FIBER COMPRISING A BIODEGRADABLE POLYMER

Abstract

The present disclosure relates to fibers implantable in the body of a human or animal and processes for manufacturing such a fiber. The fiber undergoes a reduction in surface area to volume ratio of a factor of 1.05-10 upon injection in the human or animal body. In an embodiment, a process for manufacturing a fiber comprises extruding a biodegradable polymer into a fiber capable of fitting in a syringe needle of at least 25 Gauge, and cooling the fiber below its dry glass transition temperature while the fiber is under tension.

Claims

1.-12. (canceled)

13. A process for the manufacturing of a fiber comprising a biodegradable polymer comprising the following steps: a. extruding a biodegradable polymer into a fiber capable of fitting in a syringe needle of at least 25 Gauge, and b. cooling the fiber below its dry glass transition temperature while the fiber is under tension, wherein the biodegradable polymer is a polyesteramide of formula I ##STR00005## wherein m is 0.01 to 0.99; p is 0.99 to 0.01; and q is 0.99 to 0.01; n is 5 to 350; R.sup.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.sup.3 and R.sup.4 in a single co-monomer 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.2)SH.sub.2, —(CH.sub.2).sub.2S(CH.sub.3), —CH.sub.2OH, —CH(OH)CH.sub.3, —(CH.sub.2).sub.4NH.sub.3+, —(CH.sub.2).sub.3NHC(—NH2+)NH.sub.2, —CH.sub.2COOH, —CH.sub.2—CO—NH.sub.2, —CH.sub.2CH.sub.2—CO—NH.sub.2, —CH.sub.2CH.sub.2COOH, CH.sub.3—CH.sub.2—CH(CH.sub.3)—, (CH.sub.3).sub.2—CH—CH.sub.2—, H.sub.2N—(CH.sub.2).sub.4—, Ph-CH.sub.2—, CH.sub.2═C—CH.sub.2—, HO-p-Ph-CH.sub.2—, and Ph-NH—; R.sup.5 is of (C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene, alkyloxy, or oligoethyleneglycol; R.sup.6 is a bicyclic-fragment of 1,4:3,6-dianhydrohexitol; R.sup.7 is hydrogen, (C.sub.6-C.sub.10) aryl, (C.sub.1-C.sub.6) alkyl, or a protecting group; and R.sup.8 is independently (C.sub.1-C.sub.20) alkyl or (C.sub.2-C.sub.20)alkenyl; wherein the fiber undergoes a reduction in surface area to volume ratio of a factor of 1.05-10 upon injection in the human or animal body.

14. The process according to claim 13, wherein m is about 0.3, p is about 0.45, and q is about 0.25; n is about 5-100; R.sup.1 is (CH.sub.2).sub.8 or (CH.sub.2).sub.4; R.sup.3 and R.sub.4 are (CH.sub.3).sub.2—CH—CH.sub.2—; R.sup.5 is (CH.sub.2).sub.6; R.sup.6 is 1,4:3,6-dianhydrosorbitol (DAS); R.sup.7 is a benzyl protecting group; and R.sup.8 is (CH.sub.2).sub.4.

15. The process according to claim 13, wherein the biodegradable polymer has a wet Tg below 37° C.

16. The process according to claim 13, wherein the biodegradable polymer is an amorphous biodegradable polymer.

17. The process according to claim 13, wherein the fiber further comprises a bioactive agent.

18. The process according to claim 17, wherein the fiber further comprises a small molecule drug or prodrug.

19. The process according to claim 1, further comprising the step of stretching the fiber to a diameter of from 100 to 250 μm prior to cooling the fiber below its dry glass transition temperature.

20. The process according to claim 19, wherein the biodegradable polymer has a residence time of 5 to 10 minutes at 120 to 140° C. prior to stretching the fiber.

21. A fiber formed from the process of claim 13.

22. A fiber formed from the process of claim 14.

23. A fiber formed from the process of claim 15.

24. A fiber formed from the process of claim 16.

25. A fiber formed from the process of claim 17.

26. A fiber formed from the process of claim 18.

27. A fiber formed from the process of claim 19.

28. A fiber formed from the process of claim 20.

29. The fiber of claim 21, wherein the fiber undergoes a reduction in surface area to volume ratio of a factor of from 1.25 to 5 upon injection in the human or animal body.

30. The fiber of claim 21, wherein the fiber undergoes a reduction in surface area to volume ratio of a factor of from 2 to 10 upon injection in the human or animal body.

31. The fiber of claim 26, wherein the fiber undergoes a reduction in surface area to volume ratio of a factor of from 1.25 to 5 upon injection in the human or animal body.

32. The fiber of claim 26, wherein the fiber undergoes a reduction in surface area to volume ratio of a factor of from 2 to 10 upon injection in the human or animal body.

Description

[0043] In FIG. 1 the dimensional change of the injected fiber according to the present invention is shown.

[0044] FIG. 1 relates to a PEA III fiber dry (A, 25× magn.), in rabbit vitreous after 1 day (B, 50× magn.) and after 14 days (C, 50× magn.)

[0045] It showed a decrease of the surface area to volume ratio of the fiber i.e., increase in fiber diameter from 150 μm to about 300 μm, with associated decrease in fiber length while maintaining a relatively constant volume.

[0046] FIG. 2 relates to the release of active pharmaceutical ingredients (API) from PEA-III Ac Bz fibers.

[0047] FIG. 3 shows the evolution of the length, thickness and volume of a PEA-III Ac Bz fiber containing 30 wt % API.

[0048] FIG. 4. relates to a DSM Pharma extruder Xcelera for twin-screw micro extrusion with a speed of 1-250 rpm, a temperature range of 20-400° C., a marximal torque of 9000N and a barrel capacity of 2 or 5 cm.sup.3 equipped with DSM micro fiber spin device for thin fiber spinning.

[0049] FIG. 5 shows pictures of the fibers at 0, 0.5, 1 and 6 days taken using optic microscopy. On the optical light microscopy pictures is represented the size evolution of a PEA fiber containing 30 wt % of API, after immersion in PBS.

[0050] The invention will now be further and specifically described by the following examples.

Materials

[0051] PEA-III-Ac Bz polymers are used in the following examples. A more extended description of PEA-III-Ac Bz is poly-8-[(L-Leu-DAS).sub.0.45(L-Leu-6).sub.0.34L-Lys(Bz)].sub.0.25. Structure is given in Formula III. The fractions indicate overall fractions of the monomers in the synthesis.

##STR00003##

Synthesis of PEA III Ac Bz

[0052] Trietylamine (30.9 mL, 0.222 mole, 2.2 eq) and N,N-dimethylformamide (53.07 mL, 0.689 mole) were added to a mixture of Di-OSu-sebacinate (39.940 g, 0.1008 mole, 1.0 eq), L-leucine(6)-2TosOH (20.823 g, 0.0302 mole. 0.30 eq), L-leucine-(DAS)-2TosOH (32.503 g, 0.0453 mole, 0.45 eq) and L-lysine(Bz)-2TosOH (14.628 g, 0.0252 mole, 0.25 eq) in a nitrogen flushed 500 mL round bottomed flask equipped with a overhead stirrer at room temperature. The subsequent mixture was heated to 60° C. to allow the reaction to proceed and monitored by GPC analysis in THF. After 36 hours a stable molecular weight was obtained, subsequently a portion of L-leucine(6)-2TosOH (4.338 g, 0.0063 mole) along with triethylamine (1.76 mL, 0.0126 mole) and N,N-dimethylformamide (4.54 mL, 0.0590 mole) was added to terminate the polymerization reaction. The mixture was heated additionally for 24 hours after which the viscous solution was further diluted with N,N-dimethylformamide (407.85 g, 5.301 mole) and allowed to cool to room temperature. At room temperature acetic anhydride (1.89 mL, 0.0199 mole) was added to acylate the amino functional end groups of the polymer. The mixture was stirred at room temperature for 24 hours. In scheme 1 the general reaction is shown.

##STR00004##

[0053] The obtained crude polymer mixture was precipitated in water in a 10:1 ratio (water: reaction mixture). The polymer was collected and dissolved in ethanol (500 mL, 8.57 mole) and the procedure was repeated a second time. The polymer was again dissolved in ethanol (500 mL, 8.57 mole) and precipitated in ethylacetate (5000 mL, 50.91 mole) by drop wise addition to a stirring solution. The precipitated polymer was washed with two portions ethylacetate (100 mL, 1.00 mole), dried and dissolved in ethanol (500 mL, 8.57 mole) and filtered over a 0.2 μm PTFE membrane filter. The filtered polymer solution was dried under reduced pressure at 65° C.

[0054] Yield 75%, Mn=50 kDa (Gel Permeation Chromatography (GPC) in THF relative to polystyrene standards. Glass transition temperatures were determined by Differential Scanning calorimetry (DSC). Measurements were taken from second heating, with a heating rate of 10° C./min., Tg=48° C.

EXAMPLE 1

[0055] 0.52 g of API (Active Pharmaceutical Ingredient) and 4.31 g of PEA III Ac Bz were co-dissolved in ethanol, film-casted and allowed to dry. Films were subsequently cryo-milled. The uniformed cryomilled formulation was processed into a fiber at a Pharma mini-extruder shown on FIG. 3. The cryo-milled powder was melt-extruded at a temperature of 125° C., using a twin-screw extruder. The extruder dye was of 0.75 mm. Extruded polymer was spin at a speed of 5 m/min to 5 m/min and thereafter cooled at room temperature, under nitrogen.

[0056] The resulting fibers of a diameter of ˜300 μm were cut with a length of 10 mm and individually weight. The release was performed at 37° C. in PBS. PBS was refreshed at each time point and quantity of API was measured in triplicate, by HPLC. Upon immersion in PBS at 37° C., these fibers undergo remodeling (Process 1) Resulting release is presented in the FIG. 2

COMPARATIVE EXAMPLE A

[0057] 0.03 g of API and 0.25 g of polymer were co-dissolved in 2.5 ml of methanol, film-casted and allowed to dry. Resulting films were cut into fibers of a length of 5-6 mm and a thickness of 250 μm. Release of API was performed on individually weighted fibers, releasing in PBS at 37° C. PBS was refreshed at each time point and quantity of API was measured in triplicate by HPLC.

[0058] Upon immersion in PBS at 37° C., these fibers do not remodel

(Process 2)

[0059] Resulting release is presented in the FIG. 2.

Results

[0060] Approximately 50% of API is released in 15 days from fibers without remodeling while only 20% of API is released, at the same time point, from fibers with remodeling.

[0061] This example shows that a fiber remodeling inducing a decrease of the surface to volume ratio will influence and slow down the release of API from the fiber.

EXAMPLE 2

[0062] 2.13 g of API and 5.00 g of PEA III Ac Bz were co-dissolved in ethanol, film-casted and allowed to dry. Films were subsequently cryo-milled. The cryo-milled powder was melt-extruded at a temperature of 115° C., using a twin-screws extruder. The extruder dye was of 0.75 mm. Extruded polymer was spin at a speed of 5 m/min to 15 m/min and thereafter cooled at room temperature, under nitrogen.

[0063] The resulting fibers were cut and placed into PBS at 37° C. Length and thickness were monitored by optical light microscopy.

[0064] FIG. 3 represents the evolution of length, thickness, and volume of a PEA III Ac Bz fiber, containing 30 wt % API processed as described in example 1.

[0065] This figure shows that fibers' length decrease, thickness increase but the volume stays constant. There is not any swelling of the fiber but a remodeling that result on a different surface to volume ratio than initially.