Predictive modeling of insulin release profile from cross-linked chitosan microspheres.

Insulin-loaded microspheres composed of chitosan 3% (w/v), and loading 120 IU insulin were produced by emulsion cross-linking method. Cross-linking time was 5 h and glutaraldehyde 3.5% (v/v) was used as cross-linker. Swelling ratio studies were evaluated to predict release of insulin from chitosan microspheres. Bacitracin and sodium taurocholate were incorporated in the formulations as proteolytic enzyme inhibitor and absorption enhancer, respectively. In vitro insulin release studies were performed in phosphate buffer pH 7.4 and also in HCl pH 2 with and without trypsin. Activity of bacitracin was also evaluated. In vitro release showed a controlled profile up to 12 h and the formulation containing 0.15% (w/v) of bacitracin revealed a maximum biological activity of about 49.1 ± 4.1%. Mathematical modeling using Higuchi and Korsmeyer-Peppas suggested a non-Fickian diffusion as the mechanism of insulin release. Insulin-loaded chitosan microspheres for oral delivery showed to be an innovative and reliable delivery system to overcome conventional insulin therapy.

Formulation development and statistical optimization of chronotherapeutic tablets of indometacin.

Chronotherapeutic drug delivery offers a new approach in the pharmacologic interventions design for the effective treatment in the diseases which follows circadian rhythm. In the present study chronotherapeutic tablets of indometacin was designed to match the timing of rheumatoid arthritis treatment with the intrinsic illness timing. The developed chronotherapeutic delivery system consists of a core tablet containing the active ingredient along with osmogents and other excipients, which was coated with a swellable polymer, hydroxyl propyl methyl cellulose by compression coating technique. The time controlled release was achieved by coating the entire system with a combination of pH-independent polymer, Eudragit RS 100 and Eudragit RL 100 (1:1). The optimization technique using Box-Behnken design was employed for the selection of the ideal formula. The optimization procedure was validated, and the observed value of the ideal batch was found to be similar with the predicted values within 5% of predicted error. The formulation when administered at bed time starts releasing the drug after a lag time of 4 h and provides sufficient plasma concentration after 6 h of normal sleep. Thus, the tablets can be successfully used for the chronotherapeutic drug delivery of indometacin in the treatment of rheumatoid arthritis.

Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting.

Thermo-sensitive gels containing lorazepam microspheres were developed and characterized for intranasal brain targeting. Pluronics (PF-127 and PF-68) have been selected since they are thermo-reversible polymers with the property of forming a solution at low temperatures (4-5 °C), and a gel at body temperature (37 °C). This property makes them an interesting material to work with, especially in case of controlled release formulations. The present study focuses on the development of an intranasal formulation for lorazepam, as an alternative route of drug delivery to the brain. Direct transport of drugs to the brain circumventing the brain barrier, following intranasal administration, provides a unique feature and better option to target brain. The presence of mucoadhesive microspheres in the gel vehicle via nasal route can achieve a dual purpose of prolonged drug release and enhanced bioavailability. To optimise the microsphere formulation, Box Behnken design was employed by investigating the effect of three factors, polymer concentration (chitosan), emulsifier concentration (Span 80) and cross-linking agent (glutaraldehyde) on the response variable which is the mean particle size. The concentration of 21% PF-127 and 1% PF-68 were found to be promising gel vehicles. The results showed that the release rate followed a prolonged profile dispersion of the microspheres in the viscous media, in comparison to the microspheres alone. Histopathological studies proved that the optimised formulation does not produce any toxic effect on the microscopic structure of nasal mucosa.

Cross-linked chitosan microspheres for oral delivery of insulin: Taguchi design and in vivo testing.

Insulin-loaded chitosan microspheres were engineered by emulsion cross-linking method using glutaraldehyde as cross-linker. Taguchi orthogonal method was applied to optimize the production time and reduce the number of experiments required to obtain an optimized formulation. Three variables were evaluated, i.e. chitosan and glutaraldehyde concentrations, and cross-linking time at three levels. The dependent variables were the mean particle size and the encapsulation efficiency. The optimal formulation was obtained with chitosan 3% (w/v), glutaraldehyde 3.5% (v/v), and cross-linking time of 5h, characterized by microspheres with a mean particle size of 29.5 µm, and insulin encapsulation efficiency of 71.6±1.3%. In vivo studies were carried out using male Wistar albino rats, revealing a significant reduction in blood glucose level after administration of the optimized formulation, in comparison to a subcutaneous insulin injection. Chitosan microspheres were superior in terms of sustaining protein release over conventional insulin therapy.

Colon specific chitosan microspheres for chronotherapy of chronic stable angina.

In the present work, chitosan microspheres with a mean diameter between 6.32 µm and 9.44 µm, were produced by emulsion cross-linking of chitosan, and tested for chronotherapy of chronic stable angina. Aiming at developing a suitable colon specific strategy, diltiazem hydrochloride (DTZ) was encapsulated in the microspheres, following Eudragit S-100 coating by solvent evaporation technique, exploiting the advantages of microbiological properties of chitosan and pH dependent solubility of Eudragit S-100. Different microsphere formulations were prepared varying the ratio DTZ:chitosan (1:2 to 1:10), stirring speed (1000-2000 rpm), and the concentration of emulsifier Span 80 (0.5-1.5% (w/v)). The effect of these variables on the particle size and encapsulation parameters (production yield (PY), loading capacity (LC), encapsulation efficiency (EE)) was evaluated to develop an optimized formulation. In vitro release study of non-coated chitosan microspheres in simulated gastrointestinal (GI) fluid exhibited a burst release pattern in the first hour, whereas Eudragit S-100 coating allowed producing systems of controlled release diffusion fitting to the Higuchi model, and thus suitable for colon-specific drug delivery. DSC analysis indicated that DTZ was dispersed within the microspheres matrix. Scanning electron microscopy revealed that the microspheres were spherical and had a smooth surface. Chitosan biodegradability was proven by the enhanced release rate of DTZ in presence of rat caecal contents.

Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting.

The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined chemotherapy-the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230 nm (polydispersity index, PDI<0.27) and surface electrical charge of approx. -27mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25±2°C/60±5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months.

Enhanced delivery of lopinavir to the CNS using Compritol-based solid lipid nanoparticles.

BACKGROUND: Protease inhibitors such as lopinavir have negligible permeability to the CNS due to blood-brain and blood-cerebrospinal fluid interfaces. An attempt has been made to develop solid lipid nanoparticles to increase the availability of lopinavir in the CNS. RESULTS/DISCUSSION: Solid lipid nanoparticle formulations exhibited a Cmax and T(max) of 632.86 +/- 81.61 ng/ml and 25 +/- 7.75 min, respectively, with a significant increase in bioavailability in a rat model compared with a free-drug suspension. An appreciable increase in cerebrospinal fluid concentration was detected with solid lipid nanoparticle formulations. CONCLUSION: Compritol-based solid lipid nanoparticles with a poloxamer coating can be effectively absorbed through the lymphatic system, prolong the circulation of drug in blood by acting as a reservoir and can effectively target the drug to the CNS due to the combined effect of lipophilicity and surface charge. The high biocompatibility, biodegradability and nontoxicity of compritol make the compritol-based solid lipid nanoparticles an excellent carrier for enhanced CNS delivery of lopinavir.

Unusual cause of infective discitis in an adolescent.

The first case of infective discitis caused by Eikenella corrodens in an adolescent is presented. The need for anaerobic cultures when dealing with infective pathology in the spine is stressed. A 14 year old boy presented with acute exacerbation of back pain, which showed characteristics of infective discitis after magnetic resonance imaging. Computed tomography guided biopsy grew E corrodens in anaerobic cultures that was sensitive to ampicillin, co-amoxiclav, cefadroxil, and cefotaxime. This patient responded well to co-amoxiclav and recovered without any surgical intervention.