Preparation And Evaluation Of Rop Transdermal Patch

BackgroundRopinirole as non-ergot drugs is the second-generation dopamine receptor agonists, It can effectively and selectively excite the substantia nigra-corpus striatum (dopamine D2 receptor)of the brain [1], early use of ROP only can release the symptoms of paralysis agitans ,significantly reduce the symptoms and the incidence of movement disorders, better control of the symptom of various stage of the Parkinson's disease (PD), mainly used in Parkinson's disease and restless legs syndrome[2][3] . ROP has the same mechanism as the Rotigoetine and pergolide, "The new treatment guidelines for Parkinson's disease"has used ROP as the initial first-line therapy to replace L-dopa on early disease.The ROP was first put into the market in the UK in 1996 as oral preparations forms named Requip. In September 1997, requip was eventually approvaled by the FDA. Because of ROP oral preparations'low bioavailability, gastrointestinal side effects and other issues in foreign clinical application, other formulation of ROP is under development, such as the sustained-release tablet has just been approved by FDA recently[3]. In addition, the oral spray in 2011 will enter the clinical research stage, the pre-clinical studies of osmotic pump preparation has been studied in China [6].ObjectiveFaced with ROP's main problems,such as low oral bioavailability and gastrointestinal side effects issues, aim to develop the new transdermal patch formulation of the ROP to get rid of gastrointestinal reaction caused by oral administration.Providing the reference of transdermal drug delivery system for the development of ROP and clinical application.Method1. Establish transdermal diffusion cells of horizontal two-bedroom ,comparative study of Rop.base and Rop.Hcl (ROPINIROLE API) .2. Establish transdermal Franz diffusion cells (SD rat) penetrant inspection methods of ROP transdermal patch to study the cumulative transdermal patch , the rate of penetration and the steady-state of transdermal rate etc.3. Establish RP-HPLC method for the determination of the main ingredients for ROP transdermal patch.4. Establish differential scanning calorimetry (DSC) method to study the status of ROP transdermal patch. 5. Using single factor method to study the factors of the mixed plastic DT4098 / BP4202, such as the ratio, the amount of penetration, the drug content,etc. Analyzing the impact of penetration, studying the formulation single factor of transdermal patch and optimizing the prescription.6. Establish the HPLC-MS/MS method to determine the content of ROP in plasma.Results1. Determination of ROP medication form: by comparative study in physical and chemical properties and permeability of ROP.base and ROP.HCl, Assuring that ROP.base can be used as raw materials for transdermal drug.2. The research of ROP status: using differential scanning calorimetry (DSC) method to demonstrate the existence of ROP transdermal patch is in molecular or amorphous form.3. Study of RP-HPLC determination method: The Experiment shows that this method is rapid, accurate and reproducible, its concentration of ROP : 0.71 ~ 70.66μg/mL , a good linear relationship (r = 0.9999), RSD :within 0.5%.4. Study of HPLC-MS/MS method( determination of the content of ROP in plasma): The Experiment shows that the method can achieve the requirement of biological samples detection, ROP concentration between 0.02 and 416.72ng /mL has a good linear relationship (r = 0.9998),with no more than 6.0% RSD.5. Investigation and optimization of prescription: Selecting the cumulative permeated amount, rate and steady-state penetration rate as a transdermal patch transdermal (SD rat) penetration index. Studying The mixed adhesive DT4098/BP4202 ratio, the amount of penetration, drug content factors as indexes for investigating the effect of preparation transdermal performance; Using Experiment to ensure the best prescription of ROP patch ,which is the ratio of the mixed plastic DT4098/BP4202 is 1/4, penetration enhancers Azone is 1%, drug content is 4%.6. Study of preparation technology: The Experiment shows that the coating thickness of ROP transdermal patch is 0.2 mm, drying temperature is 60℃, containing the drug-containing layer of skin adhesive, adhesive layer integrity, uniformity and good in placement appearance.7. Study of stability: After 3months Accelerating, the result show that ROP transdermal patch is of good stability, its content and the material requirements are in line with transdermal patch.8. Study of local irritation: After the study of The rabbit abdominal and back skin irritation, it shows that no skin irritation occurred during its three days of ROP transdermal patch affixing to the rabbit's back .9. Study of pharmacokinetic: The experiment of the pharmacokinetics in rabbit shows that rabbit can achieve steady penetration rate and stable plasma concentrations in 3 days, with steady plasma concentration of 25.0 ng /mL.ConclusionBased on the study of physical and chemical properties of ROP, selecting ROP as model drugs, developed the ROP transdermal patch. The vivo experiments shows that the transdermal patch has no stimulation, good biological compatibility; The rabbit can achieve steady penetration rate and stable plasma concentrations within 3 days, with steady state plasma concentration of 25.0 ng /mL.The results of the ROP research provide certain theoretical references for the development and clinical application of ROP transdermal patch and the practical value of further development .