Erem Bilensoy

Mucoadhesive, Thermosensitive, Prolonged-Release Vaginal Gel for Clotrimazole:β-Cyclodextrin Complex

The purpose of this study was to achieve a better therapeutic efficacy and patient compliance in the treatment for vaginitis. Clotrimazole (1%) has been formulated in a vaginal gel using the thermosensitive polymer Pluronic F127 (20%) together with mucoadhesive polymers such as Carbopol 934 and hydroxypropylmethylcellulose (0.2% for both). To increase its aqueous solubility., clotrimazole was incorporated as its inclusion complex with 1∶1 molar ratio with β-cyclodextrin. The inclusion complex was thoroughly characterized using various techniques, including 1H NMR spectroscopy, FT IR spectrophotometry, differential scanning calorimetry, scanning electron microscopy, phase solubility studies, and determination of stability constant (k1∶1). The gelation temperature and rheological behavior of different formulations at varying temperatures were measured. In vitro release profiles of the gels were determined in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin slowed down the release of clotrimazole considerably. Carbopol 934, on the other hand, was found to interact with β-cyclodextrin, inducing precipitation. As far as rheological properties are concerned, thermosensitive in situ gelling was obtained with formulations containing drug: cyclodextrin complex rather than with free drug. Thus, the optimum formulation for a controlled-release thermosensitive and mucoadhesive vaginal gel was determined to be clotrimazole: β-cyclodextrin 1% with 0.2% hydroxypropylmethylcellulose in Pluronic F127 gel (20%) providing continuous and prolonged release of active material above MIC values.

Intravesical cationic nanoparticles of chitosan and polycaprolactone for the delivery of Mitomycin C to bladder tumors

Cationic nanoparticles of chitosan (CS), poly-epsilon-caprolactone coated with chitosan (CS-PCL) and poly-epsilon-caprolactone coated with poly-L-lysine (PLL-PCL) were developed to encapsulate intravesical chemotherapeutic agent Mitomycin C (MMC) for longer residence time, higher local drug concentration and prevention of drug loss during bladder discharge. Nanoparticle diameters varied between 180 and 340 nm depending on polymer used for preparation and coating. Zeta potential values demonstrated positive charge expected from cationic nanoparticles. MMC encapsulation efficiency depended on hydrophilicity of polymers since MMC is water-soluble. Encapsulation was increased by 2-fold for CS-PCL and 3-fold for PLL-PCL as a consequence of hydrophilic coating. Complete drug release was obtained with only CS-PCL nanoparticles. On the other hand, CS and PLL-PCL nanoparticles did not completely liberate MMC due to strong polymer-drug interactions which were elucidated with DSC studies. As far as cellular interaction was concerned, CS-PCL was the most efficient formulation for uptake of fluorescent markers Nile Red and Rhodamine123 incorporated into nanoparticles. Especially, CS-PCL nanoparticles loaded with Rhodamine123 sharing hydrophilic properties with MMC were selectively incorporated by bladder cancer cell line, but not by normal bladder epithelial cells. CS-PCL nanoparticles seem to be promising for MMC delivery with respect to anticancer efficacy tested against MB49 bladder carcinoma cell line.

Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery

Camptothecin (CPT) is a potent anticancer agent. The clinical application of CPT is restricted by poor water solubility and instability under physiological conditions. Solubilization and stabilization of CPT were realized through nanoparticulate systems of amphiphilic cyclodextrins, poly(lactide-co-glycolide) (PLGA) or poly-epsilon-caprolactone (PCL). Nanoparticles were prepared with nanoprecipitation technique, whereas cyclodextrin nanoparticles were prepared from preformed inclusion complexes of CPT with amphiphilic cyclodextrins. Polymeric nanoparticles, on the other hand, were loaded with CPT:HP-beta-CD inclusion complex to solubilize and stabilize the drug. Mean particle sizes were under 275 nm, and polydispersity indices were lower than 0.2 for all formulations. Drug-loading values were significantly higher for amphiphilic cyclodextrin nanoparticles when compared with those for PLGA and PCL nanoparticles. Nanoparticle formulations showed a significant controlled release profile extended up to 12 days for amphiphilic cyclodextrin nanoparticles and 48h for polymeric nanoparticles. Anticancer efficacy of the nanoparticles was evaluated in comparison with CPT solution in dimethyl sulfoxide (DMSO) on MCF-7 breast adenocarcinoma cells. Amphiphilic cyclodextrin nanoparticles showed higher anticancer efficacy than PLGA or PCL nanoparticles loaded with CPT and the CPT solution in DMSO. These results indicated that CPT-loaded amphiphilic cyclodextrin nanoparticles might provide a promising carrier system for the effective delivery of this anticancer drug having bioavailability problems.

Recent advances and future directions in amphiphilic cyclodextrin nanoparticles

Cyclodextrins are known to be promising excipients in the pharmaceutical industry, with their ability to include hydrophobic guest molecules masking the physicochemical properties of the guest, such as poor water solubility, stability problems and undesired side effects. These enabling excipients, which are produced on a large scale and incorporated into various marketed products worldwide, are now modified to render amphiphilic properties that enable them to be used to prepare nanoparticles. Amphiphilic cyclodextrins have the ability to form nanoparticles without the presence of a surfactant by different preparation techniques that are discussed in this review. Classification and physicochemical properties of these interesting molecules as well as the efficacy and safety of nanoparticles prepared from different amphiphilic cyclodextrins are discussed in light of the current literature work with in vitro and in vivo findings. Cyclodextrin nanoparticles of different nature effectively carry drugs or molecules with bioavailability problems arising from poor aqueous solubility, stability under physiological conditions or side effects associated with the molecule itself or excipients used in the formulation of these problems drugs. In conclusion, amphiphilic cyclodextrins emerge as promising alternatives for tumor drug delivery and passive and active targeting with non-toxic, non-hemolytic properties as injectable, nanosized carriers.

Hyaluronic acid coated poly-ɛ-caprolactone nanospheres deliver high concentrations of cyclosporine A into the cornea

The objective of this study was to determine cyclosporine A (Cy A) levels in ocular tissues and fluids after topical administration of poly-epsilon-caprolactone (PCL)/benzalkonium chloride (BKC) nanospheres and hyaluronic acid (HA) coated PCL/BKC nanospheres onto healthy rabbit corneas. Nanospheres were prepared by nanoprecipitation and purified by gradient-rate centrifugation. Cy A (0.1%) in either castor oil solution (group 1), PCL/BKC nanosphere formulation (group 2) or HA coated PCL/BKC nanosphere formulation (group 3) was instilled onto rabbit corneas. Tear samples were adsorbed onto Schirmer tear strips. Cy A concentrations of fluid (blood, aqueous humor, tear) and specimen extracts (cornea, conjunctiva, iris/ciliary body) were determined by high performance liquid chromatography-mass spectrometry (LC-MS). The mean corneal Cy A concentration obtained at 0.5, 1, 2, 4, 8 and 24h following instillation of the formulations ranged between 0.12 and 1.2 ng/mg tissue for group 1, 5.9-15.5 ng/mg tissue for group 2 and 11.4-23.0 ng/mg for group 3 (one-way analysis of variance (ANOVA) and pairwise tests (SNK (Student-Newman-Keuls) and Tukey); p<0.05). Conjunctival Cy A levels of group 2 and 3 were not significantly different at any of the time points tested. However, there was a significant difference between Cy A concentration of castor oil formulation and that of PCL/BKC nanosphere formulation at 1 and 8h (p<0.05). The mean iris/ciliary body concentrations obtained with the three formulations were not significantly different at any time point with the exception of group 2 levels being higher than those of groups 1 and 3 at 1h (p<0.05). The lowest ocular tear Cy A concentrations (16-114 ng/ml) were found following the instillation of HA coated PCL/BKC nanoparticles (group 3) during the time period tested. Cy A loaded PCL/BKC and HA coated PCL/BKC nanospheres are able to achieve high levels of Cy A in the cornea that is 10-15-fold higher than that is achieved with Cy A solution in castor oil. Nanosphere formulation and HA may play an important role in delivering high levels of cyclosporine A into the cornea.

Antitumoral activity of camptothecin-loaded nanoparticles in 9L rat glioma model

Camptothecin (CPT), a plant alkaloid, is a potent anticancer drug in cell culture studies but it is clinically inactive due to rapid hydrolysis under physiological conditions. The drug exists in two forms depending on the pH value, an active lactone form at pH below 5 and an inactive carboxylate form at basic pH and this is a reversible reaction. In this study, nanoparticulate delivery systems were developed with either amphiphilic cyclodextrins, poly(lactide-co-glycolide) or poly-ɛ-caprolactone in order to maintain the active lactone form and prevent the drug from hydrolysis. All nanoparticles were prepared with nanoprecipitation technique. Mean particle sizes were 130-280nm and surface charges were negative. The encapsulation efficiency was significantly higher for amphiphilic cyclodextrin nanoparticles when compared to polymeric nanoparticles. Nanoparticle formulations based on cyclodextrins showed a controlled release profile extended up to 12 days. 6-O-Capro-β-cyclodextrin (1.44μg/60μL CPT) and concentrated 6-O-Capro-β-cyclodextrin (2.88μg/60μL CPT) nanoparticles significantly modified the growth or lethality of the 9L gliomas, since the median survival time was 26 days for the untreated group and between 27 and 33 days for amphiphilic cyclodextrin nanoparticle groups. These results indicate that, CPT-loaded amphiphilic cyclodextrin nanoparticles may provide a promising carrier system for the effective delivery of CPT in comparison to polymeric analogues.

Cationic nanoparticles for cancer therapy

Importance of the field: The lack of selective delivery of therapeutic molecules to cancer cells remains a problem in cancer therapy. As a result of this non-selectivity, cytotoxic agents are delivered to both healthy and cancerous cells, resulting in severe side effects for the patient, eventually causing termination of therapy or ineffective therapy resulting in progression or recurrence of the disease. In this context, cationic polymers with net positive surface charge emerge as a promising option owing to their very strong cellular interaction properties and good cellular uptake. Areas covered in this review: In this review, the structure, characteristics and preparation techniques for cationic nanoparticulate drug delivery systems are discussed in the light of cytotoxicity associated with cationic polymers and strong complement activation properties of cationic carrier systems on injection. In vivo behavior and biodistribution of cationic nanoparticles are also reviewed for a better understanding of biological interaction of cationic nanoparticles. What the reader will gain: This review will give an insight to the properties of cationic polymers, including their advantages and drawbacks and drug/gene delivery systems based on cationic polymers intended for cancer therapy. Take home message: Cationic polymer-based nanoparticles emerge as a promising group of nanosize carrier systems to the tumor cell level with a wide range of modification and application possibilities.

Alternative oral exemestane formulation: Improved dissolution and permeation

Exemestane (EXE) is an irreversible aromatase inactivator used for the treatment of advanced postmenopausal breast cancer. EXE is orally active but its bioavailability is about 5% due to its low solubility in water and the extensive first pass effect. It is known that cyclodextrin (CD) complexation enhances solubility and oral bioavailability of poorly soluble drugs. Thus, it was aimed to design and develop cyclodextrin complexes in powder and tablet forms containing EXE to improve aqueous solubility and in vitro permeability. In this study, inclusion complexes of EXE were prepared with three different CD derivatives (methyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin) and by two different preparation methods (kneading and colyophilization) and the complexes were characterized with (1)H NMR, FT-IR, SEM, X-ray and DSC analyses. Both inclusion complexes and tablet formulations prepared using EXE:CD inclusion complexes showed significant improvement in the dissolution profile of this oral antiestrogen drug. Furthermore, Caco-2 cell permeation studies revealed that apparent permeability constant for EXE was increased by 3-fold via cyclodextrin complexation. In conclusion, complexation of EXE with cyclodextrin derivatives, randomly methylated-beta-cyclodextrin in particular, results in a more efficient tablet formulation with improved dissolution and better permeation suggesting an enhancement in oral bioavailability of the drug.

Antibacterial activity of triclosan chitosan coated graft on hernia graft infection model

The use of mesh in hernia repair has become common, because of lower recurrence rate and simple application. Data from the meta-analysis and the multi-central studies support the use of meshes in hernia repair. One of the complications due to the hernia repair with mesh is the infection. The incidence range is between 1 and 10%. Triclosan embedded commercial absorbable suture materials are used to reduce surgical site infection rate. This study was planned on mesh infection model, because of the low incidence rate. The agent isolated from mesh infections was mostly Staphylococcus aureus and thus it was used as the infecting agent in this research. To achieve a better therapeutic efficacy, triclosan was formulated in chitosan gels. Chitosan is an attractive biopolymer because of its biocompatible, biodegradable, bioadhesive properties. Gel formulations using chitosans (low, medium and high molecular weight) were prepared in 1% (v/v) acetic acid solution and in vitro release profiles were evaluated. Gel formulations showed release profile extended up to 7 days and high molecular weight chitosan gel formulation was released higher quantity drug than other formulations. Meshes coated with triclosan loaded chitosan gel were used to reduce bacterial count and to prevent mesh infection in the study. 24h and simultaneous bacteria inoculation was used to model mesh infection. The rats were observed for 8 days by means of surgical site infection. On the eighth day, the animals were sacrificed and the grafts were removed. Tissue squeezers were used to liberate bacterias from removed grafts. The isolated suspensions were cultured on blood agar plates and colony-forming units were counted overnight. Grafts coated with triclosan loaded chitosan gel presented satisfactory preventive effect against graft infection.

Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism.