No abstract

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug-Gelucire 50/13-Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40 degrees C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.

The present study was performed to investigate the further increase in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs. Ternary solid-dispersion granules of the drug, a dispersion carrier, and a surface adsorbent were prepared using hot-melt granulation. Two proton-donating drugs, BAY 12-9566, naproxen, and a nonproton-donating drug, progesterone, were studied. Gelucire 50/13 and polyethylene glycol 8000 were evaluated as solid-dispersion carriers with low melting point. Neusilin US2 (magnesium aluminosilicate), a proton acceptor, was used as the surface adsorbent. The proposed mechanism for further increase in drug dissolution (BAY 12-9566 and naproxen) on storage at 40 degrees C/75% RH (relative humidity) is based on hydrogen bonding between the proton-donating drugs and the surface adsorbent, Neusilin US2 (proton acceptor). We propose that there is enough mobility in the solid-dispersion granules at elevated temperatures of storage to allow an increase in the ratio of the hydrogen bonded drug to the crystalline drug. These changes are mediated through the saturated solid solution state, and manifest themselves as increased drug dissolution upon storage. Fourier transform infrared spectroscopy studies are indicative of an increase in the amount of drugs (BAY 12-9566 and naproxen) hydrogen bonded to Neusilin on storage. A corresponding decrease in the crystallinity of these drugs was measured using x-ray powder diffractometry. Granules containing progesterone (a nonproton-donating drug) do not show an increase in the amount of drug hydrogen-bonded to Neusilin upon storage. In contrast to the proton-donating drugs, decreased drug dissolution was found on storage of progesterone-containing granules.

A competitive balance between hydrogen bonding of the drugs with Neusilin and Ostwald ripening determines drug dissolution from solid-dispersion granules upon storage.

Our objective was to evaluate the application of polyoxyethylene homopolymers in buccal bioadhesive drug (BBD) delivery device formulations. The bioadhesive strength of four different molecular weight (MW) polyoxyethylene polymers was measured by Instronâ tensile tester using glass plate and bovine sublingual tissue as substrate surfaces. Several BBD device formulations containing polyoxyethylene polymer (MW 7,000,000) were prepared by direct compression and compression molding processes. The prepared BBD devices were evaluated for their elasticity, in vitro adhesion and drug release characteristics. The in vivo bioadhesion characteristics of a placebo compression molded device were examined in 3 adult healthy male beagle dogs. The bioadhesive strength of polyoxyethylene polymers appeared to be directly related to their molecular weights. When bovine sublingual mucosa or a glass plate was used as model mucosal substrate surface, the rank order of bioadhesive strength of different molecular weight polyoxyethylene polymers was similar. The bioadhesive strength of devices prepared by the compression molding process was greater than those prepared by direct compression, but the kinetics of drug release were independent of the process used for the preparation of the devices. The drug release and the bioadhesive strength of the similarly prepared device formulations appeared to be dependent on the drug:polymer ratios. The elasticity of the BBD devices prepared by compression molding was improved by the inclusion of polyisobutylene polymer in the formulations. When adhered to the oral cavity of the dogs, the compression molded placebo BBD device exhibited adhesion for at least 4 hours and appeared to show no signs of local irritation. In conclusion, BBD devices containing polyoxyethylene polymer (MW 7,000,000) can be prepared by direct compression or compression molding process in order to provide controlled drug release to the oral cavity while maintaining appropriate bioadhesive characteristics.