Stability kinetics of 4-dedimethylamino sancycline, a new anti-tumor drug, in aqueous solutions

4-Dedimethylamino sancycline (col-3) is a new antitumor antibiotic of the tetracycline family. Preformulation studies have indicated that col-3 is not stable in aqueous solutions. The overall purpose of this research project is to investigate the stability kinetics of this drug in aqueous solutions. The physicochemical properties of col-3, including melting point, UV spectrum, mass spectrum, dissociation constants and solubility were determined. Col-3 is an acidic compound with two pKₐ values of 5.9 (pKₐ₁) and 8.1 (pKₐ₂). It is slightly soluble in water (0.01 mg/mL) and readily soluble in organic solvents such as polyethylene glycol and benzyl alcohol. Although the solubility of col-3 increases with increasing pH, its stability decreases with increasing pH. A HPLC assay was developed to quantitate col-3 and separate its degradation products. Four major degradation products of col-3 were detected under alkaline conditions. These degradates were identified by their elution times and their UV-absorption spectra. The kinetics of degradation of col-3 in aqueous solution at 25°C were investigated by HPLC over the pH-range of 2-10. The Influence of pH, buffer concentration, light, temperature and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first-order kinetics at 25°C. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions. The separation of the four initial degradation products of col-3 was investigated. Partial separation of these compounds is achieved by liquid-liquid extraction. However, due to the instability of these compounds, their complete isolation cannot be successful. The UV spectroscopic analysis of these compounds shows that an absorbance at 360 nm is partially decreased in degradates I and II and totally absent in degradates III and IV. These results suggest that the phenolic diketone moiety, which produces this absorption band, has been altered upon degradation

Enhancement of Mycophenolate Mofetil Permeation for Topical Use by Eucalyptol and N-Methyl-2-pyrrolidone

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) which can be metabolized by esterase. MMF has been approved by the United States Food and Drug Administration (USFDA) for treatment of psoriasis patient with skin symptoms. However, it remains unclear whether MMF is efficiently effective to treat skin symptoms developed from psoriasis. The insufficient amount of MMF penetrating through the skin results in the treatment failure due to the difficulty in MMF penetration through the stratum corneum. Skin permeation enhancers such as eucalyptol (EUL) and N-methyl-2-pyrrolidone (NMP) potentially aid in increasing skin penetration. This study aimed to investigate the effects of a concentration ratio (% w/v) between two enhancers (EUL and NMP). The results showed that EUL enhanced MMF permeation with an enhancement ratio (ER) of 3.44 while NMP was not able to promote the penetration of MMF. Interestingly, the synergistic effect of the two enhancers was observed with a suitable ratio given that the ER was 8.21. EUL and NMP are promising enhancers for the development of MMF based skin product

Isoniazid Proliposome Powders for Inhalation—Preparation, Characterization and Cell Culture Studies

Abstract: The aims of this study were to develop proliposome powders containing isoniazid (INH) in a dry powder aerosol form. INH-proliposome powders were prepared by a spray drying method. Proliposome physicochemical properties were determined using cascade impactor, X-ray diffraction and differential scanning calorimetry. The toxicity of proliposomes to respiratory-associated cell lines and its potential to provoke immunological responses from alveolar macrophages (AM) were determined. Free INH and INH-proliposome bioactivities were tested in vitro and in AM infected with Mycobacterium bovis (M. bovis). Aerosolization properties of INH-proliposome powders at 60 L/min, the powders showed mass median aerodynamic diameters of 2.99–4.92 �m, with fine particle fractions (aerosolized particles less than 4.4 µm) of 15–35%. Encapsulation of INH was 18–30%. Proliposome formulations containing INH to mannitol ratios of 4:6 and 6:4 exhibited the greatest overlapping peak between the drug and mannitol. INH-proliposomes were evidently nontoxic to respiratory-associated cells, and did not activate AM to produce inflammatory mediators—including interleukin-1 � (IL-1�), tumor necrosis factor-� (TNF-�), and nitric oxide—at a toxic level. The efficacy of INH-proliposome against A