Application of Lipid Microspheres to Prepare a Thromboxane A₂Receptor Antagonist Aerosol for Inhalation

Abstract

The methyl ester of a new thromboxane A2 receptor antagonist, (+)S-145, i.e. (1R,2S,3S,4S)-(5Z)-7-(3-phenyl-sulfonyl-aminobicyclo[2,2,1]he pt-2-yl)heptenoic acid, was incorporated into lipid microspheres (lipo S-145-Me) and its pharmacological effect and tissue distribution were examined in guinea pigs following aerosol delivery. Bronchoconstrictive responses induced by intravenous injection of U46619 or the inhalation of ovalbumin were suppressed in a dose-dependent manner by aerosol inhalation of lipo S-145-Me, which was 3-10 times more potent that the unencapsulated calcium dihydrate of the original drug (S-1452). There was no significant difference in the airway tissue distribution of labelled lipo S-145-Me versus S-1452 after 2 or 5 min of inhalation, but the encapsulated drug showed marked accumulation in the lungs after 30 min of inhalation. The in vitro uptake of lipo [14C] S-145-Me by fresh human neutrophils and an eosinophil cell line was respectively 7 times and 3.5 times higher than that of [14C] S-1452. These results suggest that lipo S-145-Me has the potential to be used as an inhalational antiasthma agent, and that its effect may be partly attributable to a for inflammatory cells which are responsible for allergic airway inflammation.

Possibility of lipid microsphere-encapsulated Y-24180 as an injectable drug and an inhaler for the treatment of bronchoconstriction

“…Previously, we have shown 12 that aerolized LM‐encapsulated PGE 1 could delay the onset and decrease the severity of dyspnea as well as reducing bronchial irritation when compared with free PGE 1 in animals and in asthmatics. Also, we have demonstrated 13 that inhalation of LM‐encapsulated drug led to markedly enhanced pulmonary accumulation, and its in vitro uptake by human eosinophils and neutrophils was higher than that of unencapsulated drug. Therefore, aerosol administration would be a desirable method in order to not only be more convenient but also to lower the required dose for the treatment of asthma etc.…”

“…Lipid microspheres containing Y‐24180 (Lipo Y‐24180) were prepared as described previously. 13 Briefly, 10 mg Y‐24180 was dissolved in 1 g soybean oil and mixed with 120 mg yolk lecithin. The mixture was then poured into a 2.58% glycerol aqueous solution with agitation to make a 10% (w/v) oil‐in‐water suspension.…”

Anti-tuberculosis activity and drug interaction with nevirapine of inhalable lipid microspheres containing rifampicin in murine model

“…Blood and organs were dissolved with Soluene Õ -350 (PerkinElmer Japan Co., Yokohama, Japan). An aliquot was used for determination of radioactivity concentrations and reported as percentage of radiolabelled dose per mL of blood or g of organ (% dose/mL or g) (Takenaga et al 1993).…”

Lipid Microsphere Formulation Containing Rifampicin Targets Alveolar Macrophages

“…Then blood samples and organs were harvested followed by solubilization with Soluene R -350 (PerkinElmer Japan Co., Yokohama, Japan). An aliquot was used for determination of radioactivity (Takenaga et al 1993b). …”

“…For example, the inhalation of LM-encapsulated PGE 1 delayed the onset and decreased the severity of dyspnea and bronchial irritation compared with inhalation of free PGE 1 in animals and asthma patients (Mizushima et al 1983). In addition, the inhalation of an LM-encapsulated TXA 2 antagonist (Takenaga et al 1993b) or PAF antagonist (Takenaga et al 2000) resulted in enhancement of their pharmacological activity.…”