Synthesis and evaluation of N-acetylprolinate esters - novel skin penetration enhancers.

A series of N-acetylproline esters (alkyl side chain length, 5-18) were synthesized and tested for potential skin penetration enhancement activity using modified Franz diffusion cells and hairless mouse skin as the penetration barrier. Benazepril and hydrocortisone were used as model drugs and were applied as saturated solutions in propylene glycol. The enhancers were added at a concentration of 5% (w/v). Drug flux, permeability coefficient and enhancement ratios for permeability coefficient were determined. Azone was used as the positive control. While all the compounds tested increased the skin penetration of hydrocortisone, the 5- and 8- carbon esters had no significant effect on the skin penetration of benazepril. The highest fluxes were obtained with 11, 12, and 18-carbon esters and they were comparable to Azone. There was no significant difference between the fluxes obtained with 2 and 5% (w/v) concentrations of the 12-carbon ester on hydrocortisone permeation. The 16-carbon ester, where ethanol was used as a cosolvent, significantly increased the fluxes of both the drugs compared to the control. Differential scanning calorimetric studies suggested that the enhancers may be acting on the lipids of the stratum corneum and their effect was similar to that of Azone. The membrane/vehicle partition coefficient studies indicated an increase in benazepril partition coefficient with enhancer treatment compared to the control. Maximum flux increase was obtained with the 11 and 12 carbon (alkyl chain length) esters for both benazepril and hydrocortisone. The 18- carbon ester which has a cis-double bond in the alkyl side chain, also increased the flux significantly.

Microbiological and HPLC analysis of miconazole in skin, serum and phase-solubility studies.

OBJECTIVE: To develop stability-indicating assays for miconazole. METHODS: A reversed phase high-performance liquid chromatographic assay and a bioassay were developed. RESULTS: The HPLC and the bioassay were linear in the range of 0.5-100 and 0.64-1.56 microg/ml, respectively. The sensitivity of HPLC and bioassay were 0.5 and 0. 64 microg/ml, respectively. The bioassay was less cumbersome and much faster than the HPLC assay by obviating the need for extraction from serum. Miconazole content in the phase-solubility studies and in the serum samples was comparatively evaluated by both assay methods. There was good correlation between the two methods (r2 > 0. 99). The drug extraction efficiency from the serum and the skin were 97.7 and 90.2%, respectively. Where necessary, the bioassay can be an alternative choice for the HPLC analysis. The within and between day variations of the HPLC assay were 3.6 and 4.9%, respectively.

Preparation, characterization, and evaluation of miconazole-cyclodextrin complexes for improved oral and topical delivery.

The solubility of miconazole in water increased in the presence of cyclodextrins (CDs). The apparent K1:1 values calculated from the phase solubility diagrams of gamma-CD, hydroxypropyl-beta-CD, alpha-CD, hydroxyethyl-beta-CD, hydroxypropyl-gamma-CD, and beta-CD were 695 +/- 39.6, 363 +/- 34.1, 333 +/- 18.5, 312 +/- 31.0, 305 +/- 27.6, and 293 +/- 17.6 M(-1), respectively. Solid 1:1 molar complexes were prepared by freeze-drying and kneading and characterized by UV spectroscopy, differential scanning calorimetry, and electron microscopy. The dissolution rate increased to 28-255-fold and the solubility to 9-55-fold. Oral bioavailability in rats increased to 2.3-fold by complexation with hydroxypropyl-beta-CD. Human cadaver skin retained 2.6-fold more drug from the miconazole/alpha-CD complex and hairless mice skin retained 8.4-fold more drug from the HP-beta-CD complex than from miconazole solution alone in 24 h.

Terbutaline transdermal delivery: preformulation studies and limitations of in-vitro predictive parameters.

A transdermal dosage form of terbutaline may be useful to prevent nocturnal wheezing by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of the drug would be an additional advantage as this will reduce the intersubject variability. Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of terbutaline. The drug solubility in propylene glycol was 6.3 mg mL-1. The apparent partition coefficient (n-octanol/ deionized-water, pH 6.5) of terbutaline was 0.03. A pH-partition coefficient (octanol/buffer) profile indicated that the partition coefficient values were 0.02, 0.05 and 0.4 in buffers of pH 3, 7.4 and 9, respectively. The required drug flux through the human skin to attain therapeutic concentrations in the blood was calculated to be 3.3 micrograms cm-2 h-1 for a 10-cm2 transdermal delivery system. Rabbit, guinea-pig and human skin was tested as the penetration barrier using modified Franz diffusion cells. Terbutaline flux values through the rabbit and guinea-pig skin were 8.3 and 7.7 micrograms cm-2 h-1, respectively. The flux through human full-thickness skin and human epidermis were 0.6 and 3.6 micrograms cm-2 h-1. Azone (3% w/v), a skin penetration enhancer, significantly increased the drug flux through all the membranes tested. Based on these studies, transdermal delivery of terbutaline appears to be promising.

C-reactive protein levels predict postoperative septic complications.

We studied 108 patients undergoing clean-contaminated and dirty surgical procedures to determine whether daily C-reactive protein (CRP) measurements for 14 days postoperatively could predict the occurrence of septic complications prior to clinical diagnosis. Diagnostic criteria for septic complications and positive CRP response were defined in advance of the study. The CRP assays were carried out using an automated laser nephelometer system after the patient's discharge from the hospital. Forty-six septic complications were diagnosed in 40 patients. These complications consisted of wound infection (23), urinary tract infection (11), pneumonia (six), upper respiratory tract infection (three), intra-abdominal abscess (one), and other (two). The CRP testing was found to have a positive predictive value of 69% and a negative predictive value of 78%. We conclude that serial CRP measurements may be a valuable adjunct to surgical care in patients at high risk of postoperative septic complications.