Enhanced Intestinal Permeability of Cefixime by Self-Emulsifying Drug Delivery System: In-Vitro and Ex-Vivo Characterization.

BACKGROUND: Cefixime (CFX) belongs to a group of third-generation cephalosporin antibiotics with low water solubility and low intestinal permeability, which ultimately leads to significantly low bioavailability. AIM: This study aimed to increase solubility, improve drug release, and intestinal permeability of CFX by loading into SEDDS. METHODS: Suitable excipients were selected based on drug solubility, percent transmittance, and emulsification efficiency. Pseudo-ternary phase diagram was fabricated for the identification of effective self-emulsification region. The best probably optimized formulations were further assessed for encumbered drug contents, emulsification time, cloud point measurement, robustness to dilution, mean droplet size, zeta potential, polydispersity index (PDI), and thermodynamic and chemical stability. Moreover, in vitro drug release studies and ex vivo permeation studies were carried out and apparent drug permeability Papp of different formulations was compared with the marketed brands of CFX. RESULTS: Amongst the four tested SEDDS formulations, F-2 formulation exhibited the highest drug loading of 96.32%, emulsification time of 40.37 ± 3 s, mean droplet size of 19.01 ± 1.12 nm, and demonstrated improved long-term thermodynamic and chemical stability when stored at 4 °C. Release studies revealed a drug release of 97.32 ± 4.82% within 60 min in simulated gastric fluid. Similarly, 97.12 ± 5.02% release of CFX was observed in simulated intestinal fluid within 120 min; however, 85.13 ± 3.23% release of CFX was observed from the marketed product. Ex vivo permeation studies displayed a 2.7-fold increase apparent permeability compared to the marketed product in 5 h. CONCLUSION: Owing to the significantly improved drug solubility, in vitro release and better antibacterial activity, it can be assumed that CFX-loaded SEDDS might lead to an increased bioavailability and antibacterial activity, possibly leading to improved therapeutic effectiveness.

Polymeric Nanogel for Oral Delivery of the Chemotherapeutic Agent: Fabrication and Evaluation Alongside Toxicological Studies and Histopathological Examination.

Nanogel has attracted considerable attention as one of the most versatile drug delivery systems, especially for site-specific and/or time-controlled delivery of the chemotherapeutic agent. The main objective of this study was to prepare the polymeric nanogel characterized by Fourier transform infrared spectroscopy, x-ray diffraction, thermogravimetric analysis, differential scanning, and oral acute toxicity. Free radical polymerization was done for the fabrication of polymeric nanogel. Fourier transform infrared spectroscopy was used to confirm the successful free radical polymerization. Various techniques such as x-ray diffraction, differential scanning calorimetric, and thermogravimetric analysis measurement were used to investigate the thermal behavior and crystallinity of developed nanogel. Parameters such as swelling, drug loading, and in vitro drug release is enhanced as polymers and monomers concentrations increase while these parameters decrease in case of increasing crosslinker concentration. The oral biocompatibility results of developed nanogel exhibited no toxicity in rabbits. Histopathological changes were observed between empty and loaded group. The nanosized gel offers a specific surface area which increases the stability of loaded drug (oxaliplatin) and bioavailability of the drug (oxaliplatin) as compared to the conventional drug delivery systems.

Herbal Formulation Comprised of Methanol Extracts of Tribulus terristris L. and Zingiber officinale Roscoe Has Antihypertensive Effects.

People prefer to use medicinal plants rather than chemical compounds because they are low cost and have fewer adverse events. Zingiber officinale Roscoe is a natural dietary rhizome with anti-oxidative, anti-inflammatory and anti-carcinogenic properties. Tribulus terrestris L. has been used for the treatment of impotence, to enhance sexual drive and performance and for its diuretic and uricosuric effects. The aim of this study was to evaluate the combined effect of 2 extracts, Tribulus terristris and Zingiber officinale (TZ) for antioxidant, enzyme modulation, liver function, kidney function, blood profile and anti-hypertensive effects, which may pave the way for possible therapeutic applications. Antioxidant potential was measured with the 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical method antioxidant assay (DPPH) and kojic acid was used as the standard drug for tyrosine inhibition assay. The effect of TZ on biochemical parameters of the liver (alanine transferase [ALT], alkaline phosphatase [ALP], aspartate aminotransferase [AST], total serum protein, total serum albumin, serum bilirubin), kidney (blood urea and creatinine) and hematology (hemoglobin, red blood cells [RBC], platelets, thin-layer chromatography, neutrophils, eosinophils, lymphocytes, monocytes, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration) of Wister rats were studied by administering 100, 250 and 500 mg/kg-1 body weight TZ dose orally for 28 days. Antihypertensive effects were measured by the invasive method. The results showed that the scavenging percentage of TZ was 78.5 to 80.4, with an IC50 value of 1166.7 µg/ ml and tyrosinase inhibition was 72% compared with 93% for kojic acid. Different doses (100, 250 and 500 mg/kg) did not show an increase in serum biomarkers of liver and renal parameters. A significant increase in hemoglobin, erythrocytes, hematocrit, white blood cells (WBC) and lymphocytes with no significant increase/decrease in platelet count was observed but blood pressure was significantly decreased. Therefore, we concluded that TZ is safe and can be used in the treatment of hypertension.

Co-Combination of Pregabalin and Withaniacoagulans-Extract-Loaded Topical Gel Alleviates Allodynia and Hyperalgesia in the Chronic Sciatic Nerve Constriction Injury for Neuropathic Pain in Animal Model.

The current study reports the fabrication of co-combination gel using Pregabalin and Withania coagulans fruit extract to validate its effectiveness for neuropathic pain in chronic constriction injury (CCI) rat models. Three topical gels were prepared using Carbopol 934 through a pseudo-ternary phase diagram incorporating the Pregabalin (2.5%), Withania coagulans extract (2%), and co-combination of both Pregabalin (2.5%) and Withania coagulans extract (2%). Gels were characterized. FTIR showed a successful polymeric network of the gel without any interaction. The drug distribution at the molecular level was confirmed by XRD. The AFM images topographically indicated the rough surface of gels with a size range from 0.25 to 330 nm. DSC showed the disappearance of sharp peaks of the drug and extract, showing successful incorporation into the polymeric network of gels. The in vitro drug release of co-combination gel was 73% over 48 h. The mechanism of drug release by combination gel was Higuchi+ fickian with values of n (0.282) and R2 (0.947). An in vivo study for pain assessment via four methods: (i) heat hyperalgesia, (ii) cold allodynia, (iii) mechano-hyperalgesia, and (iv) dynamic mechano-allodynia, confirmed that topical treatment with co-combination gel reduced the pain significantly as indicated by the p value: R1 (p < 0.001), R2 (p < 0.001), R3 (p < 0.015), and R4 (p < 0.0344). The significance order was R2 (****) > R1 (***) > R3 (**) > R4 (*) > R5 (ns).

Preparation, Characterization of Pregabalin and Withania coagulans Extract-Loaded Topical Gel and Their Comparative Effect on Burn Injury.

The current study depicts the comparative effects of nanogel using Withania coagulans extract, pregabalin alone, and a co-combination gel. The gels prepared were then analyzed for conductivity, viscosity, spread ability, globule size, zeta potential, polydispersity index, and TEM. The globule size of the co-combination gel, determined by zeta sizer, was found to be (329 ± 0.573 nm). FTIR analysis confirms the successful development of gel, without any interaction. Drug distribution at the molecular level was confirmed by XRD. DSC revealed no bigger thermal changes. TEM images revealed spherical molecules with sizes of 200 nm for the co-combination gel. In vivo studies were carried out by infliction of third degree burn wounds on rat skin, and they confirmed that pregabalin and Withania coagulans heals the wound more effectively, with a wound contraction rate of 89.95%, compared to remaining groups. Anti-inflammatory activity (IL-6 and TNF-α), determined by the ELISA technique, shows that the co-combination gel group reduces the maximum inflammation with TNF-α value (132.2 pg/mL), compared to the control (140.22 pg/mL). Similarly, the IL-6 value was found to be (78 pg/mL) for the co-combination gel and (81 pg/mL) in the case of the control. Histopathologically, the co-combination gel heals wounds more quickly, compared to individual gel. These outcomes depict that a co-combination gel using plant extracts and drugs can be successfully used to treat burn injury.

Appraisal of the pharmacokinetic profile, histopathology and stability studies of a fast dissolving oral film based on natural polysaccharide.

The present research is designed to evaluate the pharmacokinetic profile, histological evaluation, and stability studies of an orodispersible film (ODF) of tizanidine (TZ) and meloxicam (MX) prepared from a natural polysaccharide, i.e., xanthan gum. In vivo release study of TZ and MX was performed in rabbits and results indicated the better pharmacokinetics parameters and improved the oral bioavailability when compared to the oral aqueous suspension and solution of TZ and MX, respectively. The intermediate stability studies were performed at 30±2°C and 65±5% RH, whereas, the accelerated stability studies were carried out at 40±2°C and 75±5% RH, respectively for the duration of six months and results indicated that the ODF was stable for six months without any substantial difference in essential physico-chemical parameters, mechanical attributes, and morphological constraints. The toxicity profile of ODF was determined through histopathology of vital organs after administering the ODF to the rabbits. Histopathology revealed that the tissues of all vital organs are normal and did not exhibit any abnormalities, lesions, or hemorrhage. Therefore, the ODF prepared from xanthan gum exhibited a non-toxic and stable formulation with a better pharmacokinetics profile of MX and TZ.

Formulation and evaluation of antiviral drug sofosbuvir fast dissolving tablets using natural super disintegrants.

The main objective of this study to formulate of fast dissolving tablets of sofosbuvir, an antiviral drug used for hepatitis C virus. The direct compression method was employed for the formulation of sofosbuvir FDT and optimized for weight variation test, thickness, hardness, friability, wetting time, water absorption ratio, in-vitro disintegration test, and in-vitro dissolution studies, assay identification by using HPLC and stability studies. Master formulation of F4, Sofosbuvir showed promising results compared to others formulations and selected as the most suitable and best formulation among them. It also has better efficacy, disintegration and dissolution time. F4 was fabricated with both super disintegrants like croscarmellose sodium and sodium starch glycolate that lead to its required features. This formulation would be a good alternate for the management of viral diseases with better dissolution profile, stability and improved bioavailability for the patients.

HPLC method development and validation for in vitro and in vivo quantification of vancomycin in rabbit plasma.

Vancomycin (VAN) is an effective antibiotic due to its broad-spectrum bactericidal action. High performance liquid chromatography (HPLC), a powerful analytical technique is used for the in vitro/ in vivo quantification of VAN. The current study was aimed to detect the VAN from in vitro as well as the plasma after the extraction from blood of rabbits. The method was developed and validated according to International Council on Harmonization (ICH) Q2 R1 guidelines. Results showed that the peak of VAN was recorded at 2.96 and 2.57 min, respectively in vitro and serum. The coefficient of VAN turned out to be >0.9994 each for in vitro and in vivo samples. VAN was found linear in the range of 6.2-25000ng/mL. The values of accuracy and precision in terms of coefficient of variation (CV) were less than 2%, indicating the validity of the method. The values for LOD and LOQ were estimated to be 1.5 and 4.5ng/mL, correspondingly, which were lower than the values calculated from in vitro media. Furthermore, the score of the greenness found out to be 0.81, depicting good score using AGREE tool. It was concluded that the developed method was found accurate, precise, robust, rugged, linear, detectable and quantifiable at prepared analytical concentrations and could be used for in vitro and in vivo VAN determination.

Lipid poly (ɛ-caprolactone) hybrid nanoparticles of 5-fluorouracil for sustained release and enhanced anticancer efficacy.

AIMS: The present study aimed to develop and characterize poly (ɛ-caprolactone) (PCL) based lipid polymer hybrid nanoparticles for sustained delivery and in-vitro anti-cancer activity in MCF-7 and HeLa cells cancer cell line. MATERIALS AND METHODS: The nanoprecipitation method was used for the development of 5-fluorouracil loaded lipid polymer hybrid nanoparticles (LPHNPs). The developed LPHNPs were characterized for physicochemical characteristics and the anti-cancer effect was evaluated in MCF-7 and HeLa cells. SIGNIFICANT FINDINGS: Six formulations having fixed amount of drug and varied lipid, polymer and emulsifier concentrations were prepared. The particle size was in the range of 174 ± 4 to 267 ± 2.65 nm, entrapment efficiency (92.87 ± 0.594 to 94.13 ± 0.772%), negative zeta potential, optimum polydispersity index and spherical shape. FTIR analysis shows no chemical interaction among the formulation components, DSC analysis reveals the disappearance of 5-FU melting endotherm in the developed LPHNPs suggesting amorphization of 5-FU in the developed system, XRD analysis indicates successful encapsulation of the drug in the lipid polymer matrix. The in-vitro release shows a biphasic release pattern with an initial burst release followed by a sustained release profile for 72 h. The drug loaded LPHNPs exhibited a greater cytotoxic effect than 5-FU solution due to sustained release and increased cellular internalization. The acute toxicity study revealed the safety of the developed carrier system for potential delivery of chemotherapeutic agents. SIGNIFICANCE: The developed LPHNPs of 5-fluorouracil will provide the sustained release behavior of 5-fluorouracil to maximize the therapeutic efficacy and minimize the dose related toxicity.

Development, characterization and evaluation of in vitro anti-inflammatory activity of Withania coagulans extract and extract loaded microemulsion.

Herbal medicines are gaining importance due to more advantages and less toxic effects. Withania coagulans is natural plant that possesses multiple activities. Its main constituents are withaferin and withanolide. The purpose of present study is to identify main constituent of Withania coagulans and preparation of extract loaded micro emulsions. Withania coagulans fruit extract in methanol/chloroform (1:1) was collected in semisolid form and LCMS was done to identify active compound, and then micro emulsions were prepared using Tween 80: Transcutol (1:1) Frankincense oil, and water to enhance its stability for topical application. Five formulations were prepared by Pseudo ternary phase diagram and evaluated for pH, conductivity, viscosity, drug contents, particle size analysis, and polydispersity. Withania coagulans extract was evaluated for anti-bacterial activity against (Staphylococcus aureus, E. coli, and S. typhi) and anti-fungal activity against (Candida albicans and Aspergillus niger). Anti-inflammatory activity was checked for both extract and Extract based micro emulsion. Among all five formulations F5 shows best physiochemical properties with small globule size, good stability and high anti-inflammatory activity. Based on these results it was concluded that Withania coagulans extract loaded micro emulsions can be used for topical application with promising anti-inflammatory activities. Data for in-vivo studies for checking the topical effect of Withania coagulans is provided elsewhere.

Formulation design, characterization and in vitro drug release study of orodispersible film comprising BCS class II drugs.

Fast dissolving orodispersible film (ODF) was prepared for concurrent administration of biopharmaceutical classification system (BCS) class II drugs, i.e., meloxicam (MX) and tizanidine (TZ), using natural (xanthan gum), semisynthetic (hydroxypropyl methylcellulose and hydroxyethyl cellulose) and synthetic (polyvinyl alcohol) polymers. Compatibility of the ingredients of ODFs was ascertained through Fourier transform infra-red spectroscopy and differential scanning calorimetry. ODFs were characterized through disintegration time, pH of the surface of film, tensile strength, folding endurance, % elongation and content uniformity (MX and TZ) which were found in the range between 17±1.3-56±3.1 s, 5.11±0.07-6.28±0.05, 14.721±1.2-33.084±3.1 N/m2, > 100, 3.33±0.53-10.04±0.77 % and 98.01-99.34 % (MX) and 97.48-99.03 % (TZ), respectively. The values of moisture uptake, moisture loss and loss on drying of all formulations were in the range from 1.06±0.09-7.51±0.93 %, 0.06±0.01-2.3±0.08 % and 0.008±0.002-0.03±0.03 %, respectively. In vitro drug release study in simulated saliva fluid of pH 7.4 has shown that > 90 % MX and TZ was released within 5 min. Visual inspection, scanning electron microscope and X-ray diffraction analysis of all ODFs expressed their smooth surfaces. ODF prepared from xanthan gum (F5) exhibited better physicochemical and mechanical properties as compared to other formulations.

Cross-linked pH-sensitive pectin and acrylic acid based hydrogels for controlled delivery of metformin.

The purpose of present study is to load Metformin HCl into pH-sensitive hydrogels to have sustained release over a period of time. The hydrogel was synthesized from naturally occurring polysaccharide pectin and monomer acrylic acid (AA) using ethylene glycol dimethacrylate (EGDMA) as cross-linker under controlled conditions for polymerization at 45°C for one hr, 50°C for two hrs, 55°C for three hrs, 60°C for four hrs and finally 65˚C for 12 hrs. Hydrogels were characterized for dynamic/equilibrium swelling, sol-gel fraction analysis, diffusion coefficient and percentage porosity. Hydrogels were tested by FTIR, XRD and SEM for structure and surface morphology respectively. Experimental in-vitro drug release data was applied to kinetic models. Formation of strong bonding between pectin and AA was supported by FTIR. The intensity of XRD peaks was reduced in non-loaded and loaded hydrogels compared to active drug substance. The non-loaded hydrogel showed discrete porous structure whereas loaded hydrogels were fibrous and smooth. Hydrogels showed higher swelling in the solutions of pH 6.5 and 7.5 as compared to in the solutions of pH 1.2 and 5.5. The diffusion coefficient decreases with the increase of AA and pectin concentrations. It was observed upon increasing the EGDMA concentration porosity decreases. The release of drug from all compositions of hydrogels took place through non-Fickian diffusion mechanism.

Development, characterization and evaluation of in-vitro anti-inflammatory activity of ginger extract based micro emulsion.

Zingeber officinale is a commonly used plant which has been shown to possess anti-inflammatory activity. The active compounds present in ginger are gingerols, shagaols and paradol. The aim of this study was formulation of topical microemulsion system to enhance the solubility and stability of ginger extract, as it is unstable in the presence of light, air, heat and long term storage, and to evaluate its anti-inflammatory activity. The solubility of ginger extract in different oils, surfactants, and co-surfactants was determined in order to find the optimal components for microemulsion. IPM was selected as oil phase, tween 80 and PEG 400 were selected as surfactant and co-surfactant respectively based on highest solubility values. Pseudo-ternary phase diagram was constructed in order to find out the microemulsion region. The prepared microemulsions were evaluated for pH, viscosity, conductivity, refractive index, globular size, zeta potential, polydispersity index, ginger extract content. The formulation F1 showed best physicochemical properties with smallest globular size. It also showed significant (p<0.05) anti-inflammatory effect as compared to reference piroxicam drug solution. Based on the results, it is concluded that ginger extract can be used to develop stable microemulsion system and promising anti-inflammatory activity.

Pharmacokinetic evaluation of anticancer drugs in Hodgkin's lymphoma patients after their simultaneous administration.

A pharmacokinetic study of anticancer drugs was carried out in 18 Hodgkin's lymphoma male patients. The anticancer drugs were administered to the patient by a standard procedure and a validated HPLC method was used for plasma concentration determination. Maximum plasma concentration (Cmax) of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) were 7.71, 4.32, 7.95 and 6.51µg/ml respectively. Adriamycin and Dacarbazine exhibited longer Tmax compared to Bleomycin and Vinblastine. Area under the curve values of ABVD were 118.30, 82.11, 245.54 and 86.62µg/ml*h. The elimination rate constant of Dacarbazine was highest. Vinblastine exhibited highest half-life and mean residence time. Clearances of ABVD were 346.69, 2499.44, 45.90 and 5800.05ml/h. The apparent volume of distribution was highest for Dacarbazine and lowest for Vinblastine. The pharmacokinetic parameters can be utilized for monitoring of plasma concentrations, therapeutic drug monitoring and dosage adjustments to optimize anticancer efficacy in patients of Hodgkin's lymphoma.

Permeation study through bacterial cellulose membrane.

Abstract: The objective of this study was to fabricate topical formulations of diclofenac diethylamine (DD) using isopropyl myristate (IPM) and isopropyl palmitate (IPP) as permeation enhancers. Franz cell and bacterial cellulose were used as analytical instrument and diffusion membrane, respectively. Permeation enhancers exhibited significant effect on the permeation characteristics of DD. It was concluded from the results that improved permeation of DD was observed when IPP was used as enhancer.

In vitro-in vivo correlation study on nimesulide loaded hydroxypropylmethylcellulose microparticles.

This study involves mathematical simulation model such as in vitro-in vivo correlation (IVIVC) development for various extended release formulations of nimesulide loaded hydroxypropylmethylcellulose (HPMC) microparticles (M1, M2 and M3 containing 1, 2, and 3 g HPMC, respectively and 1 g drug in each) having variable release characteristics. In vitro dissolution data of these formulations were correlated to their relevant in vivo absorption profiles followed by predictability worth analysis of these Level A IVIVC. Nimaran was used as control formulation to validate developed formulations and their respective models. The regression coefficients of IVIVC plots for M1, M2, M3 and Nimaran were 0.834 9, 0.831 2, 0.927 2 and 0.898 1, respectively. The internal prediction error for all formulations was within limits, i.e., < 10%. A good IVIVC was found for controlled release nimesulide loaded HPMC floating M3 microparticles. In other words, this mathematical simulation model is best fit for biowaiver studies which involves study parameters as those adopted for M3 because the value of its IVIVC regression coefficient is the closest to 1 as compared to M1 and M2.

Production and stability evaluation of modified-release microparticles for the delivery of drug combinations.

Production and evaluation of novel formulations of tizanidine and tramadol microparticles was the chief purpose of this project. Microparticles of both drugs were prepared separately via temperature change method. To extend the release of formulations, ethyl cellulose was employed. Higuchi, zero-order, first-order, and Korsmeyer-Peppas kinetic models were applied to appraise the mechanism and mode of drugs release. Higuichi model was found to be best for all release profiles. Stability of microparticles at 40 degrees C/75% RH over a 3-month duration was determined by Fourier transform infrared (FTIR), X-ray diffractometry (XRD), and drugs assay. Microparticles were compatible and stable as no significant differences were observed when subjected to drug assay, FTIR, and XRD during accelerated stability studies.

In vitro-in vivo correlation study on nimesulide loaded hydroxypropylmethylcellulose microparticles / 药学学报

This study involves mathematical simulation model such as in vitro-in vivo correlation (IVIVC) development for various extended release formulations of nimesulide loaded hydroxypropylmethylcellulose (HPMC) microparticles (M1, M2 and M3 containing 1, 2, and 3 g HPMC, respectively and 1 g drug in each) having variable release characteristics. In vitro dissolution data of these formulations were correlated to their relevant in vivo absorption profiles followed by predictability worth analysis of these Level A IVIVC. Nimaran was used as control formulation to validate developed formulations and their respective models. The regression coefficients of IVIVC plots for M1, M2, M3 and Nimaran were 0.834 9, 0.831 2, 0.927 2 and 0.898 1, respectively. The internal prediction error for all formulations was within limits, i.e., < 10%. A good IVIVC was found for controlled release nimesulide loaded HPMC floating M3 microparticles. In other words, this mathematical simulation model is best fit for biowaiver studies which involves study parameters as those adopted for M3 because the value of its IVIVC regression coefficient is the closest to 1 as compared to M1 and M2.