Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits.

OBJECTIVE: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism. METHODS: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively. RESULTS: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ∼2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection. CONCLUSION: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.

Solubilization and Enhancement of Ex Vivo Vaginal Delivery of Progesterone Using Solid Dispersions, Inclusion Complexes and Micellar Solubilization.

BACKGROUND: Progesterone (PG), a natural female sex hormone is used clinically in menopausal hormone replacement therapy and to control reproductive functions. Its very limited aqueous solubility results in reduced oral bioavailability and low patient compliance when administered in high doses. The aim of this study was to enhance PG aqueous solubility and vaginal delivery using solid dispersion, inclusion complex and micellar solubilization techniques. METHODS: PG solid dispersions and inclusion complexes were prepared by solvent evaporation method using different polymers, such as cyclodextrins, polyvinyl pyrrolidone (PVP), poly (ethylene glycol) 6000, Pluronic® F-127 and Pluronic® F-68. PG was also incorporated into polymeric micelles of Pluronic® F-127, Pluronic® F- 68, Brij®35 and Myrj®52. The prepared solid dispersions, inclusion complexes and micelles were characterized using different techniques. Drug permeability across rabbit vaginal mucosa was also studied. RESULTS: Dissolution studies of PG solid dispersions showed that the highest drug dissolution rate was achieved at PG/polymer weight ratio of 5:5. Further, complete drug dissolution was obtained for PG/Pluronic® F-127 solid dispersion after 15 min compared to 42% dissolution for the drug alone. Brij®35 micelles had a drug loading capacity ~15%, which increased the drug aqueous solubility by more than 20 folds. PG permeability coefficients through rabbit vaginal mucosa for PG/Brij®35 micelles and PG/Pluronic® F-127 micelles were ~ two times higher than that of the drug alone. CONCLUSION: These results confirm that Brij®35 and Pluronic® F-127 micelles are promising carriers to overcome PG shortcomings through enhancing its aqueous solubility and vaginal permeability.