Mark Kontny

Gelatin capsule brittleness as a function of relative humidity at room temperature

Abstract The pharmaceutical literature cites many examples which indicate that hard gelatin capsule brittleness is a function of moisture content. Likewise, brittleness can be correlated with relative humidity. In this study, brittleness of empty capsules was noted at relative humidities below 40%. Mexitil capsules exhibited a similar profile, suggesting that relative humidity in the vapor phase is an important factor that can be monitored and controlled. It is known that moisture will redistribute between the various components in a given system until a single relative humidity is attained in the vapor phase. Thus, a priori prediction of the value of this thermodynamic variable for known conditions will allow prediction of capsule brittleness. For a closed system, the final value is intimately dependent upon the affinity of the various materials for water. As such, the sorption-desorption moisture transfer (SDMT) model, which is based on isotherms for the respective materials, was employed to estimate the final relative humidity for the Mexitil/gelatin capsule system. Results are presented that demonstrate the general applicability of the SDMT model for predicting the incidence of brittleness problems, as well as selecting optimal initial loss on drying (LOD) values for the empty gelatin capsules and the formulation to ensure the absence of brittleness.

The role of 5-lipoxygenase products in preclinical models of asthma

BACKGROUND The action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma. METHODS Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma. RESULTS In vitro BI-L-239 inhibited 5-lipoxygenase product generation from human lung mast cells, alveolar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmol/L. A 36-fold selectivity for immunoreactive leukotriene C4 versus immunoreactive prostaglandin D2 inhibition was demonstrated in mast cells. In anesthetized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced immunoreactive leukotriene C4 release (maximum, 73%; bronchoalveolar lavage [BAL], 20 minutes), late-phase bronchoconstriction (maximum, 41%; +6 to 8 hours), and neutrophil infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 hours). The acute bronchoconstriction was shortened, and neutrophil infiltration diminished (maximum, 61%; BAL, +8 hours) in this model. Finally in conscious actively sensitized guinea pigs pretreated with pyrilamine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconstriction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholine, +3 days) induced by three alternate-day ovalbumin inhalations. CONCLUSIONS In conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the bronchoconstriction (especially late phase), leukocyte infiltration, and airway hyperresponsiveness that characterize asthma.

Use of the sorption-desorption moisture transfer model to assess the utility of a desiccant in a solid product

Abstract Desiccants are frequently included in moisture-sensitive solid pharmaceutical products to scavenge moisture in the package and prevent this water from interacting with the product. This study has demonstrated the utility of the sorption-desorption moisture transfer (SDMT) model for predicting moisture transfer between an aspirin formulation and a silica/carbon desiccant for defined masses of each component and their initial moisture contents. Furthermore, simulations were conducted that accounted for permeation of moisture into the container for three markedly different masses of formulation that correspond to 1, 75, and 1500 tablets with 0–2 g of desiccant. For this formulation/ desiccant system, desiccant clearly had a marked effect in reducing the relative humidity inside the container for a significant time period for the single tablet and 75 tablet cases. However, the desiccant exhibited no practical effect in reducing relative humidity inside the container compared to formulation without desiccant for the 1500 tablet case. In conclusion, the SDMT model can account for the permeation properties of the package, the initial masses and moisture contents of the formulation and desiccant, and the total moisture sorption capacity of the formulation and desiccant to predict whether a desiccant will offer a significant moisture protective (i.e., reduced relative humidity inside the package) effect for a defined product.

BI-L-239, a 5-lipoxygenase inhibitor, blocks inhaled antigen-induced airway hyperresponsiveness in conscious guinea pigs

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n=5–6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10×0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143±29%, 238±73% and 102±43% in placebo and 86±34%, 45±35% (p, 0.05 vs. placebo) and 102±31% in BI-L-239 treated. OA induced a significant (p<0.05) increase in airway leukocytes in placebo (487±36 to 1615±421×103/ml) but not BI-L-239 treated (to 881±155×103/ml) and decrease in methacholine PC100 in placebo (1.487±0.49 to 0.39±0.18 mg/ml) but not BI-L-239 treated (0.99±34 to 1.04±0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.