Studies On PH-Sensitive In Situ Gel Systems For The Oral Delivery Of Ibuprofen

In situ gel refers to the preparation that is administrated as liquid and undergoes a phase transition to a non-crosslinked gel upon exposuring to physiological enviroments. The system which combines the advantages of both liquid and gel preparation has become focuses in pharmaceutical studies.Ibuprofen was selected as model drug to develop a pH-sensitive in situ gel system for the oral delivery with the basic material of deacetylated gellan gum and sodium alginate.The novel preparation can help to control the release rate, decrease the gastrointestinal side effects and increase the compliance of the patients who have difficulties in swallowing.The preformulation results showed that with the increasement of the pH value the solubility of ibuprofen increased while the octanol/water partition coefficients decreased. HPLC method was utilized to detect the ibuprofen content and in-vitro release of preparation.The absorption of ibuprofen in rat’s stomachs and intestines was studied utilizing the in situ perfusion.The absorption kinetics were obtained by utilizing investigating the effects of concentration and pH values in stomachs,the effects of segments and concentration in intestines.The results indicated that the absorption was good both in rat’s stomachs and intestines and ibuprofen could be prepared and processed into a sustained-release dosage form.The amount range of excipients（deacetylated gellan gum,sodium alginate,sodium citrate）was studied through the single-factor research.The results were that the amount range of deacetylated gellan gum was 0.25%～0.75%,sodium alginate was 0.5%～1.5%, calcium chloride was 5×10^-3～10×10^-3mol·L^-1,sodium citrate was 4×10^-3～20×10^-3 mol·L^-1,molar concentration ratio of calcium chloride and sodium citrate was less than 1. The formulation of binary ibuprofen in situ gel was optimized by monitoring the complex viscosity before and after gelling in vitro release property with the method of orthogonal design.The optimized formulation contains 1.0%sodium alginate,0.5%deacetylated gellan gum,0.21%sodium citrate and 0.056%calcium chloride.Quality evaluation was studied through pH values,sedimentation ratio,redispersibility,rheology,content determination and release property in different medium.The release of preparation could be described as First order,Higuchi and Ritger-Peppas equation.The results of the stability tests showed that the preparation had no significant changes in stress testing.The behavior in vivo was evaluated in six Beagle dogs after an oral administration of single dose of ibuprofen in situ gel（test formulation）or ibuprofen suspension（reference formulation）.The pharmacokinetic parameters were calculated.The T_maxof test formulation and reference formulation were 1.75±0.63 and 0.42±0.13 h,the C_maxvalues were 29.19±7.65 and 37.77±2.23μg·mL^-1,the T_1/2were 2.30±0.53 and 2.02±0.91 h,the AUC_0-twere 131.05±38.64 and 117.30±23.07μg·mL^-1·h respectively.Two-one sided test and rank sum test were carried out and the correlation between absorption in vivo and release in vitro for ibuprofen in situ gel was studied.The results showed that ibuprofen in situ gel had a sustained release effect and a better in vitro-in vivo correlation according to Wagner-Nelson’s formula.