Design and synthesis of molecularly imprinted stimuli-responsive hybrid sol-gels for sustained release of donepezil

Inorganic sol-gel-derived materials had been investigated and commercialized a few decades ago and due to the profound understanding of the underlying chemical and technical processes are still present as important examples of large-scale applications of the sol-gel technology. The growing interest in sol-gel science is due to the straightforwardness in tailoring the porosity in these materials, particularly in achieving molecular recognition in different systems such as adsorption or absorption, stationary phases in liquid or gas chromatography and chemical sensing applications. The production of sol-gel materials provides numerous advantages over the other conventional synthetic schemes. One of the major advantages is that these systems allow the manufacturing at low temperatures, which enables us to generate functionalized matrices, where others lack this ability. These materials are synthesized from solutions that help us to generate thin films and bulk products of desired shape. In this process, the chemical compositions of the starting material controls porosity by carefully monitoring the reaction parameters. The thin sol-gel films can easily be immobilized on glass and other silicon substrates through covalent linkage, which is an additional feature of these materials. The end product material can be configured in different forms like powder or dispersion forms, thin films, fibers and monoliths, etc. One of the most exciting achievements of this technique is that a hybrid material of organic and inorganic substances can be synthesized. To a certain extent, these hybrid materials combine the most important properties of their constituents, like high transparency, low processing temperatures, sufficient thermal stability and are easily accessible because of an unique availability of the respective precursors (commercially available metal alkoxides and organo (alkoxy)silanes as well as nanoparticles). The sol-gel process, as the name implies, involves transition from a liquid 'sol' (colloidal solution) into a 'gel' phase. Usually inorganic metal salts or metal organic compounds such as metal alkoxide are used as precursors. A colloidal suspension or a 'sol' is formed after a series of hydrolysis and condensation reaction of the precursors. Then the sol particles condense into a continuous liquid phase (gel). With further drying and heat treatment, the 'gel' is converted into dense ceramic or glass materials. Generally three reactions are used to describe the sol-gel process: hydrolysis, alcohol condensation and water condensation. Because water and alkoxides are immiscible, alcohol is commonly used as co-solvent. Many sol-gels that are used for biomedical purposes should be biocompatible and often biodegradable. This also makes them ideal candidates for a controlled drug release. Sol-gels have a porous network. Often we can control the porosity of sol-gels by controlling the density of cross-links or by changing the swell affinity of sol-gels in the environment. This porosity property of sol-gels helps the release of drugs from sol-gels. The release of drug from sol-gels can be controlled by controlling the diffusion coefficient of drugs through sol-gel matrix. We can also make a depot formulation of hydrogel-drug. The depot formulation can be made by trapping drugs into liposomes and incorporating liposomes in the hydrogel. Controlled release drug delivery system works on many different mechanisms to controlled release. Donepezil hydrochloride (DP) is a drug administered for Alzheimer's disease (AD) treatment, and it is a potential template molecule for imprinted hybrid sol-gels. AD is the most common type of dementia clinically characterized by progressive loss of memory and deficits in different cognitive domains. The nature of AD limits the effectiveness of available oral treatments. The most of drugs for AD are commercially available as oral formulations. However, due to a multitude of risk factors in the AD population, such as memory loss and high incidence of dysphagia, oral formulations has been poor. Since DP also causes gastrointestinal adverse effects, a transdermal delivery system might be a suitable method to overcome the problems of conventional oral administration of DP. Ideal drug delivery system has to be inert, biocompatible, mechanically strong, comfortable for the patient, capable of achieving high drug loading, readily processable, safe from accidental release, simple to administer and remove, easy to fabricate and sterilize, free of leachable impurities. These criteria can be obtained by molecularly imprinted sol-gel materials, which are the best candidate to design an artificial drug model for controlled drug release. Interest in stimuli-responsive polymers is steadily gaining increasing momentum especially in the fields of controlled and self-regulated drug delivery. Stimuli-responsive or smart polymers are macromolecules that display a significant physiochemical change in response to small changes in their environment such as temperature, pH, light, magnetic field, ionic factors, etc. In this study, the release of Alzheimer's drug DP from two kinds of hybrid sol-gels, which were prepared from newly synthesized precursors, was investigated. We prepared silanated O,O′-Bis(2-aminopropyl)polypropylene glycol (JD400) and O,O′-Bis(2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block-polypropylene glycol(JED600) by coupling 3-isocyanatopropyl-triethoxysilane (ICPTS) with the amine end groups of both glycols through urethane bonds. Hence, trimethoxysilane terminated O,O′-Bis(2-aminopropyl)polypropylene glycol (coded as JD400-ICPTS) and O,O′-Bis(2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block-polypropylene glycol (coded as JED600-ICPTS) were synthesized. The purified silicon-containing trifunctional monomers were identified using Attenuated Total Reflectance-Infrared (ATR-FTIR). The Donepezil hydrochloride (DP) imprinted hybrid sol-gels were prepared by using the following components: DP as a template; precursors, JD400-ICPTS and JED600-ICPTS as spacers; Aminopropyl-trimethoxysilane (APTES) as a functional monomer interacting with DP; citric acid as an acidic catalyst. The imprinted hybrid sol-gels were prepared in the presence of DP molecule using each JD400-ICPTS and JED600-ICPTS precursors, APTES and citric acid. Then, the as-prepared pre-gel solution was poured into the teflon mould and was allowed to hydrolyze. The gels with film form were obtained and kept under vacuum at 40 oC for the completion of condensation reaction. Hybrid sol-gels are indicated as JD400 gel and JED600 gel. Non-imprint hybrid sol-gels were prepared in the absence of DP at the same conditions with similar to imprinted hybrid gels. Gelation time for the formation of hybrid sol-gel network was obtained by observing the viscosity change in pre-gel solution with or without DP. Swelling degree of hybrid sol-gel films were elucidated by obtaining data depending on time in ethanol-water mixtures with different compositions at temperatures of 25 oC and 37 oC. For each of the hybrid gels, DP release in ethanol-water mixtures at 25 oC and 37 oC and, also in buffer solution with different pH values was evaluated by using the calibration curves of DP. Calibration curves of DP were obtained for each described solutions by recording the absorption spectra of DP and collecting the absorbance values of DP at 315 nm depending on concentration and, then DP released by different hybrid sol-gels was calculated. Fractional release of DP at initial of time interval and equilibrium amount from JD400 gel and JED600 gel were evaluated. The time-dependent swelling behavior of the hybrid sol-gel films and DP release characters of each hybrid gels depending on composition of water-ethanol, pH and temperature of solution compared. DP release kinetics of hybrid sol-gels and mechanism at temperatures of 25 oC and 37 oC were determined by fitting the release data to Korsmeyer-Peppas kinetic model.