Preliminary investigation of the nasal delivery of liposomal leuprorelin acetate for contraception in rats

Abstract

The purpose of the study was to investigate the nasal route as a non-invasive alternative for delivery of leuprorelin acetate (leuprolide acetate, LEU) and to achieve an effective concentration of leuprorelin acetate in blood after nasal administration for contraception in rats. The plain drug solution, physical mixture (plain drug along with constituents of liposomes), or drug encapsulated in either neutral or charged liposomes containing 5 microg leuprorelin acetate were administered to rats through the nasal route. The plain drug solution was administered subcutaneously (s.c.). Simultaneous evaluation was performed on the influence of a mucoadhesive agent (chitosan) on nasal absorption of the plain drug and the liposome-encapsulated drug. Blood samples were taken at regular time intervals and subjected to luteinising hormone (LH) analysis using a specific immunoassay kit. The plasma luteinising hormone concentration vs time data of nasal and subcutaneous treatments were plotted and compared with that of subcutaneous administration. Relative percentage of bioavailability (F) for nasal treatments was calculated from plasma concentration vs time plots. Sperm count and fertility performance studies were carried out for selected formulations in rats. Neutral liposomes (LLEU) and negatively-charged liposomes (LLEUn) showed higher relative percentage of bioavailability (F 27.83 and 21.30%, respectively) as compared with the plain drug and the physical mixture (F 10.89 and 10.96%, respectively) after nasal administration. Hence, work on neutral liposomes was continued. F was further improved after incorporation of chitosan i.e. 10.89 to 49.13% for plain leuprorelin acetate and 27.83 to 88.90% for liposomal leuprorelin acetate formulations. Liposomal chitosan formulation administered nasally and leuprorelin acetate solution subcutaneously achieved complete azoospermia. No implantation sites were observed after the mating of female rats with treated males. It was observed that in the treated female rats, the estrous cycles ceased with the same formulations from the first treatment cycle. The findings of these investigations demonstrated that the bioavailability of the nasally-administered liposomal leuprorelin acetate with chitosan formulation was comparable with that of the subcutaneously administered drug. Complete contraception was obtained in male and female rats that had been treated with either the nasally administered liposomal leuprorelin acetate with chitosan or the subcutaneously administered drug.

Nasal Route for Delivery of Emergency Contraceptives

“…Azoospermia was observed in male rats 26 days post initiation of medication as also cessation of estrous cycle in female rats was observed. Moreover, the contraceptive effect observed was reversible [20].…”

Elastic liposomes as novel carriers: recent advances in drug delivery

“…However, several attempts have been made to prolong the retention time by employing mucoadhesive materials, such as positively charged chitosan, which could increase the BA of intranasally administered vesicles. 115 Chitosan-mediated tight-junction opening (or the disruption of proteins by translocation from the membrane to the cytoskeleton) is considered as the main mechanism for ionic …”

Nasal-nanotechnology: revolution for efficient therapeutics delivery

“…Numerous advantages are offered by liposomal drug delivery systems in terms of efficient encapsulation of small and bulky molecules with a wide range of hydrophilicity. Some research reports stated that liposomes supplement nasal absorption of peptides (Wearley, 1991;Shahiwala & Misra, 2006), for example, insulin (Muramatsu et al, 1999) and calcitonin (Bijani et al, 2012) by intensifying their membrane penetration. The enhanced absorption is attributed to the elongated retention period of peptides, shielding of encapsulated peptides from enzymatic deprivation and mucosal membrane distraction.…”