betadex and vinpocetine

The purpose of this study was to develop a new delivery system based on drug cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC) to improve the oral bioavailability of vinpocetine (VP). Three different CDs and three different methods to obtain solid vinpocetine-cyclodextrin-tartaric acid complexes (VP-CD-TA) were contrasted. The co-evaporation vinpocetine-β-cyclodextrin-tartaric acid loaded NLC (VP-β-CD-TA COE-loaded NLC) was obtained by emulsification ultrasonic dispersion method. VP-β-CD-TA COE-loaded NLC was suitably characterized for particle size, polydispersity index, zeta potential, entrapment efficiency and the morphology. The crystallization of drug in VP-CD-TA and NLC was investigated by differential scanning calorimetry (DSC). The in vitro release study was carried out at pH 1.2, pH 6.8 and pH 7.4 medium. New Zealand rabbits were applied to investigate the pharmacokinetic behavior in vivo. The VP-β-CD-TA COE-loaded NLC presented a superior physicochemical property and selected to further study. In the in vitro release study, VP-β-CD-TA COE-loaded NLC exhibited a higher dissolution rate in the pH 6.8 and pH 7.4 medium than VP suspension and VP-NLC. The relative bioavailability of VP-β-CD-TA COE-loaded NLC was 592% compared with VP suspension and 92% higher than VP-NLC. In conclusion, the new formulation significantly improved bioavailability of VP for oral delivery, demonstrated a perspective way for oral delivery of poorly water-soluble drugs.

Topics: Administration, Oral; Animals; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Drug Carriers; Hydrogen-Ion Concentration; Lipids; Male; Nanostructures; Nanotechnology; Rabbits; Solubility; Tartrates; Technology, Pharmaceutical; Vinca Alkaloids; Water

In the present work, to maintain a suitable blood level of vinpocetine (VP) for a long period of time, VP-cyclodextrin-tartaric acid multicomponent complexes were prepared and formulated in hydroxypropylmethylcellulose matrix tablets. In vitro and in vivo performances of these formulations were investigated over a VP immediate release dosage form. Solubility studies were performed to evaluate the drug pH solubilization profile and to assess the effect of multicomponent complexation on VP solubility. The drug release process was investigated using United States Pharmacopeia apparatus 3 and a comparative oral pharmacokinetic study was subsequently undertaken in rabbits. Solubility studies denoted the pH-solubility dependence of VP and solubility improvement attained by complexation. Dissolution results showed controlled and almost complete release behavior of VP over a 12-h period from complex hydroxypropylmethylcellulose-based formulations. A clear difference between the pharmacokinetic patterns of VP immediate release and VP complex-based formulations was revealed. The area under the plasma concentration-time curve after oral administration of complex-based formulations was 2.1-2.9 times higher than that for VP immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VP from complex-based formulations. These results suggest that the oral bioavailability of VP was significantly improved by both multicomponent complexation and controlled release delivery strategies.

Topics: Administration, Oral; Animals; Area Under Curve; beta-Cyclodextrins; Biological Availability; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Drug Compounding; Half-Life; Hydrogen-Ion Concentration; Metabolic Clearance Rate; Methylcellulose; Molecular Weight; Rabbits; Reproducibility of Results; Solubility; Tablets; Tartrates; Therapeutic Equivalency; Vinca Alkaloids; Water

The purpose of this study was to evaluate complexes of vinpocetine (VIN), a poorly water-soluble base type drug, with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous environment and in solid state, with or without citric acid (CA) as an acidifier of the complexation medium. The apparent stability constant (Kc) calculated by phase solubility was 282 M(-1) and the complexation in solution was structurally characterized by 1H-NMR which showed VIN was likely to fit into the cyclodextrin cavity with its phenyl ring and ethyl ester bond. Solid complexes of VIN and HP-beta-CD were prepared by kneading (KE), co-evaporating (CE) and freeze-drying (FD) methods. Physical mixtures were prepared for comparison. The study in the solid state included the differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and infrared absorption spectroscopy (IR). From these analyses, CE and FD products were found in amorphous state, allowing to the conclusion of strong evidences of inclusion complex formation. However, the dissolution test showed that only VIN/HP-beta-CD+CA complexes by CE and FD method could provide satisfying dissolution behavior (rapid, complete and lasting) when compared to that of VIN/HP-beta-CD complexes. Interestingly, the addition of CA in inclusion complexes could significantly decrease the amount of HP-beta-CD needed to solubilize the same amount of VIN and thereby reducing the formulation bulk. Furthermore, in-vivo study revealed that the bioavailability of VIN after oral administration to rabbits (n=6) was significantly improved by VIN/HP-beta-CD+CA inclusion complex.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Animals; Antihypertensive Agents; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Drug Compounding; Excipients; Magnetic Resonance Spectroscopy; Male; Rabbits; Solubility; Spectrophotometry, Infrared; Vinca Alkaloids; X-Ray Diffraction

The objective of this study was to investigate the effect of multicomponent complexation (MCC) of vinpocetine (VP), a poorly soluble base-type drug, with beta-cyclodextrin (betaCD), sulfobutylether beta-cyclodextrin (SBEbetaCD), tartaric acid (TA), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), on the design of controlled release hydrophilic HPMC tablets and to evaluate their in vitro release profiles by a pH gradient method. Multicomponent complexation led to enhanced dissolution properties of VP both in simulated gastric and intestinal fluids, and became possible the development of HPMC tablet formulations with more independent pH dissolution profiles. Drug release process was investigated experimentally using USP apparatus 3 and by means of model-independent parameters. Responses studied included similarity of dissolution profiles, time for 60% of the drug to dissolve (T(60%)), percent of VP released after 7 h (PD(7 h)) and the dissolution efficiency parameter at 12 h (DE(12 h)). Influence of multicomponent complexation was proved to increase the release of VP from HPMC tablets and superior PD(7 h) and DE(12 h) values were obtained in formulations containing VP-CD-TA complexes. Results supported the use of HPMC matrices to provide a useful tool in retarding the release of VP and that dissolution characteristics of the drug may be modulated by multicomponent complexation in these delivery systems, suggesting an improvement on VP bioavailability.

Topics: beta-Cyclodextrins; Body Fluids; Drug Compounding; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Hypromellose Derivatives; Intestinal Mucosa; Kinetics; Methylcellulose; Models, Biological; Solubility; Tablets, Enteric-Coated; Tartrates; Vinca Alkaloids

The purpose of this study was to investigate the interactions between vinpocetine (VP), sulfobutyl ether beta-cyclodextrin (SBEbetaCD) and the water-soluble polymers polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC). The water-soluble polymers were shown to improve the complexation efficiency of SBEbetaCD, and thus less SBEbetaCD was needed to prepare solid VP-SBEbetaCD complexes in the presence of the polymers. The interactions between VP and SBEbetaCD, with or without PVP or HPMC, were thoroughly investigated in aqueous solutions using the phase-solubility method as well as in the solid state. The amount of VP solubilized in water or aqueous polymer solution increased linearly with increasing SBEbetaCD concentration, demonstrating A(L)-type plots. We estimated the apparent stability constant (K(c)) at room temperature of VP-SBEbetaCD binary complex to be 340 M(-1) and this value increased to 490 M(-1) or 390 M(-1), respectively, with the addition of PVP and HPMC, assuming a 1 : 1 VP-SBEbetaCD molar ratio. Improvement in the K(c) values for ternary complexes clearly confirmed the benefit of the addition of water-soluble polymers to promote higher complexation efficiency. Solid VP-SBEbetaCD binary and ternary systems were prepared by physical mixing, kneading, coevaporation, and lyophilization methods and fully characterized by scanning electron microscopy, differential scanning calorimetry, and X-ray diffractometry. The results obtained suggest that coevaporation and lyophilization methods yield a higher degree of amorphous entities and indicated formation of VP-SBEbetaCD binary and ternary complexes.

Topics: beta-Cyclodextrins; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Cyclodextrins; Solubility; Vinca Alkaloids

The studies reported in this work aimed to elucidate the inclusion complex formation of vinpocetine (VP), a poorly water-soluble base type drug, with beta-cyclodextrin (betaCD) and its sulfobutyl ether derivative (sulfobutyl ether beta-cyclodextrin (SBEbetaCD)), with or without water-soluble polymers (PVP and HPMC), by thoroughly investigating their interactions in solution and solid state. Phase solubility studies were carried out to evaluate the solubilizing power of both cyclodextrins (CDs), in association with water-soluble polymers, towards VP and to determine the apparent stability constants (Kc) of the complexes. SBEbetaCD showed higher solubilizing efficacy toward VP than the parent betaCD due to its greater solubility and complexing abilities, what was reflected in higher Kc values. Improvement in Kc values for ternary complexes clearly proves the benefit on the addition of water-soluble polymers to promote higher complexation efficiency. VP-CDs (1:1) binary and ternary systems were prepared by physical mixing, kneading, co-evaporation, and lyophilization methods. In the solid state, drug-carrier interactions were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier-transform infrared spectroscopy. The results of these analysis suggested the formation of new solid phases, some of them in amorphous state, allowing to the conclusion of strong evidences of binary and ternary inclusion complex formation between VP, CD and water-soluble polymers, particularly for co-evaporated and lyophilized binary and ternary products.

Topics: beta-Cyclodextrins; Chemical Phenomena; Chemistry, Physical; Cyclodextrins; Dose-Response Relationship, Drug; Pharmaceutical Solutions; Polymers; Solubility; Vinca Alkaloids; Water; X-Ray Diffraction

Topics: beta-Cyclodextrins; Chemistry, Pharmaceutical; Cyclodextrins; Dextrins; Starch; Tablets; Vinca Alkaloids