Study On Preparations Of 4-Amino-2-Trifluoromethyl-phenyl Retinate

4-amino-2-trifluoromethyl-phenyl-retinate (ATPR) is a new kind of retinoic acid derivatives, ATPR has powerful activity in inhibiting proliferation and inducing differentiation. Because of its poorly solubility in water, the oral administration of ATPR often results in low bioavailability, which limits its therapeutic application. In this paper, preliminary study on preparation of ATPR was introduced, with the purpose to improve in vitro dissolution rate and bioavailability of ATPR. In vitro dissolution rate of ATPR dispersible tablets, SMEDDS and solid dispersions were compared, in order to choose the formulation which had a higher in vitro dissolution rate, and study the intestinal absorption level of rats, to provide certain basis for further research. This paper includes three parts as follows:1 Pre-formulation study of ATPRIn vitro analysis method of ATPR was established. Detection wavelength 367 nm was determined by UV scanning. HPLC method was used to determin the content of ATPR, the established analysis method is feasible, reproducible and accurate. The result of solubility in water of ATPR show that, the solubility was 0.64μg/ml. When the compound solubility <1 mg/ml, suggesting that there could be certain problems in the in vivo absorption, that some methods may be adopted to improve its solubility. Results of oil/water partition coefficient showed that, ATPR has a fairly high oil/water partition coefficient, suggests that it is lipophilic.2 Study on ATPR dosage forms(1)The formulation of ATPR dispersible tablets was designed by central composite designing method, and the optimized formulation was: tablet weight 200 mg, each tablet containing ATPR 10 mg, microcrystalline cellulose 60 mg, sodium carboxymethyl starch 10 mg, cross-linked povidone 13 mg,α-lactose 106 mg, magnesium stearate 1 mg. ATPR dispersible tablets of this formulation, completely collapsed within 3 min in the specified conditions. In vitro dissolution results showed that, dissolution rate of ATPR dispersible tablets at 45 min was only 25.8%. (2)The basic components of the formulation were determined as HS15-PEG 400-ethylo blate by investigating the saturated solubility of ATPR in interaction between surfactants and oils, the area of various medium microemulsio in the pseudo-ternary phase diagram of different co-surfactant; The quality fraction of oil was determined as 15% by drawing the ternary phase diagram of SMEDDS. The solubility of ATPR and the average particle were selected as the response variables to optimize the SMEDDS formulation and the final formulation (containing HS15 59.5%, PEG 400 25.5%, ethyl oblate 15%, with 3% of drug) had been found; Prepare solid ATPR SMEDDS with solid carrier Silica powder and PVP. Dissolution rate from solid ATPR SMEDDS at 45 min was 84.3%. (3) ATPR solid dispersions was prepared with Lutrol F68 was uesd as carrier. Results of dissolution rate test, ATPR dissolution of solid dispersion was significantly higher than that of ATPR and ATPR and Lutrol F68 physical mixture.3 Study on intestinal absorption of ATPR solid dispersionsThe isolated small intestinal absorption method was used to determine the intestinal absorption of ATPR solid dispersions. The ratio of ATPR concentrations of serous side of small intestine of rats between ATPR solid dispersion group and control group was 8.7, suggests that ATPR solid dispersion can facilitate absorption.