| Transdermal patch is a kind of transdermal drug delivery system for the treatment of diseases,with drugs absorbed through skin into the whole body blood circulation.This dosage form can avoid the possible liver first pass effect and drug degradation in the gastrointestinal tract,and improve the therapeutic effect.Drugs can enter into the human body at a predetermined speed for a long time,prolong the action time,reduce the frequency of administration,and improve the compliance of medication,especially for the elderly,infants or patients who are not suitable for oral medicine.Tulobuterol transdermal patch(trade name Hokunalin Tape)is the first long-acting transdermal β2 receptor agonist,developed jointly by Abbott Japan and Nitto Denko Corporation,which was approved in Japan in December 1998.Tulobuterol has such advantages as little systemic side effects,which has been widely used to treat respiratory obstructive diseases such as bronchial asthma,acute and chronic bronchitis.With the improvement of life quality,the demand for health is also increasing day by day.The current situation of pharmaceutical industry in our country can not meet this needs,especially for health needs of special people.Therefore,it is necessary to establish the preparation technology with independent intellectual property to make the domestic products,with consistent efficacy to the reference products,in order to replace the import,reduce the burden of patients’ family and national medical expenses,and to better meet the clinical needsIn this paper,the formulation,quality control,stability,absorption mechanism and pharmacokinetics of tulobuterol transdermal patch were studied.The basic strategy of transdermal patch development and industrialization was established,and the concept of quality by design was applied to the research and development of transdermal patch.The main research contents and conclusions are as followsBased on the concept of impurity profiles,from the synthetic route of API,the impurity profiles of API was analyzed comprehensively,and the related substances,residual solvents,content,solubility and oil-water partition coefficient of tulobuterol were studied,which provided technical support for the development of subsequent patches.The tulobuterol transdermal patches were designed and prepared,based on the rationale of Quality by Design(QbD).The Quality Target Product Profile(QTPP)of the reference products was used as the starting point of the formulation process research and development,combined with the characteristics of the test preparation itself.The critical quality attributes(CQAs)of the target product were systematically analyzed.According to the critical quality attributes of the preparation,the types and dosage of pressure sensitive adhesive,ion-pair reagent,penetration enhancer,and solvent were studied to determine the formulation componentsDoE and rationale of QbD were utilized to investigate key steps and parameters of preparation process.The initial process variable risk assessment was completed by analyzing the process parameters,input material and output material properties,and so on.The process parameters were investigated systematically,including dissolution temperature,stirring speed and mixing time,coating thickness,coating rate and drying temperature and so on.Three pilot batches of tulobuterol transdermal patches were manufactured,based on the determined formulation components and process parameters.According to Chinese Pharmacopoeia 2015(General principles 0121,Patches),Japanese Pharmacopoeia(Tulobuterol transdermal patch),and the preparation process of this product,quality control items mainly included appearance,identification,adhesive substances,adhesion force,residual solvent,content uniformity,related substances,release,content and other items.Test methods have been verified,and can meet the requirements for quality control.The stability of pilot batches was investigated,including stress testing,accelerated stability,long-term stability.The results showed that appearance,contents,related substances and release of tulobuterol transdermal patch did not change significantly,compared with original quality data.The distribution of P-glycoproteins(P-gp)in the skin and its effect on the transdermal absorption of Tulobuterol were evaluated,demonstrating that tulobuterol was the substrate for P-gp,and that P-gp therefore contributed for the transdermal absorption of tulobuterol.Allergic reaction of guinea pig skin was not found in Buehler test.The skin irritation study showed that the drug had mild irritation to rabbit skin.The results showed that the the test products induced little local irritation and had good safety profiles.Pharmacokinetics of tulobuterol in rats was determined by high performance liquid chromatography-mass spectrometry(LC-MS/MS).The results showed that test products and reference products had similar pharmacokinetic characteristics in rats.The absorption rate and extent were comparable,indicating that both products showed pharmacokinetic consistency. |
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