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Based on the demonstrated and reported trypanocidal, leishmanicidal, and antiplasmodial activities of two menthol prodrugs, it was decided to proceed with preformulation studies, which are of key relevance in the drug discovery process. The aim of this study is to examine the stability and permeability of two new menthol prodrugs with antiparasitic activity. To determine the stability of menthol and its prodrugs, the corresponding studies were carried out in buffered solutions at pH values of 1.2, 5.8, and 7.4 at 37 °C. In silico permeability studies were performed using the free PerMM software and then in vitro permeability studies were performed using a biomimetic artificial membrane (BAM). Permeability studies conducted in silico predicted that both menthol and its prodrugs would pass through biological membranes via flip-flop movement. This prediction was subsequently confirmed by in vitro BAM permeability studies, where it was observed that the menthol prodrugs (1c and 1g) exhibited the highest Papp (apparent permeability) value compared to the parent compound. The study reveals that menthol prodrugs exhibit stability at a pH of 5.8 and possess sufficient in vitro permeability values as preformulation parameters. [ABSTRACT FROM AUTHOR]

The solubility of fenofibrate in pH 6.8 McIlvaine buffers containing varying concentrations of sodium lauryl sulfate was determined. The dissolution behavior of fenofibrate was also examined in the same solutions with rotating disk experiments. It was observed that the enhancement in intrinsic dissolution rate was approximately 500-fold and the enhancement in solubility was approximately 2000-fold in a pH 6.8 buffer containing 2% (w/v) sodium lauryl sulfate compared to that in buffer alone. The micellar solubilization equilibrium coefficient (k*) was estimated from the solubility data and found to be 30884 ±213 L/mol. The diffusivity for the free solute, 7.15 × 10-6 cm²/s, was calculated using Schroeder's additive molal volume estimates and Hayduk-Laurie correlation. The diffusivity of the drug-loaded micelle, estimated from the experimental solubility and dissolution data and the calculated value for free solute diffusivity, was 0.86 × 10-6 cm²/s. Thus, the much lower enhancement in dissolution of fenofibrate compared to its enhancement in solubility in surfactant solutions appears to be consistent with the contribution to the total transport due to enhanced micellar solubilization as well as a large decrease (∼8-fold) in the diffusivity of the drug-loaded micelle. [ABSTRACT FROM AUTHOR]

Abstract: The complex formation of chlorhexidine digluconate (CHX-G2) with hydroxypropyl-β-cyclodextrin (HPβCD) was studied using NMR spectroscopy. The results revealed that this surfactant agent shows an monomer/aggregate equilibrium, which is dependent on the concentration of this drug. This equilibrium can be modified by the presence of HPβCD, which reduces the aggregation of the CHX-G2 molecules. An inclusion process of the CHX-G2 aromatic residue within the cyclodextrin cavity was confirmed by 2D ROESY spectroscopy. 1H NMR titration studies of CHX-G2 with HPβCD in D2O confirmed the formation of higher order complexes between CHX-G2 and HPβCD. Moreover, the addition of HPβCD into CHX-G2 solutions forms insoluble aggregates. Such insoluble aggregates may result in the stacking of CHX-G2 molecules on the surface of the CHX-G2:HPβCD complexes. [Copyright &y& Elsevier]

Large oral doses of ACZ lower the intraocular pressure (IOP), but usually lead to a multitude of systemic side effects, including gastrointestinal upset. The present study was undertaken to evaluate the effect of ACZ on the histological structure of rat duodenal mucosa and to assess a possible protective role of the complex formation of ACZ with HP-β-CD, either separately or in combination with a third compound, on the gut epithelial layer by histological and ultrastructural examinations of sections of rat duodenum exposed to ACZ or its formulations. In addition, the transport process of ACZ and its binary or ternary complexes across the duodenal mucosa by means of the single-pass intestinal perfusion (SPIP) method in rats was evaluated. Evidence was found that ACZ alters intestinal permeability and induces damage to the rat small intestine. In contrast, ACZ-induced intestinal injury may be abrogated by ACZ complexation. In addition, the complexation of ACZ with HP-β-CD, alone or in combination with a third compound, facilitated significant levels of ACZ uptake across the rat duodenal segment. Ternary complexes of ACZ with HP-β-CD in combination with TEA (triethanolamine) or calcium ions were found to provide an excellent approach that enabled an increased apparent permeability of ACZ across the duodenal epithelium, with a concomitant ability to preserve the integrity of the gut epithelium from ACZ-induced injury. These results could be useful for the design and development of novel ACZ formulations that can reduce GI toxicity, while still maintaining their essential therapeutic efficacies. [ABSTRACT FROM AUTHOR]

Importance of the Field: Acetazolamide (ACZ), a carbonic anhydrase inhibitor (CAI), and other oral CAIs have been an integral part of antiglaucoma therapy for > 40 years. ACZ is used orally for the reduction of intraocular pressure in patients suffering from glaucoma. However, this treatment leads to unpleasant systemic side effects. The answer to the undesirable effects of ACZ is the topical delivery of this drug into the eye, where it could elicit its physiological action. However, the development of a topical formulation of ACZ is limited by its poor ocular bioavailability, which can be largely attributed to its poor penetration coefficient and poor biphasic solubility., Areas Covered in This Review: This review offers an overview of different approaches to delivering ACZ to the eye, highlighting the potential of the ternary system ACZ:HP-beta-CD:TEA as a tool for formulating aqueous ACZ eye drop solutions., What the Reader Will Gain: A critical analysis is provided to highlight the key issues to design formulations containing hydrophilic cyclodextrins., Take Home Message: The ACZ:HP-beta-CD:TEA complex is an important new approach to improve the ocular bioavailability of this drug. This approach may be applied to other CAIs in the future.