Colon-targeting of progesterone using hybrid polymeric microspheres improves its bioavailability and in vivo biological efficacy.

This study aims to enhance progesterone (PG) oral bioavailability via its incorporation into hybrid colon-targeted pectin/NaCMC microspheres (MS) cross-linked with Zn2+ and Al3+. The MS were characterized for particle morphology, encapsulation efficiency, swelling behavior, drug release, mucoadhesivity and colon-specific degradability. Response-surface methodology was adopted to optimize the fabrication conditions. Enhancement of in vivo drug performance was evaluated through pharmacokinetic and pharmacodynamic studies. The optimized formulation was typically spherical with a mean diameter of 1031 µm and drug entrapment efficiency of 88.8%. This formulation exhibited pH-dependent swelling, negligible drug release in simulated gastric fluid and sustained-release pattern in simulated small intestinal fluid with a mean t50% of 26.5 h. It also showed prolonged and preferential adhesion to rat colonic mucosa, as well as expedited degradation in presence of rat caecal contents. The MS significantly increased the area under the curve and mean residence time by 1.8 and 2.3-fold, respectively compared to the free drug. Orally administered MS showed ~10 times increase in myometrial thickness compared with the drug suspension and elicited uterine responses very similar to that obtained parenterally. These results confirm the ability of this new carrier system to improve the oral bioavailability of PG and attain adequate clinical efficacy.

Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone.

The colon is a promising target for drug delivery owing to its long transit time of up to 78 h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (∼25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580-720 µm were obtained. Drug entrapment efficiency of ∼75-100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3-9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ∼168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.

Preparation and in vitro/in vivo evaluation of the buccal bioadhesive properties of slow-release tablets containing miconazole nitrate.

Slow-release buccal bioadhesive tablets of miconazole nitrate were prepared by using polymer mixtures of buccoadhesive materials such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carbopol 934p, and sodium alginate. The physicochemical properties, swelling index, microenvironment pH, in vitro drug release, in vivo buccoadhesion time, and miconazole salivary concentrations of the prepared tablets were shown to be dependent on the type and composition of the buccoadhesive materials used. The dissolution of miconazole from all the prepared tablets into phosphate buffer (pH 6.8) was controlled and followed non-Fickian release mechanisms. All the prepared tablets gave reasonable buccoadhesion time (2.45-3.65 hr). Infrared spectroscopy and differential scan calorimetry studies revealed the absence of significant interactions between miconazole nitrate and the selected buccoadhesive materials. Duration of the antifungal activity as measured by the inhibition zone of Candida albicans by extracted human saliva was significantly longer (p < 0.05), compared with commercial miconazole oral gel (Daktaren oral gel). Based on the results obtained, the prepared slow-release buccoadhesive tablets of miconazole would markedly prolong the duration of the antifungal activity with more patient convenience.