Co-melt fluidised bed granulation of pharmaceutical powders: Improvements in drug bioavailability

This study investigates the use of co-melt fluidised bed granulation for the agglomeration of model pharmaceutical powders, namely, lactose mono-hydrate, PEG 10000, poly-vinyl pyrolidone and ibuprofen as a model drug. Granulation within the co-melt system was found to follow a nucleationâ??steady growthâ??coating regime profile. Using high molecular weight PEG binder, the granulation mechanism and thus the extent of granulation was found to be significantly influenced by binder viscosity. The compression properties of the granulate within the hot fluidised bed were correlated using a novel high temperature experimental procedure. It was found that the fracture stress and fractural modulus of the materials under hot processing conditions were orders of magnitude lower than those measured under ambient conditions. A range of particle velocities within the granulator were considered based on theoretical models. After an initial period of nucleation, the Stokes deformation number analysis indicated that only velocities within the high shear region of the fluidised bed were sufficient to promote significant granule deformation and therefore, coalescence. The data also indicated that larger granules de-fluidised preventing agglomeration by coalescence. Furthermore, experimental data indicated that dissipation of the viscous molten binder to the surface was the most important factor in the latter stages of the granulation process. From a pharmaceutical perspective the inclusion of the model drug, ibuprofen, combined with PVP in the co-melt process proved to be highly significant. It was found that using DSC analysis on the formulations that the decrease in the heat of fusion associated with the melting of ibuprofen within the FHMG systems may be attributed to interaction between PVP and ibuprofen through inter-molecular hydrogen bonding. This interaction decreases the crystallinity of ibuprofen and facilitates solubilisation and bioavailability within the solid matrix.

Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism

A side-effect of treatment with antipsychotic drugs for schizophrenia is increased body fat, which leads to further morbidity and poor adherence to treatment. The 5-hydroxytryptamine 2C receptor (5-HT2C) has been associated with this effect; we aimed to establish whether a genetic polymorphism of the promoter region of this receptor affects weight gain after drug treatment in first-episode patients with schizophrenia. We noted significantly less weight gain in patients with the -759T variant allele (p=0.0003) than in those without this allele, who were more likely to have substantial (>7%) weight gain (p=0.002). We have identified a genetic factor that is associated with antipsychotic drug-induced weight gain.

Dried blood spot liquid chromatography assay for therapeutic drug monitoring of metformin

The use of blood spot collection cards is a simple way to obtain specimens for analysis of drugs for the purpose of therapeutic drug monitoring, assessing adherence to medications and preventing toxicity in routine clinical setting. We describe the development and validation of a microanalytical technique for the determination of metformin from dried blood spots. The method is based on reversed phase high-performance liquid chromatography with ultraviolet detection. Drug recovery in the developed method was found to be more than 84%. The limits of detection and quantification were calculated to be to be 90 and 150 ng/ml, respectively. The intraday and interday precision (measured by CV%) was always less than 9%. The accuracy (measured by relative error, %) was always less than 12%. Stability analysis showed that metformin is stable for at least 2 months when stored at -70 degrees C. The small volume of blood required (10 mu L), combined with the simplicity of the analytical technique makes this a useful procedure for monitoring metformin concentrations in routine clinical settings. The method is currently being applied to the analysis of blood spots taken from diabetic patients to assess adherence to medications and relationship between metformin level and metabolic control of diabetes. (c) 2006 Elsevier B.V. All rights reserved.

Neighboring Group-Controlled Hydrolysis: Towards “Designer” Drug Release Biomaterials

To give the first demonstration of neighboring group-controlled drug delivery rates, a series of novel, polymerizable ester drug conjugates was synthesized and fully characterized. The monomers are suitable for copolymerization in biomaterials where control of drug release rate is critical to prophylaxis or obviation of infection. The incorporation of neighboring group moieties differing in nucleophilicity, geometry, and steric bulk in the conjugates allowed the rate of ester hydrolysis, and hence drug liberation, to be rationally and widely controlled. Solutions (2.5 x 10-5 mol dm-3) of ester conjugates of nalidixic acid incorporating pyridyl, amino, and phenyl neighboring groups hydrolyzed according to first-order kinetics, with rate constants between 3.00 ( 0.12 10-5 s -1 (fastest) and 4.50 ( 0.31 10- 6 s-1 (slowest). The hydrolysis was characterized using UV-visible spectroscopy. When copolymerized with poly(methyl methacrylate), free drug was shown to elute from the resulting materials, with the rate of release being controlled by the nature of the conjugate, as in solution. The controlled molecular architecture demonstrated by this system offers an attractive class of drug conjugate for the delivery of drugs from polymeric biomaterials such as bone cements in terms of both sustained, prolonged drug release and minimization of mechanical compromise as a result of release. We consider these results to be the rationale for the development of 'designer' drug release biomaterials, where the rate of required release can be controlled by predetermined molecular architecture.