The inhibition of Swiss 3T3 cell growth by the microspheres prepared from various 2-cyanoacrylate polymers was investigated to assess their cell toxicity. Poly(ethoxy-ethyl 2-cyanoacrylate) and poly(methyl 2-cyanoacrylate) microspheres inhibited cell growth in a smaller amount than poly-(isobutyl 2-cyanoacrylate) and poly (ethyl 2-cyanoacrylate) microspheres. The extent of cell growth inhibition by the microspheres decreased with the increasing molecular weight, regardless of the kind of polymers used. Every kind of the microspheres was degraded releasing formaldehyde in the culture medium. The cell growth inhibition by the medium containing the microspheres was observed within 24 h for poly(ethoxyethyl 2-cyanoacrylate) and poly(methyl 2-cyanoacrylate). The extent of inhibition was in a linear proportion with the amount of formaldehyde released. It is concluded that the cell toxicity of 2-cyanoacrylate polymers is attributed to formaldehyde released upon polymer degradation.

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.

To evaluate 2-cyanoacrylates as surgical adhesives, the bond strength in vivo as well as the tissue reaction was investigated using methyl-, ethyl-, isobutyl-, and ethoxyethyl-2-cyanoacrylate. In addition, their set time and spreading on blood were studied. When the 2-cyanoacrylates were applied to an incised site of rabbit skin, they could maintain the skin closure without suturing during the first week and the bond strength increased during the second week. Significant inflammatory response was observed around the subcutaneous tissue glued with methyl- and ethoxyethyl-2-cyanoacrylate and persisted for approximately one week. All the 2-cyanoacrylate polymers were absorbed and the tissues treated were healed two weeks after the operation. There was a mild inflammatory reaction in the tissue treated with ethyl- and isobutyl-2-cyanoacrylate, and their polymers still remained at the wound site at the second week postoperatively. The disappearance rate of the 2-cyanoacrylate polymers was roughly in proportion to the inflammatory tissue response. Ethoxyethyl-2-cyanoacrylate spread more broadly on tissues than the other 2-cyanoacrylates, while its set time was shorter than that of methyl- and ethyl-2-cyanoacrylates.

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Photoreactive poly(ethylene glycol) (PEG) was synthesized by reacting 4-fluoro-3-nitrophenyl azide (FNPA) with sodium salt of PEG. The synthesized 4-azido-2-nitrophenyl PEG (ANP-PEG) was characterized by 1H-NMR, IR, and UV spectroscopy. ANP-PEG was grafted to dimethyldichlorosilane-coated glass (DDS-glass) by photolysis without any premodification of the surface. The effects of various grafting factors, such as the polymer adsorption time, concentration of ANP-PEG, and UV irradiation time, on the PEG grafting efficiency were examined. The PEG-grafted DDS-glass was characterized by measuring surface free energies, surface-induced platelet activation, and the relative amount of PEG grafted on the surface using electron spectroscopy for chemical analysis (ESCA). Platelet adhesion and activation was analyzed by measuring the number and spread area of adherent platelets. The results showed that ANP-PEG had to be adsorbed onto DDS-glass for at least 12 h before photolysis for the maximum grafting efficiency. No platelets could adhere to the PEG-grafted DDS-glass, if the bulk concentration of ANP-PEG in the adsorption solution was between 1 mg/mL and 10 mg/mL. Above 10 mg/mL, platelet activation gradually increased and reached the maximum at 30 mg/mL. Our data indicate that the grafting of ANP-PEG requires careful control of the grafting conditions and that the grafted PEG can prevent surface-induced platelet activation.

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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.