Polymer formulations for delivery of bioactive materials
View Patent ↗Delivery of drugs in association with PLGA polymers which have crystallinity resulting from the presence of long chain alkyl groups in terminal units.
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
—CF 1 F 2 —CO—O— (1)
wherein
F 1 is hydrogen and F 2 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 —CF 1 F 2 —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.
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
—CF 1 F 2 —CO—O— (1)
wherein
F 1 is hydrogen and F 2 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 —CF 1 F 2 —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.
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.
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
—CH 2 —CO—O— (1A)
and a plurality of repeating units having the formula
—CH(CH 3 )—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 —CF 1 F 2 — 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
—CH 2 —CH(OH)—CH 2 —O—CO-Cy
and
—CH 2 —CH(O—CO—Cy)—CH 2 —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).
17. A formulation according to claim 1 wherein the drug is selected from the group consisting of proteins, polypeptides and small molecule drugs.
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
—CF 1 F 2 —CO—O—
wherein
F 1 is hydrogen and F 2 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—(—CF 1 F 2 —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
—CF 1 F 2 —CO—O— (1)
wherein
F 1 is hydrogen and F 2 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—(—CF 1 F 2 —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
—CF 1 —F 2 —CO—O— (1)
wherein
F 1 is hydrogen and F 2 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—(—CF 1 F 2 —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.