ABSTRACT
Hepatospecific delivery by ligand based receptor targeting is an established strategy to augment therapy associated with liver diseases and disorders. Previously, we have investigated the effect of ligand headgroup on cellular uptake mediated by the asialoglycoprotein receptor by in silico and in vitro approach. In this paper, we report the design of agarose based liposomes for delivery to liver cancer cells and provide a proof of concept of the targeting efficiency against galactose liposomes using an in vivo approach. Sorafenib Tosylate loaded targeting liposomes were developed and optimized using factorial design. Comparative evaluation including cell cytotoxicity, pharmacokinetics and biodistribution and hepatospecific uptake was performed for both the liposomal systems. The formulations possessed a particle size of 150 - 180 nm and a zeta potential of 30 - 60 mV depending on the amount of ligand and drug loading, with more than 90% entrapment efficiency. A two-fold increase in cytotoxicity was observed with agarose-based liposomes as compared to galactose based liposomes. In vivo PK evaluation indicated a reduction in half life of drug when loaded in agarose ligand loaded system, probably due to greater uptake in the liver as evidenced in biodistribution study. Intrahepatic disposition revealed a higher PC/NPC uptake ratio with the targeted systems as compared to conventional liposomes, although the agarose-based system resulted in highest uptake ratio. A biocompatible platform for specific delivery of drugs to hepatocytes was established validating a rational approach to design liver targeting systems.
Subject(s)
Galactose , Liposomes , Drug Delivery Systems , Ligands , Liposomes/pharmacokinetics , Liver/metabolism , Monosaccharides/metabolism , Monosaccharides/pharmacology , Particle Size , Polysaccharides/pharmacology , Sepharose/metabolism , Sepharose/pharmacology , Sorafenib/pharmacology , Tissue DistributionABSTRACT
Ligands with the polysaccharide headgroups have been recently reported by our group to possess enhanced interaction with asialoglycoprotein receptor (ASGPR) in silico as compared to ligands having galactose moieties. This enhanced interaction is a result of the polymer's backbone support in anchoring the ligand in a specific orientation within the bilayer. In this paper, we have attempted to provide an in vitro proof of concept by performing a comparative evaluation of polysaccharide and monosaccharide-based ligands. Docking was performed to understand interaction with ASGPR in silico. Agarose and galactose conjugates with behenic acid were synthesized, purified, and characterized to yield biocompatible hepatospecific ligands which were incorporated into nanoliposomes. Cellular internalization of these targeted liposomes was studied using confocal microscopy and flow cytometry. The toxicity potential was assessed in vivo. Results indicated that the polysaccharide-based ligand increased cellular uptake due to better interaction with the receptor as compared to ligand bearing a single galactose group. In addition to developing novel liver targeting ligands, the study also established proof of concept that has been suggested by earlier in silico investigations. The approach can be used to design targeting ligands and develop formulations with improved targeting efficacy.
Subject(s)
MonosaccharidesABSTRACT
AIM: To investigate comparative in vitro and in vivo performance of lipid vesicular and particulate systems in escalating oral bioavailability for superior hepatoprotection. MATERIALS AND METHODS: Systems were fabricated using easy to scale up process and novel excipients to deliver Silibinin. In vitro characterization followed by pharmacokinetic and pharmacodynamic evaluation in rats was conducted to establish a correlation. RESULTS: Nanoformulations resulted in 20 fold increase in solubilisation and significant increase in permeation. 2.5 fold increase in bioavailability was evident in vivo. Vesicles demonstrated greatest hepatoprotective potential in efficacy study. CONCLUSION: The findings establish a link between in vitro and in vivo performance to rank order lipid nanoartchitects. Concurrently, a significant potential in therapeutic intervention of hepatotoxicity is envisaged as elucidated.
Subject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Excipients/chemistry , Lipids/chemistry , Liver/enzymology , Nanotechnology/methods , Silybin/chemistry , Administration, Oral , Animals , Biological Availability , Carbon Tetrachloride , Drug Liberation , Drug Stability , Female , In Vitro Techniques , Particle Size , Permeability , Rats , Silybin/blood , Silybin/pharmacokinetics , Silybin/pharmacology , Solubility , Surface PropertiesABSTRACT
Successful cytosolic delivery enables opportunities for improved treatment of various genetic disorders, infectious diseases and cancer. Cationic nanoemulsions were designed using alternative excipients and evaluated for particle size, charge, effect of sterilization on its stability, DNA condensation potential and cellular uptake efficiency. Various concentrations of non-ionic and ionic stabilizers were evaluated to design formula for colloidally stable cationic nanoemulsion. The nanoemulsion comprised of 5% Capmul MCM, 0.5% didodecyldimethylammonium bromide (DDAB), 1% phospholipid, 1% Poloxamer 188 and 2.25% glycerol and possessed particle size of 81.6 ± 3.56 nm and 137.1 ± 1.57 nm before and after steam sterilization, respectively. DNA condensation studies were carried out at various nanoemulsion: DNA ratios ranging from 1:1 to 10:1. Cell uptake studies were conducted on human embryonic kidney (HEK) cell lines which are widely reported for transfection studies. The nanoemulsions showed excellent cellular uptake as evaluated by fluorescence microscopy and flow cytometry. Overall, a colloidally stable cationic nanoemulsion with good DNA condensation ability was successfully fabricated for efficient cytosolic delivery and potential for in vivo effectiveness.
ABSTRACT
The aim of study was to develop self-nanoemulsifying pellets (SNEP) for oral delivery of poorly water soluble drug, repaglinide (RPG). Solubility of RPG in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). The surfactants and cosurfactants were screened for their ability to emulsify oily phase. Ternary phase diagrams were constructed to identify nanoemulsification area for the selected systems. SNEDDS formulations with globule size less than 100 nm were evaluated for in vivo anti-hyperglycemic activity in neonatal streptozotocin rat model. A significant reduction in glucose levels was produced by optimized SNEDDS formulation in comparison to the control group. The optimized SNEDDS formulations were pelletized via extrusion/spheronization technique using microcrystalline cellulose and lactose. SNEP were characterized by X-ray powder diffraction and scanning electron microscopy. X-ray diffraction study indicated loss of crystallinity of RPG in SNEP. The SNEP exhibited good flow properties, mechanical strength and formed nanoemulsion with globule size less than 200 nm. SNEP showed in vitro release of more than 80% RPG in 10 min which was significantly higher than RPG containing reference pellets. In conclusion, our studies illustrated that RPG, a poorly water soluble drug can be successfully formulated into SNEP which can serve as a promising system for the delivery of poorly water soluble drugs.
Subject(s)
Carbamates/chemistry , Drug Design , Emulsions , Hypoglycemic Agents/chemistry , Nanostructures , Piperidines/chemistry , Animals , Carbamates/pharmacology , Chromatography, High Pressure Liquid , Hydrogen-Ion Concentration , Hypoglycemic Agents/pharmacology , Microscopy, Electron, Scanning , Piperidines/pharmacology , Powder Diffraction , Rats , Solubility , Surface-Active Agents/chemistryABSTRACT
The objective of the present investigation was to establish potential of commercially available soy polysaccharide (Emcosoy®) for colon drug delivery. The soy polysaccharide-ethyl cellulose films were fabricated and characterized. The effect of the pectinase enzyme on the tensile strength and surface morphology of the film was evaluated. The permeation of chlorpheniramine maleate (CPM), a model hydrophilic drug from pectinase enzyme treated and untreated films was measured in pH 7.4 buffer. The soy polysaccharide-ethyl cellulose films were also incubated with Lactobacillus sp. culture for a specific duration, and effect on the CPM permeation was evaluated. The CPM capsules were coated with the soy polysaccharide-ethyl cellulose mixture, and Eudragit S100 was applied as a secondary coat. The coated CPM capsules were radiolabelled, and their in vivo transit was evaluated in human volunteers on oral administration. The pectinase enzyme had a significant influence on the tensile strength and surface morphology of the soy polysaccharide-ethyl cellulose films. The permeability of pectinase enzyme-treated and Lactobacillus sp.-treated films was significantly higher than that of untreated films. The CPM capsules were coated with the soy polysaccharide-ethyl cellulose mixture and Eudragit S100 and were successfully radiolabelled by a simple method. Gamma scintigraphic studies in human volunteers showed that the radiolabelled capsules maintained integrity for at least 9 h after oral administration. Thus, the soy polysaccharide has a potential in colon drug delivery.
Subject(s)
Colon/metabolism , Drug Delivery Systems/methods , Polysaccharides/administration & dosage , Polysaccharides/metabolism , Soybean Proteins/administration & dosage , Soybean Proteins/metabolism , Adult , Capsules , Colon/drug effects , Drug Evaluation, Preclinical/methods , Humans , Male , Polysaccharides/chemistry , Soybean Proteins/chemistry , Young AdultABSTRACT
The potential of positively charged polymeric nanoparticles in improving therapeutic efficacy of meloxicam (MLX), a poorly water-soluble anti-inflammatory agent was evaluated. MLX loaded positively charged nanoparticles were prepared by using poly-epsilon-caprolactone (PCL) as a biodegradable polymer and didodecyldimethylammonium bromide (DDAB) as a cationic surfactant. The MLX nanoparticles were characterized for particle size and encapsulation efficiency. MLX loaded PCL nanoparticles and MLX suspension were evaluated for their in vivo anti-inflammatory activity and ulcerogenic potential. MLX loaded PCL nanoparticles had particle sizes of approximately 300 nm and the encapsulation efficiency of MLX was approximately 90%. The polymeric nanoparticles significantly improved the anti-inflammatory activity of MLX (P< 0.01) as compared to that of MLX suspension. The higher anti-inflammatory effect was maintained for a longer duration (6 h). The polymeric nanoparticles also resulted in less ulcerogenicity as compared to that of MLX suspension.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Nanoparticles/chemistry , Thiazines/administration & dosage , Thiazines/therapeutic use , Thiazoles/administration & dosage , Thiazoles/therapeutic use , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Caproates , Carrageenan , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Foot/pathology , Freeze Drying , Lactones , Male , Meloxicam , Particle Size , Polymers/chemistry , Quaternary Ammonium Compounds/chemistry , Rats , Rats, Sprague-Dawley , Stomach Ulcer/chemically induced , Surface-Active Agents/chemistry , Suspensions , Thiazines/adverse effects , Thiazoles/adverse effectsABSTRACT
Supercritical fluid extract and ethanol extract of Vitex negundo Linn. were subjected to the chromatographic evaluation for identification of their constituents. Free radical scavenging activity of both extracts was studied by subjecting them to DPPH assay. IC(50) values of ethanol and supercritical fluid extract of Vitex negundo indicate that ethanol extract has stronger reducing potential and ability to scavenge free radicals as compared to the supercritical fluid extract. The in vivo effect of extracts on lipid peroxidation was studied using ethanol induced oxidative stress model in rat. Ingestion of extracts for 14 days exhibited significant reduction in plasma MDA level of stressed animals. Ethanol extract exhibited higher in vivo antilipid peroxidation potential as compared to supercritical fluid extract which correlated well with radical scavenging potential of extract.
ABSTRACT
The aerodynamic diameter of pharmaceutical aerosols is the main factor governing their deposition in the human respiratory tract. Particle size of the pharmaceutical aerosols is characterized by liquid impingers and Andersen Cascade Impactors. The present study was aimed at comparing two metered dose inhaler formulation containing formoterol fumarate (6 µg) and budesonide (200 µg). These two formulations were evaluated by using Twin Stage Impinger and Andersen Cascade Impactor. Study revealed that developed metered dose inhaler I formulation of the formoterol fumarate and budesonide had lower mass median aerodynamic diameter and higher fine particle fraction than marketed formulation.
ABSTRACT
The present investigation describes organic volatile solvent-free approach for the single step fabrication of Eudragit nanoparticles. The solubility of various grades of Eudragit viz. Eudragit L100-55, Eudragit L100, Eudragit S100, Eudragit EPO, Eudragit RSPO and Eudragit RLPO in Labrasol (Caprylocaproyl macrogol-8 glycerides) was determined. We observed that Labrasol has the ability to solubilize various cationic Eudragits such as Eudragit RSPO, Eudragit RLPO and Eudragit EPO at a concentration as high as 200 mg/ml. We also evaluated the ability of Labrasol to act as a nanoparticle stabilizer due to its amphiphilic nature and high HLB of 14. It was observed that Eudragit EPO, Eudragit RSPO and Eudragit RLPO nanoparticles of size 110-150 nm could be easily fabricated using Labrasol as a solubilizer and nanoparticle stabilizer. Transmission electron microscopy was carried out to confirm the size and morphology of the nanoparticles. We could encapsulate hydrophobic drugs such as repaglinide and triclosan in the Eudragit RLPO nanoparticles as Labrasol also had the ability to solubilize these hydrophobic drugs. The ability of Eudragit RSPO and RLPO nanoparticles to condense plasmid DNA was also established. This is the first report that demonstrates the polymer solubilizing potential of Labrasol.
Subject(s)
Excipients/chemistry , Nanoparticles , Polymethacrylic Acids/chemistry , Anti-Infective Agents, Local/administration & dosage , Anti-Infective Agents, Local/chemistry , Carbamates/administration & dosage , Carbamates/chemistry , DNA/administration & dosage , DNA/chemistry , Drug Compounding , Glycerides , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Microscopy, Electron, Transmission , Organic Chemicals/chemistry , Particle Size , Piperidines/administration & dosage , Piperidines/chemistry , Plasmids/chemistry , Solvents , Triclosan/administration & dosage , Triclosan/chemistryABSTRACT
A simple, specific and sensitive reverse phase high performance liquid chromatographic method was developed and validated for simultaneous determination of ezetimibe and simvastatin from pharmaceutical dosage forms. The method uses C18 ODS Hypersil column and isocratic elution. The mobile phase composed of acetonitrile:phosphate buffer (pH 4.5, 0.01M) in the ratio of 65:35 v/v was used at a flow rate of 1.0 ml /min. UV detector was programmed at 232 nm for first 10 min and at 238 nm for 10 to 20 min. All the validation parameters were in acceptable range. The developed method was effectively applied to quantitate amount of ezetimibe and simvastatin from tablets. The method was also applied suitably for determining the degradation products of ezetimibe and simvastatin.
ABSTRACT
Supercritical fluid extract of leaves of Vitex negundo was tested for its antimicrobial potential and was compared with that of ethanol extract, ether extract and hydrodistilled oil of leaves. The chemical constituents of extracts were studied by chromatographic techniques. Extracts were evaluated for antimicrobial potential against bacterial strains like Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and yeast Candida albicans. Extracts showed prominent antibacterial activity against Bacillus subtilis and Staphylococcus aureus. Supercritical fluid extract exhibited good antibacterial potential.
ABSTRACT
The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid-hydroxypropyl-beta-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Ketorolac/administration & dosage , beta-Cyclodextrins/chemistry , 2-Hydroxypropyl-beta-cyclodextrin , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Biological Availability , Cricetinae , Drug Carriers , In Vitro Techniques , Ketorolac/chemistry , Ketorolac/pharmacokinetics , Liposomes , Skin Absorption , Spectrophotometry, UltravioletABSTRACT
Self-nanoemulsifying granules were formulated with the objective of improving the bioavailability of the ezetimibe and simvastatin when administered together. Composition of self-nanoemulsifying system (SNS) was optimized using various modified oils, surfactant, and cosurfactant mixtures. SNSs were mixed with water and resultant emulsions were characterized for mean globule size and stability. SNSs were adsorbed on hydrophilic colloidal silicon dioxide to give free-flowing self-nanoemulsifying granules. Self-nanoemulsifying granules were characterized by X-ray diffraction pattern, scanning electron microscopy, dissolution profile, and for in vivo performance in hypercholesterolemic rats. X-ray diffraction studies and scanning electron microscopy indicated loss of crystallinity and/or solubilization of both drugs in the self-nanoemulsifying granules. Self-nanoemulsifying granules effected substantial increase in dissolution of the drugs as compared with pure powder of drugs. In vivo evaluation in rats showed significant decrease in the total cholesterol levels and triglyceride levels in rats as compared with positive control confirming potential of self-nanoemulsifying granules as a drug delivery system for the poorly water-soluble drugs.
Subject(s)
Anticholesteremic Agents/administration & dosage , Azetidines/administration & dosage , Simvastatin/administration & dosage , Administration, Oral , Animals , Azetidines/chemistry , Azetidines/pharmacology , Chemistry, Pharmaceutical , Cholesterol/blood , Emulsions , Ezetimibe , Male , Microscopy, Electron, Scanning , Nanoparticles , Rats , Rats, Sprague-Dawley , Simvastatin/chemistry , Simvastatin/pharmacology , Solubility , X-Ray DiffractionABSTRACT
Self-nanoemulsifying granules (SNGs) were formulated with the objective of enhancing the bioavailability of the ezetimibe. Various modified oils, surfactant and cosurfactant mixtures were used and composition of self-nanoemulsifying system (SNS) was optimized. SNS diluted and resultant emulsion was characterized for mean globule size and stability. The self-nanoemulsifying systems were formulated into free flowing self-nanoemulsifying granules using varying proportions of hydrophilic colloidal silicon dioxide as an adsorbing agent. Self-nanoemulsifying granules were characterized by X-ray diffraction pattern, differential scanning calorimetry, dissolution profile and for in vivo performance in rats. X-ray diffraction studies indicated loss of crystallinity and/or solubilisation of ezetimibe in the self-nanoemulsifying granules. It was supported by SEM studies, which did not show evidence of precipitation of the drug on the surface of the carrier. Dissolution studies revealed remarkable increase in dissolution of the drug as compared to plain drug. In vivo evaluation in rats showed significant decrease in the total cholesterol levels as compared to positive control. The SNGs filled into hard gelatin capsules showed two to threefold increase in the dissolution rate as compared to plain drug filled capsules signifying its potential in improved delivery of lipophilic drugs.
Subject(s)
Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Emulsions , Hypercholesterolemia/drug therapy , Nanoparticles , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacokinetics , Azetidines/chemistry , Azetidines/pharmacokinetics , Biological Availability , Calorimetry, Differential Scanning , Capsules , Chemistry, Pharmaceutical , Cholesterol/blood , Crystallography, X-Ray , Disease Models, Animal , Ezetimibe , Hydrogen-Ion Concentration , Hypercholesterolemia/blood , Male , Microscopy, Electron, Scanning , Oils/chemistry , Rats , Rats, Sprague-Dawley , Silicon Dioxide/chemistry , Solubility , Surface-Active Agents/chemistryABSTRACT
Parenteral delivery of the hydrophobic drugs is a very challenging task. The conventional approaches such as use of co-solvents, oily vehicles and modern approaches such as mixed micelles, liposomes, complexation with cyclodextrins and emulsions have several limitations. Microemulsions have evolved as a novel vehicle for parenteral delivery of the hydrophobic drugs. Their interesting features such as spontaneity of formation, ease of manufacture, high solubilization capacity and self-preserving property make them the vehicle of choice. The review focuses on the excipients available for formulation of the parenteral microemulsions and describes the investigations reported for the various classes of therapeutic agents.
Subject(s)
Emulsions/chemistry , Nanoparticles/chemistry , Animals , Chemical Phenomena , Chemistry, Pharmaceutical , Chemistry, Physical , Drug Delivery Systems , Humans , Infusions, Parenteral , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistry , Surface-Active Agents/chemistryABSTRACT
Self-nanoemulsifying drug delivery systems (SNEDDS) were developed with the objective to overcome problems associated with the delivery of cefpodoxime proxetil (CFP), a poorly bioavailable high dose antibiotic having pH dependant solubility. Solubility of CFP in oily phases and surfactants was determined to identify components of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify selected oily phases. Ternary phase diagrams were constructed to identify area of nanoemulsification for the selected systems. The influence of CFP and the pH of dilution medium on the phase behavior of selected system were assessed. The globule size of optimized CFP SNEDDS in various dissolution media was determined to check the effect of pH on its behavior. The optimized CFP SNEDDS needed surfactant content less than 40% and yielded nanoemulsion of mean globule size 170 nm, which was not affected by the pH of dilution medium. The optimized SNEDDS released CFP completely within 20 min irrespective of the pH of dissolution medium.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Ceftizoxime/analogs & derivatives , Drug Delivery Systems , Ceftizoxime/administration & dosage , Emulsions , Hydrogen-Ion Concentration , Nanomedicine , Solubility , Cefpodoxime ProxetilABSTRACT
Acne is the most common cutaneous disorder of multifactorial origin with a prevalence of 70-85% in adolescents. The majority of the acne sufferers exhibit mild to moderate acne initially, which progresses to the severe form in certain cases. Topical therapy is employed as first-line treatment in mild acne, whereas for moderate and severe acne, systemic therapy is required in addition to topical therapy. Currently, several topical agents are available that affect at least one of the main pathogenetic factors responsible for the development of acne. Although topical therapy has an important position in acne treatment, side effects associated with various topical antiacne agents and the undesirable physicochemical characteristics of certain important agents like tretinoin and benzoyl peroxide affect their utility and patient compliance. Novel drug delivery strategies can play a pivotal role in improving the topical delivery of antiacne agents by enhancing their dermal localization with a concomitant reduction in their side effects. The current review emphasizes the potential of various novel drug delivery strategies like liposomes, niosomes, aspasomes, microsponges, microemulsions, hydrogels and solid lipid nanoparticles in optimizing and enhancing the topical delivery of antiacne agents.
Subject(s)
Acne Vulgaris/drug therapy , Dermatologic Agents/administration & dosage , Drug Delivery Systems , Administration, Cutaneous , Animals , Dermatologic Agents/adverse effects , HumansABSTRACT
Solid dispersions of Celecoxib were prepared with hydroxypropyl beta cyclodextrin by various methods such as physical mixture, cogrinding, kneading, and coevaporation. The dispersions were characterized by differential scanning calorimetry (DSC), X-ray diffraction patterns, infrared spectroscopy, and nuclear magnetic resonance studies. The DSC thermograms of the dispersions indicated potential of heat-induced interaction between Celecoxib and cyclodextrin that could influence in vitro drug dissolution. The dispersions exhibited faster rates of dissolution compared to that of Celecoxib. The kneaded dispersion with the fastest in vitro dissolution rate when compressed into tablets showed a better release profile compared to the tablets of pure Celecoxib. In vivo studies revealed that the kneaded dispersion provided for quicker response and was more effective in inhibiting rat paw edema as compared to Celecoxib alone, thus confirming the advantage of improved pharmacological activity of Celecoxib when administered as a solid dispersion with cyclodextrin.
Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/pharmacokinetics , Excipients/chemistry , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/pharmacokinetics , beta-Cyclodextrins/chemistry , 2-Hydroxypropyl-beta-cyclodextrin , Administration, Oral , Animals , Calorimetry, Differential Scanning , Celecoxib , Chemistry, Pharmaceutical , Cyclooxygenase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Rats , Rats, Wistar , Solubility , Sulfonamides/administration & dosage , TabletsABSTRACT
The purpose of this research was to improve the solubility and therefore dissolution and bioavailability of triamterene, a poorly water soluble diuretic, by complexation with beta-cyclodextrin. Triamterene has been reported to show low bioavailability after oral administration, with wide intersubject variation. This study presents the formulation of solid dispersions of triamterene with beta-cyclodextrin--by cogrinding, kneading, and coevaporation, using low pH conditions--and their characterization, evaluation of improvement in dissolution profiles, and in vivo advantage. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 167.67 M(-1). The solid dispersions were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, x-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the phenyl ring of triamterene within the nonpolar cavity of beta-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1N HCl and pH 6.8 phosphate buffer was observed with all dispersions, especially the coevaporate. The coevaporate, when administered orally in rats, also exhibited improved in vivo activity, as measured by net sodium ion excretion, as compared with triamterene powder. Thus, coevaporation of the drug and beta-cyclodextrin from acidified alcohol provide the optimum condition for inclusion complexation to give a binary system with remarkable improvement in in vitro drug release profile and in vivo performance.