Article

Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin

University of Naples Federico II, Napoli, Campania, Italy
Journal of Inclusion Phenomena (Impact Factor: 1.49). 04/2006; 54(3):289-294. DOI: 10.1007/s10847-005-9004-y

ABSTRACT

Aim of the present work was to investigate the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) on the solubility, dissolution
rate and stability of Valsartan (VAL), a drug used orally for the treatment of hypertension. Phase solubility studies demonstrated
the ability of the HP-β-CD to complex VAL and to increase drug solubility. The dissolved amount of VAL increased linearly
with the addition of HP-β-CD according to an AL type plot. The apparent stability constant of the complex, calculated supposing a 1:1 stoichiometry, was 296±7M−1. VAL/HP-β-CD interactions were also studied by 13C-NMR spectroscopy. Equimolar VAL/HP-β-CD solid systems were prepared by physical-mixing and freeze-drying, and their properties
in the solid state studied by DSC and FT-IR analysis. The results provided clear indications of the formation of a new solid
phase corresponding to the inclusion complex in the freeze-dried sample. The dissolution profiles of the drug from each solid
system were affected by its physico-chemical properties, the freeze-dried being the most rapidly dissolving form. The thermal
stability of the complex was studied, also determining the number and identity of the decomposition products of the drug.
The stability studies revealed that the VAL/HP-β-CD complex significantly decreases the rate of VAL degradation. These results
suggest that CD technology would be a very useful method to overcome the solubility and the stability problems of VAL.

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    • "The solubility of valsartan is also pH dependant with low solubility at lower pH. The drug is rapidly absorbed from the upper part of GIT and shows oral bioavailability of about 23% (Cappello et al., 2006). Furthermore, the presence of food decreases its absorption by 40% (Burnier & Brunner, 2000). "
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    ABSTRACT: The physicochemical properties of drugs such as partition coefficient play a major role in the development of lipid-based drug delivery systems. The major obstacle lies in encapsulation of a drug with low partition coefficient into these systems. The objective of this study was to design and optimize a novel lipid-based delivery system with higher loading, improved pharmacokinetics consequently enhancing the oral bioavailability of drugs with low partition coefficient like valsartan. The optimized formulation consists of Capryol 90, Cremophor RH 40, and Transcutol HP. Pseudo ternary phase diagrams were used to optimize the components and their concentrations in the formulation. Dissolution studies of the selected formulations were compared with plain drug and marketed product at three pH conditions (pH 1.2, 4.5 and 6.8). Pharmacokinetic parameters of optimized formulations were determined in Wistar rats and compared with that of plain drug. The optimized formulation with a mean particle size of 50 nm showed significant improvement (p < 0.05) in dissolution rate with pH independence compared to plain drug and marketed product. The in vivo studies in Wistar rats revealed about 2.30- and 1.68-fold increase in the oral bioavailability and Cmax of valsartan from lipid-based formulation compared to plain drug. The engineered formulation strategy by type IV lipid-based formulations can be successfully exploited to improve the dissolution rate and oral deliverability of drugs like valsartan.
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    • "It is a BCS class II drug and its low aqueous solubility contributes to poor bioavailability (23%) [23] [24]. Few approaches have been made for the improvement of solubility of valsartan such as use of hydroxypropylí µí»½-cyclodextrin and methyl-í µí»½-cyclodextrin valsartan dispersions [25] [26], but we could not predict in vivo performance of those dispersions. Apart from this, a liquid self-emulsifying formulation has been reported for valsartan, but it still has the inherent problem of liquid dosage form as discussed above [27]. "
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    ABSTRACT: The objective of the present study was to develop self micro emulsifying formulation (SMEF) of valsartan to improve its oral bioavailability. The formulations were screened on the basis of solubility, stability, emulsification efficiency, particle size and zeta potential. The optimized liquid SMEF contains valsartan (20% w/w), Capmul MCM C8 (16% w/w), Tween 80 (42.66% w/w) and PEG 400 (21.33% w/w) as drug, oil, surfactant and co-surfactant, respectively. Further, Liquid SMEF was adsorbed on Aerosol 200 by spray and freeze drying methods in the ratio of 2 : 1 and transformed into free flowing powder. Both the optimized liquid and solid SMEF had the particle size <200 nm with rapid reconstitution properties. Both drying methods are equally capable for producing stable solid SMEF and immediate release of drug in in vitro and in vivo conditions. However, the solid SMEF produced by spray drying method showed high flowability and compressibility. The solid state characterization employing the FTIR, DSC and XRD studies indicated insignificant interaction of drug with lipid and adsorbed excipient. The relative bioavailability of solid SMEF was approximately 1.5 to 3.0 folds higher than marketed formulation and pure drug. Thus, the developed solid SMEF illustrates an alternative delivery of valsartan as compared to existing formulations with improved bioavailability.
    Full-text · Article · Jul 2013
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    • "In the thermal curve of the physical mixtures, the fusion endothermic peak of icariin was much lower than that of the crystalline substance and shifted to a lower temperature as a consequence of the interaction between icariin and β-CD or HP-β-CD. However, this interaction could be induced by the thermal energy supplied to the sample in the DSC scan.38 In contrast, there were no sharp peaks attributable to the crystalline form of icariin in the inclusion complexes, indicating that icariin was no longer present as a crystalline form, but was converted into an amorphous state. "
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    ABSTRACT: Icariin is a bioactive herbal ingredient isolated from Herba epimedii, which has been widely used for the treatment of osteoporosis and male sexual dysfunction in traditional Chinese medicine. The major objective of this work is to investigate the different enhancing effects of β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the intestinal absorption of icariin, and to identify the molecular mechanisms of this action. Host-guest-type interactions of icariin with cyclodextrins nanocavities were unambiguously demonstrated by the phase-solubility diagram, ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry, and two dimensional proton nuclear magnetic resonance rotating-frame Overhauser effect spectroscopy. These results were further supported using molecular modeling studies. The rat single-pass intestinal perfusion model showed that the absorption of icariin was affected by P-glycoprotein (Pgp). The icariin/HP-β-CD inclusion complex provided greater enhancement in the intestinal absorption than the icariin/β-CD inclusion complex. Therefore, the enhancing effect was involved in a solubilizing effect and/or Pgp inhibitory effect. Finally, fluorescence anisotropy measurements and Pgp adenosine triphosphatase (ATPase) assay demonstrated that β-CD exhibited no effect on Pgp, while HP-β-CD showed inhibition by restraining the Pgp ATPase activity rather than changing the fluidity of cell membrane.
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