Influence of in vitro release methods on assessment of tobramycin ophthalmic ointments.

The current investigation was carried out to identify appropriate parameters for measuring the in vitro release of tobramycin (TOB) ophthalmic ointments and to evaluate the feasibility of in vitro release testing methods to assess the product performance. Drug release was assessed using USP dissolution apparatus IV and a modified USP dissolution apparatus I with simulated tear solution (STS) as the dissolution medium. The study variables included temperature, membrane material, source and pore size. The results demonstrated a significant influence of the membrane source and pore size on the release of TOB from the ointments. A dissolution medium temperature of 40 °C was found to be appropriate for the release studies. Both of the apparatuses were able to discriminate between the release profiles of ointments with different physicochemical/rheological properties. Maximum release rate of TOB was observed in the first hour which followed a logarithmic time dependent release. The correlation between the release rates/amounts and yield stress of the ointments was observed in both the dissolution apparatuses. These results support a rational approach to guide the in vitro release testing of TOB ophthalmic ointments.

Influence of Manufacturing Process Variables on the Properties of Ophthalmic Ointments of Tobramycin.

PURPOSE: The main purpose of this study was to evaluate qualitative (Q1) and quantitative (Q2) equivalent oleaginous ophthalmic ointments of tobramycin (TOB) with different physicochemical properties and identify critical process/quality attributes using various in vitro methods of characterization. METHODS: Various sources of petrolatum and TOB, and two mixing methods were employed to generate Q1/Q2 equivalent ointments. Characterization studies included content uniformity, microscopy, modulated temperature differential scanning calorimetry (MTDSC), gas chromatography-mass spectrometry (GC/MS), thermogravimetric analysis (TGA) and rheology. RESULTS: The particle size distribution of TOB influenced the content uniformity of ointments. Differences in the MTDSC endothermic and exothermic peaks of TOB suggested the presence of different polymorphic forms. GC/MS revealed variations in the composition and distribution of linear and branched hydrocarbons of petrolatums. Differences were also observed in the TGA derivative weight loss peaks demonstrating differences in the composition of petrolatum that may be the source of the observed variations in the rheological parameters of the ointments. CONCLUSIONS: Source and composition of the petrolatum played a more critical role in determining the rheological properties compared to the method of preparation. Results demonstrated the impact of the source of TOB, excipients and manufacturing processes on the quality attributes of TOB ophthalmic ointments.

Surface-Modified Liposomal Formulation of Amphotericin B: In vitro Evaluation of Potential Against Visceral Leishmaniasis.

Surface modification of liposomes with targeting ligands is known to improve the efficacy with reduced untoward effects in treating infective diseases like visceral leishmaniasis (VL). In the present study, modified ligand (ML), designed by modifying polysaccharide with a long chain lipid was incorporated in liposomes with the objective to target amphotericin B (Amp B) to reticuloendothelial system and macrophages. Conventional liposomes (CL) and surface modified liposomes (SML) were characterized for size, shape, and entrapment efficiency (E.E.). Amp B SML with 3% w/w of ML retained the vesicular nature with particle size of ∼205 nm, E.E. of ∼95% and good stability. SML showed increased cellular uptake in RAW 264.7 cells which could be attributed to receptor-mediated endocytosis. Compared to Amp B solution, Amp B liposomes exhibited tenfold increased safety in vitro in RAW 264.7 and J774A.1 cell lines. Pharmacokinetics and biodistribution studies revealed high t 1/2, area under the curve (AUC)0-24, reduced clearance and prolonged retention in liver and spleen with Amp B SML compared to other formulations. In promastigote and amastigote models, Amp B SML showed enhanced performance with low 50% inhibitory concentration (IC50) compared to Amp B solution and Amp B CL. Thus, due to the targeting ability of ML, SML has the potential to achieve enhanced efficacy in treating VL.

Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol(®) 888ATO as Lipid Excipient.

Tablets containing metoprolol succinate and Compritol(®) 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol(®) 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol(®) 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol(®) 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm(2) exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm(2) with 6.90% of total porosity revealing influence of compression force. Compritol(®) 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.

Compritol®888 ATO a lipid excipient for sustained release of highly water soluble active: formulation, scale-up and IVIVC study.

The potential of Compritol(®)888 ATO as a release modifier to retard the release of highly water soluble drug, metoprolol succinate (MPL) was exploited. Different ratios of Compritol(®)888 ATO versus MPL were utilized and the effect of various formulation methods was evaluated to sustain the release of MPL. MPL: Compritol(®)888 ATO in 1:2 ratio could successfully retard the release of MPL. Melt granulation method "as hot process" was found to be effective when compared to direct compression and wet granulation. The in vitro release characteristics of tablets were studied in pH 6.8 phosphate buffer at 50 rpm using USP Type II apparatus. Formulation F7 retarded MPL release with ~90% release after 20 h. Stability studies showed no significant difference (f2>50) in MPL release profile after three months of storage period at 25 ± 2°C/60 ± 5% RH and 40 ± 2°C/75 ± 5% RH. The bioavailability of sustained release tablets, F7 was compared with commercially available tablets, MetXL50 in 12 healthy human volunteers in a crossover design. Plasma concentration of MPL was determined using HPLC with fluorescence detector. IVIVC correlation was obtained by deconvoluting the plasma concentration-time curve using a model independent Wagner-Nelson method. Correlations of fraction of drug dissolved in vitro and fraction of drug absorbed in vivo displayed a significant linear relationship for sustained release tablets of MPL.

Lecithin-based novel cationic nanocarriers (Leciplex) II: improving therapeutic efficacy of quercetin on oral administration.

The objective of the present investigation was to evaluate ability of the novel self-assembled phospholipid- based cationic nanocarriers (LeciPlex) in improving the therapeutic efficacy of a poorly water-soluble natural polyphenolic agent, quercetin (QR), on oral administration. Quercetin loaded LeciPlex (QR-LeciPlex) were successfully fabricated using a biocompatible solvent Transcutol HP. The QR-LeciPlex were characterized for particle size, encapsulation efficiency, zeta potential, and particle morphology by cryo-TEM. UV and fluorescence spectral characterization was carried out to find out the association of QR with LeciPlex. Small angle neutron scattering studies (SANS) were carried out to understand the internal structure of Leciplex and to evaluate the influence of the incorporation of QR in the LeciPlex. Anti-inflammatory and antitumorigenic activity of QR-LeciPlex was determined in comparison to QR suspension to evaluate the potential of LeciPlex in improving oral delivery of QR. QR-LeciPlex exhibited a particle size of ∼400 nm and had excellent colloidal stability. The QR-LeciPlex had a zeta potential greater than +30 mV and exhibited very high encapsulation efficiency of QR (>90%). UV and fluorescence spectral characterization indicated the interaction/association of QR with LeciPlex components. Cryo-TEM studies showed that LeciPlex and QR-LeciPlex have a unilamellar structure. SANS confirmed the unilamellar structure of LeciPlex and indicated that the incorporation of QR does not have any effect on the internal structure of the LeciPlex. QR-LeciPlex exhibited significantly higher anti-inflammatory and antitumorigenic activity (p < 0.01) as compared to that of QR suspension on oral administration.

Hepatoprotective activity of polyherbal formulation (Normeta) in oxidative stress induced by alcohol, polyunsaturated fatty acids and iron in rats.

In recent years, oxidative stress has been implicated in the pathophysiology of a large number of diseases or disorders which are initiated and/or exacerbated by pro-oxidants such as various drugs including alcohol and food additives. The present study was carried out to evaluate the effects of oral treatment with polyherbal formulation Normeta (2 ml and 4 ml/kg) on hepatic damage induced by alcohol 10-30% (blood alcohol was maintained at levels between 150 and 350 mg/dl), thermally oxidized oil (polyunsaturated fatty acids) (15% of diet) and carbonyl iron (1.5-2% of diet) for 30 days in rats. In vitro studies with 1, 1-Diphenyl, 2-Picrylhydrazyl (DPPH), Nitric oxide and Ferric chloride (Fe(+3) ions) showed that Normeta possesses antioxidant and metal chelating activity. Alcohol, polyunsaturated fatty acids and iron feeding produced an increase in serum levels of iron, serum glutamate pyruvate transaminase and decrease in serum proteins. It was also associated with elevated lipid peroxidation (thiobarbituric acid reactive substances) and disruption of antioxidant defence mechanism in liver, decreased body weight and increased liver to body weight ratio. Oral administration of Normeta along with alcohol, polyunsaturated fatty acids and iron decreased the serum iron, serum glutamate pyruvate transaminase levels and increased serum protein levels. The levels of liver thiobarbituric acid reactive substances were decreased and the activities of antioxidant enzymes superoxide dismutase and catalase were increased. Improvement in body weight and liver to body weight ratio was also observed. The effects of Normeta on physico-metabolic parameters were comparable with silymarin. This indicates that Normeta has favourable effect in bringing down the severity of hepatotoxicity.