Temperature and polymer crosslinking degree influence on drug transfer from α,β-polyasparthydrazide hydrogel to model membranes. A calorimetric study

International Journal of Pharmaceutics (Impact Factor: 3.65). 11/1998; 174(1-2):81-90. DOI: 10.1016/S0378-5173(98)00249-X


A non-steroidal anti-inflammatory drug, diflunisal, has been chosen as drug model to be incorporated in α,β-polyasparthydrazide (PAHy) matrices to study the effect of polymer crosslinking degrees on the release processes from hydrogel (X=0.4 and X=0.8) to a model membrane represented by unilamellar vesicles of dipalmitoylphosphatidylcholine. The technique employed to monitor these processes was differential scanning calorimetry that appears to be particularly suitable to follow the transfer kinetics of a drug from a controlled release system to void biomembrane model. The drug release from the two PAHy hydrogels differently crosslinked by glutaraldehyde to the lipidic model was compared with that from the drug solid form, by examining the effects exerted on the thermotropic behaviour of unilamellar vesicles. The diflunisal (DFN) is able to interact with unilamellar vesicles by causing a decrease of the transitional (gel-to-liquid crystal phase transition) temperature characteristic of lipidic bilayer. The amount of DFN transferred and interacting with the dipalmitoylphosphatidylcholine (DPPC) unilamellar vesicles was quantified by comparing the effects caused on the thermodynamic parameters of bilayer (transitional temperature, Tm, and enthalpy variation, ΔH) with the effects obtained from increasing molar fractions of drug. The release kinetics of the drug from PAHy hydrogels were followed at different temperatures (25, 37 and 50°C) to determine the influence of temperature on the drug release and successive transfer at a biological membrane. Particularly, it appears evident that by increasing the polymer crosslinking degree the total amount of transferred drug and the release velocity are decreased. This behavior may be caused by the increase of the number of cruciate bonds in the hydrogels, which causes a free volume reduction obstructing the drug passing. The obtained results suggest that PAHy hydrogels constitute an innovative delivery system able to slightly release water-soluble drugs and to modulate their uptake by biomembrane.

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    ABSTRACT: Diflunisal release from poly-Lactide-co-Glycolide (50:50, 34,000 MW) microspheres loaded with two different amounts of drug (2.5 +/- 0.5% and 10 +/- 0.5% w/w) was monitored by following the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine unilamellar vesicles at different temperatures. The effects of the drug released from the microspheres on the thermotropic behavior of lipid aqueous dispersion containing different molar ratios of drug was detected by differential scanning calorimetry and was compared with the effects exerted by the free Diflunisal. Diflunisal affects mainly the temperature (Tm) of the transition characteristic of phospholipid vesicles as model biomembrane, causing a shift toward lower values. This shift was modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Afterward, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and differently Diflunisal-loaded microspheres as well as free powdered Diflunisal after incubation for increasing times at three different temperatures (25, 37, and 50 degrees C). The Tm shifts of the lipid bilayer, caused by the drug released from polymeric system as well as by the free drug during incubation periods, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres as well as by the temperature acting on drug solubility and membrane disorder. This drug release model, monitored by the calorimetric technique shows that a) the poly-Lactide-co-Glycolide microspheres are a good delivery system able to sustain the drug release; b) the differential scanning calorimetry technique applied on the drug interaction with biomembranes constitutes a good tool to follow the drug release; 3) this model, representing an innovative alternative in vitro model, should be used to determine the different kinetics involved in the drug transfer from a drug delivery system to a membrane as uptake site.
    Drug Delivery 01/2000; 7(1):45-53. DOI:10.1080/107175400266786 · 2.56 Impact Factor
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    ABSTRACT: A comparative study on the drug release capacity of four water swellable polymeric systems was carried out by differential scanning calorimetry (DSC). The polymeric systems chosen were alpha,beta-polyaspartahydrazide (PAHy) crosslinked by glutaraldehyde (GLU) (PAHy-GLU) or by ethyleneglycoldiglycidylether (EGDGE), (PAHy-EGDGE), polyvinylalcohol (PVA) crosslinked by glutaraldehyde (PVA-GLU) and alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) by gamma irradiation (PHEA-gamma matrices). The degree of crosslinking for PAHy-GLU, PAHy-EGDGE and PVA-GLU samples was about 0.4 and 0.8. These hydrogels were characterized as free of drugs and were loaded with diflunisal (DFN) (approximately 2.5% w/w). Diflunisal, a non-steroidal anti-inflammatory drug, has been chosen as a model drug to be incorporated into polymeric matrices to follow the release processes of a drug from these hydrogels to a model membrane made by unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC). Differential scanning calorimetry appears to be a suitable technique to follow the transfer kinetics of the drug from the controlled release system to the biomembrane model. The drug releases from all the considered polymeric hydrogels, were compared with the release observed from the drug solid form by examining the effects on the thermotropic behaviour of DPPC unilamellar vesicles. The release kinetics of the drug from hydrogels were followed at 25, 37 and 50 degrees C to evidence the influence of temperature on the drug release and on the successive transfer to biological membrane model. Particularly, it appears evident that the total amount of drug transferred and the release rate are affected by the polymer crosslinking degree (it increases with crosslinking decrease) as well as by the nature of crosslinking agent. In fact, the drug release profiles from PAHy-GLU samples are more differentiated than those from PAHy-EGDGE. The effect of parameters correlating with the properties of starting polymer, such as water-affinity, crystallinity, glass-to-rubber transition temperature and affinity towards drug molecules, has been also evaluated.
    Biomaterials 05/2000; 21(8):821-33. DOI:10.1016/S0142-9612(99)00252-5 · 8.56 Impact Factor
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