betadex and ziprasidone

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.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Antiemetics; Antifungal Agents; Antipsychotic Agents; Aripiprazole; beta-Cyclodextrins; Chemistry, Pharmaceutical; Dosage Forms; Drug Stability; Humans; Hungary; Multiple Myeloma; Oligopeptides; Piperazines; Pyrimidines; Quinolones; Quinuclidines; Solubility; Thiazoles; Triazoles; Voriconazole

Inclusion complexes of ziprasidone with several β-cyclodextrins [β-CDs; sulfobutylether-β-cyclodextrins (SBEβCD), hydroxypropyl-β-cyclodextrins (HPβCD), methyl-β-cyclodextrins (MβCD), and carboxyethyl-β-cyclodextrins (CEβCD)] were prepared and solution stability was evaluated at elevated temperature. Solid-state stability was assessed by subjecting various CD complexes of ziprasidone, spray-dried dispersion (SDD), partially crystalline ziprasidone-SBEβCD salts, and the physical mixture of ziprasidone-SBEβCD to γ-irradiation. Degradant I was formed by oxidation of ziprasidone, which upon aldol condensation with ziprasidone formed degradant II in both solution and solid states. In the solution state, CD complexes with electron-donating side chains, such as SBEβCD and CEβCD, produced the highest oxidative degradation followed by HPβCD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug-SBEβCD showed very little to no degradation. In contrast, amorphous βCD, MβCD, CEβCD, and SBEβCD complexes as well as the amorphous SDD exhibited greatest extent of oxidative degradation. Results suggest that electron-donating side chains of the derivatized CD interact with transition state of the oxidation reaction and catalyze drug degradation in solution, However, higher mobility in the amorphous state of CD-drug complexes promoted chemical instability of ziprasidone under accelerated conditions irrespective of the chemical nature of the side chain on CD.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antipsychotic Agents; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Crystallization; Crystallography, X-Ray; Drug Compounding; Drug Stability; Excipients; Gamma Rays; Hot Temperature; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Piperazines; Powder Diffraction; Solubility; Technology, Pharmaceutical; Thiazoles

Ziprasidone is an antipsychotic agent indicated primarily for the treatment of schizophrenia. An intramuscular dosage form of ziprasidone was developed using beta-cyclodextrin sulfobutyl ether (SBECD) to solubilize the drug by complexation. Inclusion complexation of ziprasidone mesylate (ZM) with SBECD was studied by circular dichroism (CD) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, Monte Carlo simulations, phase-solubility studies, and counterion titration. The results of the studies indicate that ZM, of which the counterion is not fully dissociated from the drug, forms a 1:1 inclusion complex with SBECD with the benzisothiazole group positioned in the cavity. A mathematical model was developed to calculate stability constants of inclusion complexes for the ion pair (Z+M-:SBECD) and the dissociated ionic form (Z+:SBECD) of ZM; the values were 7892 and 957 M(-1), respectively. The model also allowed the dissociation constants of noncomplexed and complexed ZM to be calculated; the value of the former is 8-fold greater than the value of the latter. These results indicate that the inclusion complex formation of the ion pair is favored over that of the dissociated ionic form of ZM, and that the dissociation of ZM is suppressed by inclusion complexation with SBECD.

Topics: Antipsychotic Agents; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cyclodextrins; Drug Stability; Magnetic Resonance Spectroscopy; Models, Theoretical; Molecular Structure; Monte Carlo Method; Piperazines; Thiazoles