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The evaluation of the dissolution profile of hypnotic drugs is important to promote switching from original products to generic products by removing distrust in generic hypnotics. In this study, we investigated differences in the dissolution profiles between original and generic products (GE-D, GE-S, and GE-T) in commercially available zolpidem tartrate (ZOL) products using the HPLC method using a connected microdialysis probe (microdialysis-HPLC method). Although the degree of hardness and the disintegration time were not different among the original, GE-S, and GE-T, GE-D was 1.4 times harder than the other products. The disintegration time of GE-D was approximately twice as long as that of the original product. Generic products dissolved rapidly as compared with the original product, however, the dissolution rate in the ZOL powder (milled ZOL product) was not different between the original and generic products. Macrogol 6000 (polyethylene glycol (PEG)-6000) was used in the generic products, and this additive was the only PEG difference from the original product. We investigated whether the PEG in the product affected the solubility of ZOL and found that the addition of PEG-4000 or PEG-6000 significantly increased the dissolution rate. These results suggest that the solubility of ZOL may be increased by PEG when the product is disintegrated, resulting in the increased dissolution rate in the generic products. In conclusion, we found that the difference of PEG affected the dissolution profile in the disintegration process using the microdialysis-HPLC method. This finding can help ensure the safety of milled products and the selection of additives.

The aim of this study was to find a biocompatible, lecithin-based carrier for paclitaxel (PTX) suitable for intravenous infusion and ensuring a soluble PTX concentration of 100 mg/100 ml or higher for at least 24 h. Aqueous dispersions of egg or soya lecithin (water-lecithin dispersions, WLD), mixed micellar (MM) solutions of egg lecithin and sodium deoxycholate, and formulations containing lecithin plus the co-surfactants and co-solvents poloxamer, polysorbate, Span, benzalkonium chloride, and macrogol were investigated. Amorphous PTX was prepared by lyophilization. PTX co-lyophilized with surfactants was also studied. Unlike crystalline PTX, the drug in an amorphous form is easily soluble in 1-5% (w/w) WLD or in MM. The highest solubility (up to 570 mg/100 ml) was achieved in 5% WLD. Dissolved PTX precipitated from all tested formulations over 24 h. Despite this, concentrations of dissolved PTX of 100 mg/100 ml or higher were observed after 24 h in 5% egg WLD, 1-5% soya WLD, and in 5% MM (lecithin : deoxycholate ratio 1 : 1 w/w). When four different batches of 5% egg WLD were prepared, containing PTX in clinically relevant concentration of 100 mg/100 ml, no precipitation of PTX was observed within 24 h and this formulation is the most promising candidate for further in vivo studies. Neither additional surfactants nor co-lyophilization increased PTX solubility in the lecithin-based carriers. The use of parenteral emulsions as solvents for the co-lyophilized PTX also failed to increase the solubility of the drug up to the target concentration.

Adsorption studies in vitro of mexiletine onto activated charcoal were performed in macrogol (polyethylene glycol)-electrolyte solution (PEG-ELS) and JP XII disintegration medium No. 2 (second medium). Mexiletine was adsorbed more extensively onto activated charcoal in PEG-ELS than that in JP XII second medium. The maximum adsorptive capacity of activated charcoal for the drug was 328 and 284 mg per gram of charcoal in PEG-ELS and JP XII second medium, respectively. In addition, the equilibrium constant of activated charcoal estimated according to the Langmuir equation was 0.079 and 0.034 l per gram of charcoal in PEG-ELS and JP XII second medium, respectively. Adsorption of mexiletine onto activated charcoal was decreased by omitting macrogol, sodium sulfate or sodium bicarbonate from a standard PEG-ELS formulation. Oral activated charcoal will be useful in combination with whole bowel irrigation with PEG-ELS in mexiletine overdose because of its excellent adsorbability in the solution.

Adsorption of imipramine onto activated charcoal and a cation exchange resin, sodium polystyrene sulfonate were evaluated in macrogol (polyethylene glycol) electrolyte solution (PEG-ELS) and JP XII second medium. The maximum adsorptive capacity of activated charcoal for imipramine was 610 mg and 372 mg per g of charcoal in PEG-ELS and JP XII second medium, respectively. On the other hand, the maximum adsorptive capacity of sodium polystyrene sulfonate for the drug was 272 mg and 667 mg per g of the resin in PEG-ELS and JP XII second medium, respectively.Adsorption of imipramine onto both adsorbents was greater when macrogol was omitted from PEG-ELS than in PEG-ELS itself. Adsorption of the drug onto activated charcoal was decreased when sodium sulfonate or sodium bicarbonate was omitted from PEG-ELS, whereas that onto sodium polystyrene sulfonate was decreased only when sodium bicarbonate was omitted from PEG-ELS.

Phenobarbital was dissolved faster from a β-cyclodextrin complex than from phenobarbital powder, and it was released faster from suppositories containing its β-cyclodextrin complex than from those containing phenobarbital powder. After rectal administration of the suppository containing the β-cyclodextrin complex to rabbits, the blood concentration of the drug was higher than that following administration of the phenobarbital suppository. Since β-cyclodextrin tended to retard absorption of the drug in solution from the rectum, enhanced absorption of the drug from the complex was attributed to fast release from the suppository due to rapid dissolution.

The absorption of indomethacin (IM) from suppositories containing surface-modified IM microcapsules (MC) after rectal administration in rabbits was investigated with the aim of producing sustained-release suppositories. The IM-MC were prepared by phase separation of ethylcellulose (EC) from cyclohexane, and the IM surface was modified with a carboxy-vinyl polymer (Hiviswako® 104, HW) by a dry blend technique before encapsulation.As a sustained plasma level of IM was not obtained when IM-MC-containing suppositories which showed a zero-order release profile were administered, the factors affecting the IM absorption, that is, the EC and HW contents in the MC, and the suppository base and type, were investigated. The EC and HW contents in the MC affected the IM release rate but had little effect on the IM absorption. When the IM-MC were directly administered, the IM plasma level was significantly lower than that after administration of the macrogol base suppository containing the IM-MC. The area under the concentration-time curve (AUC) in the case of the Witepsol® base was smaller than that in the case of the macrogol one. The plasma concentration-time curve of the hollow-type suppository showed a lag time, and the Tmax was delayed by 1 h compared with that of the conventional suppository. Thus, it was found that a suitable kind and amount of suppository base and an appropriate suppository type should be selected to prepare sustained-release suppositories containing IM-MC.