Bicomponent fibers of two semi-crystalline (co)polymers, poly(ε-caprolactone), PCL and poly(oxyethylene-b-oxypropylene-b-oxyethylene), Lu were obtained by electrospinning. Acetazolamide and timolol maleate were loaded in the fibers in different concentrations (below and above the drug solubility limit in polymer) in order to determine the effect of drug solubility in polymer, drug state, drug loading and fiber composition on fiber morphology, drug distribution and release kinetics. The high loadings fibers (with drug in crystalline form) showed higher burst and faster release than low drug content fibers, indicating the release was more sustained when the drug was encapsulated inside the fibers, in amorphous form. Moreover, timolol maleate was released faster than acetazolamide, indicating that drug solubility in polymer influences the partition of drug between polymer and elution medium, while fiber composition also controlled drug release. At low loadings, total release was not achieved (cumulative release percentages smaller than 100 %), suggesting that drug remained trapped in the fibers. The modeling of release data implied a three stage release mechanism: a dissolution stage, a desorption and subsequent diffusion through water filled pores, followed by polymer degradation control.

Please cite this article as: M.V. Natu, M.H. Gil, H.C. de Sousa, Supercritical Solvent Impregnation of Poly( -caprolactone/poly(oxyethylene-b-oxypropylene-boxyethylene) and Poly( -caprolactone/poly(ethylene-vinyl acetate) Blends for Controlled Release Applications, The Journal of Supercritical Fluids (2007Fluids ( ), doi:10.1016Fluids ( /j.supflu.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractPoly(ε-caprolactone) blends were successfully impregnated with timolol maleate, an antiglaucoma drug, using a Supercritical Solvent Impregnation (SSI) technique. Supercritical fluid impregnation efficiency results suggested that the best impregnating conditions were obtained when a cosolvent was used and when specific drug-polymer interactions occurred as a consequence of different chemical structures due to polymer blending. Pressure can be either a favourable factor, when there is enough drug affinity for the polymers, or an unfavourable factor when weaker bonding is involved. In order to determine the relative * ManuscriptPage 2 of 40 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 hydrophilicity/hydrophobicity of the blends, contact angle analysis was performed, while crystallinity determination was also useful to understand the obtained release profiles.Drug loading, heterogeneous/homogeneous dispersion of drug inside the matrix, hydrophilicity, crystallinity, all seem to influence the obtained drug release rates. The "in vitro" release results suggested that a sustained drug release rate can be obtained by changing the SSI operational conditions and by modulating the composition of blends, as a mean to control crystallinity, hydrophilicity and drug affinity for the polymer matrix. After a first day burst release, all samples showed a sustained release profile (1.2-4 µg/ml/day, corresponding to a mass of 3-10 µg/day) which is between the therapeutic and toxic levels of timolol maleate, during a period of 1 month. These drug-loaded polymeric matrices can be a feasible alternative treatment modality for the conventional repeated daily administration of eye drops.

Hydrogels and lyophilisates were obtained by chemical crosslinking of gelatin using N-hydroxysuccinimide and N, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. The systems were characterized with respect to the degree of crosslinking, morphology, water uptake, in vitro drug release and biocompatibility studies. Pilocarpine hydrochloride, a drug for the treatment of glaucoma, was loaded by soaking in an aqueous solution containing the drug. In vitro, the released drug percentage varied between 29.2% and 99.2% in 8 h of study. The release data were fitted to the Korsmeyer-Peppas equation to calculate the release exponent, which indicated anomalous transport for the release of pilocarpine. The corneal endothelial cell culture tests indicated that the prepared biomaterials are not cytotoxic.

Films, fibers, sponges and disks, based on poly(ε-caprolactone), PCL were prepared using solvent-casting, electrospinning, supercritical fluid processing and melt-compression, respectively. The extent of degradation was determined by measuring the change in morphology, crystallinity and molecular weight (MW). The influence of processing method, MW and drug presence on degradation rate was also evaluated. The different processing techniques produced samples of various morphology and crystallinity. Nevertheless, the differences in degradation rate were not so significant during the advanced stage (18 e36 months), while some differences existed during the initial stage (up to 18 months). MW had an important effect on degradation rate, while drug did not. The low MW disks had a degradation rate that was lower by one order of magnitude than high MW constructs.

Implantable disks for glaucoma treatment were prepared by blending poly(ε-caprolactone), PCL, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) and dorzolamide. Their in vivo performance was assessed by their capacity to decrease intraocular pressure (IOP) in normotensive and hypertensive eyes. Drug mapping showed that release was complete from blend disks and the low molecular weight (MW) PCL after 1 month in vivo. The high MW PCL showed non-cumulative release rates above the therapeutic level during 3 months in vitro. In vivo, the fibrous capsule formation around the implant controls the drug release, working as a barrier membrane. Histologic analysis showed normal foreign body reaction response to the implants. In normotensive eyes, a 20 % decrease in IOP obtained with the disks during 1 month was similar to Trusopt R eyedrops treatment. In hypertensive eyes, the most sustained decrease was shown by the high MW PCL (40 % after 1 month, 30 % after 2 months). It was shown that the implants can lower IOP in sustained manner in a rabbit glaucoma model.