Formulation of Extended-Release Metformin Hydrochloride Matrix Tablets

Purpose: To develop and characterize an oral extended-release matrix tablet of metformin hydrochloride using a combination of a hydrophobic carrier and a hydrophilic polymer, and two types of formulation techniques.Methods: Various metformin hydrochloride formulations containing a hydrophobic carrier (stearic acid) and a hydrophilic polymer (polyethylene oxide) were prepared using a 32 factorial design. Two types of formulation techniques – melt granulation and direct compression – were evaluated. The influence of the carrier, polymer and preparation method on metformin release from the formulations in vitro as well as other physicochemical properties were studied. The release data were subjected to various release kinetic models and also compared with those of a commercial brand.Results: The physicochemical characteristics of all the granules and tablets were generally satisfactory. Optimization results indicate that the release rate of metformin HCl was directly proportional to the levels of stearic acid (SA) and polyethylene oxide (PEO) in the tablet formulations. Release rate was also dependent on the method of granulation used. Kinetic analysis showed that the formulation containing 30 %w/w of polymer exhibited release similar to that of the commercial brand with a similarity factor (f2) of 81.1. Melt granulation was more effective in extending drug release than direct compression. Release mechanism followed most closely the Korsemeyer-Peppas model with a correlation coefficient (r2) and 0.991.Conclusion: The use of a hydrophobic carrier along with a hydrophilic polymer effectively controls the initial rapid release of a highly water soluble drug such as metformin HCl. Hot melt granulation method was especially more effective in achieving this than the direct compression method.Keywords: Metformin hydrochloride, Matrix tablets, Polyethylene oxide, Stearic acid, Hot melt granulation, In vitro release

Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides