FIBERS COMPRISING POLYESTERAMIDE COPOLYMERS FOR DRUG DELIVERY

Abstract

The present invention relates to fibers comprising a polyesteramide (PEA) having a chemical formula described by structural formula (iv), wherein m+p varies from 0.9-0.1 and q varies from 0.1 to 0.9, m+p+q=1 whereby m or p could be 0, n is about 5 to about 300; (pref. 50-200), .sub.-Ri in independently selected from the group consisting of .sub.(C2-C20) alkykene or .sub.(C2-C20) alkenylene and combinations thereof; R and R in a single backbone unit m or p, respectively, are independently selected from the group consisting of hydrogen, ()alkyl, ()alkenyl, (C-C)alkynyl, (C-.sub.Cio)aryl, (CH.sub.2)SH, (CH.sub.2).sub.2S(CH), .sub.CH2OH, CH(OH)CH, (CH.sub.2)NH.sub.3, (CH.sub.2)NHC(NH.sub.2)NH.sub.2, CH.sub.2COOH, (CH.sub.2)COOH, CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2CONH.sub.2, .sub.CH2CH2COOH, CHCH.sub.2CH(CH), (CH).sub.2CHCH.sub.2, H.sub.2N(CH.sub.2), Ph-CH.sub.2, CHCCH.sub.2, HO-p-Ph-CH.sub.2, (CH).sub.2CH, Ph-NH, NH(CH.sub.2).sub.3C, NHCHNCHCCH.sub.2; .sub.R.sub.5 is selected from the group consisting of (C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene, alkyloxy or oligoethyleneglycol, R is selected from bicyclic-fragments of 1,4,3,6-dianhydrohexitols of structural formula (III); R is selected from the group consisting of (C.sub.6-C.sub.io)aryl, (GCeJalkyl, .sub.R.sub. is (CH.sub.2)4; whereby a is at least 0.05 and b is at least 0.05 and a+b.

##STR00001##

Claims

1.-14. (canceled)

15. A fiber comprising a bioactive agent dispersed in a biodegradable poly(esteramide) copolymer (PEA) according to structural Formula (IV), ##STR00008## wherein m+p is from 0.9 to 0.1 and q is from 0.1 to 0.9; m+p+q=1 whereby one of m or p could be 0; n is about 5 to about 300; a is at least 0.05, b is at least 0.05, a+b=1, qa=q*a, and qb=q*b; wherein units of m (if present), units of p (if present), units of qa, and units of qb are all randomly distributed throughout the copolymer; R.sub.1 is (C.sub.2-C.sub.20) alkylene; R.sub.3 and R.sub.4 are independently selected from 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.2SH, (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(NH.sub.2+)NH.sub.2, CH.sub.2COOH, CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2COOH, CH.sub.3CH.sub.2CH(CH.sub.3), (CH.sub.3).sub.2CHCH.sub.2, H.sub.2N(CH.sub.2).sub.4, Ph-CH.sub.2, CHCCH.sub.2, (CH.sub.3).sub.2CH-, or Ph-NH; R.sub.5 is (C.sub.2-C.sub.20)alkylene; R.sub.6 is according to structural formula (III); ##STR00009## 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.

16. The fiber according to claim 15, wherein a is at least 0.5.

17. The fiber according to claim 15, wherein a is at least 0.75.

18. The fiber according to claim 15, wherein a is at least 0.8.

19. The fiber according to claim 15, wherein n is from 50 to 200, a is at least 0.5.

20. The fiber according to claim 15, wherein R.sub.3 and R.sub.4 are independently hydrogen, (C.sub.1-C.sub.6)alkyl, CH.sub.3CH.sub.2CH(CH.sub.3), (CH.sub.3).sub.2CHCH.sub.2, Ph-CH.sub.2, or (CH.sub.3).sub.2CH.

21. The fiber according to claim 15, wherein R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

22. The fiber according to claim 15, wherein R.sub.1 is (CH.sub.2).sub.8, R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

23. The fiber according to claim 16, wherein R.sub.3 and R.sub.4 are independently hydrogen, (C.sub.1-C.sub.6)alkyl, CH.sub.3CH.sub.2CH(CH.sub.3), (CH.sub.3).sub.2CHCH.sub.2, Ph-CH.sub.2, or (CH.sub.3).sub.2CH.

24. The fiber according to claim 16, wherein R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

25. The fiber according to claim 16, wherein R.sub.1 is (CH.sub.2).sub.8, R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

26. The fiber according to claim 19, wherein R.sub.3 and R.sub.4 are independently hydrogen, (C.sub.1-C.sub.6)alkyl, CH.sub.3CH.sub.2CH(CH.sub.3), (CH.sub.3).sub.2CHCH.sub.2, Ph-CH.sub.2, or (CH.sub.3).sub.2CH.

27. The fiber according to claim 19, wherein R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

28. The fiber according to claim 19, wherein R.sub.1 is (CH.sub.2).sub.8, R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

29. The fiber according to claim 15, wherein m=0.3; p=0.45; qa=0.19; and qb=0.06; R.sub.1 is (CH.sub.2).sub.8, R.sub.3 and R.sub.4 are (CH.sub.3).sub.2CHCH.sub.2, and R.sub.7 is benzyl.

30. The fiber according to claim 15, wherein the bioactive agent comprises a prostaglandin or a prodrug thereof.

31. The fiber according to claim 24, wherein the bioactive agent comprises a prostaglandin or a prodrug thereof.

32. The fiber according to claim 15, further comprising a poly(ortho ester), poly(anhydride), poly(D,L-lactic acid), poly (L-lactic acid), poly(glycolic acid), copolymers of poly(lactic) and glycolic acid, poly(L-lactide), poly(D,L-lactide), poly(glycolide), poly(D,L-lactide-co-glycolide), or poly(L-lactide-co-glycolide), poly(phospho esters), poly(trimethylene carbonate), poly(oxa-esters), poly(oxa-amides), poly(ethylene carbonate), poly(propylene carbonate), poly(phosphoesters), poly(phosphazenes), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), poly(tyrosine derived iminocarbonates), or combinations thereof.

33. The fiber according to claim 24, further comprising a poly(ortho ester), poly(anhydride), poly(D,L-lactic acid), poly (L-lactic acid), poly(glycolic acid), copolymers of poly(lactic) and glycolic acid, poly(L-lactide), poly(D,L-lactide), poly(glycolide), poly(D,L-lactide-co-glycolide), or poly(L-lactide-co-glycolide), poly(phospho esters), poly(trimethylene carbonate), poly(oxa-esters), poly(oxa-amides), poly(ethylene carbonate), poly(propylene carbonate), poly(phosphoesters), poly(phosphazenes), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), poly(tyrosine derived iminocarbonates), or combinations thereof.

34. A method for treating a condition associated with the eye of a patient comprising the step of implanting the fiber according to claim 15 into the eye of the patient, wherein the step of implanting comprises intravitreal or subconjunctival implantation.

Description

FIGURES

[0072] FIG. 1; In vivo degradation of PEA-III-Ac Bz and PEA-III-25% H fibers.

[0073] FIG. 2: In vitro/In vivo correlation of degradation of PEA-III-Ac Bz and PEA-III-25% H fibers.

[0074] FIG. 3: Molecular weight decrease during hydrolytic degradation in PBS buffer over 180 days

[0075] FIG. 4: Weight loss of the fibers during hydrolytic degradation in PBS buffer over 180 days.

[0076] FIG. 5: Evaluation of form stability is graphically represented by fiber length.

[0077] FIG. 6: In vivo degradation of PEA-III-Ac Bz and PEA-III-25% H fibers over 6 months.

[0078] FIG. 7: In vitro/In vivo correlation of degradation of PEA-III-Ac Bz and PEA-III-25% H fibers over 6 months.

[0079] FIG. 8: Molecular weight decrease during hydrolytic degradation in PBS buffer over 266 days.

[0080] FIG. 9: Weight loss of the fibers during hydrolytic degradation in PBS buffer over 266 days.

EXAMPLES

Example 1

[0081] Fibers of PEA-III-Ac Bz, PEA-III-H/Bz 25% H and PEA-III-H/Bz 50% H were prepared via extrusion with a diameter of approximately 16. The obtained fibers were cut into pieces with a length of 4-5 mm and were individually weighted on a microbalance. The single fibers were immersed in 3 ml PBS buffer containing 0.05% sodium azide as a biocide. Hydrolytic degradation was performed under gentle orbital shaking at 37 C. Samples were taken in triplicate; the fibers were dried under reduced pressure at 37 C. overnight. The weight of the fibers post degradation was again determined with a microbalance. Relative molecular weights of the remaining polymer fiber were determined using a Waters GPC system consisting of a Waters RI detector type 2414, a Waters separation module with column heater type e2695. The system was equipped with a Styragel HR5E and Styragel HR2 column run at 50 C. As the mobile phase tetrahydrofuran (THF) with a flow rate of 1.O mL/min was used. Samples were dissolved in 200 l THF, of which 100 l was injected onto the column. Evaluation of data was performed with Waters Empower.sup.2 software. Calculations of molecular weights were relatively to polystyrene standards. Results are represented in FIGS. 3 and 8 which show molecular weight decrease during hydrolytic degradation in PBS buffer over 180 days and 266 days respectively. FIGS. 4 and 9 show the weight loss of the fibers during hydrolytic degradation in PBS buffer over 180 days and over 266 days respectively.

Example 2

[0082] The polymers applied were synthesized via polycondensation of pre-calculated amounts of di-p-toluenesulfonicacid salts of bis-(L-leucine) 1,4-dianhydro sorbitoi diester, bis-(L-leucine) ,-hexane dioldiester, lysine benzyl ester, lysine and di-N-hydroxysuccineimid ester of sebacic acid in anhydrous DMSO and triethylamine added in a glass vessel with overhead stirrer under a nitrogen atmosphere. The usage of pre-activated acid in the reaction allows polymerization at relatively low temperature (65 C; 48 h) affording side-products free polycondensated and predictable degradation products. The polymers were isolated from the reaction mixture in two precipitation steps to result in white amorphous material of average number molecular weight of 50 kDa as determined by THF based GPC relative to polystyrene standards. The ratio of the different building blocks in the polymer was calculated from the 1H NMR spectrum. Co-polymer composition matched well theoretical prediction. Next the polymers were cryomilled in Retsch ZM200 equipment in presence of 0.20% w/w Chromoionophore II in order to obtain a uniform mixture.

[0083] The uniformed cryomilled formulation was processed to fibres at the Pharma mini-extruder with a speed of 1-250 rpm, a temperature range of 140 C, equipped with DSM micro fiber spin device for thin fiber spinning. The polymer had a residence time of 5-10 min at 140 C before to be stretched into a fiber with diameter in the range of 120-300 m. The extrusion was performed under inert atmosphere in order to minimize the oxidative degradation of the polymer during the process. The obtained fiber was cut to about 4 mm long and 150 l in diameter pieces and sterilized via gamma radiation 25 kGy under cooling conditions at BGS, Wiehl, Germany.

Implantation and Clinical Follow Up

[0084] Female Chinchilla Bastard rabbits (Charles River Company, Sulzfeld, Germany) with an average body weight of 2-3 kg were used. All animal experiments were conducted in accordance with the principles for the care and use of research animals and were carded out with permission and supervision of the Office for the Nature, Environment and Consumer Protection (LANUV), Recklinghausen, Germany.

[0085] For subconjunctival implantation a radial incision was made into the rabbit conjunctiva and a chamber was prepared by dissecting the conjunctiva from the sclera. One dry fiber was placed into the chamber and the incision was closed with one vicryl 9-0 suture. One sample of PEA per eye was implanted. The implant was monitored weekly and read-outs were scheduled after one, three, six, and twelve months.

[0086] For intravitreal implantation of dry fibers a customized 26 G intravenous catheter was used. A transscleral paracenthesis was made with a 26 G needle 1.5 mm below the limbus and the modified catheter was inserted. After removing the catheter needle the PEA fiber was inserted to the catheter with a micro forceps and moved forward with the catheter needle into the vitreous. The catheter was removed and the intravitreal position of the fiber was documented by video photography. PEA fibers were explanted after 1 and 3 months. Clinical examinations by funduscopy were done weekly to confirm presence and shape of the fibrils and to observe status of the fundus.

[0087] After mentioned observation periods eyes were enucleated and macroscopically analyzed. In addition, the explanted fibers were evaluated by weight and GPC in order to assess the changes occurring with the polymer.

Implantation and Clinical Follow Up

[0088] Female Chinchilla Bastard rabbits (Charles River Company, Sulzfeld, Germany) with an average body weight of 2-3 kg were used. All animal experiments were conducted in accordance with the principles for the care and use of research animals and were carried out with permission and supervision of the Office for the Nature, Environment and Consumer Protection (LANUV), Recklinghausen, Germany.

[0089] For subconjunctival implantation a radial incision was made into the rabbit conjunctiva and a chamber was prepared by dissecting the conjunctiva from the sclera. One dry fiber was placed into the chamber and the incision was closed with one vicryl 9-0 suture. One sample of PEA per eye was implanted. The implant was monitored weekly and read-outs were scheduled after one, three, six, and twelve months.

[0090] For intravitreal implantation of dry fibers a customized 26 G intravenous catheter was used. A transscleral paracenthesis was made with a 26 G needle 1.5 mm below the limbus and the modified catheter was inserted. After removing the catheter needle the PEA fiber was inserted to the catheter with a micro forceps and moved forward with the catheter needle into the vitreous. The catheter was removed and the intravitreal position of the fiber was documented by video photography. PEA fibers were explanted after 1 and 3 months. Clinical examinations by funduscopy were done weekly to confirm presence and shape of the fibers and to observe status of the fundus.

[0091] After mentioned observation periods eyes were enucleated and macroscopically analyzed. In addition, the explanted fibers were evaluated by weight and GPC in order to assess the changes occurring with the polymer.

[0092] Fibers of PEA-III-H/Bz 25% H were prepared via injection moulding with a diameter of approximately 200 m. The obtained fibers were cut into pieces with a length of 5-10 mm and were individually weighted on a microbalance. Each individual fiber was imaged using a Motic stereoscope equipped with a Moticam2000 digital camera.

[0093] Single fibers were immersed in 1 ml PBS buffer and placed on a gentle orbital shaker at 37 C. The experiment was performed in duplicate. At given time points, fibers were gently removed, from the buffer and blotted on tissue. Images were taken with the stereoscope and the fiber length and diameter were measured. Buffer was refreshed and the samples were returned to the orbital shaker. In FIG. 5 a calculation of form stability is graphically represented by measuring fiber length. The injection moulded fibers had an initial length of 10 mm and the extruded fiber had initial length of 5 mm. Differences in form stability are deary expressed by the loss in length of the extruded fiber.