Zero-order therapeutic release from imprinted hydrogel contact lenses within in vitro physiological ocular tear flow.
ABSTRACT Zero-order or concentration independent release kinetics are highly desirable from drug delivery devices. In this paper we demonstrate experimentally, for the first time, zero-order release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted hydrogels used as therapeutic contact lenses. We performed dynamic, in vitro drug release studies from imprinted hydrogel contact lenses within a novel microfluidic device that simulates the volumetric flow rates, tear volume and tear composition of the eye. Imprinted gels with multiple functional monomers and complexation points to the drug demonstrated a significantly delayed release of drug compared to less functionalized systems. There were no statistical differences in experimentally determined equilibrium swollen polymer volume fractions, which correlate with molecular weight between crosslinks and mesh size of the gel. Under infinite sink conditions, imprinted contact lenses demonstrated Fickian (concentration dependent) release kinetics with diffusion coefficients ranging from 4.04 x 10(-9) to 5.57 x 10(-10) cm(2)/s. The highest functionalized gel exhibited a diffusion coefficient averaging ten times smaller than less functionalized gels and released drug for over 5 days with 3 distinct rates of release. Under physiological volumetric flow rates, the release rate was constant for a duration of 3.5 days delivering a therapeutically relevant dosage and was fit to a power law model indicating zero-order release characteristics with n=0.981+/-0.006 (r(2)=0.997). This work demonstrates the potential of micro/nanofluidic devices to determine physiological release rates and stresses the importance of matching local conditions to adequately characterize drug delivery devices. It also demonstrates the enormous potential for molecular imprinting to further tailor therapeutic release kinetics via the imprinting process.
- [show abstract] [hide abstract]
ABSTRACT: A double-blind cross-over comparative study on the effect of Lacrisert versus oculoguttae viscosae and saline has been conducted. Lacrisert is a soluble solid tear substitute which is applied once-a-day. The object was to compare the safety and patient acceptability of Lacrisert and oculoguttae viscosae, and to compare the efficacy of Lacrisert to oculoguttae viscosae and saline. Twenty-nine patients suffering from primary Sjögren's syndrome (Copenhagen criteria), 2 male and 27 female, age: median 56 years, range 32-79 years. Lacrisert was applied once-a-day, and saccharose crystals of similar appearance was used as placebo. All patients were treated for 4 periods of 3 weeks: Lacrisert + saline versus placebo + saline and Lacrisert + oculoguttae viscosae versus placebo + oculoguttae viscosae. The patients were examined before entering the study and after each of the 4 periods using: slit-lamp, corneal sensitivity, BUT, Schirmer-1-test and Rose-bengal staining. Comparing Lacrisert to saline a significant improvement in BUT (p less than 0.01) and in Rose-bengal staining (p less than 0.01) was found, whereas other patients were unchanged. Comparing Lacrisert with oculoguttae viscosae no significant difference in clinical parameters could be detected. The patients complained of minor discomfort. Most prominent was a tendency to loose the Lacrisert due to an inadequate solubilisation of the rod caused by the lack of aqueous tears. We conclude that Lacrisert may help patients with primary Sjögren's syndrome provided that they have some secretory capacity left in the tear glands.Scandinavian journal of rheumatology. Supplement 02/1986; 61:261-3.
- [show abstract] [hide abstract]
ABSTRACT: Temperature-dependent drug release from disintegrating tablets made of NaCl-containing agglomerated micronized cellulose (AMC) granules has been studied to characterize the release process. Release measurements on tablets compacted at three different compaction pressures; 50, 100, and 200 MPa, were performed at seven different temperatures; 6, 23, 33, 43, 50, 55, and 63 degrees C using the recently developed alternating ionic current method. Tablets compacted at different compaction pressures showed similar release rates. The release process was found to be diffusion-controlled, and the activation energy of the diffusion coefficient was comparable to that obtained for diffusion in pure water. The results show that the AMC granules in contact with water swell to a size and shape that is only slightly affected by their compaction history and the ion diffusion operates mainly within liquid-filled pores within the AMC granules. By using the temperature dependence of the release process, it was possible to reach this conclusion without any assumptions concerning the number and radii of the granules into which the tablets disintegrated. Further, the magnitude of the effective diffusion coefficient was found to be approximately 7.5 x 10(-10) cm(2)/s, which is approximately four orders of magnitude lower than for unhindered diffusion of Na(+) and Cl(-) in water but similar to the diffusion coefficient for protons and OH(-) ions in microcrystalline cellulose.Journal of Pharmaceutical Sciences 08/2004; 93(7):1796-803. · 3.13 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The aim of this study was to evaluate "in vivo" the usefulness of molecular imprinting technology to obtain therapeutic soft contact lenses capable of prolonging the permanence of timolol in the precorneal area, compared to conventional contact lenses and eyedrops. Soft contact lenses (diameter 14 mm, center thickness 0.08 mm) consisted of N,N-diethylacrylamide (DEAA; main component of the matrix), methacrylic acid (MAA; functional monomer) and ethylene glycol dimethacrylate (EGDMA; cross-linker) were prepared by the conventional methodology (non-imprinted) or by applying a molecular imprinting technique using timolol as the template (imprinted ones). After washing and reloading, timolol release studies carried out in rabbits showed that the soft contact lenses made by the molecular imprinting method (34 microg dose) provided measurable timolol concentrations in the tear fluid for 2.0- and 3.0-fold longer than the non-imprinted contact lenses (21 microg dose) and eyedrops (doses of 34 and 125 microg), respectively. Furthermore, the area under the timolol concentration-time curve (AUC) was 3.3- and 8.7-fold greater for imprinted contact lenses than non-imprinted contact lenses and eyedrops, respectively. The timolol concentration of the eyedrops did not affect the precorneal residence time of drug significantly. On the other hand, timolol loading capacity of the contact lenses was improved by the molecular imprinting method; the sustaining of the drug levels in the tear fluid being proportional to the loading capacity of the contact lenses. These results indicate that imprinted soft contact lenses are promising drug devices able to provide greater and more sustained drug concentrations in tear fluid with lower doses than conventional eyedrops.Biomaterials 05/2005; 26(11):1293-8. · 7.60 Impact Factor