| Tamsulosin hydrochloride?TSH?is a high select blocker to?1A adrengic receptor which is widely used in the treatment of lower urinary tract symptoms?LUTS?caused by benign prostatic hyperplasia?BPH?.It can selectively block?1A receptor of the smooth muscle of bladder neck,prostate and its capsule.It improves symptoms by relaxing smooth muscle,reducing the urethral pressure,increasing the urinary flow rate,improving the urine reflux in prostate and ejaculation tube,relieving prostatitis inflammation and eliminating pathogens in the prostate tube.But BPH is a chronic disease which needs long-term drug treatment,while TSH fast oral absorption and onset of action could cause orthostatic hypotension and dizziness and other adverse reaction.So TSH sustained-release formulations is advised in clinical to improve patient compliance.So far,TSH capsules and tablets are still its main sustained-release forms,eg.the brand of Flomax?,Harnal?and so on.In China,the original product Harnal?sustained-release capsule dominate the TSH pharmaceutical market.But more and more researchers and enterprises have noticed TSH's good market potential and started the development on its sustained-release products,especially on multi-units system like TSH sustained-release pellets.But for most studies of the preparations like the processes of extrusion-spheronization and centrifugal granulation and the release control way of two-layer coating and pellet mixing,the equipments and processes are more complicated.And more factors not easy to be controlled in these processes cause the unsatisfactory batch reproducibility.In order to simplify the process and improve controllablity and reproducibity on the formulation and process,this study used the most common equipment fluid bed to finish drug laying on sugar pellets and sustained-release coating on drug pellets directly to preprare TSH sustained-release pellets for once a day dosing of 0.2mg TSH per day.And this study also developed a new one-layer sustained-release coating formulation of the combination of EUDRAGIT?NE 30D,EUDRAGIT?L 30 D-55 and Methocel?E3 to control TSH release.The main contents of the study are as follows:1.Reference to the National Standard of Tamsulosin Hydrochloride Sustained-release Capsule and other literatures,the analytical methods of contents and in-vitro release were firstly set up for using in the study of formulation and process.Standard curve studies showed TSH has a good linear relationship in the range of 16?g/m L for content determination and in the range of 0.020.48?g/mL in both pH1.2 HCl and pH7.2 phosphate buffer medium for drug release testing.TSH self-made sustained-release pellets from preparation feasibility study batches and reference product Harnal?were both used for methodological investigation.Results showed the methods established have good specificity,precision,repeatabililty and recovery rate and sample solution was stable within 12h.Meanwhile,the release profile of the reference drug was acquired and that was as the target release in developing formulaiton and process of this study.2.Formulation and process study included drug laying and sustained-release coating.In-vitro drug release was as a main invesigated item and Harnal?was as reference product for comparison in this part of the study.Detailes includes:?1?.Feasibility study of formulation and process:The formulation based on TSH properties and target of 0.2mg dosing once a day was designed and then preliminary experiments were done.Through the experiments,it was determined that the drug laying medium system was 50%?W/W?ethanol solution and time for drug laying was 60 minutes to acquire good drug yield and uniformity.Through the experiments,it was also determined that one-layer sustained release coating could be combination of EUDRAGIT?NE 30 D,EUDRAGIT?L 30 D-55 and Methocel?E3 and the percentage of Methocel?E3in total polymers?%?,the percentage of EUDRAGIT?L 30 D-55 dry polymer in total polymers?%?and weith gain of total polymer applied on drug pellets?%?were three independent factors to influence TSH in-vitro release.?2?.Curing study:Aqueous collodial film needs curing after coating to speed up film's stability to get final product with good storage stability.Preliminary curing study were done with the cheap theophylline pellets instead after film ingredients type was determined from the above feasibility study.Different curing temperature?45oC,50°C?,humidity?40%RH,75%RH?and time?5h,15h,24h?were investigated.Results showed the recommended curing condition is 45oC,40%RH and 24h.This condition was applied to curing TSH self-made sustained-release pellet after coating and then to check in-vitro drug release during 6M storage with PE bag sealed under 25oC?60%RH.The result confirmed the curing condition of 45oC,40%RH and 24h was suitable for TSH self-made sustained pellets.?3?.Optimization:Box-Behnken three factors three levels design was used for optimizing sustained-release coating formulation on three independent factors of the percentage of Methocel?E3 in total polymers?%?,the percentage of EUDRAGIT?L 30D-55 dry polymer in total polymers?%?and weith gain of total polymer applied on drug pellets?%?.Based on the optimization range of 2h release at 12%39%,3h release at44%70%and 5h release?70%and their middle value as target,through software Design Expert 8.0,appropriate model and its response surface were built and best formulation was predicted:Three levels of three factors in one-layer sustained-release coating formulation based on acrylic copolymer as main release control material are that the weight gain of total polymer applied on drug pellets is 12%with the percentage of Methocel?E3 and EUDRAGIT?L 30 D-55 dry polymer each in total polymers of 2%and 7%.Three repeated batches with the predicted formulation showed the observed values were close to predicted value in in-vitro release testing.Comparison results of similarity factors?2showed good similarity of TSH self-made sustained-release pellets to reference product Harnal?pellets in drug release(?2:71,73,80).So best formulation was determined.3.Based on the previous established analytical method,through study on three batches of self-made TSH sustained-release pellets,quality specification was set up including appearance,content uniformity,drug release and content determination.Samples of three batches packed in PE bag and sealed were stored under the condition of 25°C and60%RH for 12 months.Results showed every quality item was stable and self-made TSH sustained-release pellets had good storage stability.4.Three batches of pilot scale were prepared.The process was smooth and had good reproducibility.The appearance,content and its uniformity and drug relase of the product pellets all conformed to the related items in the national standard.Results of in-vitro drug showed small deviation among batches and good similarity to the reference product??2:74,74,89?and lab scale self-made pellets??2:89,97,86?.These meant that self-made TSH sustained-release pellets had equivalent in-vitro drug release profile to the reference product,good reproducibility in formulation and process and good transfer to production. |
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