The rutin/beta-cyclodextrin interactions in fully aqueous solution: spectroscopic studies and biological assays

In the present work the feasibility of β-cyclodextrin complexation was explored, as a tool for improving the aqueous solubility and antioxidant efficacy of rutin. By means of ¹H NMR, UV–vis and circular dichroism spectroscopy the single aromatic ring of rutin was found to be inserted into the β-cyclodextrin cavity to form a 1:1 inclusion complex. The effect of β-cyclodextrin on the spectral features of rutin was quantitatively investigated, in fully aqueous medium, by holding the concentration of the guest constant and varying the host concentration. The associated binding constants were estimated to be 142 ± 20 and 153 ± 20 M⁻¹, respectively, on the basis of the observed UV–vis absorption and circular dichroism intensities. The antioxidant activity of rutin was also investigated, as affected by molecular encapsulation within β-cyclodextrin (batophenanthroline test; comet assay; lipid peroxidation); the inclusion complex revealed improved antioxidant efficacy that may be in part explained by an increased solubility in the biological moiety.     

Influence of membrane-solvent-solute interactions on solute permeation in skin

The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. Previously, we have studied the effect of different vehicles on the permeation of caffeine, benzoic acid (BA) and salicylic acid (SA) through silicone membranes. The present paper investigates diffusion of the selected permeants from different saturated solutions through human epidermis.

The permeation of caffeine was strongly affected by the vehicle chosen and the maximum enhancement observed for the permeation of caffeine was 288-fold. A maximum of 12-fold enhancement in the flux was observed for the permeation of SA and a maximum of 10-fold enhancement was observed for the permeation of BA. The diffusion profiles obtained for SA in the different solvents were very similar when compared with those obtained for BA but the permeation rates were higher for BA than for SA. This similarity results from the similar chemical structure and lipophilicity.     

Thermodynamic properties of flufenamic and niflumic acids--specific and non-specific interactions in solution and in crystal lattices, mechanism of solvation, partitioning and distribution

Temperature dependency of saturated vapour pressure and the thermochemical characteristics of the fusion process were measured for flufenamic acid and niflumic acid, and thermodynamic functions of sublimation, fusion and evaporation calculated. An approach to split specific and non-specific energetic terms in crystal lattices is developed. The melting points of the considered molecules correlate with the ratio between specific and non-specific interactions in crystal lattices. Temperature dependencies of the solubility in buffers with pH 2.0 and 7.4, in n-octanol and in n-hexane were measured. The thermodynamic functions of solubility, solvation and transfer processes were deduced. Specific and non-specific solvation terms were distinguished by the transfer from "inert"n-hexane to the other solvents. Comparison of the ratio between specific and non-specific interactions in solid state and in the solutions was carried out. A diagram to analyse energetic terms of partitioning and distribution processes is introduced.     

羟丙基-β-环糊精对他克莫司的增溶作用

目的:制备他克莫司/羟丙基-β-环糊精包合物,考察羟丙基-β-环糊精对药物的增溶作用。方法:采用搅拌法制备他克莫司/羟丙基-β-环糊精包合物,相溶解度法考察羟丙基-β-环糊精对药物的增溶作用,并用差式扫描量热法和X-射线衍射法对包合物进行鉴定。结果:羟丙基-β- 环糊精可显著增加他克莫司在水中的溶解度,并且随着羟丙基-β-环糊精质量浓度和试验温度的增加,他克莫司的溶解度明显增加,在25 ℃及羟丙基-β-环糊精浓度为0.50g.mL-1条件下,他克莫司的溶解度从2.07μg.mL-1增加到167.74μg.mL-1;差式扫描量热法和X-射线衍射法确证包合物已形成。结论:羟丙基-β-环糊精对他克莫司有显著的增溶作用。     

Solubility Enhancement of Indomethacin with Poly(amidoamine) Dendrimers and Targeting to Inflammatory Regions of Arthritic Rats

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and ¹H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A_N curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A_N solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79±3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.     

HPMA Copolymer-1,5-Diazaanthraquinone Conjugates as Novel Anticancer Therapeutics

1,5-Diazaanthraquinones (DAQs) are promising anticancer drugs, however, their clinical potential is limited due to poor solubility. Conjugation of anticancer agents to hydrophilic water-soluble polymers can overcome this problem and has already been used to generate conjugates with demonstrated clinical benefit. Here a library of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing a novel amino-functionalised 1,5-diazaanthraquinone derivative (amino-DAQ) have been synthesised. The conjugates were fully characterised by UV, HPLC, SEC, FT-Raman and NMR spectroscopy. Conjugation to HPMA copolymers improved amino-DAQ aqueous solubility (>7-fold). The HPMA copolymer-amino-DAQ conjugates were slightly less haemolytic than the parent compound (2% Hb released in 1 h for conjugate HPMA copolymer-GFLG (5 mol%)-amino-DAQ conjugate compared to 13% obtained with amino-DAQ). When conjugates were incubated with isolated rat liver lysosomal enzymes (Tritosomes) the rate of amino-DAQ release was influenced by both drug loading and the composition of the peptidyl side chain used to link the drug to the carrier. The higher the drug loading the lower the rate of drug release. Whereas the GG linker did not release amino-DAQ, up to 26% of the amino-DAQ was released from a GFLG linker over 24 h. The in vitro cytotoxicity of these conjugates was evaluated against two different cell lines, B16F10 murine melanoma and MCF-7 human breast cancer cells. HPMA copolymer-amino-DAQ conjugates, which are internalised by cells by the endocytic pathway, showed much lower in vitro cytotoxicity (IC₅₀ for HPMA copolymer-GFLG (5 mol%)-amino-DAQ conjugate > 397 μM drug-equiv.) than the free drug (the IC₅₀ for amino-DAQ was 12.6 and 2.8 μM against the B16F10 murine melanoma and the MCF-7 breast cancer cell line, respectively). Nonetheless, the observed lysosomal activation of the HPMA copolymer-GFLG-amino-DAQ conjugates, suggests that evaluation of the antitumour potential in vivo is warranted.     

The Effects of pH and Mixed Solvent Systems on the Solubility of Oxytetracycline

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pK′_a) of OTC were determined by a solubility method. The pK′_a values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5–9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pK′_a values in each solvent system. pK′_a values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.     

葛根素及其纳米混悬剂平衡溶解度测定

目的：测定葛根素及其纳米混悬剂在pH1.2盐酸溶液、水、pH7.4 PBS缓冲液介质中的平衡溶解度.方法：采用高效液相色谱法（HPLC）测定葛根素及其纳米混悬剂在各个介质中的浓度.结果：在37℃下,葛根素纳米混悬剂在pH1.2盐酸溶液、水、pH7.4磷酸盐（PBS）缓冲液中的平衡溶解度分别为4.43、5.28、6.32mg·mL-1.结论：葛根素纳米混悬剂比原料药在各介质的溶解度均增加,在弱碱性介质中溶解度大于酸性介质,随pH升高而增大.葛根素水溶性较差,将其制备成纳米混悬剂有利于提高其溶解度.