99mTc-Labeled, Colistin Encapsulated, Theranostic Liposomes for Pseudomonas aeruginosa Infection.

Infectious diseases are still the major issue not only due to antibiotic resistance but also causing deaths if not diagnosed at early-stages. Different approaches including nanosized drug delivery systems and theranostics are researched to overcome antibiotic resistance, decrease the side effects of antibiotics, improve the treatment response, and early diagnose. Therefore, in the present study, nanosized, radiolabeled with 99mTc, colistin encapsulated, neutral and cationic liposome formulations were prepared as the theranostic agent for Pseudomonas aeruginosa infections. Liposomes exhibited appropriate physicochemical properties thanks to their nano-particle size (between 173 and 217 nm), neutral zeta potential value (about - 6.5 and 2.8 mV), as well as encapsulation efficiency of about 75%. All liposome formulations were radiolabeled with over 90% efficiency, and the concentration of stannous chloride was found as 1 mg.mL-1 to obtain maximum radiolabeling efficiency. In alamar blue analysis, neutral liposome formulations were found more biocompatible compared with the cationic formulations. Neutral colistin encapsulated liposomes were found to be more effective against P. aeruginosa strain according to their time-dependent antibacterial effect, in addition to their highest bacterial binding capacity. As conclusion, theranostic, nanosized, colistin encapsulated, neutral liposome formulations were found as promising agents for the imaging and treating of P. aeruginosa infections.

Chitosan-bovine serum albumin-Carbopol 940 nanogels for mupirocin dermal delivery: ex-vivo permeation and evaluation of cellular binding capacity via radiolabeling.

The goal of this study was to develop and examine the nanogel-based topical delivery system of mupirocin. Nanogels were prepared with chitosan and bovine serum albumin by ionic gelation and Carbopol 940 was added to improve the gelling/adhesive properties. Detailed characterization studies were performed and the cellular binding capacity of radiolabeled nanogels was investigated on CCD-1070Sk cell lines. Results indicate the successful formation of nanogels with particle size and zeta potential ranged between 341.920-603.320 nm and 13.120-24.300 mV, respectively. The mechanical and rheological studies proved pseudoplastic and strong elastic gel behavior (G' > G''). Mupirocin was successfully entrapped into nanogels with a ratio of more than 95% and the loaded drug was slowly released up to 93.89 ± 3.07% within 24 h. The ex vivo penetration and permeation percentages of mupirocin were very low (1.172 ± 0.202% and 0.161 ± 0.136%) indicating the suitability of nanogels for dermal use against superficial skin infections. The microbiological studies pointed out the effectiveness of nanogels against Staphylococcus aureus strains. Nanogels did not show toxicity signs and the cell binding capacity of radiolabeled formulations was found to be higher than [99mTc]NaTcO4 to CCD-1070Sk cell line. Overall, mupirocin nanogels might be considered as a potential and safe topical treatment option for bacterial skin infections.

Radiolabeled Tedizolid Phosphate Liposomes for Topical Application: Design, Characterization, and Evaluation of Cellular Binding Capacity.

Nowadays, the incidence of acute bacterial skin and skin structure infection (ABSSSI) is increasing. The increased bioavailability and reduced drug resistance of antibiotics are crucial to obtain a more effective treatment response in these infections. These favorable properties could be achieved by different drug delivery systems such as liposomes. In this study, nanosized, radiolabeled tedizolid phosphate liposomal formulations were prepared and evaluated with their in vitro cellular binding capacity and biocompatible profile for topical treatment of ABSSSI. Liposomes were characterized by evaluation of their visual inspection, particle size (about 190-270 nm), zeta potential value (around 0), and encapsulation efficiency (nearly 10%). The release rate of tedizolid phosphate from liposomes was also studied using dialysis membranes and evaluated kinetically. The stability of formulations was observed at three different temperatures and humidity conditions for 28 days. Afterward, liposomes were labeled with 99mTc, and the optimal amount of reducing agent (stannous chloride) was determined as 500 µg in this direct labeling procedure. All liposome formulations were successfully radiolabeled with high efficiency and exhibited high radiochemical purity (> 80%) during 6 h in different media. Furthermore, the cellular bindings of liposomal formulations were evaluated in human skin fibroblast cells by measuring the radioactivity. Higher radioactivity values were obtained in CCD-1070Sk cells incubated by liposome formulations compared to sodium pertechnetate. This finding suggested that liposomal formulation increased the cellular binding of radioactivity. By the result of our study, nanosized, tedizolid phosphate encapsulated liposome formulation was found to be a favorable carrier system in the treatment of ABSSSI.

Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation.

The purpose of this study was to develop a suitable mucoadhesive in situ gel formulation of clotrimazole (CLO) for the treatment of vaginal candidiasis. For this aim, the mixture of poloxamer (PLX) 407 and 188 were used to prepare in situ gels. Hydroxypropyl methylcellulose (HPMC) K100M or E50 was added to in situ gels in 0.5% ratio to improve the mucoadhesive and mechanical properties of formulations and to prolong the residence time in vaginal cavity. After the preparation of mucoadhesive in situ gels; gelation temperature/time, viscosity, mechanical, mucoadhesive, syringeability, spreadibility and rheological properties, in vitro release behavior, and anticandidal activities were determined. Moreover vaginal retention of mucoadhesive in situ gels was investigated with in vivo distribution studies in rats. Based on the obtained results, it was found that gels prepared with 20% PLX 407, 10% PLX 188 and 0.5% HPMC K100M/E50 might be suitable for vaginal administration of CLO. In addition, the results of in vivo distribution studies showed that gel formulations remained on the vaginal mucosa even 24 h after application. In conclusion, the mucoadhesive in situ gels of CLO would be alternative candidate for treatment of vaginal candidiasis since it has suitable gel properties with good vaginal retention.

Bioadhesive Nanoparticles as Potent Drug Delivery Carriers.

BACKGROUND: In recent years, numerous scientists have gained interest in nanotechnology- based systems, especially for biomedical applications. Then, nanocarriers present tunable abilities and can be easily functionalized to target specific epithelial cells, tissues, and organs, while various materials can be chosen and generate nanosized particles. At present, nanoparticles that possess bioadhesion have been studied as potent drug carriers since they can easily penetrate and target organs. OBJECTIVE: Aim of this study was to explore the various applications of the bioadhesive nanoparticles found in the literature. METHODS: Authors have studied the literature finding that bioadhesive nanoparticles can be administered via routes such as oral, topical, ocular, dermal, vaginal, etc., according to the clinician's opinion and treatment choice. Therefore, the knowledge of general characteristics of bioadhesive nanoparticles, the bioadhesion theory, and other properties of nanoparticles should be known for developing innovative bioadhesive drug nanocarriers. RESULTS: In this review article, the authors state the current knowledge of theories. In addition, the present categories of nanoparticles and their basic characteristics are also discussed. Finally, the biomedical applications of bioadhesive nanocarriers and the several administration routes are extensively reviewed. CONCLUSION: The review article aims to cover the most current bioadhesive nanoparticles for drug delivery to assist any scientist who desires to study or develop innovative bioadhesive formulations.

An Innovative Formulation Based on Nanostructured Lipid Carriers for Imatinib Delivery: Pre-Formulation, Cellular Uptake and Cytotoxicity Studies.

Imatinib (IMT) is a tyrosine kinase enzyme inhibitor and extensively used for the treatment of gastrointestinal stromal tumors (GISTs). A nanostructured lipid carrier system (NLCS) containing IMT was developed by using emulsification-sonication methods. The characterization of the developed formulation was performed in terms of its particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, loading capacity, sterility, syringeability, stability, in vitro release kinetics with mathematical models, cellular uptake studies with flow cytometry, fluorescence microscopy and cytotoxicity for CRL-1739 cells. The particle size, PDI, loading capacity and zeta potential of selected NLCS (F16-IMT) were found to be 96.63 ± 1.87 nm, 0.27 ± 0.15, 96.49 ± 1.46% and -32.7 ± 2.48 mV, respectively. F16-IMT was found to be stable, thermodynamic, sterile and syringeable through an 18 gauze needle. The formulation revealed a Korsmeyer-Peppas drug release model of 53% at 8 h, above 90% of cell viability, 23.61 µM of IC50 and induction of apoptosis in CRL-1739 cell lines. In the future, F16-IMT can be employed to treat GISTs. A small amount of IMT loaded into the NLCSs will be better than IMT alone for therapy for GISTs. Consequently, F16-IMT could prove to be useful for effective GIST treatment.

In vitro evaluation of mucoadhesive vaginal tablets of antifungal drugs prepared with thiolated polymer and development of a new dissolution technique for vaginal formulations.

The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.

Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base.

This study described the thermosensitive formulations composed of poloxamer mixtures for use as drug delivery platform via mucosal route. It also characterized the poloxamer mixtures' rheological, mechanical and mucoadhesive properties. Poloxamer (Plx) 407 and Plx 188 were used alone and together for preparing the mucosal drug delivery platform. The mixtures of Plx 407 and Plx 188 in ratio of 15:15 (F5); 15:20 (F6); 20:10 (F7) existed liquid at room temperature, but gelled at physiological temperature. Flow rheometry studies and oscillatory analysis of each formulation were performed at 20 ± 0.1°C and 37 ± 0.1°C. F5 and F7 formulations exhibited typical gel-type mechanical spectra (G' > G″) after the determined frequency value at 37°C whereas F6 behaved as weakly cross-linked gel. Texture profile analysis presented that F5 and F7 showed similar mechanical properties and can be used as base for mucosal dosage form. Mucoadhesion studies indicated the difference among the formulations and the effect of the mucosal surface on mucoadhesive properties. Mucin disc, bovine vaginal and buccal mucosa were used as mucosal platform for mucoadhesion studies. It is suggested that these investigations may be usefully combined to provide a more rational basis for selecting the ratio of Plx to prepare a topical thermosensitive drug delivery system for mucosal administration.

Recent trends on wound management: New therapeutic choices based on polymeric carriers.

Wound healing is an unmet therapeutic challenge among medical society since wound assessment and management is a complex procedure including several factors playing major role in healing process. Wounds can mainly be categorized as acute or chronic. It is well referred that the acute wound displays normal wound physiology while healing, in most cases, is seemed to progress through the normal phases of wound healing. On the other hand, a chronic wound is physiologically impaired. The main problem in wound management is that the majority of wounds are colonized with microbes, whereas this does not mean that all wounds will be infected. In this review, we address the problems that clinicians face to manage while treat acute and chronic wounds. Moreover, we demonstrate the pathophysiology, etiology, prognosis and microbiology of wounds. We further introduce the state of art in pharmaceutical technology field as part of wound management aiming to assist health professionals to overcome the current implications on wound assessment. In addition, authors review researches which included the use of gels and dermal films as wound healing agents. It can be said that natural and synthetic drugs or carriers provide promising solutions in order to meet the wound management standards. However, are the current strategies as desirable as medical society wish?

The effect of radiolabeled nanostructured lipid carrier systems containing imatinib mesylate on NIH-3T3 and CRL-1739 cells.

The aim of current study is to develop new nanostructured lipid carrier systems (NLCSs) containing imatinib mesylate (IMT) and evaluate their targeting efficiency on NIH-3T3 as fibroblast cells and CRL-1739 as gastric adenocarcinoma cells with radiolabeled formulations. Three formulations (F1-IMT, F2-IMT and F3-IMT) were prepared and radiolabeled with 1 mCi/0.1 mL of [99mTc]Tc. The effect of reducing and antioxidant agents on radiolabeling process was evaluated and radiochemical purity of formulations was performed by radio thin-layer radiochromatography (RTLC). The results demonstrated that the radiochemical purity was found to be above 90% for [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT, while radiochemical purity of [99mTc]Tc-F3-IMT was found to be 85.61 ± 2.24%. Also, [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT have better stability in cell medium and saline than [99mTc]Tc-F3-IMT. Targeting efficiency of [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT comparatively evaluated by cell binding studies with [99mTc]NaTcO4 on NIH-3T3 and CRL-1739 cells. The cell binding capacity and targeting/non-targeting cell uptake ratio of these two formulations was found to be higher than [99mTc]NaTcO4 in CRL-1739. It is thought that the knowledge achieved in this study would contribute to using [99mTc]Tc-F1-IMT and [99mTc]Tc F2-IMT as an diagnosis and treatment agents.

Strategies to prolong the intravaginal residence time of drug delivery systems.

The vagina has been studied as a favorable site for local and systemic delivery of drugs for female-related conditions. There are a large number of vaginal medications on the market and most of them require frequent application due to their short vaginal residence time. A prolonged vaginal residence time of formulations is therefore a key parameter for improved therapeutic efficacy. Promising approaches to prolong the residence time base on mucoadhesion, in- situ sol-gel transition and mechanical fixation. Mucoadhesive drug delivery systems can be tailored to adhere to the vaginal tissue. In-situ gelling systems offer the advantage of increased viscosity in vaginal cavity and consequently reduce outflow from the vagina. Mechanical fixation needs specially shaped drug delivery systems and reduce the frequency of administration significantly. Within this review an overview on these different strategies and systems is provided. Furthermore, the techniques to evaluate the potential of these systems for prolonged vaginal residence time are described.

Gemcitabine hydrochloride microspheres used for intravesical treatment of superficial bladder cancer: a comprehensive in vitro/ex vivo/in vivo evaluation.

INTRODUCTION: Bladder cancer is responsible for more than 130,000 deaths annually worldwide. Intravesical delivery of chemotherapeutic agents provides effective drug localization to the target area to reduce toxicity and increase efficacy. This study aimed to develop an intravesical delivery system of gemcitabine HCl (Gem-HCl) to provide a sustained-release profile, to prolong residence time, and to enhance its efficiency in the treatment of bladder cancer. MATERIALS AND METHODS: For this purpose, bioadhesive microspheres were successfully prepared with average particle size, encapsulation efficiency, and loading capacity of 98.4 µm, 82.657%±5.817%, and 12.501±0.881 mg, respectively. For intravesical administration, bioadhesive microspheres were dispersed in mucoadhesive chitosan or in situ poloxamer gels and characterized in terms of gelation temperature, viscosity, mechanical, syringeability, and bioadhesive and rheological properties. The cytotoxic effects of Gem-HCl solution, Gem-HCl microspheres, and Gem-HCl microsphere-loaded gel formulations were evaluated in two different bladder cancer cell lines: T24 (ATCC HTB4TM) and RT4 (ATCC HTB2TM). RESULTS: According to cell-culture studies, Gem-HCl microsphere-loaded poloxamer gel was more cytotoxic than Gem-HCl microsphere-loaded chitosan gel. Antitumor efficacy of newly developed formulations were investigated by in vivo studies using bladder-tumor-induced rats. CONCLUSION: According to in vivo studies, Gem-HCl microsphere-loaded poloxamer gel was found to be an effective and promising alternative for current intravesical delivery-system therapies.

Effect of microemulsion formulation on biodistribution of 99mTc-Aprotinin in acute pancreatitis models induced rats.

BACKGROUND: Aprotinin is a monomeric globular polypeptide, which derived from bovine lung tissue and theoretically attractive molecule in ameliorating the effects of acute pancreatitis. Acute pancreatitis is an inflammatory condition of the pancreas that is painful and at times deadly. Over the following two decades Aprotinin therapeutic potential on pancreatitis is proven experimentally, its clinical therapeutic success is limited due to low targeting to pancreas. OBJECTIVE: The aim of this study was to evaluate the biodistribution of Technetium-99m (99mTc)-Aprotinin solution (99mTc-Aprotinin-S) and 99mTc-Aprotinin loaded microemulsion, which was prepared for the aim of treatment for acute pancreatitis. METHOD: Aprotinin was radiolabeled with 99mTc. Radiochemical purity was determined with radioactive thin layer chromatography studies. 99mTc-Aprotinin-S and 99mTc-Aprotinin loaded microemulsion (99mTc-Aprotinin-M) was administered to acute edematous, severe necrotizing pancreatitis and air pouch model induced rats. Tissue distribution of Aprotinin was investigated with gamma scintigraphy and biodistribution studies. RESULTS: Aprotinin was radiolabeled by 99mTc with high radiochemical purity (95.430 ± 0.946%). The complex was found to be stable at room temperature up to 6 h. Animal studies have shown that similar to that of other small proteins Aprotinin is accumulated primarily in the kidney. The scintigraphy and biodistribution studies showed that, while i.v. administration of 99mTc-Aprotinin-S distributed mostly in kidneys and bladder, 99mTc-Aprotinin-M, with droplet size of 64.550 ± 3.217 nm, has high uptake in liver, spleen and pancreas. CONCLUSION: This might be concluding that microemulsions may be suggested as promising formulations for selectively targeting Aprotinin to pancreas inflammation.

Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan-thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers.

This study aimed to develop an intravesical delivery system of gemcitabine HCl for superficial bladder cancer in order to provide a controlled release profile, to prolong the residence time, and to avoid drug elimination via urination. For this aim, bioadhesive nanoparticles were prepared with thiolated chitosan (chitosan-thioglycolic acid conjugate) and were dispersed in bioadhesive chitosan gel or in an in situ gelling poloxamer formulation in order to improve intravesical residence time. In addition, nanoparticle-loaded gels were diluted with artificial urine to mimic in vivo conditions in the bladder and were characterized regarding changes in gel structure. The obtained results showed that chitosanthioglycolic acid nanoparticles with a mean diameter of 174.5±3.762 nm and zeta potential of 32.100±0.575 mV were successfully developed via ionotropic gelation and that the encapsulation efficiency of gemcitabine HCl was nearly 20%. In vitro/ex vivo characterization studies demonstrated that both nanoparticles and nanoparticle-loaded chitosan and poloxamer gels might be alternative carriers for intravesical administration of gemcitabine HCl, prolonging its residence time in the bladder and hence improving treatment efficacy. However, when the gel formulations were diluted with artificial urine, poloxamer gels lost their in situ gelling properties at body temperature, which is in conflict with the aimed formulation property. Therefore, 2% chitosan gel formulation was found to be a more promising carrier system for intravesical administration of nanoparticles.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

Aprotinin revisited: formulation, characterization, biodistribution and therapeutic potential of new aprotinin microemulsion in acute pancreatitis.

The aim of this study was to develop aprotinin-loaded microemulsion (MA) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (SA). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with (99m)Tc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of (99m)Tc-MA and SA were different. While MA was highly uptake by reticuloendothelial system, SA was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with MA significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, MA may be suggested as a promising alternative for treatment of acute pancreatitis.

Evaluation of chitosan based vaginal bioadhesive gel formulations for antifungal drugs.

The aim of the present study was to evaluate chitosan as a vaginal mucoadhesive gel base for econazole nitrate and miconazole nitrate. To this aim, different types of chitosan with different molecular masses and viscosity properties [low molecular mass chitosan (viscosity: 20,000 mPa s), medium molecular mass chitosan (viscosity: 200,000 mPa s), high molecular mass chitosan (viscosity: 800,000 mPa s)] have been used. First, rheological studies were conducted on chitosan gels. Mechanical, syringeability and mucoadhesive properties of chitosan gels were determined. Release profiles of econazole nitrate and miconazole nitrate from chitosan gels were obtained and evaluated kinetically. In addition, anticandidal activities of formulations were determined. Finally, vaginal retention of chitosan gels in rats was evaluated by in vivo distribution studies. Based on the results, it can be concluded that gels prepared with medium molecular mass chitosan might be effectively used for different antifungal agents in the treatment of vaginal candidiosis, since it has high mucoadhesiveness, suitable mechanical and release properties with good vaginal retention.

A comprehensive in vitro and in vivo evaluation of thiolated matrix tablets as a gastroretentive delivery system.

The aim of this study was to investigate the potential of thiolated matrix tablets for gastroretentive delivery systems. Poly(acrylic acid)-cysteine (PAA-Cys) and chitosan-4-thiobuthylamidine (chitosan-TBA) were evaluated as anionic and cationic thiolated polymers and riboflavin was used as a model drug. Tablets were prepared by direct compression and each formulation was characterized in terms of disintegration, swelling, mucoadhesion, and drug release properties. Thereafter, the gastric residence times of tablets were determined with in vivo study in rats. The resulting PAA-Cys and chitosan-TBA conjugates displayed 172.80 ± 30.33 and 371.11 ± 72.74 µmol free thiol groups, respectively. Disintegration studies demonstrated the stability of thiolated tablets up to 24 h, whereas tablets prepared with unmodified PAA and chitosan disintegrated within a time period of 1 h. Mucoadhesion studies showed that mucoadhesion work of PAA-Cys and chitosan-TBA tablets were 1.341- and 2.139-times higher than unmodified ones. The mucoadhesion times of PAA, PAA-Cys, chitosan, and chitosan-TBA tablets were 1.5 ± 0.5, 21 ± 1, 1 ± 0.5, 17 ± 1 h, respectively. These results confirm the theory that thiol groups react with mucin glycoproteins and form covalent bonds to the mucus layer. Release studies indicated that a controlled release was provided with thiolated tablets up to 24 h. These promising in vitro results of thiolated tablets were proved with in vivo studies. The thiolated tablets showed a gastroretention time up to 6 h, whereas unmodified tablets completely disintegrated within 1 h in rat stomach. Consequently, the study suggests that thiolated matrix tablets might be promising formulations for gastroretentive delivery systems.

In-situ gel formulations of econazole nitrate: preparation and in-vitro and in-vivo evaluation.

OBJECTIVES: This study describes the in-situ gelling of econazole nitrate containing thermosensitive polymers composed of poloxamer 407 and 188 as a novel treatment platform for vaginal candidiasis. METHODS: Aqueous thermosensitive formulations containing 1% of econazole nitrate and poloxamer 407 and/or 188 were prepared and their rheological, mechanical and drug-release properties determined at 20 ± 0.1°C and/or 37 ± 0.1°C. Based on their biologically suitable thermorheological properties, formulations containing the mixtures of poloxamer 407 and 188 in ratios of 15:15 (F1), 15:20 (F2) and 20:10 (F3) were chosen for comprehensive analysis. KEY FINDINGS: Formulations based on F3 exhibited typical gel-type mechanical spectra (G' > G″) at 37°C whereas formulations based on F1 and F2 exhibited properties akin to weakly cross-linked gels. Texture profile analysis demonstrated that F3 showed the highest cohesiveness, adhesiveness, hardness and compressibility. No statistically significant differences (P > 0.5) were observed in the release of econazole nitrate from the formulations at pH 4.5, which in all cases followed anomalous diffusion kinetics. Formulations based on 20% poloxamer 407:10% poloxamer 188 were chosen for in-vivo studies and were shown to be effective for the treatment of the vaginal candidiasis. Histopathologic evaluation also supported the effectiveness of the thermosensitive formulation administered intravaginally. CONCLUSION: By careful engineering of the rheological properties, in-situ thermosensitive gel formulations of econazole nitrate were prepared and were shown to be efficacious in the treatment of vaginal candidiasis.

Gastroretentive particles formulated with thiomers: development and in vitro evaluation.

The objective of this study is to develop and evaluate gastroretentive particulate delivery systems using Riboflavin-5'-monophosphate sodium salt dihydrate (RF5'PNa) as model drug. Poly(acrylic acid)-cysteine and chitosan-4-thiobuthylamidine were evaluated and compared as anionic and cationic polymers for gastroretentive particles. Permeation studies were performed with freshly excised stomach mucosa from rats. Polymers and combination with glutathione were evaluated for permeation enhancing properties. Furthermore, particles were prepared by air jet milling and characterized. Permeation studies showed that the apparent permeability coefficients for RF5'PNa with thiomers and glutathione are 1.511-fold and 2.354-fold higher than control, respectively. It can be seen from the results glutathione in combination with thiomers has a significant influence for increasing permeation. Poly(acrylic acid)-cysteine and chitosan-4-thiobuthylamidine particles demonstrated a mean diameter of 336.5 +/- 16.5 and 396.3 +/- 17.0 nm and zeta potential of -19.98 +/- 1.015 and 27.15 +/- 0.500 mV, respectively. The drug loading of Poly(acrylic acid) particles was significantly higher than chitosan particles. The release rate of RF5'PNa from the thiolated particles was slower compared with unmodified particles. Moreover, thiolated particles showed higher mucoadhesive properties compared to unmodified particles. Overall, thiolated particles of both anionic and cationic polymers had improved mucoadhesive and controlled release properties. Therefore, they could be promising for gastroretentive delivery systems.