Preparation And Evaluation Of Self-double-emulsifying Drug Delivery System Containing Biopolyphenolics

Biopolyphenolicsare secondary metabolites present in the root,shell,peel and flesh of plants,and constitute a large family of ubiquitous and varied substances.To date,several thousands of polyphenolic compounds have been demonstrated various health beneficial effects in studies of antioxidant activity,anti-inflammatory,chemopreventive effects,cardiovascular diseases,neurodegenerative diseases,diabetes,obesity,and several other adverse medical conditions.Unfortunately,the activity and potential health benefits of polyphenols are limited by their low solubility,low bioavailability as well as instability under conditions encountered in and storage(temperature,oxygen,light).The utilization of encapsulated polyphenols instead of free compounds can overcome their drawbacks.Thus,self-double-emulsifying drug delivery system(SDEDDS)is composed of water in oil(w/o)emulsions and hydrophilicsurfactants,which could spontaneously emulsify into w/o/w double emulsions in the aqueous media.Conventional SDEDDS,however,are mostly prepared in a liquid form,which can produce some disadvantages,for example,high-production costs,low stability and portability,and few choices of dosage forms.Accordingly,solid SDEDDS could gain popularity.The thesis investigated theself-double-emulsifying drug delivery system containing epigallocatechin-3-gallate(EGCG)and/or resveratrol for topical and oral application.The drawbacks of conventional system were overcome by two solidified strategy.The specific contents are as follows.?.A self-double-emulsifying drug delivery system loaded with EGCG and a-lipoic acid(EA-SDEDDS)was investigated firstly.SDEDDS combined the advantages of double emulsions and SMEDDS,thus SDEDDS could be used for the loading hydrophilic(EGCG)and lipophilic(ALA)active compounds and they had the unique ability to form fine multiple emulsions upon mild agitation followed by dilution in aqueous media.The EA-SDEDDS revealed a spherical morphology and achieved high drug entrapment efficiency.In view of the data from physicochemical particularity,samples were kept stable for at least 30 days under simulated sunlight.A prolonged release profile of EGCG from EA-SDEDDS was demonstrated.In vitro cellstudies,EA-SDEDDS provided protection for 3T3 fibroblasts that underwent H2O2 oxidative stress due to sustained release property,ALA and EGCG incorporated in SDEDDS remained effective similarly to EA solution.In vitro transdermal studies showedSDEDDS was a very attractive carrier system for skin applications due to its skin targeting effect.Therefore,all these positive attributes made this system amenable for application of EGCG in topical products.?.To improve the oral absorption of EGCG,we investigated a SDEDDS in solid form.Solubility of EGCG was determined in various components,including water,oils and surfactants.Pseudo-ternary phase diagrams were constructed to identify the most efficient self-emulsification region.The EGCG-SDEDDS in solid formulation rapidly formed fine water-in-oil-in-water emulsion.In this study,solid EGCG-SDEDDS showed the same crystallinity with GMS in the ?-form.The encapsulation of EGCG in the inner aqueous phase of double emulsion did not affect the crystal structure of SDEDDS.Furthermore,in vitro cellular experiments have shown increase in the cellular uptake of EGCG incorporated in SDEDDS compared to pure drug was mainly attributed to the cellular caveolae-mediated endocytosis,and in an in vivo pharmacokinetic study in rats,the SDEDDS formulation exhibited 1.93-fold greater area-under-curve value than that of the drug solution.Stability studies have shown solid EGCG-SDEDDS was stable up to 6 months under long-term test.These studies demonstrated that the novel SDEDDS in solid form could be a promising formulation strategy for the drug delivery of hydrophilic compounds with low oral bioavailability.?.The present studies have clearly demonstrated the potential utility of non-aqueous SDEDDS for formulating trans-resveratrol with sustained release and improved skin retention in vitro.The optimal formulation of the trans-res-SDEDDS was successfully developed.The non-aqueous SDEDDS readily released the oil phase to form fine oil-in-oil-in-water double emulsions,with a sustained release of trans-resveratrol.In vitro transdermal studies revealed that trans-resveratrol from SDEDDSwill most likely be higher than the drug permeation from the same dose of the free form aqueous solution without any additives.Moreover,the SDEDDS were found to be stable over a period of 3 months under 30? and 40?.Our studies illustrated the potential use of non-aqueous self-double-emulsifying drug delivery systems for topical delivery drug with low solubility and permeability.?.To improved solubility,dissolution,and in vivo oral absorption of trans-resveratrol and EGCG,this sectiondescribes the development and characterization of solid non-aqueous self-double-emulsifying drug delivery system(S-SDEDDS).Solubility of actives was determined in various excipients,including oils and surfactants.Pseudo-ternary phase diagrams were constructed to identify the most efficient self-double-emulsification region.The optimized liquid non-aqueous self-double-emulsifying drug delivery system(L-SDEDDS)was developed using the suitable excipients,i.e.evening primrose seed oil and glycerolas oil phase,PGPR,soy phosphatidylcholine,Tween 80 and Labrasol as surfactant mixture.The optimized L-SDEDDS was transformed into S-SDEDDS using DCPA(Dibasic calcium phosphate anhydrous)as adsorbent carrier.S-SDEDDS was evaluated for fourier transform infrared spectroscopy,powder X-ray diffraction and scanning electron microscopic studies,which shown transformation of crystalline drugs into amorphous form or molecular state without any chemical interaction.S-SDEDDS was found to be stable up to 6 months under long-term conditions.Plasma concentration-time profiles from pharmacokinetic studies in rats dosed with S-SDEDDS showed 2.36-and 9.38-fold increased absorption of EGCG and trans-resveratrol,respectively,compared to the aqueous solution/suspension.Finally,S-SDEDDS was found to be stable over a period of 6 months under long-term condition.These studies demonstrate that the new solid non-aqueous self-double-emulsifying system is promising strategies for the formulation of lipophilic and hydrophilic compounds with low oral bioavailability.