Study Of Transdermal Drug Delivery System Of Risperidone

Risperidone (RSP) is an atypical antipsychotic drug with potent antagonistic properties at serotonin 5-HT₂A and dopamine D₂ receptors. It is effective to treat both positive and negative symptoms in schizophrenia, and their associated behavioral abnormality. RSP is also used to cure dementia in old patients. The available types of products in the market are tablets and solutions for oral administration, and long-acting microspheres for im injection. Upon oral administration, RSP undergoes hepatic first-pass elimination (60% in humans), and RSP long-actiong formulation is quite expensive, as well as exists safty problems. The daily dosage of RSP is small (between 0.5-6mg), so RSP is potential to be developed into transdermal drug delivery products. The purpose of this study was to investigate the RSP percutaneous penetration characteristics, and develop transdermal patches of RSP with enough high transdermal penetration rates for clinical use. That kind of patch can offer long-period administration and improved patients' compliance.The study of RSP transdermal drug delivery system can be divided into four parts: 1) the preformulation study involving establishing analysis methods and screening proper enhancers for transdermal delivery of RSP; 2) Formulation study and developing adhesive dispersion-type transdermal patch for RSP administration with enough high percutaneous penetration rate; 3) quality study including setting up of quality standards and quality control; 4) bioavailability study of RSP patch.In the preformulation study, the HPLC method for the analysis of RSP was established firstly and RSP solubility in various vesicles such as water, 20%PEG400, series of ethanol and propylene glycol was determined. By employing physiochemical descriptors of RSP, the skin permeability can be predicted using Quantitative structure-permeability relationships (QSPRs). Seven QSPR models used in the study were equations of Potts-Guy, Cronin, Moss, Morrimoto, Kitagawa, Magnusson and Lien-Gao. The predicted results and pharmacokinetic parameters indicated that RSP was a proper candidate for transdermal drug delivery. The in vitro skin penetration experiment was carried out on modified Franz- Diffusion Cells, using excised human skin. Solubility results revealed the RSP was almost insoluble in water, with a solubility of 100μg·mL^-1. The solubility was increased by the above vesicles. Study on penetration enhancers showed ethanol was a good vesicle, and the enhancing ability was proportional to ethanol concentration, while propylene glycol is much less. The enhancing ability followed as: dodecyl alcohol > Azone > IPM > oleic acid. Combination enhancing effect of propylene glycol with Azone/ dodecyl alcohol is less potent than Azone or dodecyl alcohol used alone.Drug-in-adhesive transdermal patches of risperidone (RSP) were developed using acrylic ester as pressure-sensitive adhesive (PSA) material. Different kinds of penetration enhancers were investigated, such as Azone, dodecyl alcohol (DA), oleic acid (OA), menthol and propylene glycol (PG), as well as their concentrations. According to percutaneous penetration rate and clinical needs, the above enhancers were screened to obtain the best one. The preparation parameters, both the thickness and drug loading, were also evaluated to obtain the optimal technical formulation. The general trend for penetration rates was as follows: 10%Azone>6% Azone, 6%dodecyl alcohol >2%oleic acid>8%menthol, and PG conbined with Azone can has a synergistic effect. Based upon the a combination of thickness and drug loading data, The optimal technical parameter for risperidone patch was the ratio of drug and acrylic ester (w/w) =0.125.Under the optimal preparation condition, the greatest steady state flux was obtained from the formulation 8, with a penetration rate of 7.73±0.43μg·cm^-2·h^-1, and cumulated amount of 173.76±10.27μg·cm^-2 after 24h.This was 2.64 times higher than the control. It was determined that a simple patch with an area of 2 cm² could deliver a therapeutic in vivo dose, with possible for treatment of behavior disturbances in schizophrenia and dementia in old patients.The quality of the optimal patch was investigated including quality standard and quality control. HPLC method was used to analyze drug content in the patch, and the diffusion concentrations. Under HPLC condition, RSP and its degradation products of basic, acid, light, temperature and humidity were separated from each other. The drug content, release profile and adhesion of patch can be well controlled. Study on influence factors showed drag was stable under high temperature and humidity, or intensive light, but patch adhesion was decreased under high tempreture. High temperature also influenced release profiles, making it slower; while the other two factors didn't. RSP patch was stable in accelerate experiment unless a bit decrease in release, while stay stable for six months'under ambient circumstance.That means the patch should be kept under room temperature.At last, Bioavailability of RSP was studied on rabbits, using pharmacokinetic methods. RSP concentration in the plasma was analyzed by HPLC, then the area under curve (AUC) was calculated. Relative bioavailability of RSP patch was obtained by comparing AUC data of transdermal administration with AUC data from oral administration. Results showed patch had relatively high bioavailability of RSP of more than 90%, penetration could reach the clinical requirement.Drag-in-adhesive transdermal patches of RSP have high percutaneous permeability and bioavailability, and the preparation of the adhesive-matrix patch is simple, as well as it is of stability and quality controllable. It is potential to be developed into a new transdermal product.