Does the Ethnic Difference Affect the Pharmacokinetics of Favipiravir? A Pharmacokinetic Study in Healthy Egyptian Volunteers and Development of Level C In-vitro In-vivo Correlation.

Favipiravir is an antiviral drug used to treat influenza and is also being investigated for the treatment of SARS-CoV-2. Its pharmacokinetic profile varies depending on ethnic group. The present research examines the pharmacokinetic features of favipiravir in healthy male Egyptian volunteers. Another goal of this research is to determine the optimum dissolution testing conditions for immediate release tablets. In vitro dissolution testing was investigated for favipiravir tablets in three different pH media. The pharmacokinetic features of favipiravir were examined in 27 healthy male Egyptian volunteers. The parameter "AUC0-t" vs. percent dissolved was used to develop level C in vitro in vivo correlation (IVIVC) to set the optimum dissolution medium to achieve accurate dissolution profile for favipiravir (IR) tablets. The in vitro release results revealed significant difference among the three different dissolution media. The Pk parameters of twenty-seven human subjects showed mean value of Cpmax of 5966.45 ng/mL at median tmax of 0.75 h with AUC0-∞ equals 13325.54 ng.h/mL, showing half-life of 1.25 h. Level C IVIVC was developed successfully. It was concluded that Egyptian volunteers had comparable Pk values to American and Caucasian volunteers, however they were considerably different from Japanese subjects. AUC0-t vs. % dissolved was used to develop level C IVIVC to set the optimum dissolution medium. Phosphate buffer medium (pH 6.8) was found to be the optimum dissolution medium for in vitro dissolution testing for Favipiravir IR tablets.

Development and optimization of amphiphilic self-assembly into nanostructured liquid crystals for transdermal delivery of an antidiabetic SGLT2 inhibitor.

The anti-hyperglycemic sodium glucose co-transporter 2 inhibitor Canagliflozin (CFZ) represents a recent antihyperglycemic modality, yet it suffers from low oral bioavailability. The current work aims to formulate CFZ-loaded transdermal nanostructured liquid crystal gel matrix (NLCG) to improve its therapeutic efficiency. Pre-formulation study included the construction of pseudoternary phase diagrams to explore the effect of two conventional amphiphiles against amphiphilic tri-block copolymer in the formulation of NLCG. The influence of different co-solvents was also investigated with the use of monooleine as the oil. Physical characterization, morphological examination and skin permeation were performed for the optimized formulations. The formula of choice was further investigated for skin irritation and chemical stability. Pharmacodynamic evaluation of the successful formula was conducted on hyperglycemic as well as normoglycemic mice. In addition, oral glucose tolerance test was conducted. Results revealed the supremacy of Poloxamer for stabilizing and maximizing liquid crystal gel (LCG) area percentage that reached up to 12.6%. CFZ-NLCG2 isotropic formula showed the highest permeation parameters; maximum flux value of 7460 µg/cm2 h and Q24 of 5327 µg/cm2. Pharmacodynamic evaluation revealed the superiority of the antihyperglycemic activity of CFZ-NLCG2 in fasting mice and its equivalence in the oral glucose tolerance test (OGTT) compared to the oral one. The obtained results confirmed the success of CFZ-NLCG2 in the transdermal delivery of CFZ in therapeutically effective concentration compared to the oral route, bypassing first pass effect; in addition, eliminates the possible gastrointestinal side effects related to the inhibition of intestinal sodium glucose co-transporter (SGLT) and maximizes its selectivity to the desired inhibition of renal SGLT.

Pharmaceutical nanotechnology: from the bench to the market.

BACKGROUND: Nanotechnology is considered a new and rapidly emerging area in the pharmaceutical and medicinal field. Nanoparticles, as drug delivery systems, impart several advantages concerning improved efficacy as well as reduced adverse drug reactions. MAIN BODY: Different types of nanosystems have been fabricated including carbon nanotubes, paramagnetic nanoparticles, dendrimers, nanoemulsions, etc. Physicochemical properties of the starting materials and the selected method of preparation play a significant aspect in determining the shape and characteristics of the developed nanoparticles. Dispersion of preformed polymers, coacervation, polymerization, nano-spray drying and supercritical fluid technology are among the most extensively used techniques for the preparation of nanocarriers. Particle size, surface charge, surface hydrophobicity and drug release are the main factors affecting nanoparticles physical stability and biological performance of the incorporated drug. In clinical practice, many nanodrugs have been used for both diagnostic and therapeutic applications and are being investigated for various indications in clinical trials. Nanoparticles are used for the cure of kidney diseases, tuberculosis, skin conditions, Alzheimer's disease, different types of cancer as well as preparation of COVID-19 vaccines. CONCLUSION: In this review, we will confer the advantages, types, methods of preparation, characterization methods and some of the applications of nano-systems.

A new design for a chronological release profile of etodolac from coated bilayer tablets: In-vitro and in-vivo assessment.

Repeated dose medication usually maximizes adverse effects, while sustained release systems did not offer a fast onset of action. Etodolac was formulated to enable pulsatile and sustained drug release, which was chronologically more suitable as an anti-inflammatory drug. Eudragit® RSPO, Eudragit® RLPO, and HPMC K15M were added in the sustained release layer and tried in different ratios. Croscarmellose sodium or sodium starch glycolate were used as superdisintegrants for the fast release layer offering the loading dose for rapid onset of drug action. Bilayer tablets were successively coated with Opadry®II, HPMC K4M and E5 (1:40), and Surelease®. All formulations complied with the Pharmacopeial standards for post-compression parameters. In-vitro release profile illustrated a lag-time of 4 h followed by a rapid loading dose release for 2 h. A prolonged steady state release with a t1/2 of 11 h lastly occurred. The coated bilayer tablet showed pulsatile and sustained release effects in rats. The licking time and swelling degree were tested and results demonstrated significant difference (P < 0.05) between the sustained anti-inflammatory action of formulation C1 compared to other groups. Therefore the new chronological design could provide a consistent drug release over 24 h with good protection against associated symptoms of gastric release.

Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: formulation and clinical study.

Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ-SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan® 1% cream. Follow up was done for 4 weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloidal sizes with no aggregation. The drug entrapment efficiency ranged from 55.49% to 83.04%. The zeta potential values lie between -21 and -33 mV presenting good stability. FLZ showed prolonged in vitro release from SLNs dispersion and its Carbapol gel following Higuchi order equation. Clinical studies registered significant improvement (p < .05) in therapeutic response (1.4-fold; healing%, 4-fold; complete eradication) in terms of clinical cure and mycological cure rate from PV against marketed cream. Findings of the study suggest that the developed FLZ loaded SLNs topical gels have superior significant fast therapeutic index in treatment of PV over commercially available Candistan® cream.

Quantification of sofosbuvir and ledipasvir in human plasma by UPLC-MS/MS method: Application to fasting and fed bioequivalence studies.

A rapid and sensitive LC-MS/MS method was developed, optimized and validated for quantification of sofosbuvir (SF) and ledipasvir (LD) in human plasma using eplerenone as an internal standard (IS). Analytes and IS were extracted from plasma by simple liquid-liquid extraction technique using methyl tertiary butyl ether. The prepared samples were chromatographed on Acquity UPLC BEH C18 column. Separation was done using a mobile phase formed of 0.1% formic acid and acetonitrile (50:50, v/v) in an isocratic mode at a flow rate of 0.4ml/min. The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. A full validation of the method was performed according to the FDA guidelines. Linearity was found to be in the range of 0.25-3500ng/ml for SF and 5-2000ng/ml for LD. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A short run time of 2min allows analysis of more than 400 plasma samples per day. The developed method was successfully applied to both fasting and fed bioequivalence studies in healthy human volunteers.

Development and validation of sensitive and rapid UPLC-MS/MS method for quantitative determination of daclatasvir in human plasma: Application to a bioequivalence study.

A rapid and sensitive UPLC-MS/MS method was developed and validated for determination of daclatasvir (DAC) in human plasma using sofosbuvir (SOF) as an internal standard (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Precipitation with acetonitrile was used in sample preparation. The prepared samples were chromatographed on Acquity UPLC HSS C18 (50×2.1mm, 1.8µm) column by pumping 10mM ammonium formate (pH 3.5) and acetonitrile in an isocratic mode at a flow rate of 0.30ml/min. Method validation was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 5-4000ng/ml for DAC. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A very short run time of 1.2min made it possible to analyze more than 500 human plasma samples per day. The wider range of quantification of DAC allowed the applicability of the developed method for its determination in a bioequivalence study in human volunteers.

Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: in-vitro-in-vivo evaluation.

In order to target celecoxib which is a COX2 inhibitor, with potentials in the prevention and treatment of colitis and colon cancer, it was formulated as microparticles using the solvent/evaporation method and various pH-dependent Eudragit polymers. The in-vitro evaluation of the prepared microparticles showed spherical and smooth morphology. The encapsulation efficiency and yield were high, indicating that the method used is simple and efficient at this scale. The in-vitro release study showed no release in the acidic medium for 2 h followed by the release of the drug in pH 6.8 in case of Eudragit L100-55 and L100 and pH 7.4 in case of Eudragit S100. The pharmacokinetic parameters were calculated and method validation was performed to insure that it is suitable and reliable. Pharmacokinetic parameters were investigated by determining the Cmax, Tmax, AUC0-t, Kel, and t1/2 of the drug as a suspension and as microparticles. There was a significant difference (p < 0.05) in Tmax between the drug as a suspension and as microparticles. The effect of celecoxib on the degree of inflammation was examined on acetic acid induced colitis rat model and the drug was given as a suspension and as microparticles. The evaluation was done using macroscopical, microscopical and biochemical examination. There was a significant difference between the acetic acid control group and the treatment groups regarding all examination criteria in the order microparticles formulated using Eudragit S100 followed by Eudragit L100-55 while microparticles using Eudragit L100 and drug suspension showed almost the same results.

Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency.

Migraine attack is a troublesome physiological condition associated with throbbing, intense headache, in one half of the head. Zolmitriptan is a potent second-generation triptan, prescribed for patients with migraine attacks, with or without an aura, and cluster headaches. The absolute bioavailability of zolmitriptan is about 40% for oral administration; due to hepatic first metabolism. Nasal administration would circumvent the pre-systemic metabolism thus increasing the bioavailability of zolmitriptan. In addition, due to the presence of microvilli and high vasculature, the absorption is expected to be faster compared to oral route. However, the bioavailability of nasal administered drugs is particularly restricted by poor membrane penetration. Thus, the aim of this work is to explore the potential of novel nanovesicular fatty acid enriched structures (novasomes) for effective and enhanced nasal delivery of zolmitriptan and investigate their nose to brain targeting potential. Novasomes were prepared using nonionic surfactant, cholesterol in addition to a free fatty acid. A 23 full factorial design was adopted to study the influence of the type of surfactant, type of free fatty acid and ratio between the free fatty acid and the surfactant on novasomes properties. The particle size, entrapment efficiency, polydispersity index, zeta potential and % zolmitriptan released after 2 h were selected as dependent variables. Novasomes were further optimized using Design Expert® software (version 7; Stat-Ease Inc., Minneapolis, MN), and an optimized formulation composed of Span® 80:Cholesterol:stearic acid (in the ratio 1:1:1) was selected. This formulation showed zolmitriptan entrapment of 92.94%, particle size of 149.9 nm, zeta potential of -55.57 mV, and released 48.43% zolmitriptan after 2 h. The optimized formulation was further examined using transmission electron microscope, which revealed non-aggregating multi-lamellar nanovesicles with narrow size distribution. DSC, XRD examination of the optimized formulation confirmed that the drug have been homogeneously dispersed throughout the novasomes in an amorphous state. In-vivo bio-distribution studies of 99mTc radio-labeled intranasal zolmitriptan loaded novasomes were done on mice, the pharmacokinetic parameters were compared with those following administration of intravenous 99mTc-zolmitriptan solution. Results revealed the great enhancement in zolmitriptan targeting to the brain, with drug targeting potential of about 99% following intranasal administration of novasomes compared with the intravenous drug solution. Zolmitriptan loaded novasomes administered via the nasal route may therefore constitute an advance in the management of acute migraine attacks.

In vitro and in vivo evaluation of self-nanoemulsifying drug delivery systems of cilostazol for oral and parenteral administration.

The current investigation was aimed to improve the solubility of poorly soluble drug, cilostazol (CLZ). Self-nanoemulsifying drug delivery system (SNEDDS) composed of oil, surfactant and co-surfactant for both oral and parenteral administration of CLZ was formulated. The components for SNEDDS were identified by solubility studies, and pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsification regions. The optimum formula, composed of Capryol 90 as an oil phase, Cremophor EL as a surfactant, and Transcutol HP as a co-surfactant in a ratio of 19.8:30.5:49.7 by weight, was able to solubilize CLZ 2000 times higher than its solubility in water. This formula was able to form grade "A" nanoemulsion when diluted with water, resulted in emulsification time of 50±1.1 s, particle size of 14.3 nm, PDI of 0.5 and % transmittance was 97.40%±0.65. It showed excellent in vitro dissolution of 93.1% and 81.5% after 5 min in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively when compared with the marketed tablet formulation and drug suspension as the tablets showed only 44.3% and 9.9% while CLZ suspension showed 33.9% and 8.8% in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively. It was found to be robust to dilution, thermodynamically stable with low viscosity values of 14.20±0.35 cP. In vivo study revealed significant increase in bioavailability of CLZ in rabbits to 3.94 fold compared with the marketed tablet formulation after oral administration. This formula could be sterilized by autoclaving and did not cause significant hemolysis to human blood which indicates its safety for intravenous administration with a 1.12 fold increase in bioavailability compared with its oral administration. Our study illustrated the potential use of SNEDDS of poorly soluble CLZ orally, and its successful administration of parenterally when required in acute cases of myocardial and cerebral infarction.

Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride.

The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product.

Instantaneous enteric nano-encapsulation of omeprazole: pharmaceutical and pharmacological evaluation.

Recently, great attention has been paid to nanocapsules. The interest of these structures is due to their promising applications as drug delivery systems. The objective of this study was to develop novel enteric coating technique based on instantaneous encapsulation of the acid-labile drug, omeprazole in innovative enteric nanocapsules. Omeprazole enteric nanocapsules were formulated by varying the type and amount of the enteric polymer. The particle size (PS), polydispersity index (PDI), zeta potential (ZP) and encapsulation efficiency (EE) values of the prepared enteric nanocapsules were determined. A full 2(1)×3(1) factorial design was used for planning and analysis of the experimental trials to select the optimized formulation. The highest desirability value was 0.7463 for formula E3 (containing 200mg hydroxypropyl methylcellulose phthalate (HPMCP)). The stability of omeprazole was reflected by the absence of the exothermal peak when the drug was encapsulated as detected by differential scanning calorimetry (DSC) thermograms. In vitro drug release study confirmed the USP specifications required to meet the key formulation characteristics of gastro-resistance. In vivo pharmacological assessment showed that the optimized nanocapsules were able to protect rat stomach against ulcer formation compared to the aqueous suspension of the drug which showed less significant protection.

The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle.

Topical 5% alpha lipoic acid (ALA) has shown efficacy in treatment of photo-damaged skin. The aim of this work was to evaluate the potential of poloxamer (P407) gel as a vehicle for the novel lipid base particulate system (cubosome dispersions) of ALA. Cubosome dispersions were formulated by two different approaches, emulsification of glyceryl monoolein (GMO) and poloxamer (P407) in water followed by ultrasonication, and the dilution method using a hydrotrope. Three different concentrations of GMO were used to formulate the cubosome dispersions using the first method, 5% (D1), 10% (D2) and 15% w/w (D3). In the second technique an isotropic liquid was produced by combining GMO with ethanol, and this isotropic liquid was then diluted with a P407 solution (D4). The dispersions were characterized by zeta potential, light scattering techniques, optical and transmission electron microscopy, encapsulation efficiency and in vitro drug release. Results showed that D4 was not a uniform dispersion and that D1, D2 and D3 were uniform dispersions, in which by increasing the GMO content in the dispersion, the size of the cubosomes decreased, zeta potential became more negative, encapsulation efficiency increased up to 86.48% and the drug release rate was slower. P407 gels were prepared using the cold method. Two concentrations of P407 gel were fabricated, 20 and 30% w/w. P407 gels were loaded with either ALA or dispersions containing ALA cubosomes. P407 gels were characterized by critical gelation temperature, rheological measurements and in vitro drug release studies. Results suggested that by increasing P407 concentration, the gelation temperature decreases and viscosity increases. Drug release in both cases was found to follow the Higuchi square root model. Gel loaded with ALA cubosomes provided a significantly lower release rate than the gel loaded with the un-encapsulated ALA. A double blinded placebo controlled clinical study was conducted, aiming to evaluate the efficacy as an anti-wrinkle agent and volunteer's satisfaction upon application of topical 30% P407 gel loaded with ALA cubosomes. Results indicated reduction in facial lines, almost complete resolution of fine lines in the periorbital region and upper lip area and overall improvement in skin color and texture in most volunteers. There were no instances of irritation, peeling or other apparent adverse side effects.

Hydroxychloroquine niosomes: a new trend in topical management of oral lichen planus.

The work aimed at studying a novel topical niosomal gel formulation of hydroxychloroquine for the management of oral lichen planus. Niosomes have been reported as conceivable vesicles to deliver drug molecules to the desired mucous membrane or skin layers. Hydroxychloroquine niosomes were designed using different methods of preparation. Tween 20 and cholesterol in molar ratio (1:0.5) were used. The prepared systems were characterized for entrapment efficiency, particle size and in vitro drug release. Different factors affecting the encapsulation of hydroxychloroquine in niosomes were studied vs. varying the type of surfactant, the cholesterol:surfactant molar ratio and the amount of the drug. The selected noisome formulation was dispersed in different gel formulations and evaluated according to the in vitro drug release and the physical stability. The results showed that the type of surfactant, cholesterol ratio and incorporated amount of drug altered the entrapment efficiency and the in vitro release of hydroxychloroquine from niosomes. The optimum formulation was prepared by reverse phase evaporation technique using Brij 98:cholesterol molar ratio (1:1.5) and containing 20mg of hydroxychloroquine and incorporated in 20% w/v Pluronic F-127 gel. A double-blind, controlled clinical study was performed using two groups of patients. Group A (n=11) who received hydroxychloroquine niosomal gel formulation, one application-a-day over 4 months showed 64.28% reduction in the size of lesions and the average score of pain was reduced from "4" to "1". Compared to placebo group B (n=5), who showed only 3.94% reduction in the lesion size and the average score of pain was remained "3". Our results suggest that these niosomal formulations could constitute a promising approach for the topical treatment of oral lichen planus in short time with less side effects and no recurrence after stopping the treatment.

Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability.

Paroxetine (PAX) is the most potent serotonin reuptake blocker antidepressant clinically available. This study is aimed to reduce the side effects accompanied with the initial high plasma concentration after oral administration of PAX and fluctuations in plasma levels and also to decrease the broad metabolism of the drug in the liver by developing and optimizing liposomal transdermal formulation of PAX in order to improve its bioavailability. PAX liposomes were prepared by reverse phase evaporation technique using lecithin phosphatidylcholine (LPC), cholesterol (CHOL) and drug in different molar ratios. The prepared liposomes were characterized for size, shape, entrapment efficiency and in vitro drug release. The studies demonstrated successful preparation of PAX liposomes. The effect of using different molar ratios of (LPC:CHOL) on entrapment efficiency and on drug release was studied. Liposomes showed percentage entrapment efficiency (%EE) of 81.22 ± 3.08% for optimized formula (F5) which composed of (LPC:CHOL, 7:7) and 20mg of PAX, with average vesicle size of 220.53 ± 0.757 nm. The selected formula F5 (7:7) was incorporated in gel bases of HPMC-E4M (2%, 4%, and 6%). The selected formula of PAX liposomal gel of HPMC-E4M (2% and 4%) were fabricated in the reservoir type of transdermal patches and evaluated through in vitro release. After that the selected formula of PAX liposomal gel transdermal patch was applied to rabbits for in vivo bioavailability study in comparison with oral administration of the marketed PAX tablet. An HPLC method was developed for the determination of PAX in plasma of rabbits after transdermal patch application and oral administration of the marketed PAX tablets of 20mg dose. The intra- and inter-day accuracy and precision were determined as relative error and relative standard deviation, respectively. The linearity was assessed in the range of 5-200 ng/ml. Pharmacokinetic parameters were determined as the C(max) of PAX liposomal transdermal patch was found to be 92.53 ng/ml at t(max) of 12h and AUC(0-48) was 2305.656 ngh/ml and AUC(0-∞) was 3852.726 ngh/ml, compared to the C(max) of 172.35 ng/ml after oral administration of the marketed PAX tablet with t(max) of 6h and AUC(0-24) was 1206.63 ngh/ml and AUC(0-∞) was 1322.878 ngh/ml. These results indicate improvement of bioavailability of the PAX after liposomal transdermal patch application and sustaining of the therapeutic effects compared to oral administration.

Effect of formulation parameters on the preparation of superporous hydrogel self-nanoemulsifying drug delivery system (SNEDDS) of carvedilol.

The purpose of this study was to formulate a superporous hydrogel (SPH) containing carvedilol self-nanoemulsifying drug delivery system. Effects of formulation parameters (amount of SPH and 0.1 N HCl used during drug loading) were studied in 3(2) factorial design. Response surface plots showed significant effect of the parameters on hydrogel swelling, carvedilol content, and carvedilol in vitro release. Regression equations were generated to calculate the desirable responses.

Development and in vitro evaluation of mesalamine delayed release pellets and tableted reservoir-type pellets.

BACKGROUND: The basic objective of this study was to develop a novel technique that aids in compaction of coated pellets into tablets and obtain a release pattern from compressed pellets resembling the same pattern before compression. METHOD: Multi-unit dosage forms of mesalamine targeted to the colon were formulated by extrusion-spheronization, and then coated with Eudragit S (30%). These pellets were filled into gelatin capsules or further formulated and compressed into tablets. Tablets for colonic delivery of mesalamine were prepared by mixing the coated beads with cushioning agents like stearic acid and Explotab, or by applying an additional coat of gelatin (4% weight gain) onto the Eudragit S coated pellets, and then compressing into tablets (tableted reservoir-type pellets). Then additional coating of the tablets prepared by the coating technique was applied utilizing Eudragit L 100-55 (5% weight gain). RESULTS: This technique provides additive protection for the coated beads to withstand the compression force during tableting. Excellent in vitro dissolution results were obtained, which were comparable to the results of the release of mesalamine from uncompressed beads filled in capsules. Mesalamine release from the capsules was 0.3% after 2 hours in gastric pH, 0.37% was released after an additional 1 hour in pH 6, and 89% was released after 1.5 hours in colonic pH 7.2. CONCLUSION: Various formulation and process parameters have to be optimized in order to obtain tableted reservoir-type pellets having the same release properties as the uncompressed pellets. The coating technique delays the release of mesalamine until the beads reach the terminal ileum and colon. Once released in the colon, mesalamine is minimally absorbed and can act locally to treat ulcerative colitis.

Two different approaches for the prediction of in vivo plasma concentration-time profile from in vitro release data of once daily formulations of diltiazem hydrochloride.

The aim of this study was to employ two different mathematical approaches: first, a convolution approach using computer software; second, a mathematical calculation exploiting Wagner-Nelson calculation to predict in vivo plasma concentration-time profile from the in vitro release study for the once daily formulations of a model drug diltiazem hydrochloride. The once daily extended release tablets (120 mg) were prepared by the wet granulation technique. Ethanol or ethanolic solutions of ethylcellulose (N22), were used as granulating agents along with hydrophilic matrix polymers like hydroxypropyl methylcellulose (HPMC) (K 15M). The granules showed satisfactory flow properties, compressibility, moisture content and drug content. All the tablet formulations showed acceptable properties and complied with pharmacopeial limits. The in vitro drug release study revealed that formula F7-T which contains drug: HPMC ratio 1:1 and 20 mg of ethylcellulose was able to sustain the drug release for 24 h and satisfied the USP dissolution limits. Fitting the in vitro drug release data to Korsmeyer-Peppas equation indicated that the mechanism of drug release could be zero-order. The capsule formulation F14-C which consists of drug: HPMC ratio 1:2, 12 mg of ethylcellulose and 20 mg of polyox 100 showed in vitro drug release similar to the tablet F7-T using the similarity factor (f 2). The mechanism of drug release could be coupled diffusion, and polymer matrix relaxation. The percent dissolved data from the two formulations were used as input function to predict the in vivo plasma data by the two approaches (Convolution by Kinetica software and Wagner-Nelson calculation). The two methods were validated by prediction of plasma data from in vitro release data of FDA approved 300 mg extended release capsule. Prediction errors were estimated for Cmax and area under the curve (AUC) to determine the validity of the methods. The percent prediction error for each parameter is not exceeding 15%.

Intranasal microemulsion of sildenafil citrate: in vitro evaluation and in vivo pharmacokinetic study in rabbits.

The purpose of the present study was to prepare intranasal delivery system of sildenafil citrate and estimate its relative bioavailability after nasal administration in rabbits to attain rapid onset of action with good efficacy at lower doses. Sildenafil citrate saturated solubility was determined in different solvents, cosolvents, and microemulsion systems. For nasal application, sildenafil citrate was formulated in two different systems: the first was a cosolvent system (S3) of benzyl alcohol/ethanol/water/Transcutol/taurodeoxy cholate/Tween 20 (0.5:16.8:47.7:15.9:1:18.1% w/w). The second was a microemulsion system (ME6) containing Oleic acid: Labrasol/Transcutol/water (8.33:33.3:16.66:41.66% w/w). The prepared systems were characterized in relation to their clarity, particle size, viscosity, pH, and nasal ciliotoxicity. In vivo pharmacokinetic performance of the selected system ME6 (with no nasal ciliotoxicity) was evaluated in a group of six rabbits in a randomized crossover study and compared to the marketed oral tablets. The targeted solubility (>20 mg/ml) of sildenafil citrate was achieved with cosolvent systems S1, S3, and S5 and with microemulsion systems ME3-ME6. The saturated solubility of sildenafil citrate in cosolvent system S3 and microemulsion system ME6 were 22.98 +/- 1.26 and 23.79 +/- 1.16 mg/ml, respectively. Microemulsion formulation ME6 showed shorter t (max) (0.75 h) and higher AUC((0-infinity)) (1,412.42 ng h/ml) compared to the oral tablets which showed t (max) equals 1.25 h and AUC((0-infinity)) of 1,251.14 ng h/ml after administration to rabbits at dose level of 5 mg/kg. The relative bioavailability was 112.89%. In conclusion, the nasal absorption of sildenafil citrate microemulsion was found to be fast, indicating the potential of nasal delivery instead of the conventional oral administration of such drug.

Preparation and evaluation of self-nanoemulsifying tablets of carvedilol.

The purpose of this study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form emphasizing the excipients' effect on the development of a new dosage form. Systems composed of HCO-40, Transcutol HP, and medium-chain triglyceride were prepared. Essential properties of the prepared systems regarding carvedilol solubility, a model drug, and self-emulsification time were determined. In order to optimize self-nanoemulsifying drug delivery systems (SNEDDS), formulation dispersion-drug precipitation test was performed in the absence and presence of cellulosic polymers. Furthermore, SNEDDS was loaded onto liquisolid powders. P-glycoprotein (P-gp) activity of the selected SNEDDS was tested using HCT-116 cells. Carvedilol showed acceptable solubility in the selected excipients. It also demonstrated improvement in the stability upon dilution with aqueous media in the presence of cellulosic polymers. Use of granulated silicon dioxide improved the physical properties of liquisolid powders containing SNEDDS. It improved the compressibility of the selected powders and the tested SNEDDS showed marked P-gp inhibition activity. Prepared self-nanoemulsifying tablet produced acceptable properties of immediate-release dosage forms and expected to increase the bioavailability of carvedilol.