Multimodal molecular encapsulation of nicardipine hydrochloride by β-cyclodextrin, hydroxypropyl-β-cyclodextrin and triacetyl-β-cyclodextrin in solution. Structural studies by H NMR and ROESY experiments

Proton nuclear magnetic resonance spectroscopy (¹H NMR), which has become an important tool for in vitro study of cyclodextrin (CD) complexes, was used to study and structurally characterize the inclusion compounds formed in solution between nicardipine hydrochloride (NC) and β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) and triacetyl-β-cyclodextrin (TAβCD). The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (i.e. H-3, H-5 and H-6) coupled with minimal variation of shifts from protons located on the outer sphere of the βCD (i.e. H-1, H-2 and H-4) provided clear evidence of inclusion complexation. In the presence of the different CDs, the aromatic protons of NC were the most affected, suggesting a strong involvement of the phenyl groups in the inclusion mechanism. The application of continuous variation method indicated the presence of complexes with a 1:1 host/guest stoichiometry for all the studied CDs. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode. Inspection of the ROESY spectra allowed the establishment of spatial proximities between several aromatic hydrogens of the guest and the CD protons, indicating that the inclusion occurs by accommodation of the two aromatic groups of NC. All the experimental data were further rationalized to elaborate possible three-dimensional geometric models of inclusion complexes. From the aforementioned observations, we concluded there is no preference for inclusion of a particular aromatic ring. Instead, two types of 1:1 complexes with different inclusion structures may exist simultaneously in solution, being alternatively included through the wider side of the cavity, i.e. the so-called multimodal inclusion occurs in the interaction of NC with the different CDs.     

Enantiomeric separation of denopamine by capillary electrophoresis and high-performance liquid chromatography using cyclodextrins

Direct separation of enantiomers of denopamine was investigated by two separation methods. One is capillary zone electrophoresis (CZE) using cyclodextrins (CDs) (CD-CZE) and the other is high-performance liquid chromatography (HPLC) using CD immobilized chiral stationary phases (CD-CSPs). Enantiomers of denopamine were successfully resolved by employing heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and acetyl-β-cyclodextrin (AC-β-CD), and partially resolved with heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and β-CD polymer under acidic conditions. Separation of enantiomers of denopamine by HPLC was also successful with one of the CD-CSPs, where perphenylated β-CD (Phβ-CD) was immobilized. In CD-CZE, some polymeric additives, such as hydroxypropylmethylcellulose (HPMC) and polyvinylalcohol (PVA), and a coated capillary were used to improve the enantioseparation of denopamine. Method validations such as linearity, recovery and repeatability, etc., were investigated for HPLC, and the method was applied to the optical purity testing of the drug substances and in tablet form.     

Minoxidil-containing dosage forms: skin retention and after-rinsing hair-growth promotion

Three kinds of topical dosage forms of minoxidil (MXD), namely vesicles, double emulsions, and an inclusion complex with hydoxypropyl- β-cyclodextrin (HP- β-CD), were prepared. The skin retention of MXD in the preparations was evaluated in vitro using hairless mouse skins. After applying the preparations onto the skin and rinsing it, the amount of the drug left on the skin was determined using HPLC. Retention was the highest when the drug was encapsulated in cationic vesicles. Nonionic vehicle, the double emulsion, and HP- β-CD left no significant amount of the drug after rinsing the skin. Thus, an ionic interaction between the cationic vehicle and negatively charged skin is likely responsible for the relatively high skin retention. In vivo hair growth-promotion effect of each dosage form was investigated, in which the sample application onto the clipped backs of female mice (C57BL6) and the subsequent rinsing of the backs were done once a day for 30 days. Only MXD in the cationic vesicles had hair growth promotion effect, possibly due to significant skin retention.     

Studies on the interaction of diflunisal ion with cyclodextrins using ion-selective electrode potentiometry

The interaction of diflunisal ion (DF) with β-cyclodextrin (βCD), γ-cyclodextrin (γCD), and hydroxypropyl-β-cyclodextrin (HPβCD) was studied in phosphate buffer, pH 7.4, at 5–37°C and various CD concentrations using a home-made diflunisal ion-selective electrode. Typical direct binding plots and Scatchard plots were obtained with HPβCD. The Scatchard model for one class of binding sites was used for the estimation of binding parameters for the DF/HPβCD interaction. The estimates for n (number of binding sites per CD molecule) were in all cases very close to unity, indicating 1:1 complexation. The association constant (K) estimates decrease with increasing temperature. Sigmoidal direct binding plots and concave-downwards Scatchard plots were obtained with various βCD or γCD concentrations. The Hill model was used for the estimation of the binding parameters for the DF/βCD and DF/γCD interactions. Both the Hill coefficients and the binding constants were markedly dependent on the CD concentration. These findings indicate the cooperative character of DF/βCD and DF/γCD interactions. The free energy change, ΔG, and the thermodynamic parameters, ΔH and ΔS, were estimated for each of the interactions studied using the Van't Hoff equation.     

Chiral separation of methoxamine and lobeline in capillary zone electrophoresis using ethylbenzene-deactivated fused-silica capillary columns and cyclodextrins as buffer additives

The complete chiral separation of methoxamine and lobeline was achieved by capillary zone electrophoresis on an ethylbenzene-deactivated fused-silica capillary column and with cyclodextrins (CDs) as buffer additives. Among the CDs investigated in this study, i.e. -CD, β-CD, dimethyl-β-CD, hydroxypropyl-β-CD and γ-CD, all the three β-type CDs showed chiral recognition on the two drugs investigated. Under the investigated conditions, the baseline chiral separation of methoxamine can be achieved with 90 mM Tris–H₃PO₄ (pH 2.5) containing 11.5 mM of the three β-type CDs, with dimethyl-β-CD giving the best resolution, whereas the baseline chiral separation of lobeline can be realized by using 90 mM Tris–H₃PO₄ buffer (pH 2.5) containing 5.8 mM dimethyl-β-CD or 29.5 mM hydroxypropyl-β-CD.     

Structure elucidation of the tetrahydrocannabinol complex with randomly methylated β-cyclodextrin

The low aqueous solubility of the bioactive cannabinoid tetrahydrocannabinol (THC) is a serious obstacle for the development of more efficient administration forms. In this study the aqueous solubility of THC was tested in the presence of -, β- and γ-CD, and randomly methylated β-CD (RAMEB). It was found that only RAMEB was able to increase the aqueous solubility of THC to a significant level. A THC concentration of about 14 mg/ml was reached by using a 24% (187 mM) RAMEB solution, which means an increase in solubility of four orders of magnitude. The resulting THC/RAMEB complex was investigated through phase-solubility analysis, complemented by ¹H NMR, NOESY- and UV-studies in order to obtain details on the stoichiometry, geometry and thermodynamics of the complexation. The binding ratio of THC to CD was found to be 2:1, with the second THC molecule bound by non-inclusion interactions. Based on the obtained results a model for the complex structure is presented. Stability of the complex under laboratory room conditions was tested up to 8 weeks. Results show that complexation with RAMEB seems to be promising for the development of water-based THC formulations.     

In vivo evaluation of a transdermal codrug of 6-β-naltrexol linked to hydroxybupropion in hairless guinea pigs

6-β-Naltrexol is the major active metabolite of naltrexone, NTX, a potent μ-opioid receptor antagonist used in the treatment of alcohol dependence and opioid abuse. Compared to naloxone, NTX has a longer duration of action largely attributed to 6-β-naltrexol. This study was carried out in order to determine percutaneous absorption of a transdermal codrug of naltrexol, 6-β-naltrexol-hydroxybupropion codrug (CB-NTXOL-BUPOH), in hairless guinea pigs as well as to evaluate the safety of 6-β-naltrexol for development as a transdermal dosage form. This codrug may be useful in the simultaneous treatment of alcohol dependence and tobacco addiction. The carbonate codrug traversed the skin at a faster rate than 6-β-naltrexol. 6-β-Naltrexol equivalent steady state plasma concentrations of 6.4 ng/ml were obtained after application of the codrug as compared to 1.2 ng/ml from 6-β-naltrexol base. The steady state plasma concentration of hydroxybupropion after codrug application was 6.9 ng/ml. Skin sensitization and irritation tested in the hairless guinea pigs using the Buehler method revealed that 6-β-naltrexol had no skin sensitizing potential. The method was validated with a known sensitizer, p-phenylenediamine, which induced sensitization in 90% of the animals. 6-β-Naltrexol caused only mild transient skin irritation after the initial application of the patch. During subsequent applications, erythema was slightly increased but no skin damage was observed. In conclusion, a transdermal codrug of 6-β-naltrexol could be a viable alternative treatment for alcohol and opiate abuse.     

Solid state studies of drug–cyclodextrin inclusion complexes in PEG 6000 prepared by a new method

The melting method was investigated as a possible method for producing drug–cyclodextrin (CD) inclusion compounds in a carrier. Various solid dispersions of -, β- and γ-CD in polyethylene glycol (PEG) 6000 with and without the addition of 5% w/w indomethacin or griseofulvin were prepared using the original components. Characterisations of the samples included X-ray powder diffraction, modulated-temperature differential scanning calorimetry and dissolution tests by the paddle method according to USP XXI standard. Evidence of a complex between indomethacin and β-CD in PEG 6000 was found. An indomethacin–γ-CD complex formed a well defined phase in the PEG carrier, with tetragonal structure and unit cell parameters a=23.885(35) Å and c=23.181(64) Å. No complexation of indomethacin with -CD, or with griseofulvin and β-CD could be detected. It is suggested that competition between PEG and the drug for the binding to different CDs along with varying patterns of water loss from the CDs influence the inclusion reaction. The formation of complexes was accompanied by a decrease in the relative crystallinity of the dispersions. Dissolution tests showed that the CDs have a delaying effect on the release of indomethacin from PEG 6000 in the order -CD<γ-CD≤β-CD.     

Randomly methylated β-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer

Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated β-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated β-cyclodextrin (RAMEB) is cytotoxic in high concentrations. Second-generation derivatives containing monoamino (MaRAMEB) and succinylated (SuRAMEB) ionic substituents with similar inclusion capacity but less toxicity could be promising alternatives of RAMEB. Our aim was to examine and compare the efficacy of MaRAMEB and SuRAMEB with the parental RAMEB on taxol bidirectional permeability using the Caco-2 model. Taxol permeability was not changed by 30-min pretreatment with CDs. In co-treatment with β-cyclodextrins, the apical to basolateral taxol flux was 4 to 6 times greater than in untreated monolayers and it was also higher than in cells treated with Pgp inhibitor cyclosporin A. No decrease in basolateral to apical taxol flux was observed in pretreatment or co-treatment with CDs, suggesting no Pgp inhibition. All three CDs showed similar effects on taxol permeability but RAMEB altered tight junction protein distribution and significantly decreased transepithelial electrical resistance. None of the CDs modified paracellular permeability to mannitol and polyethylene glycol 4000. In conclusion, second-generation derivatives of methyl-β-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB.     

Transdermal Permeation Modulation by Cyclodextrins: A Mechanistic Study

ABSTRACT

The purpose of this study was to investigate permeation modulation by β- and 2-hydroxypropyl–β-cyclodextrins (β-CD and HP–β-CD, respectively) alone and complexed with penetration enhancers for the test drugs 5-fluorouracil and estradiol through human skin, and to probe the value of the CDs in a barrier cream against toluene exposure. Methods include phase solubility studies, permeation experiments, and thermal analysis of stratum corneum; inclusion complexes were characterized by Karl Fischer titrimetry, infrared spectroscopy, and thermal analysis. Results show that complexes of terpenes or toluene with β-CD were insoluble, whereas those with HP–p-CD were soluble. The CDs did not enhance flux of either the polar or lipophilic drugs through skin; estradiol permeation was reduced following membrane pretreatment with either CD. Complexation of the lipophilic terpenes with the CDs reduced enhancer efficacy. When formulated into a barrier ointment both CDs, but particularly p-CD, retarded toluene permeation through the skin and delayed the onset of maximum flux. It is concluded that the CDs themselves are not penetration enhancers for 5-fluorouracil or estradiol in human skin, and that they may be usefully incorporated into a barrier formulation to reduce percutaneous absorption of toxic materials on occupational exposure.     

Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: Preparation and in-vitro evaluation

The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified β-cyclodextrins: hydroxypropyl-β-cyclodextrin (HP-β-CD) and heptakis-[2,6-di-O-methyl]-β-cyclodextrin (DM-β-CD), in comparison with the natural β-cyclodextrin (β-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest–host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A_p-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-β-CD > HP-β-CD > β-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-β-CD and DM-β-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-β-CD and DM-β-CD yielded better performance than the corresponding ones prepared using β-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the β-CD derivatives.     

Formation and antimycotic effect of cyclodextrin inclusion complexes of econazole and miconazole

The stability constants between β-cyclodextrin (β-CD) and the two antimycotic imidazole derivatives, miconazole and econazole were measured. Increased ionization of the imidazole derivatives decreased the size of the stability constants. The same phenomenon was observed for miconazole and hydroxypropyl-β-cyclodextrin. In addition, the type of solubility diagram obtained was dependent on the degree of ionization of the imidazole derivatives. A type Bs solubility diagram was obtained for econazole and β-CD in buffer solution, pH 7.1. An econazole β-CD complex with a molar ratio of 1:1 was isolated. In a fluid medium the antimycotic effect of the econazole β-CD complex against a strain of Candida albicans was superior to the effect of a physical mixture of the two compounds. A small inhibitory effect of β-CD on the growth of the test organism was observed.     

Evaluation of cholesterol depletion as a marker of nephrotoxicity in vitro for novel β-cyclodextrin derivatives

Cyclodextrins (CDs) have been shown to improve physicochemical and biopharmaceutical properties of drugs when low solubility and low safety limit their use in the pharmaceutical field. Recently, we have developed new multi-substituted-β-CDs, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HPn-SBEm-β-CD). HPn-SBEm-β-CD exhibit low hemolysis, good solubility, strong inclusion ability, and an appropriate average molecular weight. In this study, we chose two products of HPn-SBEm-β-CD (HP₃-SBE₂-β-CD and HP₂-SBE₃-β-CD) and compared their effects to sulfobutyl ether-β-cyclodextrin (SBE₇-β-CD), methyl-β-cyclodextrin (M-β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD). We evaluated viability, membrane damage, induction of apoptosis and necrosis, cholesterol depletion, and morphological changes in human embryonic kidney 293A cells (HEK293A) in vitro. CDs caused a reduction of cell viability and increased LDH levels in a concentration-dependent manner. The effect of HP₃-SBE₂-β-CD or HP₂-SBE₃-β-CD on cell viability, membrane damage, and the induction of apoptosis and necrosis resembled that of SBE₇-β-CD, whereas the effects were significantly lower for M-β-CD or DM-β-CD. HP₃-SBE₂-β-CD and HP₂-SBE₃-β-CD exhibited morphological changes at high concentrations. In conclusion, the results showed that cholesterol depletion may be as a marker for evaluating the cytotoxicity of novel β-CD derivatives. These results will provide useful information for HPn-SBEm-β-CD as a promising safe adjuvant for intravenous administration in the future.     

Influence of cyclodextrins on in vitro human skin absorption of the sunscreen, butyl-methoxydibenzoylmethane

The effects of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-CD (SBE7-β-CD) on in vitro human skin penetration and retention of the sunscreen agent butyl-methoxydibenzoylmethane (BM-DBM) were investigated. The interaction between the UV filter and the cyclodextrins was studied in water by phase-solubility analysis. Solid complexes were prepared by the co-evaporation method and characterized by ¹H NMR spectroscopy, thermal analysis and powder X-ray diffraction. Solutions containing BM-DBM free or complexed with cyclodextrins were applied to excised human skin in Franz diffusion cells and the amount of sunscreen permeated after 6 h into the stratum corneum, viable epidermis, dermis and receptor fluid was assessed by HPLC. As much as 14.10–16.78% of the applied dose of BM-DBM penetrated within the skin tissue. No sunscreen was detected in the dermis and in the receiver phase. The greater proportion (84.6–95.5%) of the absorbed UV filter was localized in the stratum corneum with no significant differences between uncomplexed or complexed BM-DBM. Notable levels (2.29% of the applied dose) of the sunscreen agent accumulated in the epidermis from the preparation containing free BM-DBM. The epidermal concentration of the UV filter was markedly reduced (0.66% of the applied dose) by complexation with SBE7-β-CD, whereas HP-β-CD had no effect. The decreased BM-DBM retention in the epidermal region achieved by SBE7-β-CD limits direct contact of the sunscreen and of its reactive photolytic products with the skin viable tissues.     

Investigations into the structure and composition of β-cyclodextrin/poly(acrylic acid) microspheres

Microspheres composed of the hydrophilic polymer poly(acrylic acid) (PAA), with and without β-cyclodextrin (β-CD), were prepared by a water-in-oil (w/o) solvent evaporation technique. Microspheres were characterised for particle size, β-CD and residual oil content. The type of matrix formed during microsphere synthesis was investigated by solid state carbon ¹³C NMR, in vitro release of β-CD and swelling measurements. A high encapsulation efficiency of the β-CD was observed (>90%). The in vitro release of β-CD in water over 24 h was initially rapid (≈70% in 3 h) with no further loss thereafter, suggesting potential covalent binding of the residual β-CD. NMR indicated that in the presence of β-CD, two concomitant chemical processes occur during microsphere synthesis: (i) esterification of the hydroxyl group(s) of the β-CD with the carboxylic acid groups of the PAA; and (ii) the formation of intra-/inter-polymer acid anhydrides.     

Influence of sulfobutyl ether beta-cyclodextrin (Captisol) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion

The aim of this study was to investigate the influence of sulfobutyl ether β-cyclodextrin (SBE₇-β-CD; Captisol^®) on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also produced for comparative evaluation to assess the benefits of SBE₇-β-CD. Hot-melt extrudates were produced at 100 °C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE₇-β-CD and β-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE₇-β-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE₇-β-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.     

Complexation of the interferon inducer, bropirimine, with hydroxypropyl-β-cyclodextrin

Bropirimine (ABPP) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines used clinically against carcinoma in situ of the bladder. The oral absorption of ABPP is poor because its low solubility in water. The purpose of this study is to develop a technological procedure useful to increase the water solubility of ABPP. To this end, the interaction of ABPP with several cyclodextrin derivatives--, β-, γ- and hydroxypropyl-β-cyclodextrin with a degree of substitution 2.7 (HPβCD) was studied and the effect of the complexation process on the water solubility of the drug was evaluated. The best results were obtained with the hydroxypropyl derivative, HPβCD, that interacts in a 1:1 drug:cyclodextrin molar ratio. The inclusion complex ABPP–HPβCD was characterized in solution by nuclear magnetic resonance (¹H-NMR). The solid inclusion complex was obtained by freeze-drying and characterized by differential scanning calorimetry (DSC), X-ray diffractometry and mass spectrometry. The dissolution rate of ABPP from the HPβCD solid inclusion complex was increased compared to the powdered drug but not differences were found between the complex and a physical mixture with a similar molar ratio. The increase of the dissolution rate of the drug can be attributed to the breakdown in solution of the drug dimers in the presence of the cyclodextrin and to the complex formation.     

Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent β-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% β-CD had no significant impact on the integrity of the intestinal membrane. One percent β-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% β-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.     

Physico-chemical characterization of benzocaine-β-cyclodextrin inclusion complexes

Local anesthetics are able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Benzocaine (BZC) is a local anesthetic whose low water-solubility limits its application to topical formulations. The present work focuses on the characterization of inclusion complexes of BZC in β-cyclodextrin (β-CD). Differential scanning calorimetry and electron microscopy gave evidences of the formation and the morphology of the complex. Fluorescence spectroscopy showed a BZC/β-CD 1:1 stoichiometry. Phase-solubility diagrams allowed the determination of the association constants between BZC and β-CD (549 M⁻¹) and revealed that a three-fold increase in BZC solubility can be reached upon complexation with β-CD. The details of BZC/β-CD molecular interaction were analyzed by ¹H 2D NMR allowing the proposition of an inclusion model for BZC into β-CD where the aromatic ring of the anesthetic is located near the head of the β-CD cavity. Moreover, in preliminary toxicity studies, the complex seems to be less toxic than BZC alone, since it induced a decrease in the in vitro oxidation of human hemoglobin. These results suggest that the BZC/β-CD complex represents an effective novel formulation to enhance BZC solubility in water, turning it promising for use outside its traditional application, i.e., in infiltrative anesthesia.     

基于药物-皮肤的相互作用探究盐酸特比萘芬体外透皮特性

目的 考察盐酸特比萘芬的体外透皮特性，探究盐酸特比萘芬与皮肤的相互作用，基于药物-皮肤相互作用阐明盐酸特比萘芬透皮特性的机制。方法 比较盐酸特比萘芬经皮渗透及其皮内滞留以及在皮肤各层的分布；利用衰减全反射红外光谱、差示扫描量热、拉曼光谱研究药物与皮肤的相互作用，并对药物与角质层角蛋白及脂质的相互作用进行计算机模拟和计算。结果 盐酸特比萘芬经皮渗透后高滞留低渗透，滞留的药物多分布于角质层。盐酸特比萘芬与角质层中脂质和角蛋白均有相互作用，该作用使药物自身难于透过皮肤，并导致较大的透过变异性。结论 盐酸特比萘芬与皮肤脂质和角蛋白的相互作用是其表现出典型的皮肤低渗透、高滞留特性的机制之一。本研究为盐酸特比萘芬体外透皮高滞留、低渗透特性提供理论依据。