Daniel L. Parsons

Development and in-vitro evaluation of sustained release poloxamer 407 (P407) gel formulations of ceftiofur.

The objective of this study was to develop sustained release Poloxamer 407 (P407) gel formulations of ceftiofur for treating foot infections in cattle. The formulations contained 25-35% (w/v) P407 alone or with polyvinyl pyrrolidone (PVP), carboxy methylcellulose (CMC), or hydroxylpropyl methylcellulose (HPMC) as an additive. The in-vitro release profiles of ceftiofur from the P407 formulations and the gel dissolution profiles were obtained simultaneously. Ceftiofur release followed zero order kinetics and correlated well with the weight percentage of P407 dissolved, indicating that the overall rate of release of ceftiofur is controlled by dissolution of the P407. An increase in P407 content from 25 to 35% resulted in a decrease in the rate of ceftiofur release. However, it appears that other factors may have also affected the drug release rate. Inclusion of PVP, CMC, and HPMC in the gel decreased the rate of release of ceftiofur to some extent. A decrease in the temperatures of the release medium decreased the release rate of ceftiofur, but not the rate of gel dissolution. The pH of the release medium showed a very slight effect on the release of ceftiofur and did not affect gel dissolution due to the non-ionic nature of P407.

Amorphous‐state characterization of efavirenz—polymer hot‐melt extrusion systems for dissolution enhancement

The aim of this study was to improve the dissolution rate of efavirenz (EFV) by formulating a physically stable dispersion in polymers. Hot-melt extrusion (HME) was used to prepare solid solutions of EFV with Eudragit EPO (a low-glass transition polymer) or Plasdone S-630 (a high-glass transition polymer). The drug-polymer blends were characterized for their thermal and rheological properties as a function of drug concentration to understand their miscibility and processability by HME. The solid-state stability of extrudates was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and dissolution studies. Thermal and rheological studies revealed that the drug is miscible with both polymers, and a decrease in melt viscosity was observed as the drug concentration increased. XRD and DSC studies confirmed the existence of amorphous state of EFV in the extrudates during storage. The dissolution rate of EFV from the extrudates was substantially higher than the crystalline drug. FTIR studies revealed an interaction between the EFV and Plasdone S-630, which reduced the molecular mobility and prevented crystallization upon storage. EFV and Eudragit EPO systems lack specific interactions, but are less susceptible to crystallization due to the antiplasticization effect of the polymer.

Gefitinib–cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies

Background: Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs). Methods: Phase solubility studies of gefitinib with hydroxypropyl βCD (HPβCD) and randomly methylated βCD (RMβCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC). Results: Gefitinib formed stable complexes with HPβCD and RMβCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M−1 for HPβCD and RMβCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an AN type of phase-solubility diagrams, whereas gefitinib and HPβCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in AP-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPβCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC. Conclusion: Gefitinib formed stable inclusion complexes with HPβCD and RMβCD, and the solubility and dissolution rate of the drug was significantly increased.

Perfluorochemical Erythrocyte Substitutes: Disposition and Effects on Drug Distribution and Elimination

As a result of their ability to transport oxygen, PFC emulsions are being investigated for possible use in a wide variety of conditions. The recent FDA approval of F-DA to diminish myocardial ischemia during angioplasty is the first marketing approval for such a product in the world. The many potential uses of such products may result in their common application in the future, especially as new and better products are developed. The elimination, distribution, and tissue retention of PFC emulsions as well as the physiological changes that occur upon their administration have been the subject of many investigations. The results indicate that these agents may influence the pharmacokinetic properties of other drugs by a wide variety of mechanisms. Several studies have shown significant, but not necessarily consistent, changes in drug elimination and distribution following PFC emulsion infusion. Changes appear dependent on the drug examined, emulsion utilized, degree of blood exchange, species utilized, and the controls chosen for comparison. Often, the changes are time dependent indicating the importance of conducting long-term studies. While PFC emulsions do not appear to alter renal elimination of drugs, several studies have demonstrated that these agents have the potential to induce drug metabolism from several days to possibly months after exposure. Observed changes in drug volumes of distribution, which are often time dependent, may be due to changes in normal drug transport throughout the circulation and/or changes in membrane permeability and cell transport mechanisms. Changes in drug transport may result from depletion of plasma proteins or increases in alpha 1-acid glycoprotein levels due to trauma or PFC emulsion effects. The binding of drugs by PFC emulsion droplets varies greatly and PFC emulsion components displace some plasma protein bound drugs. The wide variability in the results and conclusions of the pharmacokinetic studies conducted to date emphasize the importance of utilizing adequate controls to identify which alterations are PFC emulsion specific.

In vitro percutaneous absorption of genistein from topical gels through human skin

The objective of this study was to formulate genistein as a topical gel with various penetration enhancers for increased permeation and retention in human skin. The high performance liquid chromatography assay method was validated for precision and reproducibility. The intra-day and inter-day precision as represented by the coefficient of variation (CV) of the peak areas were <0.44% and <0.67%, respectively. Further, the reproducibility was demonstrated by the CV of the assay at different genistein concentrations, which were <1.64%. Genistein was subjected to various stress conditions to obtain basic information on the appropriate pH and aqueous vehicle for formulating topical gels. Genistein was highly stable under neutral and oxidative conditions, but degraded to highly polar and nonpolar compounds under basic and acidic conditions, respectively. Menthol produced a 9- and 22-fold increase in the flux and skin retention of genistein, respectively, after 24 h of gel application as compared with the control (no enhancer). Cineole showed an approximately 7-fold increase in flux, but skin retention did not increase significantly. Transcutol increased the flux and skin retention of genistein by 5- and 7-fold, respectively. When Transcutol was formulated with Lauroglycol, there was a 13- and 9-fold increase in the flux and skin retention, respectively. Incorporation of penetration enhancers into the topical gel increased the skin permeation of genistein, so that the target delivery rate for its therapeutic effects can be achievable based on the in vitro human skin data generated in this study.

Microneedle assisted iontophoretic transdermal delivery of prochlorperazine edisylate

This paper investigates the microneedle (MN) mediated in vitro transdermal iontophoretic delivery of prochlorperazine edisylate (PE) across dermatomed human skin. The Dermaroller™ induced microchannels were visualized using methylene blue staining and scanning electron microscopy. In vitro skin permeation studies were performed using vertical static Franz diffusion cells. Iontophoretic protocols involved application of direct current at a density of 0.4 mA/cm2 using Ag as an anode and Ag/AgCl as a cathode. The effect of PE concentration (20, 50 and 100 mg/mL), number of passes of microneedles (0, 5, 10 and 20) on both iontophoretic and passive delivery of PE was studied. The Dermarollertm was found to successfully breach the skin barrier and a linear relationship (r2 = 0.99) was observed between the number of passes of the Dermaroller™ and the number of microchannels created. Passive transdermal flux of PE (0.060 ± 0.003 µg/cm2/h) at 50 mg/mL donor PE concentration) was low and increased (4.15 ± 0.57 µg/cm2/h) with the application of direct current. Application of iontophoresis in conjunction with microneedle pre-treatment resulted in enhanced flux (4.90 ± 0.39 µg/cm2/h at 50 mg/mL donor PE concentration) of PE. The projected transdermal PE flux indicates that a 9 cm2 patch could deliver PE in a sufficient amount to maintain therapeutic levels of the drug. In conclusion, microneedles when used in conjunction with iontophoresis significantly enhanced the transdermal delivery of PE and it may be feasible to develop an iontophoretic transdermal patch that could be integrated with MN.

Transdermal iontophoretic delivery of selegiline hydrochloride, in vitro

Transdermal iontophoretic delivery of selegiline hydrochloride (SH) across dermatomed human skin was studied. Electrochemical stability and various factors affecting the skin permeation were investigated. SH was stable under the influence of an electrical field. The permeation of SH was very low by passive delivery (2.29 ± 0.05 μg/cm2/h) as compared to iontophoresis at 0.5 mA/cm2 (65.10 ± 5.04 μg/cm2/h). An increase in drug concentration from 1 to 20 mg/mL increased the iontophoretic flux by 13-fold. Optimal pH and salt (NaCl) concentration for iontophoretic delivery of SH were found to be pH 5 and 100 mM, respectively. Overall, with 20 mg/mL SH and a current density of 0.4 mA/cm2, a maximum flux of 305.5 μg/cm2/h was obtained. Based on reported pharmacokinetic parameters, input target delivery rate to achieve effective plasma concentration of SH (2.2 ng/mL) was calculated. With a surface area of 40 cm2, iontophoretic delivery can provide six to seven times higher levels of SH than the target delivery rate, which enables lowering of the dose and/or patch surface area. Further in vivo studies will be required to prove the efficacy of ionophoresis for enhanced delivery of SH.

Enhancement of transdermal delivery of phenylbutazone from liposomal gel formulations through deer skin.

Phenylbutazone (PBZ) is a nonsteroidal anti-inflammatory drug used in the treatment of chronic pain and arthritis. Topical and transdermal administration of PBZ would be beneficial in large animals in terms of minimizing gastro-intestinal ulcerations and other side effects, easy administration to legs and joints and minimizing the dose to reduce systemic toxicity of the drug. A topical liposomal preparation with different concentrations of a mono-substituted alkyl amide (MSA) and PBZ was formulated. The formulations were evaluated by in vitro skin-permeation kinetics through deer skin using Franz diffusion cells. By increasing drug loading from 1% to 5% w/w, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Similarly, by increasing the MSA concentration from 0% to 4%, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Overall, by increasing the drug load and the use of an appropriate amount of the penetration enhancer, the steady-state flux of PBZ through skin was increased fourfold (P < 0.001). MSA at both 2% and 4% w/w concentrations significantly increased the skin levels of PBZ as compared with control (P < 0.05). In conclusion, MSA served as an effective skin-penetration enhancer in the liposomal gel of PBZ for deer.