| OBJECTIVETo prepare indomethacin submicron emulsion gel and establish quality evaluation method, and study the transdermal permeation behavior in vitro rat skin and adsorption discipline in rabbit,to build a foundation for research of new IMC transdermal drug delivery.METHODS and RESULTSIMC submicron emulison was prepared by high pressure homogenization method, and evaluated by appearance, particle size, polydispersity index and centrifugal stability.Single factor study and orthogonal test was carried to study prescription and technology process respectively, the optimal prescription was as follows:main drug (1.0%), MCT (medium-chain triglycerides,15%), phospholipids (2.5%), sodium deoxycholate (SDOC,1.5%), propylene glycol (5.0%); the best technology conditions were:dispersion time (10～15 mins), spread speed (10000～15000 rpm), preparation temperature (60℃), homogeneous pressure (10000～15000 psi),homogeneous times(10-15times).Submicron emulsion gel was prepared by physical mixture of emulsions and gel matrix (2% carbomer 934 solution), mass ratio of emulsion and matrix was 4:1.The submicron emulsion gel prepared was light milky white semi-solid, with good uniforml and fluidity;particle size detected by nano-particle size dynamic light scattering instrument was 140.47±0.18 nm;polydispersity was 0.18±0.12;Zeta potencial was-44.47±3.70 mv; pH was about 7.0; Stability results showed the IMC submicron emulsion gel should be stored at low temperature(4℃), low humidity conditions, shading from light and closed save.To study the permeation behavior of submicron emulsion gel and commercial cream in vitro rat skin by modifed FRANZ diffusion cell,the IMC cumulative permeation amount (Q) had a liner relationship with time,it could be concluded that permeation bahavior of IMC in vitro rat skin followed zero order rate process.In contrast test, Q24h of this IMC submicron emulsion gel and general cream was 1311.4±75.0μg·cm-2, 653.8±49.0μg·cm-2 respectively; permeation rate (P)was 54.2±4.9μg·cm-2·h; 27.6±1.0μg·cm-2·h respectively, they all had significant difference by T-tset(P<0.05). Compared to general cream IMC submicron emulsion gel had larger Q, and P got faster,it indicated that submicron emulsion gel could accelerate IMC passing though the skin,and increased the permeation amount of drug.To study the in-vitro penetration enhance effect of IMC in submicron emulsion gel with different natural volatile oil and azone, the enhance effect from strong to weak was peppermint> azone> eugenol> lemon oil> eucalyptus oil> non-penetration enhancer group. Enhancing rate were 4.07,3.52,3.67,2.53,1.21-fold respectively. This indicated that a variety of essential oil can contribute to penetration enhancement of IMC in submicron emulsion gel, and peppermint oil had the strongest enhance effect.To compare the difference of uptake and adsorption rate between IMC general cream and submicron emulsion gel in preliminary pharmacokinetic process research of rabbits,after a single dose of 10 g(equvalient IMC 100 mg) submicron emulsion gel or general cream on abdominal skin of both sides for an area of 40 cm2, Tmax were 4.9±2.5 h,5.2±3.0 h respectively; Cmax were2571±892 ng-mL-1,2443±1864 ng·mL-1 respectively; AUC0-24 were 25018±8570ng-h-mL-1,12968±8102 ng·h·mL-1 respectively; AUC0-∞were 26293±8951 ng·h·mL-1 13110±8088 ng·h·mL-1 respectively. Compared to the general cream, AUC0-24, AUC0-∞increased,the relative bioavailability of IMC submicron emulsion gel to general cream was about 2 times.CONCLUSIONIMC submicron emulsion gel with particle size of 140.47 nm had a permeation behaviour of zero order rate process in vitro rat skin,cummutive permeation amount Q increase, permeation rate P raised when compared to general cream. Submicron emulsion gel had a faster adsorption rate,and more adsorption amount,the relative bioavailability was about 2 times of general cream.
|
PDF Full Text Request