Zita Sebestyén’s research while affiliated with Semmelweis University and other places

Sulfobuthylether-beta-cyclodextrin (SBECD) is a substituted derivative of a cyclic oligosaccharide containing seven glucopyranose units, which bear pH-independent negative charges because of sulfonate groups. This derivative has better solubility and toxicological characteristics than the unsubstituted beta-cyclodextrin, and the presence of sulfobuthyl groups opens new dimensions in the interactions acting the part of the complex formation. These create opportunities for the pharmaceutical applications of this compound. Currently six pharmaceutical preparations circulate--moiety of these circulates in Hungary also--which have a composition containing SBECD as pharmaceutical excipient. Out of the main effects of the complex-forming agent the solubility enhancement is utilized in these compositions to achieve the solution of a therapeutic dose in the case of intravascular administration. Available experimental evidences and published patents are indicative of broadening the circle of the applications in point of both technological advantages and dosage forms.

The active pharmaceutical ingredient can be administered by several different routes. Although the oral route (per os) has been one of the most convenient and widely accepted delivery system for most drugs, it has number of disadvantages like the very low pH of the stomach, the high enzymatic activity, and extensive first-pass metabolism. Difficulty in swallowing (dysphagia) is common among all age groups, especially in "problematical" subpopulations like children and the elderly. Several novel intraoral dosage forms (IODs) have recently become available to modulate the physicochemical and pharmacokinetic characteristics of drugs, while improving patient compliance. The present article summarizes and categorizes their formulation possibilities.

Stability constants for the complexes of anionic, neutral (zwitterionic) and protonated forms of l- and d-enantiomers of eight amino acids with β-cyclodextrin and the positively charged quaternary ammonium β-cyclodextrin (QA-β-CD, DS = 3.6 ± 0.3) have been determined by spectrophotometric and pH-potentiometric methods. The highest stability constants have been obtained for the aromatic amino acids phenylalanine, tyrosine and tryptophan. Except the dianion of tyrosine and QA-β-CD, values for the anions in the range of 80–120 have been found, the stability constants for the zwitterionic forms are much smaller and complex formation is negligible with the protonated species. In the case of the other amino acids the differences are less pronounced. The results are interpreted in terms of hydrogen bonding, steric effects and electrostatic interactions between the amino acid moiety and the rims of the cyclodextrins, in addition to the inclusion of the side chain, and are supported by 1H and 13C NMR investigations on the systems containing l-phenylalanine and l-tyrosine. The differences between the complex formation constants of the l- and d-enantiomers do not exceed the limits of experimental error in most cases.

Complex formation reactions of phenylboronic, phenylphosphonic, phenylarsonic and 4-aminophenyl arsonic acids with β-cyclodextrin (cycloheptaamylose, β-CD) and some simple carbohydrates (mannitol, sorbitol, glucose) have been studied using spectrophotometric, potentiometric methods and solubility measurements, supplemented with HPLC and IR analyses of the solid samples. Equilibrium constants have been determined at ionic strength of 0.2M (NaCl) and 25°C. β-CD forms the most stable complexes with the neutral, undissociated forms of the acids, the stability constants are as follows: phenylboronic acid: 320 ± 36, phenylphosphonic acid: 108 ± 25, phenylarsonic acid: 97 ± 4 and 4-aminophenyl arsonic acid: 107 ± 10. The stability constants for the β-CD-complexes of the ionic forms are much lower. Ternary complexes of low stability could be detected in the case of phenylphosphonic acid and sorbitol with the undissociated form and with glucose and the dianion. In more concentrated solutions phenylboronic acid forms insoluble complexes with mannitol, sorbitol and β-CD. The solid phases obtained in the ternary systems are predominantly mixtures of ester type 3:1 complexes with the carbohydrate and 1:1 inclusion complex with the β-CD. No significant interaction has been found with glucose. The phenomena can be explained by the differences in the structures of the components and by the changes in the H-bonding network of β-CD on the complex formation.