Creating a sustained release of clomiphene citrate upon administration in nano phosal-based formulation (PBF) and assessment of endometrial receptivity genes by influence of Nano clomiphene citrate

Background: Stimulation of ovulation by clomiphene citrate can cause side effect on endometrial receptivity. Formulation Nano may be an alternative therapeutic for women with ovulatory disorders.Objective: The overall objective of this study was to develop an oral sustained release clomiphene citrate by using Phosal-Based Formulation (PBF) and evaluation decreased its side effect on endometrium and compare the expression of endometrial receptivity genes in implantation, in mice stimulated with clomiphene citrate encapsulated in PBF (CC/PBF) and clomiphene citrate free clomiphene citrate.Materials and Methods: In in vitro study CC loaded PBF was analyzed using zeta sizer, FTIR, TEM. In in vivo study, 18 female mice were randomly divided into 3 groups CC/PBF, CC, normal saline (SS) and daily administered 200μl and injected with 5IU HCG and mated after two days. At day 4.5, pregnant mice were euthanized, and endometrial tissue were extracted for Q-PCR analysis.Results: The optimized PBF contained Phosal 50PG/glycerol in a 2:8 ratios (w/w) and mean particle size of Nano drug used were 67±9.0 nm, the release of CC from Nano emulsion was slightly faster in the first 24 hours; during this period, 29% of CC was released. After 120 hours 76% of CC was released. LIF, LIFR, HOXA10, HBEGF, EGF mRNA levels were significantly upregulated and MUC1, PGR mRNA levels were significantly downregulated in the CC/PBF treated animals compared with the CC group (p<0.05).Conclusion: Formulation sustained release of clomiphene citrate increased its targeting efficiency and improved the impact of the CC on the serum levels of estradiol and expression of genes involve implantation. A new Phosal-Based Formulation (PBF) was introduced to decrease side effect of clomiphene citrate on endometrium, this drug formulation could react better in implantation and preventing abortion by increasing genes involved in implantation, the in vivo study demonstrated that the PBF in mice has a significantly higher genes expression involved implantation than that of the systemic formulations.

Keywords:

Endometrial receptivity , Clomiphene citrate , PBF , Sustained release , Drug delivery , Ovarian stimulation , OHSS , Nano drug.