Research On Film-forming Hydrogels And Their Transdermal Mechanism

Overactive bladder (OAB) is a chronic disease that causes much inconvenience indaily life. Its pathogenesis is not clear now and patients don’t have obviously histologicallesion. OAB could be cured by restraining muscarinic (M) receptor activity. Tolterodine isa main drug used for the treadment of OAB at present. Oral administration of M receptorinhibitors would lead some drug being metabolized to their active metabolites by P450enzyme in human liver and the later were very relevant to side effects. Recent years, sideeffects of M receptor inhibitors could be dicreased by trandermal administration, whoseliver first pass effect was lower. There was only one M receptor inhibitor was developedas transdermal drug delivery system and was successly available on the market, which wasoxybutynin.Most of M receptor inhibitors were not suited to developed as transdermal drugdelivery system, especially hydrogels. Firstly, their solubility was low in most polarsolvent used to prepare hydrogels and they would separate out, which was difficult to besolved. Then drug transdermal flux would be low and could not gain high curative effect.Secondly, structures of M receptor inhibitors were usually complex and their transdermalabbility were weak and also could not gain high bioavailability. Another problem fortolterodine was that it was viscous semisolid, whose tranfering and weighing was hard. Inthis study，considering about drug properties, different methods of tolterodine l-tartratepre-treatment were developed and each methods had its own hydrogels preparationmethod. Formulation optimization was conducted scientificly. The introduction offilm-forming materials let hydrogels own good drug release property which could gainstable administration dose and curative effect. In mechanism study, tolterodinetransdermal forms and skin paths was researched and reason for hydrogels highbioavailability was revealed.1. Study of tolterodine physicochemical property and gel materials’swelling property This study was done in chapter2. Tolterodine usually existed as its tartrate. In orderto make tolterodine more suitable to be prepared hydrogels and to own high transdermalflux, the tartrate in tolterodine tartrate (TT) should be removed, then TT transformed totolterodine free base (TB). Solubility and oil-water partition coefficient (Log P) oftolterodine were key fators for hydrogels preparation. Firstly, there were two benzenerings and much paraffin chains and they caused solubility of tolterodine in water was low,about107.11μg/ml. It also suggested tolterodine would separate out in water rich matrixand at this condition the bioavailability of hydrogels would be low. Secondly, if the logPof compounds was closed to1, they would easily went through biomembrane. Because ofexisting of phenolic hydroxyl group and tertiary amine structure, the logP of TB would beimpacted by pH, particularly at pH7.0, the logP was lowest, about0.072±0.149, and thebioavailability of hydrogels would be low. To insure tolterodine could dissolve inhydrogel matrixes, it would be difficult to prepared tolterodine hydrogels with highdrug-loading (DL) and high cumulative drug release rate (f). On the other hand， swellingproperty of Cabopol980and high-substituted hydroxypropyl cellulose (H-HPC)， andhydroxypropyl methyl cellulose (HPMC) in water and ethyl alcohol was studied. All thegel materials could in the solvent except when HPMC was in ethyl alcohol. For hydrogelformulation was water rich system， Cabopol980， H-HPC and HPMC could be usedrespectively or congregately to prepare tolterodine hydrogels.2. Preparation of hydrogels and formulation optimizationThis study was done in chapter3and4. To solve the tranfering and weighing difficultyof TB, ethyl alcohol and base solution transformation of tolterodine L-tartrate andtriethanolamine transformation of tolterodine L-tartrate were developed. Method aboutloading drug after matrixes swelling to prepare hydrogels was based on ethyl alcohol andbase solution transformation of tolterodine L-tartrate. Key factors of the hydrogelspreparation craft were studied， such as content of carbopol980and H-HPC informulation; Water content， time， size of H-HPC， temperature of matrixes swelling;How did Tween80， ethyl acetate， and silicone rubber elastomer impact DL;Feasibility research of film-forming materials gelatin， polyving akohol (PVA)，and HPMC in such hydrogels matrixes. Franz diffusion cell was used for in vitro study. Drugrelease quantity (Q)， cumulative drug release rate (f)， and Steady-state flux (J) werecalculated. Results shown15%or above Tween80content could increase DL tolterodinehydrogels to4.2%with drug dissolved，but without film-forming property. When HPMCk4m was used as film-forming material，2%DL transparent hydrogels could be preparedwith film-forming property. Both Tween80and ethyl acetate could not increase DL oftransparent film-forming hydrogels to2%. Silicone rubber elastomer would destroy thematrixes， so should not be used in such hydrogels. If tolterodine dissolved in thematrixes，steady-state flux would be relatively high，which was180.55μg/cm2/h forformulation lx2d019， and173.81μg/cm2/h for formulation lx2d021. The absolutelybioavailability of formulation lx2d021was23.9in rat.Method about loading drug beforematrixes swelling to prepare hydrogels was based on triethanolamine transformation oftolterodine L-tartrate. In this study， a transparent film-forming hydrogel formulation fortolterodine was developed using ternary phase diagram and Box-Behnken design (BBD).Carbopol980(neutralized by triethanolamine)， hydroxypropyl cellulose (H-HPC)，hydroxypropyl methyl cellulose (HPMC) and Tween80were used as matrices. Solventwas the mixture of water and ethyl alcohol. The measured f24h(86.02%) was consistentwith the predicted value in mice. In the pharmacokinetic studies， sustained-release over24h and absolute bioavailability of the hydrogels (24.53%) was higher than tolterodinetablets (15.16%) in rats. The hydrogels were suitable for systemic administration oftolterodine for the treatment of overactive bladder3. Study of transdermal mechanism and pharmacology of hydrogelsThis study was done in chapter5and6, aims to understand tolterodine transdermalforms and paths. We also want to know why the bioavailability of the optimizedformulation was high.Firstly we studied the distribution power of tolterodine in different skin structures anddetemined tolterodine skin permeability at different pH. Steady-state flux (J) of tolterodinein optimized formulation across rat full skin，epidermal，dermis and subcutaneous tissuewere15.83，18.55，37.15and81.82mg cm-2h-1， respectively. The results conformed that tolterodine was suit to dermis delivery.Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry(DSC) results suggested that the hydrogels could impact lipid status in SC， which wasconsistent with Ea (8.638kcal/mol) of tolterodine from optimized formulation in rats andit also confirmed that tolterodine transdermal by permeating through lipid bilayer in SC inionized form.Pharmacodynamics study showed optimized tolterodine hydrogels could significantlyreduce12h cumulitive urine output of SD rats，who were treated by100μg/kg pilocarpinehydrochloride.