Formulation And Study Of R Dry Emulsion

Objective: With the organ transplantation of clinical work developcontinuously, immunosuppressant plays a very important role in theprevention and treatment of organ transplant rejection. At present, thedevelopment of high efficacy, safety and low toxicity immunosuppressantbecome one of the main focus of drug research. R is a novel macrolide classpotent immunosuppressant, can prolong the graft survival capacity, andreduce the occurrence of acute rejection. Compared with Cyclosporine andother immunosuppressive agents, its toxicity and immunosuppressive activityhigher, provides a new treatment alternative therapies for organ transplantpatients. However, R is insoluble in water, its solubility in water is only0.30mgl^-1.And the chemical properties of R is less stable, its bioavailability is low.Therefore, this experiment will prepare it into stable dry emulsion,on onehand it can increase the solubility and improve the chemical stability of R,onthe other hand it also can increase the oral bioavailability, to make clinicalmedication more safe and effective.Dry emulsion is a new type of drug delivery system which is exist in thestate of solid, through the appropriate methods to remove the liquid water inthe O/W type of emulsion to get the formulation of powder contain oil. Dryemulsion with the double nature of the ordinary emulsion andmicroemulsion,is the same as microemulsion can quickly dispersed into thewater or the gastrointestinal fluid in the digestive tract as the originalliquid,has the characteristics of self-emulsifying. Dry emulsion can improvethe bioavailability in vivo and permeability of insoluble drugs.In thepreparation added a small amount of emulsifiers and auxiliaryemulsifiers,there is no extensive of the toxicity of use surfactant and securityissues.In the process of storage it does not occur stratification、broken、and turn equal phenomenon, physical stability,it also can improve the stability of thedrug.Method:Filter for the suitable oil phase,emulsifier and auxiliaryemulsifier to preparation blank self-microemulsion. Stabilizers were screenedto identify a stabilizer which can significantly improve the stability of R.Putdrug and stabilizer dissolved in ethanol,then mixed with the blankmicroemulsion and add a certain amount of water,stir and dispersion withsolid adsorption,using the wet granulation process preparation of emulsionparticles,dry through a vacuum oven, then prepare it in to capsules.Ascertainthe main factor of drug releasebehavior through the single factorinvestigation.Selected the best preparation process by using the orthogonal testfor prescription optimization.Quality evaluation and stability studies:Investigated the redispersionand particle size of dry emulsion after adding water.And establish the HPLCanalysis method of R dry emulsion for content determination anddissolution.Preparation R dry emulsion capsules according to the bestprescription,with appearance、content、dissolution and related substances asthe index,respectively conduct the influence factors test and acceleratedtest,then investigate its stability.Pharmacokinetics study in vivo:Using the sold solid nano-tablet asreference preparation,the pharmacokinetics study in vivo of R dry emulsionwas performed on beagle dogs.Arrange experiment as the crossover designs oftwo preparations and two periods.Plasma samples were obtained at differenttimes. After the treatment to plasma,then determine the content of R in wholeblood by HPLC method.Compare to the reference preparation and calculatethe pharmacokinetics parameter.Results:According to the single factor and orthogonal experimentaldesign determined the best technology and the optimal prescription topreparation R dry emulsion.The optimal formula was as follow: EL-35,0.6g;propylene glycol,0.25g;（LAB）,0.15g;ethanol,0.8g;antioxidant B,15mg;pregelatinized starch,1g; starch ,14g。The content and in vitro dissolution of R is determinationed by HPLCmethod at the detection wavelength277nm.And the blank excipient had nointerference in this wavelengths. The standard curve of R dry emulsionindicated that the linearity range was25²25μg/ml.The regression equationwas A=4.850×10⁴X+1.026×10⁵,（r=0.9998， n=6）.The recovery was98.77%¹00.06%.The winth-day precision of three concentration samples was0.41%,0.49%,0.36%,and the between-day precision was0.63%,0.71%,0.56%.Evaluation and stability test of R dry emulsion:The particles of R dryemulsion prepared by the best prescription have good liquidity,and the particlesize of redispersion was247²68nm. The result of high temperature test showthat the appearance, particle size after redispersible and dissolution of samplehave no significant change,and the related substances increase of0.78%; theresult of high humidity test show that the appearance, particle size afterredispersible and dissolution of sample have no significant change,and therelated substances increase of0.83%; the result of strong light test show thatthe related substances increase of0.80%have no significant increase under thestrong light4500±500lx for10days.The results of accelerated test（40±2℃） after6month show that theappearance, particle size after redispersible and dissolution of the threebatches sample have no significant change, stable content,and the relatedsubstances was controlled in less than2%.Pharmacokinetics study in vivo: Determine the content of R in wholeblood by HPLC method.Deal with the concentration date by3p97Compare thepharmacokinetics parameter with the reference preparation:t_1/2（α）:1.07h,2.28h;t_1/2（β）:14.26h,17.68h;T（peak）:1.24h,1.07h;C（max）:46.05ng/mL,38.90ng/mL;AUC:268.4（ng/mL）*h,211.74（ng/mL）*h.Conclusions:The physical and chemical stability of self-made dryemulsion capsules are high.The apperence、content、dissolution and theparticle size of redispersion have no obvious change after6month under thetemperature of25±2℃.The related substance was controlled in less2%.The bioavailability of R dry emulsion is higher than the reference preparation.Thepreparation of R dry emulsion have significance for research.