In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

This work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the serum drug profile following oral administration of the microcapsules and the commercial product to rabbits. The obtained serum concentration time profile of the EC microcapsules exhibited a sustained-release pattern similar to the commercial product and consistent with the in vitro results.     

Design and characterization of enteric-coated controlled release mucoadhesive microcapsules of Rabeprazole sodium

The objectives of present work was to design and characterize the rabeprazole sodium loaded microcapsules prepared by solvent evaporation technique using ethyl cellulose (EC) based various mucoadhesive polymer, followed by a triple coating with Eudragit L100. The Box-behnken design (BBD) was applied for optimization of formulations containing EC, HPMCK100M and Eudragit L100 as factors for selected responses like entrapment efficiency, mucoadhesive property and drug release in 24 h. The prepared microcapsules were characterized for particle size, drug content, swelling index, mucoadhesive strength, and in vivo antiulcer activity. FT-IR studies revealed that there was no drug-polymer interaction. SEM studies revealed that microcapsules were non-aggregated, spherical shape and smooth appearance. In vitro drug release data from microcapsules was fitted to different kinetic models to explain release profiles. The correlation coefficient value (r²) indicated that the drug release followed Higuchi model. Analysis of variance (ANOVA) showed significant difference in the release of drug from all formulations at p < 0.05 level. Accelerated stability study of optimized formulation (F4) upto 6 months showed there was no change in drug content and release characteristics during storage. In vivo antiulcer activity showed that the optimized microcapsules were able to protect rat stomach against ulcer formation vis-à-vis aqueous solution of the drug showed only negligible and minimum effect.     

Development of sustained-release tablets containing sodium valproate: in vitro and in vivo correlation

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

In vitro dissolution of two oral controlled release preparations of diclofenac sodium.

The development of controlled release formulations has brought about the need for appropriate quality control methods such as in vitro dissolution testing. Such tests are principally designed to obtain correlation with the in vivo performance of the formulation (1,2,3). If an in vitro test can be defined offering a good correlation the test may serve for routine quality control or may be useful in screening new drug formulations.     

In vitro and in vivo evaluation of hydrophilic and hydrophobic polymers-based nicorandil-loaded peroral tablet compared with its once-daily commercial sustained-release tablet

Context: Hydrophilic and hydrophobic polymer-based nicorandil (10 mg)-loaded peroral tablets were prepared using the wet granulation technique. The influence of varying amounts of hydroxypropyl methylcellulose (HPMC) (30–50 mg), ethylcellulose (2–4 mg), microcrystalline cellulose (5–20 mg) and Aerosil^® (5–12 mg) in conjunction with the constant amounts (3 mg) of glidant and lubricant (magnesium stearate and talc) on the in vitro performances of the tablets (hardness, friability, weight variation, thickness uniformity, drug content, and drug release behavior) were investigated. Objective: The objectives of this study were (i) to select a nicorandil-loaded peroral tablet that matched the in vitro dissolution profile of once-daily commercial sustained-release tablet, and (ii) to compare the in vivo sustaining/controlling efficacy of the selected peroral tablet with that of its commercial counterparts. Results and Discussion: Because the nicorandil (10 mg)-loaded tablet prepared based on F-IX composition (50 mg HPMC, 4 mg ethylcellulose, 10 mg MCC and 3 mg glidant and lubricant) showed a release profile comparable to that of the Nikoran^® OD SR tablet release profile, the tablet with this composition was considered to be the optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in rabbits. Despite of the higher C_max and AUC values obtained with the optimized tablet, there was no sign of difference between the optimized- and Nikoran^® OD SR- tablets following a single-dose crossover oral administration into rabbit. Conclusion: The optimized tablet could be used as an alternative to the commercial once-daily tablet.     

In vitro evaluation and in vivo performance of lyophilized gliclazide

Enhancement of the dissolution rate of the poorly water-soluble hypoglycemic agent, gliclazide, by the aid of lyophilization was investigated. Mannitol, sodium lauryl sulfate (SLS) and polyvinyl pyrrolidone (PVP-k-30) were employed in different weight ratios (43%, 56% and 64% w/w, respectively) as water-soluble excipients in the formulation. Lyophilized systems were found to exhibit extremely higher in vitro dissolution rate compared to the unprocessed drug powder. Solid state characterization of the lyophilized systems using X-ray powder diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry techniques revealed that dissolution enhancement was attributable to transformation of gliclazide from the crystalline to an amorphous state in the solid dispersion formed during the lyophilization process. The gastrointestinal absorption and hypoglycemic effect of the lyophilized gliclazide/SLS system were investigated following oral administration to Albino rabbits. C_max and area under the plasma concentration–time curve of gliclazide (AUC_0–12) after administration of the lyophilized formulations were significantly higher than those obtained after administration of the unprocessed gliclazide.     

Excipient-excipient interaction in the design of sustained-release theophylline tablets: in vitro and in vivo evaluation

Sustained-release (SR) theophylline (TPH) tablets were prepared by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29-31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%-4.2%), depending on SAL:CG ratios. The corresponding tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). The release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for Quibron. The in vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for up to 24 h. The formulated tablets showed 104.65% bioavailability relative to that of the commercial tablets. The rate and extent of absorption of TPH showed no significant differences from that of the commercial tablets. Moreover, no significant differences were found in the pharmacokinetic parameters related to the rate and extent of TPH absorption from the prepared and commercial tablets.     

In vivo andin vitro evaluation of a biomachinable glassceramic

In this paper we describe the toxicological tests done on a machinable glassceramic, prepared at the Defence Metallurgical Research Laboratory. Tests show no toxicity and biocompatibility is inferred.     

In vitro and in vivo evaluation of glibenclamide in solid dispersion systems

The purpose of this work is to improve the dissolution and bioavailability characteristics of glibenclamide as compared to Daonil tablets (Hoechst). Solid dispersions of glibenclamide in Gelucire 44/14 (Formula 1) and in polyethylene glycol 6000 (PEG 6000) (Formula 2) were prepared by fusion method. In vitro dissolution studies showed that the dispersing systems containing glibenclamide and Gelucire 44/ 14 or PEG 6000 gave faster dissolution rates than the reference product Daonil. The in vivo bioavailability study was assessed in six healthy male volunteers in crossover design with a 1-week washout period. Both formulas were found to be significantly different from Daonil with regard to the extent of absorption as indicated by the area under serum concentration-time curve. Both formulas are not significantly different from Daonil with respect to time of peak plasma concentration Tmax. It is concluded from this pilot study that the ranking of the in vitro dissolution is similar to the ranking of in vivo availability. The ranking of the three preparations in term of dissolution rate and extent of absorption is as follows: Formula 2>Formula 1 >Daonil.     

In vitro and in vivo evaluation of puerarin-loaded PEGylated mesoporous silica nanoparticles

Puerarin, which is extracted from Chinese medicine, is widely used in China and mainly used as a therapeutic agent for the treatment of cardiovascular diseases. Owing to its short elimination half-life in human beings, frequently intravenous administration of high doses of puerarin may be needed, which possibly leads to severe and acute side effects. The development of an effective sustained-release drug delivery system is urgently needed. In this study, PEGylated mesoporous silica nanoparticles (PEG-MSNs) had become a preferred way to prolong the half-life and improve the bioavailability of drugs. The release of puerarin from PEG-MSNs was pH dependent, and the release rate was much faster at lower pH than that at higher pH. Moreover, the PEG-MSNs exhibited improved blood compatibility over the MSNs in terms of low hemolysis, and it could also reduce the side effect of hemolysis induced by PUE. Compared with puerarin, PUE-loaded PEG-MSNs showed a 2.3-fold increase in half-life of puerarin and a 1.47-fold increase in bioavailability. Thus, the PEG-MSNs hold the substantial potential to be further developed as an effective sustained-release drug delivery system.     

The physicochemical characterization and in vitro/in vivo evaluation of natural surfactants-based emulsions as vehicles for diclofenac diethylamine

Two sugar-based emulsifiers, cetearyl alcohol & cetearyl glycoside and sorbitan stearate & sucrose cocoate, known as potential promoters of lamellar liquid crystals/gel phases, were investigated in order to formulate an optimal vehicle for amphiphilic drug—diclofenac diethylamine (DDA).

Physico-chemical characterization and study of vehicle's physical stability were performed. Then, the in vitro DDA liberation profile, dependent on the mode of drug incorporation to the system, and the in vivo, short-term effects of chosen samples on skin parameters were examined.

Droplets size distribution and rheological behavior indicated satisfying physical stability of both types of vehicles. Unexpectedly, the manner of DDA incorporation to the system had no significant influence on DDA release. In vivo study pointed to emulsion's favorable potential for skin hydration and barrier improvement, particularly in cetearyl glycoside-based vehicle.     

In vitro studies and preliminary in vivo evaluation of silicified concentrated collagen hydrogels

Hybrid and nanocomposite silica-collagen materials derived from concentrated collagen hydrogels were evaluated in vitro and in vivo to establish their potentialities for biological dressings. Silicification significantly improved the mechanical and thermal stability of the collagen network within the hybrid systems. Nanocomposites were found to favor the metabolic activity of immobilized human dermal fibroblasts while decreasing the hydrogel contraction. Cell adhesion experiments suggested that in vitro cell behavior was dictated by mechanical properties and surface structure of the scaffold. First-to-date in vivo implantation of bulk hydrogels in subcutaneous sites of rats was performed over the vascular inflammatory period. These materials were colonized and vascularized without inducing strong inflammatory response. These data raise reasonable hope for the future application of silica-collagen biomaterials as biological dressings.     

In vitro and in vivo evaluation of silicated hydroxyapatite and impact of insulin adsorption

This study evaluates the biological behaviour, in vitro and in vivo, of silicated hydroxyapatite with and without insulin adsorbed on the material surface. Insulin was successfully adsorbed on hydroxyapatite and silicated hydroxyapatite bioceramics. The modification of the protein secondary structure after the adsorption was investigated by means of infrared and circular dichroism spectroscopic methods. Both results were in agreement and indicated that the adsorption process was likely to change the secondary structure of the insulin from a majority of α-helix to a β-sheet form. The biocompatibility of both materials, with and without adsorbed insulin on their surface, was demonstrated in vitro by indirect and direct assays. A good viability of the cells was found and no proliferation effect was observed regardless of the material composition and of the presence or absence of insulin. Dense granules of each material were implanted subcutaneously in mice for 1, 3 and 9 weeks. At 9 weeks of implantation, a higher inflammatory response was observed for silicated hydroxyapatite than for pure hydroxyapatite but no significant effect of adsorbed insulin was detected. Though the presence of silicon in hydroxyapatite did not improve the biological behaviour, the silicon substituted hydroxyapatite remained highly viable.     

In vitro dissolution studies of sodium diclofenac granules coated with Eudragit L-30D-55 by fluidized-bed system

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to USP XXIII (1995) “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

In vitro and in vivo evaluation of a desonide gel-cream photostabilized with benzophenone-3

Context: Our group previously reported the photoinstability of some desonide topical commercial formulations under direct exposure to UVA radiation.

Objective: This study aimed to prepare and characterize a gel-cream containing desonide, with greater photostability than the commercial gel-cream (C-GC). Benzophenone-3 (BP-3) was used as a photostabilizing agent.

Methods: The gel-cream developed (D-GC) containing BP-3 at 0.1% was prepared and characterized regarding its pH, drug content, spreadability, viscosity, in vitro drug release and in vitro permeation. The in vivo anti-inflammatory effect was assessed by ear edema measurement, croton oil-induced acute skin inflammation and myeloperoxidase assay.

Results and Discussion: D-GC presented characteristics compatible with topical application, appropriate drug content and good spreadability, and non-Newtonian behavior with pseudoplastic flow. D-GC showed a good photostability profile, presenting a desonide content of 95.70% after 48?h of exposure to UVA radiation, and stability under room conditions during 60 days. The amount of desonide released from D-GC and C-GC was 57.8 and 51.7?µg/cm², respectively, measured using the vertical Franz cell. The in vitro skin permeation showed that desonide reached the site of action of the topical corticosteroids, from both formulations; however, the desonide amount retained in the dermis was lower with D-GC. The in vivo evaluation of topical anti-inflammatory activity indicated that D-GC presented the same biological effect as C-GC.

Conclusion: D-GC represents a promising approach to treat dermatological disorders, since it presented satisfactory physicochemical characteristics, the same biological activity as C-GC and superior photostability, conferred by the addition of BP-3 at 0.1%.     

In vitro degradation and cytocompatibility evaluation of novel soy and sodium caseinate-based membrane biomaterials

Soy- and casein-based membranes are newly proposed materials disclosing a combination of properties that might allow for their use in a range of biomedical applications. Two of the most promising applications are drug delivery carrier systems and wound dressing membranes. As for all newly proposed biomaterials, a cytotoxic scanning must be performed as a preliminary step in the process of the determination of the compatibility with biological systems (biocompatibility). In this study, the cytotoxicity of both soy- and casein-based protein biomaterials has been evaluated and correlated with the materials degradation behavior. It was possible to show, through morphological and biochemical tests that these natural origin materials do not exert any cytotoxic effect over cells, and in some cases can in fact enhance cell proliferation. The different treatments to which the membranes were subjected during their processing (that include crosslinking with glyoxal and tannic acid, and physical modification by thermal treatment) seemed to have a clear effect both on the materials mechanical properties and on their in vitro biological behavior.     

In vitro and in vivo evaluation of two extended release preparations of combination metformin and glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

In vitro and in vivo evaluation of a novel nonscrotal matrix-type transdermal delivery system of testosterone

A matrix-type testosterone (TS) transdermal delivery system for nonscrotal skin was developed with DuroTak 87-2510 as an adhesive polymer. When 3% dodecylamine was used in combination with 10% span 80, the in vitro rat permeation rate increased from 2.29 microg/cm2/hr to 6.51 microg/cm2/ hr as the TS loading dose increased from 2% to 6%. The maximum flux of experimental patch was about 14-fold higher than that of Testoderm. Release kinetics of TS from the patches was proportional to t1/2 following the Higuchi equation, and the release rate of TS increased as TS loading dose increased. Also, a good linear relationship between the skin permeation rate and the release rate was observed, which implies that the release rate is the rate-limiting process of the skin permeation. In vivo study showed that the plasma concentration of TS promptly increased and reached the peak level within 3-6 hours of application of the experimental patch. Area under the curve (AUC0 approximately 48) and Cmax also linearly increased in a dose-dependent manner up to 6% of TS. These results demonstrate the feasibility of developing a nonscrotal matrix-type transdermal delivery system of TS.     

In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium

The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7?±?12.9 to 423?±?15.9?nm while zeta potential values varied from ?21.7?±?0.90 to ?22.7?±?0.85?mV. The loading capacity varied from 17.9?±?1.21 to 34.1?±?1.16%. DSC, FT–IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p?in vivo performance of AC.