14 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(3) the polymer has a number average molecular weight, Mn, of less than 10,000; and

(4) the polymer is the reaction product of starting materials consisting of

(i) a preformed polymer which comprises a plurality of repeating units having the formula (1) and which has a terminal hydroxyl group, and

(ii) a carboxylic acid, acid chloride or anhydride containing said Cy moiety.

28. A formulation according to claim 27 wherein the preformed polymer has the formula

HO—

(—

CF¹F²—

CO—

O—

)_n—

H

where n is an integer less than 170.

29. A formulation according to claim 27 wherein the preformed polymer was prepared by the polymerization of lactide and glycolide.

30. A formulation according to claim 27 wherein the preformed polymer was prepared by the polymerization of lactic and glycolic acids.

31. A formulation according to claim 27 wherein the reaction product has a number average molecular weight less than 5000.

32. A formulation according to claim 27 wherein the Cy moiety consists of an n-alkyl moiety containing 22 carbon atoms.

33. A formulation according to claim 27 wherein the drug is a protein, a polypeptide or a small molecule drug.

34. A pharmaceutical formulation comprising a drug and a polymer, wherein

(1) the polymer comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹—

F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b—

Cy 

 

(2)

wherein

Cy consists of an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

(2) the polymer has a crystalline melting temperature, Tp, of at least 40°

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(3) the polymer has a number average molecular weight, Mn, of less than 10,000; and

(4) the polymer is the reaction product of a method which comprises the steps of

(A) reacting

(i) a preformed polymer which comprises a plurality of repeating units having the formula (1) and which has a terminal carboxyl group, and

(ii) a polyol, and

(B) reacting the product of step (A) with a carboxylic acid, acid chloride or anhydride containing said Cy moiety.

35. A formulation according to claim 34 wherein the preformed polymer has the formula

HO—

(—

CF¹F²—

CO—

O—

)_n—

H

where n is an integer less than 170.

36. A formulation according to claim 34 wherein the preformed polymer was prepared by the polymerization of lactide and glycolide.

37. A formulation according to claim 34 wherein the preformed polymer was prepared by the polymerization of lactic and glycolic acids.

38. A formulation according to claim 34 wherein the reaction product has a number average molecular weight less than 5000.

39. A formulation according to claim 34 wherein the Cy moiety consists of an n-alkyl moiety containing 22 carbon atoms.

40. A formulation according to claim 34 wherein the drug is a protein, a polypeptide or a small molecule drug.