Title:  Aerosol pharmaceutical formulation for pulmonary and nasal delivery

United States Patent:  6,294,153

Assignee:  Generex Pharmaceuticals, Inc. (Ontario, CA)

Filed:  September 16, 1999

An aerosol pharmaceutical formulation for pulmonary and nasal delivery is provided. The formulation comprises a pharmaceutical agent, water, a phenol and a propellant. Optionally, an excipient such as glycerin or polyglycerin, lysine or polylysine, or other salts, flavoring or coloring agents, protease inhibitors or stabilizers can be added. A method of administering the formulation with a metered dose dispenser, and a dispenser containing the formulation are also provided.

SUMMARY OF THE INVENTION

It has now been found that improvements in penetration and absorption of certain micellar formulations can be achieved by mixing the mixed micellar formulation with propellants such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other non-CFC and CFC propellants, especially when delivered (e.g. applied to the buccal mucosa) through aerosol devices, e.g. metered dose inhalers (MDIs). Metered dose inhalers are a proven technology and a popular drug delivery form for many kinds of drug. The use of the present novel formulations and excipients can improve the quality (in terms of absorption), stability and performance of MDI formulations. The formulation ingredients are selected specifically to give enhancement in the penetration through the pores and facilitate the absorption of the drugs to reach therapeutic levels in the plasma. With the proper formulation changes and changes in administration technique, the formulation can be delivered to the deep lungs, through the nasal cavity and the buccal cavity.

Pressurized inhalers also offer a wide dosing range, consistent dosing efficiency. In this local delivery greater than 95% of the dose is reached to the target area. The smaller particle size (4-15 microns) of pressurized inhalers also enhances dosing due to broader coverage within the lung cavity. In this situation, increased coverage can help more absorption of drug like insulin. Furthermore, because these devices are self-contained, the potential for contamination is avoided.

Accordingly the present invention provides an aerosol pharmaceutical formulation comprising i) a proteinic pharmaceutical agent, ii) water, iii) a phenol selected from the group consisting of phenol and methyl phenol in a concentration of from 1 to 10 wt./wt. % of the total formulation, and v) a propellant selected from the group consisting of C1-C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof, and optionally iv) at least one excipient selected from the group consisting of salts, antioxidants, coloring agents, flavouring agents, protease inhibitors, stabilizers, glycerin, polyglycerin, lysine, polylysine and mixtures thereof.

In one embodiment, the proteinic pharmaceutical agent is in micellar form.

In another embodiment, the ratio of proteinic pharmaceutical agent, e.g. insulin, to propellant is from 5:95 to 25:75.

In a further embodiment, the methyl phenol is m-cresol.

In yet a further embodiment, the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane.

In yet another embodiment, the aerosol pharmaceutical formulation is contained in an aerosol dispenser.

The present invention also provides a metered dose aerosol dispenser with the aerosol pharmaceutical composition of the present invention therein.

The present invention also provides a method for administering an aerosol pharmaceutical compositions of the present invention, by spraying a predetermined amount of the composition into the mouth with a metered dose spray device.

The present invention also provides a method for administration of a proteinic pharmaceutical agent in a buccal cavity of a human being by spraying into the cavity, without inhalation, from a metered dose spray dispenser, a predetermined amount of an aerosol pharmaceutical formulation comprising i) a proteinic pharmaceutical agent, ii) water, iii) a phenol selected from the group consisting of phenol and methyl phenol in a concentration of from 1 to 10 wt./wt. % of the total formulation, and v) a propellant selected from the group consisting of C1-C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof, and optionally iv) at least one excipient selected from the group consisting of salts, antioxidants, coloring agents, flavouring agents, protease inhibitors, stabilizers, glycerin, polyglycerin, lysine, polylysine and mixtures thereof.

Claim 1 of 16 Claims

What is claimed is:

1. An aerosol pharmaceutical formulation for pulmonary or nasal delivery comprising i) a pharmaceutical agent, ii) water, iii) a phenol selected from the group consisting of phenol and methyl phenol is a concentration of from 1 to 10 wt./wt. % of the total formulation, and v) a propellant selected from the group consisting of C1-C2 dialkyl ether, butanes, fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof, and optionally iv) at least one excipient selected from the group consisting of salts, antioxidants, coloring agents, flavouring agents, protease inhibitors, stabilizers, glycerin, polyglycerin, lysine, polylysine and mixtures thereof.

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