A double-blind placebo-controlled study of 5-fluorouracil:cyclodextrin complex loaded thermosensitive gel for the treatment of HPV induced condyloma

Objective of this double-blind placebo-controlled study was to determine the efficacy of thermosensitive mucoadhesive gel loaded with 5-fluorouracil (5-FU):hydroxypropyl-ß-cyclodextrin (HP-ß-CD) complex via topical administration or intralesional injection for the treatment of human papilloma virus induced condyloma in 44 women. The diagnosis of human papilloma virus was established with clinical, histopathological and polymerase chain reaction techniques. Subjects were randomized into four parallel groups to evaluate topical or intralesional administration of drug-loaded or blank gel. The formulation used in the study consisted of 20% Pluronic PF 127 and 0.2% hydroxypropylmethylcellulose (HPMC) to render thermosensitive and mucoadhesive properties to the blank and drug-loaded gels. 5-FU was complexed to hydroxypropyl-ß-cyclodextrin to improve its solubility and this complex was loaded into thermosensitive gel to obtain controlled release of the cytotoxic drug in administration site over a two-week period cure regimen aiming therapeutic efficacy with lower 5-FU doses. Complete response was achieved in 61% of patients through intralesional administration while topical administration resulted in only 29% complete cure. Relapse rates of all therapy groups were significantly low in the 6-month follow-up time.     

温度及pH敏感的β-环糊精聚合物微球的合成及药物控制释放研究

以反相乳液聚合得到了β-CD聚合物微球,对β-CD微球进行氯乙酰化改性后,利用原子转移自由基聚合的方法把聚甲基丙烯酸N ,N 二甲氨基乙酯(PDMAEMA)接枝到β-CD微球上,从而得到了具有温度和pH响应性的β- CD聚合物微球.通过红外光谱、元素分析确定了PDMAEMA接枝的β- CD微球的结构,采用热台偏光显微镜直接观测到了β- CD微球的温度和pH敏感性.对模型药物染料木素(GNT)和苯丁酸氮芥(CLB )进行了控制释放研究,结果表明pH值可对微球的“内环境”起到“开 关”作用,从而可构筑出一种新型的药物控制释放体系.     

New solid mucoadhesive systems for benzydamine vaginal administration

The aim of this work was the realization of new formulations for vaginal application to improve the pharmacological effect of benzydamine, displaying both anti-inflammatory and antiseptic activities. For this reasons, this drug was formulated in solid dispersions, by using the mucoadhesive polymers HPMC and/or Carbopol(?), then compressed. Tablets were characterized by studies of friability, hardness, hydration, DSC, mucoadhesion and in vitro release. Kinetics, responsible for drug delivery, was investigated as well. Tablets prepared by using only HPMC showed the best results in terms of swelling and mucoadhesion (time and force) together with prolonged and complete drug release, by diffusive mechanism, through gelled layer. Despite the good mucoadhesive properties, Carbopol(?) does not represent a good excipient because, after the contact with water, it generates a spongy gel layer, not homogeneous, stiff, brittle and with breaking tendency when highly swelled. This kind of gel does not guarantee a linear drug release and could provoke discomfort because of fragment release. HPMC mucoadhesive tablets could be a proper delivery system for benzydamine administration representing a good alternative to traditional dosage forms for vaginal topical therapy.     

Formulation and evaluation of gel containing nanostructured lipid carriers of tretinoin–Epi-β-CD binary complex for topical delivery

The objective of present research work was to formulate and evaluate topical gel containing tretinoin–cyclodextrin (CD) binary complex loaded into nanostructured lipid carriers (NLCs). Use of cyclodextrin and nanolipid carrier together in a system produced a synergistic effect by increasing the drug release and skin permeation, thus improving the overall therapeutic effect. Two different cyclodextrins i.e. β-CD and its water soluble polymeric derivative epichlorohydrin-β-cyclodextrin (EPI-β-CD) were used to obtain binary inclusion complex of drug-cyclodextrin (D-CD) systems by two different techniques (kneading and co-evaporation). The prepared solid complexes were characterized by FTIR, DSC, XRD etc. and the best system was selected for loading into nanolipid carriers. NLC comprising glyceryl mono stearate (GMS) and oleic acid were obtained by slightly modified emulsification evaporation method. Four different formulations of NLCs were suitability characterized for particle size, zeta potential, entrapment efficiency, drug loading and drug release. EPI-β-CD was found to be more effective than β-CD in enhancing solubility and dissolution properties of tretinoin. The most effective NLC formulation was incorporated into carbopol hydrogel which showed better permeation properties than that of the reference gel (0.1%).     

Formulation and evaluation of thermoreversible,mucoadhesive in situ intranasal gel of rizatriptan benzoate

The present study was aimed to formulate and evaluate in situ thermoreversible intranasal gel of an antimigraine drug rizatriptan benzoate. The poloxamer 407 and carbopol 934 were used as thermoreversible and mucoadhesive polymers respectively. The gels were prepared with cold method. The phase transition temperature was determined with visual method. The gels were evaluated for their pH, mucoadhesive strength, in vitro release and ex vivo drug permeation through goat nasal mucosa. The histopathological study of the nasal mucosa was carried out to check for its damage during drug permeation. The 18 % w/v poloxamer solution was found to be showing phase transition at physiologic conditions (34–35 °C). As the percentage of carbopol 934 was increased from 0.1 to 0.5 % w/v the gelling temperature was found to be decreased. All formulations were showing mucoadhesive strength above 4,000 dynes/cm². Drug permeation studies have indicated that the drug permeation rate can be increased by using carbopol 934 above 0.3 % w/v concentration. The histopathological evaluation of nasal mucosa after drug permeation study has not shown any evidence of damage. Thus in situ thermoreversible mucoadhesive gel of rizatriptan benzoate can be a promising approach to treat migraine.     

Study of the interaction between modified cyclodextrin and octopriox : potential applications in drug delivery

Host–guest interactions between the antifungal agent Octopirox^® (Oc) and modified β-cyclodextrin-derivatives were studied using ¹H- and 2D-ROESY NMR spectroscopy, Job-Plot and isothermal titration calorimetry (ITC). In addition to β-cyclodextrin (β-CD) a number of derivatives, namely randomly methacrylated β-cyclodextrin (RM-β-CD), mono-methacrylated β-cyclodextrin (MM-β-CD), randomly methylated β-cyclodextrin (RAMEB), hydroxypropyl-β-cyclodextrin (HP-β-CD) and randomly methacrylated hydroxypropyl-β-cyclodextrin (RM-HP-β-CD) were used. NMR data suggests the formation of highly ordered complexes, while ITC measurements allowed the identification of their stoichiometries and the thermodynamic data. To evaluate the possibility of retarded drug release from complexes prepared from polymeric materials like artificial nails, the complexes were polymerized with comonomers and subjected to aqueous extraction followed by quantification of Oc release by means of UV-spectroscopy.     

Chitosan and a modified chitosan as agents to improve performances of mucoadhesive vaginal gels

New mucoadhesive formulations were designed and studied in order to improve local vaginal therapy by increasing formulation retention prolonging thus drug-mucosa contact time. Some gels were prepared using hydroxyethylcellulose (HEC) alone or mixed with chitosan (CS) or its derivative 5-methyl-pyrrolidinone-chitosan (MPCS) and were loaded with the antibacterial metronidazole (MET) (0.75%). All formulations showed pseudoplastic flow and viscosity increase was observed proportionally to chitosan content (CS>MPCS). Prepared gels showed better extrusion properties (yield stress) than market formulation Zidoval. Mucoadhesion force studies permitted to point out that: (i) CS decreases mucoadhesion force; (ii) MPCS addition increases the mucoadhesion force at high percentage; (iii) all gels containing chitosan showed better mucoadhesive performances than Zidoval. Gels containing MPCS showed higher and faster drug release than those containing CS. All the preparations were able to release higher drug amounts if compared to market formulation. In conclusion MPCS improved gel characteristics in terms of mucoadhesion force, rheological behaviour and drug release pointing out that this modified chitosan is very suitable to obtain manageable and more acceptable vaginal formulation.     

Hydrogels containing 5-Fluorouracil obtained by γ-irradiation. Synthesis, characterization and in vitro release studies

The functionalization of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) with glycidyl methacrylate (GMA) gives rise to a water-soluble copolymer PHEA-GMA (PHG) containing double bonds and ester groups in the side chain. Aqueous solutions of PHG alone or in combination with N,N′ methylenbisacrylamide (BIS) have been exposed to a γ-ray source at different irradiation doses in order to obtain polymeric networks. All samples have been prepared both as water-swellable microparticles and as gel systems. Microparticles have been characterized by FT-IR spectrophotometry and swelling measurements in aqueous media mimicking biological fluids. The effect of irradiation dose and BIS presence on rheological behavior of the gel systems had also been investigated. All prepared hydrogels are able to incorporate, during γ-irradiation, 5-Fluorouracil, (5-FU) chosen as a model drug and to release it in simulated biological fluids, as confirmed by the in vitro drug release studies at pH 1 and pH 7.4. Gels of PHG containing 5-FU, obtained in the presence or in the absence of BIS, are able to release this drug in a prolonged way, more slowly than a commercial ointment, as confirmed by in vitro studies at pH 5.5 and pH 7.4 using a Franz diffusion cell system and a synthetic membrane. Received: 12 July 2000 Revised: 10 October 2000 Accepted: 17 October 2000     

Mucoadhesive Sustained Drug Delivery System Based on Cationic Polymer and Anionic Cyclodextrin/Triclosan Complex

In this study the interactions between a cationic polymer and an anionic cyclodextrin were investigated. The system has the potential for use in a sustained release dosage forms for use on mucous membranes. As mucous membranes are negatively charged the objective of this study was to investigate whether a drug delivery system based on a cationic polymer and an anionic cyclodextrin would be more mucoadhesive than a system containing a cationic polymer and a neutral cyclodextrin. For this purpose the cationic polymer hexadimethrine bromide (HDMBr) and anionic sulfobutylether -cyclodextrin (SBECD) were utilized as well as the neutral hydroxypropyl-cyclodextrin (HPCD). Triclosan was used as a model drug. The drug delivery system was formulated as a solution or semi-solid and its adhesion to porcine buccal mucosa and cation exchange media was measured. In addition the release of triclosan from the system was quantified. No difference was observed between the two systems when they were applied to the mucosal surface. However, the formulations showed improved adhesion, compared to the neutral cyclodextrin/drug delivery system, when they could also reach the underlying surface of the excised tissue. The drug delivery system was much better retained on the cation exchange media than the uncharged system. Significant interactions were observed between the negatively charged cyclodextrin and the positively charged polymer. The results indicate that the interactions could be used to obtain a mucoadhesive sustained drug delivery system under certain circumstances. The positive charge of HDMBr did not have the expected effect on the buccal mucosa and it can be concluded that although a positive charge is likely to promote mucoadhesion, other attributes of polymers, such as molecular weight and viscosity, may have equally beneficial effect.     

Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

The objectives of this research were to prepare and characterize inclusion complex of Ezetimibe (EZE) with cyclodextrins (β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD)) and to study the effect of complexation on the dissolution rate of EZE, a water insoluble drug. Phase solubility curve was classified as A _P -type for both cyclodextrins, indicating the 2:1 stoichiometric ratio for β-CD–EZE and HPβ-CD – EZE inclusion complexes. The inclusion complexes in the molar ratio of 2:1 (β-CD–EZE and HPβ-CD–EZE) were prepared by various methods such as kneading, coevaporation and physical mixing. The molecular behaviors of drug in all samples were characterized by fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies. The results of these studies indicated that complex prepared by kneading and coevaporation methods showed inclusion of the EZE molecule into the cyclodextrins cavities. The highest improvement in in-vitro dissolution profiles was observed in complex prepared with hydroxypropyl-β-cyclodextrin using co-evaporation method. Mean dissolution time and similarity factor indicated significant difference between the release profiles of EZE from complexes and physical mixtures and from pure EZE.     

Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

Nasal in situ gel containing hydroxy propyl ��-cyclodextrin inclusion complex of artemether: development and in vitro evaluation

The objective of the present investigation was to explore the formulation and evaluation of in situ gel for the nasal delivery of artemether (ARM), a poorly water-soluble antimalarial agent using temperature induced gelation technique using Pluronic with mucoadhesive polymer Hydroxy Propyl Methyl Cellulose (HPMC) K4M in different ratios. Initially, due to low water solubility, an inclusion complex of the antimalarial artemether (ARM) in hydroxypropyl-??-cyclodextrin (HP??CD) was prepared and characterized. The in situ gels so prepared were characterized for its gelation properties, viscosity, gel strength, mucoadhesion, drug content, drug release rate and for its histopathological studies. Pluronic and HPMC based in situ gel (PLH2) showed the effective gelation, viscosity, gel strength and drug release properties along with good mucoadhesive strength, it is further subjected for stability studies carried out at 30 ± 2 °C and 60 ± 5% RH for 90 days in order to know the influence of temperature and relative humidity on drug content and on drug release profile. Histological examination of formulations did not show any remarkable damage to nasal mucosa. The formulation also retained the good stability at accelerated conditions over the period of 90 days. Owing to these properties it can be used as an effective delivery system for the nasal route. These in situ gelling systems would be definitely useful for cerebral malaria.     

Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.     

Drug loading in cyclodextrin polymers: dexamethasone model drug

In pharmaceutical formulations cyclodextrins (CDs) are used to improve the aqueous solubility, stability, dissolution rate, bioavailability and/or local tolerance of drugs. Moreover, water-soluble polymers can be used to stabilize drug/CD complexes through formation ternary complexes. Alternative approach is to use CD-polymers, which can both enhance the aqueous solubility of a drug and result in sustained drug release. The aim of this work was to compare the solubilizing effects of ternary drug/CD/polymer complexes with two novel high molecular weight CD-polymers, i.e. poly(ethylene glycol) based ??-cyclodextrin (??CD) polymer (PEG/??CD) and epichlorohydrin-??-cyclodextrin polymer (EPI/??CD) using dexamethasone (Dex) as a model drug, as well as the drug loading capacity of those selected CD-polymers. Hydroxypropyl methylcellulose and carboxymethylcellulose sodium salt were shown to have negligible effect on the solubilizing efficacy of ??CD while hexadimethrine bromide increases the solubilization efficacy. The stability of the polymers was tested and it was adequate for the experimental conditions used. The solubilization efficacy of both CD-polymers was higher than that of the parent ??CD and these ??CD based polymers are able to load greater amount of Dex than the parent ??CD.     

A novel β-cyclodextrin polymer modified by sulfonate groups

Based on the special properties and advantages of β-cyclodextrin (β-CD), β-CD polymers have been widely studied and used in recent years. A lot of researches have focused on the adsorption and separation properties of β-CD polymers. In this paper, β-CD polymer modified by sulfonate groups, which was named S-β-CDP, was prepared using epichlorohydrin as crosslinker and tiron (1,2-dihydroxybenzene-3,5-disulfonic acid disodium salt) as modifier. β-CD polymer without modification, which was named β-CDP, was also prepared for comparison. Infrared spectra, elemental analysis and adsorption tests of S-β-CDP were carried out and compared with β-CDP. The content of sulfonate groups in S-β-CDP was obtained from elemental analysis. The dramatically increased adsorption capability toward methylene blue and basic magenta confirmed the existence and chemical activity of sulfonate groups in S-β-CDP. Due to the convenient preparation process and modified adsorption properties, S-β-CDP will find its applications in various fields such as water purification, drug loading, separation and analysis.     

壳层悬挂β-环糊精单元的两亲性超支化聚合物的分子包合与识别行为

采用紫外分光光度法研究了两种壳层悬挂β-环糊精单元的两亲性超支化聚合物在缓冲溶液(25 ℃, pH=11)中的分子包合与识别行为. 结果表明, 两种聚合物具有来自环糊精单元和两亲性超支化聚合物的双重包合能力, 可分别与水溶性染料分子酚酞(PP)、甲基橙(MO)、有机小分子对硝基苯酚(p-NP)等3种客体分子发生单客体包合效应, 而且其包合能力强于单一的环糊精或两亲性超支化聚合物; 通过客体分子PP和MO证实了这两种聚合物还具有双重识别能力, 可以与PP和MO发生双客体包合效应.     

Hydrogel matrices containing single and mixed natural cyclodextrins. Mechanisms of drug release

Hydrogel networks of α, β or γ-cyclodextrin (CD) and mixtures of α/β or β/γ CDs have been obtained using epichlorohydrin (EP) as a crosslinking agent. Discs of the resulting polymers were evaluated as drug carriers for controlled release using the antiinflammatory naproxen (NAP) as a model drug. βCD polymer (βCDP) has shown the highest amount of drug loaded and the lowest one corresponds to the polymer containing αCD, in agreement with the affinities of NAP for the corresponding cyclodextrins.     

Bipolymeric Pectin Millibeads Doped with Functional Polymers as Matrices for the Controlled and Targeted Release of Mesalazine

Targeted drug delivery systems are a very convenient method of treating inflammatory bowel disease. The properties of pectin make this biopolymer a suitable drug carrier. These properties allow pectin to overcome the diverse environment of the digestive tract and deliver the drug to the large intestine. This investigation proposed bipolymeric formulations consisting of the natural polymer pectin and a synthetic polymer containing the drug 5-aminosalicylic acid. Pectin beads were prepared via ionotropic gelation involving the interaction between the hydrophilic gel and calcium ions. The obtained formulations consisted of natural polymer, 5-aminosalicylic acid (5-ASA) and one of the synthetic polymers, such as polyacrylic acid, polyvinylpyrrolidone, polyethylene glycol or aristoflex. The release of the drug was carried out employing a basket apparatus (USP 1). The acceptor fluid was pH = 7.4 buffer with added enzyme pectinase to reflect the colon environment. The amount of the released drug was determined using UV-Vis spectrophotometry at a wavelength of λ = 330 nm. The kinetics of the drug dissolution revealed that none of the employed models was appropriate to describe the release process. A kinetic analysis of the release profile during two release stages was carried out. The fastest drug release occurred during the first stage from a formulation containing pectin and polyethylene glycol. However, according to the applied kinetic models, the dissolution of 5-ASA was rather high in the formulation without the synthetic polymer during the second stage. Depending on the formulation, 68–77% of 5-ASA was released in an 8-hour time period. The FTIR and DSC results showed that there was no interaction between the drug and the polymers, but interactions between pectin and synthetic polymers were found.     

The screening and evaluating of chitosan/β-cyclodextrin nanoparticles for effective delivery mitoxantrone hydrochloride

The complex of chitosan and β-cyclodextrin (CS-CMβ-CD) has been widely used as drug carrier because it binds the advantages of GCH and β-CDs. But further investigation is still needed to improve their delivery performance before CS-β-CD derivatives can be used as clinical cancer-drug carriers. The aim of the study is to screen suitable carriers of the deviants of chitosan and β-cyclodextrin by evaluating the delivery performance of several carriers towards anticancer drugs. Three kinds of GCS _n -CM _m β-CD polymers made of different amount of glycol chitosan (GCS) and carboxymethyl-β-cyclodextrin (CMβ-CD) were synthesized and GCS_7.5-CM_3-7β-CD was chosen to deliver the drugs due to its better properties. GCS_7.5-CM_3-7β-CD polymers have better cell adhesion performance than GCS, help to directional drug delivery. Then, mitoxantrone hydrochloride (MAH) was used as a model drug to evaluate the loading and releasing properties of GCS_7.5-CM_3-7β-CD polymers. GCS_7.5-CM_3-7β-CD polymers could encapsulate MAH with higher loading efficiency and provide pH sensitive MAH release. The amount of MAH released in acidic medium (pH 5.0) was greater than that in weakly basic medium (pH 7.4). The MAH-loaded nanoparticles shows similar inhibition ability as free MAH to HCT116 cell lines, indicate that MAH can be release from the carrier and kill the cancer cells. In addition, the blank GCS_7.5-CM_3-7β-CD nanoparticles show good biocompatibility to the cell. That is to say, GCS_7.5-CM_3-7β-CD polymers not only have the ability to targeting drug delivery but also can realize pH sensitive release, which make them perspective in cancer pharmaceutical application.     

Synthesis and Characterization of Linear Water-soluble γ-Cyclodextrin based Polymers as Drug Carrier Systems

A series of new linear water-soluble homo and copolymers of γ-cyclodextrin are reported. These water-soluble polymers were synthesized from γ-cyclodextrin (γ-CD) and triazine through a single pot condensation polymerization procedure and the synthetic parameters optimized. Lactose and maltose based γ-cyclodextrin copolymers were also prepared. The physicochemical properties of these synthesized polymers were characterized by FT-IR spectroscopy, XRD analysis, thermogravimetry analysis (TGA) and aqueous solubility determination. The formation of a 1:1 efavirenz (an anti HIV drug)/γ-CD polymer inclusion complex was confirmed from FT-IR and UV–VIS spectroscopy and phase solubility studies. The release performance of efavirenz was investigated through phase solubility and dissolution studies. It was found that these copolymers showed improved drug dissolution abilities.