2023, Vol. 27 ›› Issue (12): 1892-1899

Establishment of a drug release model of leuprorelin acetate implant in vitro and release kinetic behavior and thermodynamic characteristics

Zhu Boru1, 2, Tang Hai2, Sun Jiahui1, Wang Xiaowen1, Li Puchao1, Liu Quanli1   

Abstract: BACKGROUND: At present, China has not made clear guidance on the in vitro dissolution of subcutaneous preparations. Because the release cycle of slow-release and controlled-release preparations with poly(lactic-co-glycolic acid) copolymer as carrier is generally long, it is very important to develop an in vitro release method that can better simulate in vivo absorption.
OBJECTIVE: To prepare leuprorelin acetate subcutaneous implant, develop an in vitro release method with good correlation with in vivo, establish an in vitro accelerated release model, investigate the correlation between drug release kinetics and thermodynamics, and elaborate the release mechanism.
METHODS: Poly(lactic-co-glycolic acid) was used as a carrier. Leuprolide acetate implants were synthesized by hot-melt extrusion technology, and its physicochemical properties were characterized during the molding process. According to the developed in vitro drug release method, the in vitro drug release test was carried out. Taking the release degree as the index, the formulation with a release cycle of 1 month was screened. Adult male SD rats were used as animal models and subcutaneously implanted with leuprolide acetate implants with a release cycle of 1 month. Blood was obtained from the orbit at the set time point. The concentration of leuprorelin in plasma was determined by liquid chromatography-tandem mass spectrometry to analyze the correlation between in vivo and in vitro drug release. The leuprolide acetate implant was taken with a release cycle of 1 month. The in vitro accelerated test was carried out with temperature as a single variable to fit the release kinetic equation. Simultaneously, the microscopic morphology of the implants was observed under scanning electron microscope.
RESULTS AND CONCLUSION: (1) The experiment set up five kinds of implants. The in vitro drug release experiment demonstrated that the release cycle of the 5th formula implant (the feeding ratio of leuprolide acetate was 25%; the feeding ratio of the carrier was 75%; and the mass ratio of poly(lactic-co-glycolic acid) copolymer with molecular mass of 10 kD and 30 kD in the carrier was 1:1) was 30 days, which met the requirements and was used for subsequent experiments. (2) The established in vitro release method had good correlation with drug release in vivo (y=0.945x-5.586 18, R2=0.945 4). (3) The cumulative release curve in vitro accorded with the S-type three-phase model: sudden release period, hysteresis period, and zero order rapid release period. In the process of heating up, based on the zero order drug release rate of 312.15 K, the thermodynamic and drug release kinetic rates accorded with the equation r=7.768 25E-30×e(4.787 45)+0.883 03. (4) The results show that the developed in vitro release method can better describe the dynamic information of drug release in vivo. The in vitro release curve is S-shaped. The release mechanism is the combination of diffusion and dissolution, and the drug release kinetics and thermodynamics in the zero order rapid release period are exponential.
Key words: poly(lactic-co-glycolic acid) copolymer, leuprolide acetate, subcutaneous implant, in vitro release, drug release mechanism