Investigation Of Preparation And Pharmacokinetics For All-Trans-Retinoic Acid Oral Emulsion

Background and Objective: All-trans-retinoic acid (ATRA), alsoknown as retinoic or vitamin A acid, is a primary active metabolite ofvitamin A. ATRA is now included in many antitumor therapeutic schemesfor the treatment of acute promyelocytic leukemia, head and necksquamous cell carcinoma, ovarian carcinoma. ATRA shows anti-canceractivities, especially in patients with acute promyelocytic leukemia (APL).Standard treatment consists of ATRA that results in complete remission(CR) rates in excess of 90%. Unfortunately oral administration of ATRA is associated with rapidlyand progressively diminishing ATRA levels in plasma, despite highremission rates with oral ATRA, these CRs are short-lived (3 to 5 months)and ATRA monotherapy is not able to maintain long-term remissions inthe patients with APL.Once ATRA level is decreased, increasing the oraldose cannot elevate plasma ATRA concentration and it remains at lowerlevels even if the dose is doubled. Pharmacokinetic studies havedemonstrated that systemic exposure to ATRA as measured by area undercurve (AUC) value decreases at least 5-fold and in some patients evenreturn to baseline levels by day 21 during continuous daily oraladministration. Due to the highly variable bioavailability of ATRA andinduction of its own metabolism after oral treatment, development ofalternative parenteral dosage form is required. The purpose of this workwas to improve the oral bioavailability of poorly soluble drugs by utilizingphospholipid-based emulsion system as a carrier. Methods and results:In order to control the quality of ATRAemulsion, ATRA concentration of ATRA emulsion was determinated byHPLC and the diameter of ATRA emulsion was measured by Photoncorrelation spectroscopy. in this test,proemulsion was prepared by vaporization in vacuum andATRA emulsion was threatened by Ultrasonic. According to the recoveryof ATRA concentration and diameter,oils,PNO/EPC ratio,ATRA/(PNO+EPC) ratio, mix round speed of proemulsion, time andintension of Ultrasonic were studied.Finally,under the optimalformulation,ATRA emulsion was encapsulated 98.68%,the particle sizewas 354.7 ±231.8nm. Different formulations of emulsion loaded with ATRA weresuccessfully prepared by method above.According to particle size anddistribution, drug loading capacity and emulsion appearance,the long-termphysical stability without light and air of the ATRA emulsion wereinvestigated in detail in 4℃ and 40±2℃ conditions within 0,5,10,days.The results showed that two formulations were stable. A single -dose pharmacokinetic study was conducted in rabbits afteroral administration of 2 mg/ kg ATRA in different formulations ,Pharmacokinetic parameters shows that the relative bioavailability ofATRA in emulsion was significantly increased compared with that of anATRA tablet. Area under the plasma concentration-time curve [AUC (0,infinity)] and maximum plasma concentration [C(max)]emulsion is2019.79±54.95ng/h.ml and 825.01±8.52ng/ml,Capsule is1029.36±69.38ng/h.ml and 508.64±35.67ng/ml, F is 1.817,suggesting thatits bioavailability was not impaired by loading in emulsion ,ATRAemusion had better absorbtion and high ATRA levels in plasma. Conclusion: Our study herein demonstrates emulsion offers a newform doesage to improve the oral bioavailability and concentration levelsof poorly soluble drugs in plasma and ATRA have better absorbablitily inrabbits body.Phospholipid-based emulsion may provide an betterparenteral formulation of ATRA.