DRUG DELIVERY SYSTEM FOR DELIVERY OF ACID SENSITIVITY DRUGS

Abstract

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.

Claims

1.-16. (canceled)

17. 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: ##STR00005## 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.sub.1 is independently selected from the group consisting of (C.sub.2-C.sub.20) alkylene, C.sub.2-C.sub.20) alkenylene, and combinations thereof; R.sub.3 and R.sub.4 in a single backbone unit m or p, respectively, are independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl, —CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2COOH, —(CH.sub.2)COOH, —CH.sub.2CH.sub.2COOH, CH.sub.3—CH.sub.2—CH(CH.sub.3)—, (CH.sub.3).sub.2—CH—CH.sub.2—, CH═C—CH.sub.2—, and (CH.sub.3).sub.2—CH—; R.sub.5 is selected from the group consisting of (C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene, or alkyloxy; R.sub.6 is a bicyclic-fragment of 1,4:3,6-dianhydrohexitols of structural formula (III); ##STR00006## R.sub.7 is (C.sub.6-C.sub.10) aryl (C.sub.1-C.sub.6)alkyl; R.sub.8 is —(CH.sub.2).sub.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.

18. The fiber according to claim 17, wherein R.sub.3 and R.sub.4 are independently selected from the group consisting of (C.sub.1-C.sub.6)alkyl, CH.sub.3—CH.sub.2—CH(CH.sub.3)—, (CH.sub.3).sub.2—CH—CH.sub.2—, and (CH3)2—CH—;

19. The fiber according to claim 17, wherein the polyesteramide copolymer comprises at least pendant 15% acid groups based on the total amount of pendant functionalities of the polyesteramide copolymer.

20. The fiber according to claim 17, wherein the bioactive agent is an acid sensitive bioactive agent.

21. The fiber according to claim 17, wherein the bioactive agent comprises tanercept, ranibizumab, bevacizumab, latanoprost, bimatoprost or travoprost.

22. The fiber according to claim 17, wherein n is from 50 to 200, a is at least 0.015, and a divided by b is from 3/17 to 19.

23. The fiber according to claim 17, wherein n is from 50 to 200, a is at least 0.05, and a divided by h is from 1 to 19.

24. The fiber according to claim 17, wherein n is from 50 to 200, a is at least 0.08, and a divided by b is from 4 to 19.

25. The fiber according to claim 18, wherein n is from 50 to 200, a is at least 0.015, and a divided by b is from 3/17 to 19.

26. The fiber according to claim 17, 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.sub.1 is —(CH.sub.2).sub.8—; R.sub.3 and R.sub.4 respectively, are (CH.sub.3).sub.2—CH—CH.sub.2—; R.sub.5 is (C.sub.2-C.sub.20)alkylene; and R.sub.7 is benzyl.

27. The fiber according to claim 17, 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.sub.1 is —(CH.sub.2).sub.8—; R.sub.3 and R.sub.4 are (CH.sub.3).sub.2—CH—CH.sub.2—; R.sub.5 is (C.sub.2-C.sub.20)alkylene; and R.sub.7 is benzyl.

28. The fiber according to claim 17, 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.sub.1 is —(CH.sub.2).sub.8—; R.sub.4 is (CH.sub.3).sub.2—CH—CH.sub.2—; R.sub.5 is (C.sub.2-C.sub.20)alkylene; and R.sub.7 is benzyl.

29. The fiber according to claim 17, 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.

30. The fiber according to claim 17, wherein the cylindrical 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.

31. The fiber according to claim 17, 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.

32. The fiber according to claim 17, wherein the core consists of the polyesteramide copolymer, the bioactive agent, and optionally an excipient.

33. The fiber according to claim 17, wherein the hydrolytically degradable polymer consists of poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.

34. The fiber according to claim 32, wherein the hydrolytically degradable polymer consists of poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), polycaprolactone, or a combination thereof.

35. A method for treating glaucoma, ocular hypertension, diabetic retinopathy or macular degeneration comprising the step of injecting the fiber according to claim 17 into the eye or subconjunctival space of a mammal in need of treatment thereof.

36. 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: ##STR00007## 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.sub.1 is independently selected from the group consisting of (C.sub.2-C.sub.20) alkylene, (C.sub.2-C.sub.20) alkenylene, and combinations thereof; R.sub.3 and R.sub.4 in a single backbone unit m or p, respectively, are independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl, —CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2COOH, —(CH.sup.2)COOH, —CH.sub.2CH.sub.2COOH, CH.sub.3—CH.sub.2—CH(CH.sub.3)—, (CH.sub.3).sub.2—CH—CH.sub.2—, CH═C—CH.sub.2—, and (CH.sub.3).sub.2—CH—; R.sub.5 is selected from the group consisting of (C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene, or alkyloxy; R.sub.6 is a bicyclic-fragment of 1,4:3,6-dianhydrohexitols of structural formula (III); ##STR00008## R.sub.7 is (C.sub.6-C.sub.10) aryl (C.sub.1-C.sub.6)alkyl; R.sub.8 is —(CH.sub.2).sub.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.

Description

FIGURES

[0085] FIG. 1: shows cumulative release percentages of Latanoprost indicating constant drug release for the PEA-III-X25 core-shell fiber, while the PEA-III-X25 core, no shell exhibits a burst release. daily doses of Latanoprost are presented with a fiber comprising no shell displaying significant burst in the first 20 days of the release.

[0086] FIG. 2: shows the release of Latanoprost in daily doses with a fiber comprising no shell displaying significant burst in the first 20 days of the release.

[0087] FIG. 3: shows the release of Latanoprost with a constant daily dose of Latanoprost of 0.05 μg/day during 140 days.

[0088] FIG. 4: show cumulative release curves and daily doses for PEA-III-AcBz and PEAIIIX25 cores. The results show a decrease in daily doses over time due the non-degradation PEA-III-AcBz polymer core during the release time scale.

[0089] FIG. 5: show cumulative release curves and daily doses for PEA-III-AcBz and PEA-III-X25 cores. The results show a decrease in daily doses over time due the non-degradation PEA-III-AcBz polymer core during the release time scale.

[0090] FIG 6: show cumulative release curves and daily doses of Latanoprost from PLGA and show poor control over daily doses with high Latanoprost burst when the polymer matrix is degraded.

[0091] FIG. 7: show cumulative release curves and daily doses of Latanoprost from PLGA and show poor control over daily doses with high Latanoprost burst when the polymer matrix is degraded.

[0092] FIG. 8: show that core shell fibers made of PEA-III-X25 and PEA-III-AcBz do not reduce burst effect, exhibiting a similar drug release profile as fibers comprising no shell.

[0093] FIG. 9: show that core shell fibers made of PEA-III-X25 and PEA-III-AcBz do not reduce burst effect, exhibiting a similar drug release profile as fibers comprising no shell.

[0094] FIG. 10: shows the morphology of the fiber after 1 week.

[0095] FIG. 11 shows the morphology of the fiber after 1 month.

[0096] FIG. 12 shows the morphology of the fiber after 3 months.

[0097] FIG. 13 shows the morphology of the fiber after 8 months.

[0098] FIG. 14: shows cumulative release percentages of bimatoprost indicating controlled drug release for the PEA-III-X25 core-shell fiber, while the PEA-III-X25 core, no shell exhibits a burst release.

[0099] FIG. 15: shows daily doses of bimatoprost with a fiber comprising no shell displaying significant burst in the first 10 days of release.

EXAMPLES

Example 1

Latanoprost Release from Core Shell Fibers Comprising PEA-III-X25/PLGA and Fibers of PEA-III-X25 Comprising No Shell

[0100] Fibers made of PEA-III-X25 with a loading percentage of 10% latanoprost were prepared by extrusion and coated with PLGA. Four individual fibers with a diameter of 240 μm and 5 mm long were placed in 1.2 ml PBS buffer solution at 37° C. At varying time points 0.9 mL PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured. Typically, samples were measured every day in the first week and weekly at later time points. For the quantitative analysis of the release of latanoprost samples a Waters e2695 Alliance HPLC with a photodiode array detector was used. An isocratic HPLC method was used with a Agilent Zorbax Eclipse XBD-C18 4.6×250 mm, 5 μm column. The mobile phase was Acetonitrile/H2O (60/40 containing 0.05% TFA) and the flow was 1.0 ml/min. Column temperature was set to 25° C. and sample temperature to 15° C. Samples were measured at a wavelength of 210 nm. The system of Latanoprost showed linearity in a range of 1 μg-200 μg which was also the range used for a standard calibration curve. FIG. 1 shows cumulative release percentages of latanoprost indicating constant drug release for the PEA-III-X25 core-shell fiber, while the PEA-III-X25 core, no shell exhibits a burst release. In FIG. 2 daily doses of latanoprost are presented with a fiber comprising no shell displaying significant burst in the first 20 days of release.

Example 2

Latanoprost Release from PEA-III-X25/PLLA Core-Shell Fibers

[0101] Fibers made of PEA-III-X25 with a loading percentage of 15% latanoprost were prepared by melt injection and coated with PLLA. Four individual fibers with a diameter of 200 μm and 5 mm long were placed in 1.2 ml PBS buffer solution at 37° C. At varying time points 0.9 mL PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured.

FIG. 3 shows a constant daily dose of latanoprost of 0.05 μg/day during 140 days.

Example 3

Latanoprost Release from Core Shell Fibers Comprising PEA-III-X25/PEA-III-X25, PEA-III-X25/PEA-III-AcBz Core-Shell and Fibers of PEA-III-X25 Comprising No Shell

[0102] Fibers made of PEA-III-X25 with a loading percentage of 10% latanoprost were prepared by melt injection and coated with PEA-III-X25 and PEA-III-AcBz. Three individual fibers with a diameter of 200 μm and 5 mm long were placed in 1.2 ml PBS buffer solution at 37° C. At varying time points 0.9 mL PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured.

FIG. 8 and FIG. 9 show that core shell fibers made of PEA-III-X25 and PEA-III-AcBz do not reduce burst effect, exhibiting a similar drug release profile as fibers comprising no shell.

Example 4

PEA-III-X25/PLGA Core-Shell Fibers During Drug Release

[0103] Fibers made of PEA-III-X25 with a loading percentage of 15% latanoprost were prepared by injection molding and coated with PLGA. Four individual fibers were placed in 1.4 ml PBS buffer solution at 37° C. At selected timepoints, fibers were imaged immersed in PBS using a Olympus CX-41 light microscope at 4× magnification. FIGS. 10-13 show the morphology of the fiber at 1 week, 1 month, 3 months and 8 months. As the PEA-III-X25 core degrades and leaches out of the coating, the surface area of the fiber ends increases, increasing the surface available for drug diffusion. The observed effect compensates for the decrease in the drug concentration gradient, producing a more constant drug release profile.

Example 5

Bimatoprost Release from PEA-III-X25/PLLA Core-Shell Fibers

[0104] Fibers made of PEA-III-X25 with a loading percentage of 30% bimatoprost were prepared by melt injection and coated with PLLA. Five individual fibers with a diameter of 200 μm and 1.2 mm long were placed in 0.25 ml PBS buffer solution at 37° C. At varying time points 0.15 mL PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured. FIG. 14 shows cumulative release percentages of bimatoprost indicating controlled drug release for the PEA-III-X25 core-shell fiber, while the PEA-III-X25 core, no shell exhibits a burst release. In FIG. 15 daily doses of bimatoprost are presented with a fiber comprising no shell displaying significant burst in the first 10 days of release.

Comparative Experiment A: Latanoprost Release from PEA-III-AcBz/PLGA, PEA-III-X25/PLGA Core-Shell and PEA-III-AcBz No Shell Systems

[0105] Fibers made of PEA-III-AcBz [(poly-8-[(L-Leu-DAS).sub.0.45(L-Leu-6).sub.0.3-[L-Lys(Bz)].sub.0.25. ] structure is given in Formula III with a loading percentage of 10% latanoprost were prepared by extrusion and coated with PLGA. PEA-III-X25 fibers with a loading percentage of 10% latanoprost were prepared by extrusion and coated with PLGA. Four individual fibers with a diameter of 250 μm and 5 mm long were placed in 1.2 ml PBS buffer solution at 37° C. At varying time points 0.9 mL PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured.

FIG. 4 and FIG. 5 present cumulative release curves and daily doses for PEA-III-AcBz and PEA-III-X25 cores. The results show a decrease in daily doses over time due the non-degradation PEA-III-AcBz polymer core during the release time scale. In contrast, fibers made of PEA-III-X25 show an increase in daily dose due to polymer degradation.

##STR00004##

Comparative Experiment B: Latanoprost Release from PLGA Disks

[0106] Drug loaded disks of PLGA with a loading percentage of 10% latanoprost were prepared by solvent casting films and punching out samples from the films. Three individual disks with a diameter of 7 mm were placed in 5.0 ml PBS buffer solution at 37° C. At varying time points the complete PBS solution was refreshed to assure sink conditions and the drug concentration was subsequently measured.

FIG. 6 and FIG. 7 present cumulative release curves and daily doses of latanoprost from PLGA and show poor control over daily doses with high latanoprost burst when the polymer matrix is degraded.