Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel

The aim of this work was to study the effect of the combination between 2-hydroxypropyl-β-cyclodextrin (HPCD) and bioadhesive nanoparticles on the encapsulation and intestinal permeability of paclitaxel (PTX). In this context, a solid inclusion complex between PTX and HPCD was prepared by an evaporation method. Then, the complex was incorporated in poly(anhydride) nanoparticles by a solvent displacement method. The resulting nanoparticles, PTX–HPCD NP, displayed a size of about 300 nm and a drug loading of about 170 μg/mg (500-fold higher than in the absence of HPCD). The effect of these nanoparticles on the permeability of intestinal epithelium was investigated using the Ussing chamber technique. The apparent permeability (P_app) of PTX was found to be 12-fold higher when formulated as PTX–HPCD NP than when formulated as Taxol^® (control). Furthermore, when interaction between nanoparticles and the mucosa was avoided, the permeability of PTX significantly decreased. In summary, the association between PTX–HPCD and poly(anhydride) nanoparticles would induce a positive effect over the intestinal permeability of paclitaxel, being the bioadhesion a mandatory condition in this phenomena.     

Influence of hydroxypropyl-β-cyclodextrin on transdermal penetration and photostability of avobenzone

The objective of the present study was to determine the effects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the transdermal penetration and photostability of a model ultraviolet A (UVA) absorber, butyl methoxydibenzoylmethane (avobenzone), and to determine the influence of complexation on in vivo photoprotection. Avobenzone-HPCD complexation was demonstrated by differential scanning calorimetry. Formulations containing 0.12 mg/ml avobenzone and up to 30% (w/w) HPCD were prepared. Transdermal penetration was conducted using a modified Franz diffusion cell apparatus. As the concentration of HPCD was increased from 0% to 20%, transdermal permeation increased. Maximum flux occurred at 20% HPCD, where sufficient cyclodextrin was present to completely solubilize all avobenzone. When the concentration of HPCD was increased to 30%, transdermal penetration decreased, suggesting the formation of an avobenzone reservoir on the skin surface. Photostability of avobenzone was investigated under 100, 250, and 500 kJ/m2 UVA irradiation. The 30% HPCD formulation was the most photostable, followed by 20%, 10%, and 0% formulations. In vivo, the 30% HPCD formulation afforded the best photoprotection, as evidenced by the lowest extent of sunburn cell formation and edema induction. This work indicates that inclusion of HPCD in sunscreen formulations may enhance photoprotection by reducing both skin penetration and photodecomposition of UV absorbers.     

Enhanced dissolution,stability and physicochemical characterization of ATRA/2-hydroxypropyl-β-cyclodextrin inclusion complex pellets prepared by fluid-bed coating technique

The aim of this work was to prepare stable all-trans-retinoic acid (ATRA)/2-hydroxypropyl-β-cyclodextrin (HPCD) inclusion complex pellets with industrial feasible technology, the fluid-bed coating technique, using PVP K30 simultaneously as binder and reprecipitation retarder. The coating process was fluent with high coating efficiency. In vitro dissolution of the inclusion complex pellets in 5% w/v Cremopher EL solution was dramatically enhanced with no reprecipitation observed, and significantly improved stability against humidity (92.5% and 75% RH) and illumination (4500 lx ± 500 lx) was achieved by HPCD inclusion. Differential scanning calorimetry and powder X-ray diffractometry confirmed the absence of crystallinity of ATRA. Fourier transform-infrared spectrometry revealed interaction between ATRA and HPCD adding evidence on inclusion of ATRA moieties into HPCD cavities. Solid-state ¹³C NMR spectrometry indicated possible inclusion of ATRA through the polyene chain, which was the main reason for the enhanced photostability. It is concluded that the fluid-bed coating technique has the potential use in the industrial preparation of ATRA/HPCD inclusion complex pellets.     

Effect of hydroxypropyl-beta-cyclodextrin on the solubility, stability and in-vitro release of ciprofloxacin for ocular drug delivery

Eye drops in the form of an aqueous solution with a lower viscosity are preferred for local administrations in ophthalmology. In ophthalmic formulations, cyclodextrins (CDs) are frequently used in recent years in order to increase water solubility, stability and bioavailability of an active substance and decrease an irritation to the eye. The scope of the present study was to investigate the influence of hydroxypropyl-beta-cyclodextrin (HPCD) on the solubility, stability and in vitro release of ciprofloxacin (CIP). According to the phase solubility studies, A(L) type solubility curve was obtained. HPCD improved the solubility of CIP 3 times at pH 5.5 and 2 times at pH 7.4. The two month stability studies indicated that CIP was more stable at pH 5.5 than at pH 7.4 and the stability of CIP was significantly increased by HPCD. The stability constant of the HPCD:CIP complex was increased further by a-ddition of 0.1% (w/v) polymer (HPMC and PVP) to the aqueous medium including HPCD. Stability constant of solutions prepared in an ultrasonic water bath was higher than solutions prepared by heating in an autoclave. The results indicated that the CIP:HPCD complex increased in vitro release of CIP and the addition of polymer promoted this increase even more.     

Use of 2-Hydroxypropyl-β-cyclodextrin as a Solubilizing and Stabilizing Excipient for Protein Drugs

A chemically modified, amorphous -cyclodextrin, namely, 2-hydroxypropyl--cyclodextrin (HPCD), was examined as a solubilizing and stabilizing agent for protein drugs. The aqueous solubility of ovine growth hormone at pH 7.4 was increased through the use of HPCD. This effect was manifested by higher UV transparency at 600 nm. Interleukin-2 (IL-2) is rendered insoluble upon lyophilization in the absence of stabilizers. Use of aqueous HPCD provides a clear solution, as indicated by fluorometric light scattering, and inhibits aggregate formation, as shown by ultracentrifugation and Western blot analyses. In addition, there were no major conformational changes of IL-2 in HPCD formulation as indicated by fourth-derivative ultraviolet spectroscopy. Finally, IL-2 retained 100% of its biopotency when prepared in HPCD solutions. Aggregation of insulin was also suppressed by HPCD. These data, as well as the i.v. safety of HPCD and its well-characterized chemical composition, suggest that this starch derivative may be a potentially useful excipient for protein drugs intended for parenteral use.     

Effects of 2-hydroxypropyl-beta-cyclodextrin on pharmacokinetics of digoxin in rabbits and humans

Considering the narrow therapeutic index of digoxin and the low range between the safe and toxic serum concentrations of this drug, to evaluate the relative bioavailability of tablets and oral solution is necessary. The pharmacokinetic properties of digoxin after oral administration of its hydroxypropyl-beta-cyclodextrin (HPCD) inclusion complex to rabbits and human volunteers were investigated in comparison with those of commercially available tablets. The aqueous solubility of digoxin was enhanced by HPCD for about 2000 times at HPCD concentration of 50% (w/v). But in a human bioavailability study no significant difference was observed in the extent of absorption (AUC(0-t)) and Cmax between the two formulations. Time to reach peak was significantly shorter for the solution than for the tablets (p < 0.01). The pharmacokinetic results from the rabbit study were similar to human studies and no significant difference was observed for AUC, Cmax and Tmax. As the bioavailability of both tablets and solution is equivalent HPCD based oral digoxin solution could serve as an alternative to tablets.     

Ocular Absorption and Irritation of Pilocarpine Prodrug Is Modified with Buffer,Polymer, and Cyclodextrin in the Eyedrop

The influence of buffer, viscosity and cyclodextrin on the ocular absorption and irritation of a pilocarpine prodrug, O,O-dipropionyl-(1,4-xylylene) bispilocarpic acid diester, was studied in albino rabbits. The prodrug solutions, equivalent to 0.5% pilocarpine, were prepared in 0, 10, 20, 50, or 75 mM citrate buffer at pH 5.0. Viscosity of the solutions (20, 50 or 115 cP) was modified with hydroxypropyl methylcellulose. 2-hydroxypropyl--cyclodextrin (HPCD) was included at concentrations 5,10 and 15% (w/v). The formulations were compared to a commercial pilocarpine eyedrop (1.7%). Ocular irritation was graded in a double-masked experiment and miosis was used as a bioassay for pilocarpine delivery to the iris. The prodrug showed decreased peak and prolonged duration of miosis compared to pilocarpine, but it caused ocular irritation. Increasing buffer strength decreased and elevated viscosity intensified the miotic response and irritation by the pilocarpine prodrug. HPCD decreased both the ocular delivery of pilocarpine and the irritation by the pro-drug, but the net effect was positive. Thus, administering 1.0% of pilocarpine as a prodrug with 15% (w/v) HPCD, the irritation was at the same level with the commercial pilocarpine eyedrop, but the ocular delivery was substantially improved. In conclusion, the ocular delivery of the pilocarpine prodrug may be enhanced in relation to its local irritation by properly combining buffer, viscosity and HPCD.     

Piroxicam/2-hydroxypropyl-beta-cyclodextrin inclusion complex prepared by a new fluid-bed coating technique

This work was aimed at investigating the feasibility of fluid-bed coating as a new method to prepare cyclodextrin inclusion complex. The inclusion complex of the model drug piroxicam (PIX) and 2-hydroxypropyl-beta-cyclodextrin (HPCD) in aqueous ethanol solution was sprayed and deposited onto the surface of the pellet substrate upon removal of the solvent. The coating process was fluent with high coating efficiency. Scanning electron microscopy revealed a coarse pellet surface, and a loosely packed coating structure. Significantly enhanced dissolution, over 90% at 5 min, was observed at stoichiometric PIX/HPCD molar ratio (1/1) and at a ratio with excessive HPCD (1/2). Differential scanning calorimetry and powder X-ray diffractometry confirmed absence of crystallinity of PIX at PIX/HPCD molar ratio of 1/1 and 1/2. Fourier transform-infrared spectrometry and Raman spectrometry revealed interaction between PIX and HPCD adding evidence on inclusion of PIX moieties into HPCD cavities. Solid-state (13)C NMR spectrometry indicated possible inclusion of PIX through the pyridine ring. It is concluded that fluid-bed coating has potential to be used as a new technique to prepare cyclodextrin inclusion complex.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on the Ocular Absorption of Dexamethasone and Dexamethasone Acetate

Complexation of dexamethasone (DX) and dexamethasone acetate (DXA) with 2-hydroxypropyl--cyclodextrin (HPCD) was investigated with an ultimate goal of formulating a topical ophthalmic solution of DXA. Aqueous solubility of DX and DXA was markedly increased due to formation of soluble inclusion complexes with HPCD. Based on characterization of complex formation by phase solubility and UV-spectroscopy methods, a stoichiometry of 1:1 and 1:1, 1:2 was assumed for DX-HPCD and DXA-HPCD complexes, respectively. The stability constants for complex formation estimated by phase solubility and UV-spectroscopy methods, respectively, were as follows: for DX-HPCD complex, K_{l :l} = 2193 and 2221 M^–1; and for DXA-HPCD complex, K _1:1 = 2240 and 2445 M ^–l and K _l:2 = 3 and 17 M ^–1. K _{l :l} of 2266 M ^–l and K _{l :2} of 20 M ^–l were also estimated for the DXA-HPCD complex by kinetics. The kinetics of DXA degradation in pH 7 phosphate buffer at 25°C followed pseudo first order. The addition of HPCD decreased the rate but the order of reaction remained unchanged. Free DXA degraded at a faster rate than complexed DXA. Ocular bioavailability in conjunctiva, cornea, iris, and aqueous humor postadministration of a 25-µl dose of formulations containing an equivalent of 0.1% (w/v) DX followed a rank-order of DXA-HPCD solution > DXA suspension > DX-HPCD solution > DX suspension.     

Solubilization and Stabilization of a Benzylpenicillin Chemical Delivery System by 2-Hydroxypropyl-β-cyclodextrin

A dihydropyridine pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl--cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720–940 M ^–1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.     

Growth Hormone (GH) Secretory Dynamics in Animals Administered Estradiol Utilizing a Chemical Delivery System

We have utilized a redox chemical delivery system (CDS) for the brain targeting of estradiol (E₂) to ascertain its effects on GH secretory patterns in adult intact male rats. The E₂-CDS (1.0 mg/kg) dissolved in 20% hydroxypropyl-cyclodextrin (HPCD), E₂ (1.0 mg/kg) alone in 20% HPCD, or 20% HPCD was administered intravenously. GH secretory profiles, plasma steroid levels, and anterior pituitary levels of hormones were determined 1 week following steroid injection. Whereas E₂ in HPCD and HPCD treatment did not alter masculine GH secretory patterns, animals administered the E₂-CDS displayed disrupted GH patterns with attenuated individual pulse amplitudes and significantly elevated GH baseline levels. Moderate pituitary hyperplasia was evident only in the E₂-CDS group of animals. Plasma testosterone (T) concentrations were reduced in only the E₂-CDS group. T replacement reduced E₂-CDS-associated pituitary hyperplasia and preserved the masculine GH secretory profiles, with only a slight reduction in individual GH peak amplitudes being observed. T replacement did not prevent the increase in pituitary and plasma levels of PRL associated with E₂-CDS treatment but did block both the increase in pituitary GH content and the hyperplasia associated with prolonged E₂ exposure. E₂ given alone induced a significant increase in both GH and PRL in the pituitary without establishment of pituitary hyperplasia or elevated plasma PRL levels. These data indicate that E₂-CDS is an effective mode of steroid administration. Changes in GH secretory dynamics, pituitary levels of GH, and degree of hyperplasia are dependent upon the chemical design of the delivery system for E₂. Concomitant T therapy can prevent some of the changes in GH secretion associated with high-dose E₂ exposure.     

2-羟丙基β-环糊精对美洛昔康的包合作用

目的测定美洛昔康在不同浓度 2 羟丙基 β 环糊精溶液中的溶解度曲线 ,以及包合物的组成量比例和稳定性常数。方法在 2 5℃运用相溶解度法进行实验 ,采用紫外分光光度法测定美洛昔康在溶液中的浓度。结果随着 2 羟丙基 β 环糊精浓度增加和 pH的增大 ,美洛昔康的溶解度显著提高。计算了表观稳定常数、确定了不同pH条件下包合物的摩尔比。 结论难溶性药物美洛昔康与 2 羟丙基 β 环糊精可形成 1 :1包合物。     

那格列奈—2-羟丙基-β-环糊精包合物的制备及其理化性质

目的考察2-羟丙基-β-环糊精(HPCD)对那格列奈的增溶作用;研究那格列奈-HPCD包合物的制备工艺;考察包合物的光谱表征及包合物胶囊的体外释放行为。方法考察不同pH值、不同浓度的HPCD对那格列奈的增溶作用;通过研磨法和冷冻干燥法制备包合物;采用X-射线衍射及差示扫描热量法2种技术手段确证包合物的形成;在不同介质中考察不同方法制备的包合物的溶出度。比较不同环糊精用量比例的包合物、混合物及普通原料药的溶出度。结果不同pH条件下HPCD对那格列奈的增溶作用不同;差热分析及X-射线衍射证明了那格列奈与HPCD形成了包合物;那格列奈-HPCD包合物的水溶性好,在水介质中溶出度较高,在那格列奈与HPCD摩尔比为1∶2的情况下,冷冻干燥法制备的包合物,在pH 1.0的条件下体外溶出度达到100%,研磨法制备的包合物溶出度大于85%,而原料药溶出度仅为20%,显示出了那格列奈包合后的优势。结论包合物的光谱表征同那格列奈有明显不同;经包合后那格列奈的溶解度明显增大;用包合物制的胶囊体外溶出速度快,溶出度高。     

Ranking novel extraction systems of seedless barberry (Berberis Vulgaris) bioactive compounds with fuzzy logic-based term weighting scheme

In this study, various extraction systems of seedless barberry fruit bioactive compounds (Berberis vulgaris) were ranked using a fuzzy logic-based term weighting scheme (inputs: extraction yield, total phenolic content (TPC), vitamin C content, anthocyanin content, antioxidant activity, time, temperature, pressure). Hot water bath as a control method (C), high-pressure CO₂ (HPCD), subcritical water (SCW), and cold press (CP) methods were applied to extract bioactive compounds of the fruit. High-performance liquid chromatography (HPLC) revealed the types of anthocyanins. The results show that the highest and lowest yield were obtained for HPCD and SCW treatment (92.5% and 88.7%, respectively; P > 0.05). The TPC ranged from 214.16 (HPCD) to 457.20 (SCW) mg GAE/100 mL (P < 0.05). The suitable content of TPC was extracted by CP (310 mg GAE/100 mL) in less than 5 min. The most and lowest anthocyanin and vitamin C were obtained by HPCD and SCW extract (P < 0.05). In the control and cold press extracts, Delphinidin-3-O-glucoside and Cyanidin -3-O-glucoside were dominant, while in HPCD extract Cyanidin -3-O-glucoside had the highest value. The antioxidant activity of various extraction methods decreased in the order of SCW > CP > HPCD > C. The experts introduced all of the extraction factors as important to very important (defuzzification score>75). The final results of fuzzy logic showed that CP, HPCD, and Control methods; had a total score above average (score> 50: 70.44, 67.30, and 65.55, respectively) and can be recommended to extract bioactive compounds from barberry depending on the final purpose and the cost-effectiveness.     

2-羟丙基-β-环糊精对羟基喜树碱的增溶及稳定作用研究

目的:考察不同pH条件下2-羟丙基-β-环糊精(HPCD)对羟基喜树碱(HCPT)的增溶作用以及HCPT内酯环开闭环平衡的影响。方法:运用相溶解度法进行增溶试验,采用高效液相色谱法分别测定HCPT内酯环形式与开环羧酸盐形式药物浓度,考察不同量的HPCD对HCPT内酯环开闭环转化pH平衡点。结果:随着HPCD浓度增加,HCPT的溶解度增加;包合物表观稳定常数随pH上升而下降;HPCD浓度在0%、10%、25%时,HCPT开闭环pH平衡点分别为6.5、7.0、7.3。结论:HPCD可以提高HCPT的溶解度,对HCPT内酯环有稳定作用。     

Use of photoacoustic spectroscopy in the characterization of inclusion complexes of benzophenone-3-hydroxypropyl-β-cyclodextrin and ex vivo evaluation of the percutaneous penetration of sunscreen

This work is aimed to evaluate the application of photoacoustic spectroscopy (PAS) in the characterization of inclusion complexes of benzophenone-3 (BZ-3) and hydroxypropyl-β-cyclodextrin (HPCD) and to analyze the ex vivo percutaneous penetration of sunscreens and their reaction with the skin. The formation of inclusion complexes of BZ-3 and HPCD was performed by co-precipitation in stoichiometric ratios of 1:1 and 1:2. Thermal analysis and PAS characterized these inclusion complexes, and they indicated that the stoichiometric ratio of 1:2 was best. Sunscreen formulations were prepared and applied on the ears of rabbits. PAS suggested that the formulation with the complex resulted in lower penetration of BZ-3. Histological analysis demonstrated that the use of the formulation with BZ-3 was associated with an increase in the comedogenic effect and the presence of acanthosis, while no such effect was found in the formulation with the complex. The formulation with the BZ-3-HPCD complex is a promising strategy for improving the photoprotective effect of BZ-3. PAS can be used in the study of inclusion complexes with cyclodextrins and the evaluation of the percutaneous penetration of sunscreen formulations. Further tests are being conducted using PAS to monitor in vivo changes in the optical absorption spectra of formulations and to investigate their photostability.     

Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen.

Each year millions of people are overexposed to the sun resulting in photodamage of the skin. Secondary photoprotection is the application of medicinal agents to the body after sun exposure to reduce this damage. The objective of this study was to determine the affects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the secondary photoprotective properties of topically applied ibuprofen. Complexation of ibuprofen by HPCD was demonstrated by differential scanning calorimetry, while solubilities were determined using HPLC. A linear (r2>0.999) relationship was found between ibuprofen solubility and HPCD concentration. For subsequent experiments, the concentration of ibuprofen was held constant at the solubility in 10% HPCD (10.6 mg/ml), while the HPCD concentration varied from 0 to 20% (w/w). In vitro transdermal permeation experiments demonstrated a parabolic relationship between transdermal kinetic parameters and HPCD concentration, with maximum values for both flux and skin accumulation occurring with the 10% HPCD formulation. In vivo experiments were performed by exposing hairless mice to UV radiation and applying ibuprofen-HPCD formulations topically at various times following UV exposure. Edema and epidermal lipid damage data demonstrated that application of ibuprofen-HPCD formulations within 1h of UV exposure provided significant photoprotection.     

Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

The effects of the hydroxypropyl-β-cyclodextrin (HPCD) on the solubility of 2-hydroxy-N-(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine (I) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (pK_a=5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.     

羟丙基-β-环糊精对冬凌草二萜类成分的包合作用

目的研究羟丙基-β-环糊精(HPCD)在溶液中对冬凌草二萜类成分的包合作用。方法采用相溶解度法进行研究。结果在水溶液中,冬凌草甲素的浓度随HPCD浓度的增加而呈线性增加,为典型的AL型相溶解度图。在不同pH值、不同温度、不同离子强度等条件下计算包合表观稳定常数。包合过程的热力学参数为:ΔH=17.31 kJ.mol-1,ΔS=39.57 J.mol-1,且不同温度条件下的ΔG均小于零。结论羟丙基β环糊精可以提高冬凌草甲素的溶解度。HPCD与冬凌草甲素形成摩尔比为1∶1的包合物,包合过程为吸热过程,而且是自发进行。     

Effect of Solubilizing Agents on Mupirocin Loading into and Release from PEGylated Nanoliposomes

Mupirocin was identified by quantitative structure property relationship models as a good candidate for remote liposomal loading. Mupirocin is an antibiotic that is currently restricted to topical administration because of rapid hydrolysis in vivo to its inactive metabolite. Formulating mupirocin in PEGylated nanoliposomes may potentially expand its use to parenteral administration by protecting it from degradation in the circulation and target it (by the enhanced permeability effect) to the infected tissue. Mupirocin is slightly soluble in aqueous medium and its solubility can be increased using solubilizing agents. The effect of the solubilizing agents on mupirocin remote loading was studied when the solubilizing agents were added to the drug loading solution. Propylene glycol was found to increase mupirocin loading, whereas polyethylene glycol 400 showed no effect. Hydroxypropyl-β-cyclodextrin (HPCD) showed a concentration-dependent effect on mupirocin loading; using the optimal HPCD concentration increased loading, but higher concentrations inhibited it. The inclusion of HPCD in the liposome aqueous phase while forming the liposomes resulted in increased drug loading and substantially inhibited drug release in serum.