United States Patent:  6,086,376

Assignee:  RTP Pharma Inc. (Quebec, CA)

Filed:  January 30, 1998

Aerosol formulations containing stabilized particles of drug microparticles with a mean size range of 0.1 to 10 microns coated with a membrane-forming, amphiphatic lipid and dispersed in 1,1,1,2-tetaafluoroetiane (HFA 134a) of 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) propellant.

SUMMARY OF THE INVENTION

In accordance with the present invention it has now surprisingly been found that particularly stable suspensions of microparticles in HFA 134a or HFA 227 are obtainable. These microparticles consist of drug microparticles coated with a phospholipid containing membrane. Preferably the drug particles are coated with a mixture of phospholipid(s) and at least one surfactant forming a membrane layer enveloping the outside of the microparticles. The mean particle size of the drug is reduced to between 100 nm to 10 microns, preferably 0.1 to 10 microns, by sonication or other processes inducing high shear and/or impaction in the presence of phosphlolipids or other membrane-forming amphiphatic lipids and, preferably, at least one surfactant. Dry powder is then obtained by drying the suspension. The dry powder of coated particles is conveniently suspended in the propellant. The membrane forming ingredients are used to obtain appropriate densities and polarities and decreased drug particle-coalescence, thus leading to well dispersible and stable drug suspensions in the hydrofluorocarbon propellants HFA 134a or HFA 227.

DESCRIPTION OF INVENTION

In a preferred aspect of the invention drug particles are coated with mixtures of phospholipids and at least one surfactant with simultaneous size reduction to give a resultant mean particle size of 0.1 to 10 microns. These excipients are used in order to adjust the density, the polarity and the surface tension of the drug particles suspended in the propellant. Control of the density reduces the tendency of dispersed particles to either cream or sediment. The density of the formulation is preferred to be in the range of 1.0 to 1.5 g/ml so as to match with the density of the HFA propellants. Also, appropriate control of the polarity and surface tension of the particles decrease drug-particle coalescence and to yields easily dispersible and stable drug suspensions.

In the membrane coating the weight ratio of phospholipid(s) to surfactant(s) is in the range of 0.01 to 100, preferably in the range of 0.02 to 50 and more preferably in the range of 0.04 to 25. The type and amount of surfactant and cosurfactant used is based on the relative solubility and/or polarity of these ingredients. The formulation compositions are hence optimized with respect to each drug individually. The encapsulation process minimizes the amounts of excipients needed to obtain acceptable formulations.

Importantly, the total amount of surface active agents, including phospholipids, is preferably more than 0.1% and less than 200% of the drug content.

Claim 1 of 16 Claims

1. A dry suspension aerosol formulation having a density in the range of from 1.0 to 1.5 g/ml consisting essentially of stabilized drug microcrystals in a mean size range of 0.1 to 10 microns as a core coated with an envelope of one or more membrane-forming phospholipids and at least one surfactant surrounding the drug core and dispersed in 1,1,1,2-tetrafluoroethane HFA134a or 1,1,1,2,3,3,3-heptafluoropropane HFA 227 propellant, wherein the density of the coated drug microparticles substantially matches the density of the propellant and the amount of phospholipid coating on the drug microparticles is more than 0.1% and less than 200% of the weight of the drug.

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