Title:  Pressurized container having an aerosolized pharmaceutical composition

United States Patent:  6,315,984

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

Filed:  September 3, 1999

A pressurized container with an aerosol pharmaceutical formulation, and a process for making the formulation, are provided. The formulation comprises a pharmaceutical agent, a phenol, glycerin or polyglycerin, and an additional ingredient such as an alkali metal alkyl sulfate, polidocanol alkyl ether or the like. The formulation is placed in the pressurized container, which is then charged with a propellant. A method of treating a medical condition, by spraying the formulation into the mouth or lungs, is also provided.

SUMMARY OF THE INVENTION

Accordingly the present invention provides a pressurized container containing a stable solubilized mixture of propellant which is liquid under pressure and an intermediate formulation which comprises a proteinic pharmaceutical agent, water, first ingredient, second ingredient and at least one third ingredient, wherein the first ingredient is selected from glycerin and polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation, the second ingredient is selected from phenol, methyl phenol and mixtures thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation, each third ingredient is selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxo-cholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chenodeoxycholate, deoxycholate, chamomile extract, cucumber extract, borage oil and evening of primrose oil and mixtures thereof, in an amount of from 1-50 wt./wt. % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients is less than 90 wt./wt. % of the intermediate formulation.

In one embodiment, the alkali metal C8 to C22 alkyl sulphate is in a concentration of from 2 to 20 wt./wt. % of the intermediate formulation, especially 5 to 15 wt./wt. %.

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

In another embodiment, the alkali metal C8 to C22 alkyl sulphate is sodium lauryl sulphate.

In a further embodiment the polidocanol alkyl ether is a polidocanol 10 or 20 lauryl ether.

In another embodiment, the polyoxyethylene ether is polyoxyethylene sorbitan ether, and particularly polyoxyethylene sorbitan 80 lauryl ether.

In yet another embodiment, the third ingredient is present in a concentration of from about 1 to about 25 wt./wt. %.

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

In a further embodiment, the weight ratio of intermediate formulation to propellant is from 5:95 to 25:75.

In one embodiment, the pharmaceutical agent, water, first, second and third ingredients and propellant have been solubilized by a process comprising the steps of:

a) dissolving the proteinic pharmaceutical agent in water and adjusting the pH to a level suitable for pharmaceutical use;

b) mixing with the first ingredient in an amount of from 1-50 wt./wt. % of the intermediate formulation;

c) then mixing with the second ingredient in an amount of from 1-20 wt./wt. % of the intermediate formulation;

d) subsequently adding and mixing at least one third ingredient to form the intermediate formulation;

e) charging the intermediate formulation to a pressurizable container and subsequently charging the container with the propellant.

The invention also provides a process for making a stable aerosol pharmaceutical composition in which a propellant and an intermediate formulation, which comprises a pharmaceutical agent, water and first, second and third ingredients, has been solubilized by a process comprising the steps of:

a) dissolving the proteinic pharmaceutical agent in water and adjusting the pH to a level suitable for pharmaceutical use;

b) mixing with a first ingredient selected from glycerin, polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation;

c) then mixing with a second ingredient selected from phenol, methyl phenol and mixtures thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation;

d) subsequently adding and mixing at least one third ingredient to form the intermediate formulation, said third ingredient being selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxocholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chenodeoxycholate, deoxycholate, chamomile extract, cucumber extract, borage oil and evening of primrose oil and mixtures thereof, each of said third ingredients being present in an amount of from 1-50 wt./wt. % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients ate less than 90 wt./wt. % of the intermediate formulation;

e) charging the intermediate formulation to a pressurizable container and subsequently charging the container with the propellant.

In one embodiment, the alkali metal C8 to C22 alkyl sulphate is in a concentration of from 2 to 25 wt./wt. % of the intermediate formulation.

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

In another embodiment, the alkali metal C8 to C22 alkyl sulphate is sodium lauryl sulphate.

In a further embodiment the polidocanol alkyl ether is a polidocanol 10 or 20 lauryl ether.

In another embodiment, the polyoxyethylene ether is polyoxyethylene sorbitan ether, particularly polyoxyethylene sorbitan 80 lauryl ether.

In yet another embodiment, the third ingredient is present in a concentration of from about 1 to about 25 wt./wt. %.

In another embodiment, in step a) the pH is adjusted to between 6.0 and 9.0, and preferably between 7.0. and 8.0.

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

In a further embodiment, the weight ratio of intermediate formulation to propellant is from 5:95 to 25:75.

In yet another embodiment, step d) is accomplished with a high speed mixer or sonicator.

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

The present invention also provides a method for administering stable 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 stable solubilized mixture of propellant which is liquid under pressure and an intermediate formulation which comprises a proteinic pharmaceutical agent, water, first ingredient, second ingredient and. at least one third ingredient, wherein the first ingredient is selected from glycerin and polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation, the second ingredient is selected from phenol, methyl phenol and mixtures thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation, each third ingredient is selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxo-cholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chenodeoxycholate, deoxycholate, chamomile extract, cucumber extract, borage oil and evening of primrose oil and mixtures thereof, in an amount of from 1-50 wt./wt. % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients is less than 90 wt./wt. % of the intermediate formulation.

Claim 1 of 27 Claims

What is claimed is:

1. A pressurized container containing a stable solubilized mixture of propellant which is liquid under pressure and an intermediate aerosol formulation which comprises a pharmaceutical agent, water, first ingredient, second ingredient and at least one third ingredient, wherein the first ingredient is selected from the group consisting of glycerin and polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation, the second ingredient is selected from the group consisting of phenol, methyl phenol and mixture's thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation, each third ingredient is selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy sodium oxo-cholanyl glycines, polyoxethylene sorbitan ethers, alkyl-aryl polyether alcohols, hyaluronic acidl and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chenodeoxycholate, deoxycholate, chamomile extract, cucumber extract, borage oil and evening primrose oil and mixtures thereof, in an amount of from 1-50 wt./wt. % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients is less than 90 wt.lwt. % of the intermediate formulation.

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