Drug delivery system for delivery of acid sensitivity drugs
The present invention relates to a drug delivery system comprising a core and a shell in which the core comprises a hydrolytically degradable polymer X which polymer backbone comprises pendant ester and acid functionalities and in which the shell comprises a hydrolytic degradable polymer Y. The hydrolytic degradable polymers X and Y are different polymers. Polymer X further comprises amino-acids in the polymer backbone and degrades via zero order degradation kinetics for a period of at least 3 months. Polymer Y degrades via auto-acceleration degradation kinetics.
1. A fiber for the delivery of a bioactive agent to an eye of a mammal, the fiber comprising a cylindrical core and a shell partially surrounding the core, the core comprising a bioactive agent and a polyesteramide copolymer according to the following chemical formula:
wherein
m+p is from 0.9-0.1 and a+b is from 0.1 to 0.9;
m+p+a+b=1 whereby one of m or p could be 0;
n is from 5 to 300;
a is at least 0.005, b is at least 0.005, a divided by b is from 1/19 to 19; wherein units of m (if present), units of p (if present), units of a, and units of b are all randomly distributed throughout the copolymer;
R 1 is independently selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, and combinations thereof;
R 3 and R 4 in a single backbone unit m or p, respectively, are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 COOH, —(CH 2 )COOH, —CH 2 CH 2 COOH, CH 3 —CH 2 —CH(CH 3 )—, (CH 3 ) 2 —CH—CH 2 —, CH═C—CH 2 —, and (CH 3 ) 2 —CH—;
R 5 is selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, or alkyloxy;
R 6 is a bicyclic-fragment of 1,4:3,6-dianhydrohexitols of structural formula (III);
R 7 is (C 6-10 ) aryl (C 1 -C 6 )alkyl;
R 8 is —(CH 2 ) 4 —; and
the shell comprising a hydrolytically degradable polymer, the hydrolytically degradable polymer comprising poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.
2. The fiber according to claim 1 , wherein R 3 and R 4 are independently selected from the group consisting of (C 1 -C 6 )alkyl, CH 3 —CH 2 —CH(CH 3 )—, (CH 3 ) 2 —CH—CH 2 —, and (CH 3 ) 2 —CH—.
3. The fiber according to claim 1 , wherein the polyesteramide copolymer comprises at least pendant 15% acid groups based on the total amount of pendant functionalities of the polyesteramide copolymer.
4. The fiber according to claim 1 , wherein the bioactive agent is an acid sensitive bioactive agent.
5. The fiber according to claim 1 , wherein the bioactive agent comprises tanercept, ranibizumab, bevacizumab, latanoprost, bimatoprost or travoprost.
6. The fiber according to claim 1 , wherein n is from 50 to 200, a is at least 0.015, and a divided by b is from 3/17 to 19.
7. The fiber according to claim 1 , wherein n is from 50 to 200, a is at least 0.05, and a divided by b is from 1 to 19.
8. The fiber according to claim 1 , wherein n is from 50 to 200, a is at least 0.08, and a divided by b is from 4 to 19.
9. The fiber according to claim 2 , wherein n is from 50 to 200, a is at least 0.015, and a divided by b is from 3/17 to 19.
10. The fiber according to claim 1 , wherein
m+p+a+b=1, m=0.3, p=0.45, a=0.125, and b=0.125;
wherein the m, p, a, and b units are randomly distributed;
R 1 is —(CH 2 ) 8 —; R 3 and R 4 respectively, are (CH 3 ) 2 —CH—CH 2 —; R 5 is (C 2 -C 20 )alkylene; and R 7 is benzyl.
11. The fiber according to claim 1 , wherein
m+p+a+b=1, m=0.3, p=0.45, a=0.0625, and b=0.1875;
wherein the m, p, a, and b units are randomly distributed;
R 1 is —(CH 2 ) 8 —; R 3 and R 4 are (CH 3 ) 2 —CH—CH 2 —; R 5 is (C 2 -C 20 )alkylene; and R 7 is benzyl.
12. The fiber according to claim 1 , wherein
m+p+a+b=1, m=0.3, p=0.45, a=0.1875, and b=0.0625;
wherein the m, p, a, and b units are randomly distributed;
R 1 is —(CH 2 ) 8 —; R 4 is (CH 3 ) 2 —CH—CH 2 —; R 5 is (C 2 -C 20 )alkylene; and R 7 is benzyl.
13. The fiber according to claim 1 , wherein the cylindrical core comprises a side and two ends, and wherein the shell surrounds the side and one end of the cylindrical core, and the shell does not surround one end of the cylindrical core.
14. The fiber according to claim 1 , wherein the cylindrical co core comprises a side and two ends, and wherein the shell surrounds the side of the cylindrical core, and the shell does not surround the ends of the cylindrical core.
15. The fiber according to claim 1 , wherein the fiber has an average diameter of from 50 to 500 μm and the shell has a thickness of between 0.5 and 5 μm.
16. The fiber according to claim 1 , wherein the core consists of the polyesteramide copolymer, the bioactive agent, and optionally an excipient.
17. The fiber according to claim 1 , wherein the hydrolytically degradable polymer consists of poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.
18. The fiber according to claim 16 , wherein the hydrolytically degradable polymer consists of poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.
19. A method for treating glaucoma, ocular hypertension, diabetic retinopathy or macular degeneration comprising the step of injecting the fiber according to claim 1 into the eye or subconjunctival space of a mammal in need of treatment thereof.
20. A method of forming a fiber for the delivery of a bioactive agent to an eye of a mammal, the fiber comprising a cylindrical core and a shell partially surrounding the core, comprising the following steps:
a. forming the core by injection molding a formulation comprising a bioactive agent and a polyesteramide copolymer according to the following chemical formula:
wherein
m+p is from 0.9-0.1 and a+b is from 0.1 to 0.9;
m+p+a+b=1 whereby one of m or p could be 0;
n is from 5 to 300;
a is at least 0.005, b is at least 0.005, a divided by b is from 1/19 to 19; wherein units of m (if present), units of p (if present), units of a, and units of b are all randomly distributed throughout the copolymer;
R 1 is independently selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, and combinations thereof;
R 3 and R 4 in a single backbone unit in or p, respectively, are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 COOH, —(CH 2 )COOH, —CH 2 CH 2 COOH, CH 3 —CH 2 —CH(CH 3 )—, (CH 3 ) 2 —CH—CH 2 —, CH═C—CH 2 —, and (CH 3 ) 2 —CH—;
R 5 is selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, or alkyloxy;
R 6 is a bicyclic-fragment of 1,4:3,6-dianhydrohexitols of structural formula (III);
R 7 is (C 6 -C 10 ) aryl (C 1 -C 6 )alkyl;
R 8 is —(CH 2 ) 4 —; and
b. forming the shell by dip coating or spray coating the core, the shell comprising a hydrolytically degradable polymer, the hydrolytically degradable polymer comprising poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.