Binary,ternary and microencapsulated celecoxib complexes with β-cyclodextrin formulated via hydrophilic polymers

Cyclodextrins are cyclic oligosaccharides, capable of forming inclusion complexes with many active substances. This way, the aqueous solubility and rate of dissolution of active substances can be changed. For this research we have selected celecoxib as the model active substance, due to its low water solubility, high lipophilicity, and high intestinal permeability. Usually, the amount of cyclodextrin complex that can be incorporated into a pharmaceutical dosage form is limited. The usage of hydrophilic polymers can overcome this problem. In this study, we wanted to point out the potential of various types of hydrophilic polymers for enhancing the complex formation efficiencies, and to highlight the possible use of alginate as a solubility stabilizer/enhancer and as a microsphere matrix polymer. The phase solubility investigation showed greater stability constants (> 250 M^?1) in ternary complexes than in the binary complex, which is a good indicator of the complex formation enhancer properties of these hydrophilic polymers. The relative solubilizing efficiency decreased in the next order: PVP K25 (6.49) > Sodium alginate (6.26) > PEG 6000 (5.72) > without polymer (4.81). The DSC curves showed that all samples that were prepared with β-cyclodextrin (both complexes and physical mixtures) had lower melting endotherms at 160 °C than pure celecoxib. XRD confirmed the complex formation by partial celecoxib amorphisation. The dissolution studies of the prepared microspheres revealed that all samples had different release rates (shown by the similarity factor f₂, which was 36.37, 42.46 and 38.11 % respectively) and that the use of β-cyclodextrin increased the dissolution rate of celecoxib from alginate microspheres in a controlled manner. We concluded that sodium alginate could act as a complex stabilizing/enhancing agent and as a microsphere matrix polymer, at the same time.     

Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer

Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic^® F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of β-CD and HP-β-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.     

Energy absorption behavior of stiffness optimized graded lattice structures fabricated by material extrusion

The objective of this study is to investigate the energy absorption performance of the graded lattice energy absorbers designed by a stiffness-based size optimization process under static loadings applied during the in-service conditions. The energy absorber geometry is modeled using three different lattice types, namely complex cubic, octet cubic, face- and body-centered cubic. The stiffness-based size optimization subjected to a static bending load is conducted to determine the optimal strut diameters which produced graded lattice structure designs. To investigate the energy absorption behavior of these graded lattice designs, the nonlinear dynamic explicit finite element analysis (FEA) is conducted under quasi-static compression for each design. The lattice designs are fabricated by a material extrusion technique using the polylactic acid material and the quasi-static uniaxial compression tests are conducted on the fabricated designs. The FEA results are found to be in good agreement with the experimental results. When compared with uniform counterparts, the presented graded lattices exhibit the improved energy absorption in response to uniaxial compression although their designs were derived from a stiffness-based size optimization with bending load.

     

A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers

Clinically, different approaches are adopted worldwide for the treatment of cancer, which still ranks second among all causes of death. Immunotherapy for cancer treatment has been the focus of attention in recent years, aiming for an eventual antitumoral effect through the immune system response to cancer cells both prophylactically and therapeutically. The application of nanoparticulate delivery systems for cancer immunotherapy, which is defined as the use of immune system features in cancer treatment, is currently the focus of research. Nanomedicines and nanoparticulate macromolecule delivery for cancer therapy is believed to facilitate selective cytotoxicity based on passive or active targeting to tumors resulting in improved therapeutic efficacy and reduced side effects. Today, with more than 55 different nanomedicines in the market, it is possible to provide more effective cancer diagnosis and treatment by using nanotechnology. Cancer immunotherapy uses the body’s immune system to respond to cancer cells; however, this may lead to increased immune response and immunogenicity. Selectivity and targeting to cancer cells and tumors may lead the way to safer immunotherapy and nanotechnology-based delivery approaches that can help achieve the desired success in cancer treatment.     

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.     

Determination of water (moisture) and dry matter in animal feed, grain, and forage (plant tissue) by Karl Fischer titration: collaborative study

A Karl Fischer method for determining water (dry matter) in animal feed and forages was collaboratively studied. Water was extracted from animal feed or forage material into methanol-formamide (1 + 1) directly in the Karl Fischer titration vessel by high-speed homogenization. The water was titrated at 50 degrees C with one-component Karl Fischer reagent based on imidazole. Ten blind samples were sent to 9 collaborators in the United States, Canada, and Germany. The within-laboratory relative standard deviation (repeatability) ranged from 1.14 to 6.99% for water or from 0.09 to 0.56% for dry matter. Among-laboratory (including within-) relative standard deviation (reproducibility) ranged from 5.35 to 10.73%, or from 0.44 to 0.77% for dry matter. The authors recommend that the method be adopted as Official First Action by AOAC INTERNATIONAL. A comparable alternative extraction procedure using boiling methanol is also recommended for Official First Action.     

Development of implantable hydroxypropyl-β-cyclodextrin coated polycaprolactone nanoparticles for the controlled delivery of docetaxel to solid tumors

Treatment of cancer is one of the most challenging problems and conventional therapies are inadequate for targeted, effective and safe therapy. Development of nanoparticle-based drug delivery systems emerge as promising carriers in this field to ensure delivery of anticancer drug to tumor site. The aim of this study was to design hydroxypropyl-β-cyclodextrin (CD) coated nanoparticles using poly(ε-caprolactone) (PCL) and its derivative poly(ethylene glycol)-block-poly(ε-caprolactone) (mePEG-PCL) to be applied as implants to tumor site following surgical operation in cancer patients. CD coated PCL and mePEG-PCL nanospheres were developed to encapsulate poorly soluble chemotherapeutic agent docetaxel (DOC) to improve solubility of drug and to enhance cellular penetration with longer residence time and higher local drug concentration. Nanospheres were prepared according to the nanoprecipitation method and coated with hydroxypropyl-β-cyclodextrin (Cavasol^® W7HP). Cyclodextrin coating was performed for higher drug encapsulation and controlled but complete drug release from nanoparticles. Nanoparticle diameters varied between 60 and 136 nm depending on polymer used for preparation and coating. All nanoparticles have negative surface charge and zeta potential values varied between ?22 and ?37 mV. Encapsulation efficiency of formulations were found to be between 46 and 73 % and CD coated nanoparticles have significantly higher entrapment efficiency. Drug release profiles of nanoparticles were similar to each other and all formulations released encapsulated drug in approximately 12 h. Especially, CD-PCL nanoparticles were found to have highest entrapment efficiency and anticancer efficacy against MCF-7 human breast adenocarcinoma cell lines. Our study proved that polycaprolactone and its PEGylated derivatives can be suitable for development of implantable nanoparticles as a potential drug delivery system of DOC for cancer treatment and a good candidate for further in vivo studies.     

Rapamycin-cyclodextrin complexation: improved solubility and dissolution rate

The objective of this study was to improve poor aqueous solubility and dissolution properties of anticancer drug rapamycin through formation of inclusion complexes with natural and modified cyclodextrins. Of the cyclodextrins tested, ??-cyclodextrin and hydroxypropyl-??-cyclodextrin did not complex with rapamycin. However, complexes of rapamycin with ??-cyclodextrin, methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin were prepared and characterized by techniques such as Fourier Transform infrared spectroscopy, differential scanning calorimetry, phase solubility analysis and in vitro dissolution studies. According to the characterization data for the complexes, rapamycin water solubility was highly enhanced by all three ??-cyclodextrins with methyl-??-cyclodextrin complex resulting in particularly higher solubility enhancement. FTIR spectra and DSC thermograms supported the formation of inclusion complexes. The complexes showed highly improved dissolution rate in water. Complexation with cyclodextrin derivatives such as methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin can provide promising alternatives for the formulation of rapamycin.     

Investigation of photophysical and photochemical properties of phthalocyanines bearing fluorinated groups

This study presents synthesis of novel peripherally tetrasubstituted Zn(II) and In(III) phthalocyanine complexes bearing 3,5-bis(trifluoromethyl)phenoxy groups. These phthalocyanines were characterized by performing elemental analysis, mass spectrometry, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and ultraviolet visible spectrophotometric techniques. Aggregation properties of the resulting phthalocyanines were studied in different concentrations of DMSO. Aggregation behavior of the newly synthesized phthalocyanines was investigated in various organic solvents, as well. Photochemical and photophysical characterization of the resulting compounds were carried out to evaluate their photodynamic therapy properties in DMSO. The new metallophthalocyanines have high singlet oxygen quantum yields ranging from 0.72 to 0.88.     

Complexation behavior of antiestrogen drug tamoxifen citrate with natural and modified β-cyclodextrins

Inclusion complexes of the poorly-soluble antiestrogen drug tamoxifen citrate (TMX) were prepared with β-cyclodextrin (β-CD) and 2,3-di-O-hexanoyl-β-cyclodextrin (β-CDC6) being natural and amphiphilic cyclodextrins, respectively using the co-lyophilization technique. Complexation occurred in aqueous medium for natural cyclodextrin β-CD and a medium of water:ethanol mixture for the amphiphilic cyclodextrin β-CDC6. The complexes were characterized using analytical techniques including Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FTIR) and proton Nuclear Magnetic Resonance Spectrometry (¹H NMR). Anticancer efficacies of the complexes were determined against MCF-7 human breast carcinoma cell line with MTT assay. It was found that tamoxifen citrate can be incorporated in the cavity for β-CD and both in the cavity and the aliphatic chains for β-CDC6. The latter having two hydrophobic sites for inclusion of water-insoluble drug exhibited significantly higher anticancer efficacy accordingly.