Title:  Proteinic drug delivery system using aerosolized membrane-mimetic amphiphiles

United States Patent:  6,271,200

Assignee:  Generex Pharmaceuticals Inc. (Toronto, CA)

Filed:  September 16, 1999

A mixed liposome pharmaceutical composition with multilamellar vesicles is provided. The vesicles are comprised of a pharmaceutical agent, membrane-mimetic amphiphiles and various phospholipids. A method of making the composition using high speed mixing of the amphiphiles and phospholipids is also provided.

SUMMARY OF THE INVENTION

Accordingly the present invention provides an aerosol pharmaceutical formulation with multilamellar vesicles, comprising i) a pharmaceutical agent, ii) water, iii) an alkali metal C8 to C22 alkyl sulphate in a concentration of from 1 to 10 wt./wt. % of the total formulation, iv) at least one membrane-mimetic amphiphile, v) at least one phospholipid, vi) 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 vi) a propellant selected from the group consisting of C1 to C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof,

wherein the membrane-mimetic amphiphile is selected from the group consisting of lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, sulphosuccinates, stearamide DEA, sodium tauro dihydro fusidate, fusidic acid, alkali metal isostearyl lactylates, alkaline earth metal isostearyl lactylates, panthenyl triacetate, cocamidopropyl phosphatidyl PG-diammonium chloride, stearamidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidylcholine, polysiloxy pyrrolidone linoleyl phospholipid, octylphenoxypolythoxyethanol, and combinations thereof, and

wherein the phospholipid is selected from the group consisting of, phospholipid GLA (glycolic, lactic acid), phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, polysiloxy pyrrolidone linoleyl phospholipid, sphingomyelin, ceramides, cephalin, triolein, unsaturated lecithin, saturated lecithin and lysolecithin, and combinations thereof, and

wherein the amount of each membrane-mimetic amphiphile and phospholipid is present in a concentration of from 1 to 10 wt./wt. % of the total formulation, and the total concentration of membrane-mimetic amphiphiles and phospholipids is less than 50 wt./wt. % of the formulation.

Preferably the mixed liposome pharmaceutical formulation has a pH of between 6.0 and 8.0.

The preferred number of membrane mimetic amphiphiles are from 2 to 5.

The preferred number of phospholipids are from 1 to 4.

In one embodiment, the alkali metal C8 to C22 alkyl sulphate is sodium C8 to C22 alkyl sulphate, and preferably is sodium lauryl sulphate.

Preferably, 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 another 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 mixed liposome pharmaceutical formulation is contained in an aerosol dispenser.

In a preferred embodiment at least one protease inhibitor is added to the formulation to inhibit degradation of the pharmaceutical agent by the action of proteolytic enzymes. Of the known protease inhibitors, most are effective at concentrations of from 1 to 3 wt./wt. % of the formulation.

Non-limiting examples of effective protease inhibitors are bacitracin, soyabean trypsin, aprotinin and bacitracin derivatives, e.g. bacitracin methylene disalicylate. Bacitracin is the most effective of those named when used in concentrations of from 1.5 to 2 wt./wt. %. Soyabean trypsin and aprotinin may be used in concentrations of about 1 to 2 wt./wt. % of the formulation.

Preferably the lecithin is saturated lecithin.

It will be recognized by those skilled in the art that for many pharmaceutical compositions it is usual to add at least one antioxidant to prevent degradation and oxidation of the pharmaceutically active ingredients. It will also be understood by those skilled in the art that colorants, flavouring agents and non-therapeutic amounts of other compounds may be included in the formulation.

In one embodiment the antioxidant is selected from the group consisting of tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben and ascorbic acid and mixtures thereof. A preferred antioxidant is tocopherol.

The pharmaceutical agent may be selected from a wide variety of macromolecular agents, depending on the disorder being treated, generally with molecular weights greater than about 1000 and especially between about 1000 and 2,000,000. Pharmaceutical agents useful in the present invention include insulin, heparin, low molecular weight heparin, hirugen, hirulos, hirudin, interferons, interleukins, cytokines, mono and polyclonal antibodies, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, growth hormones, parathyroid hormone (PTH), leutenizing hormones, oestrogens, androgens, calcitonins, insulin like growth factors (IGF), glucagon like peptides (GLP-1 and GLP-2), steroids and retinoids, injectable large molecule antibiotics, protein based thrombolytic compounds, platelet inhibitors, DNA, gene therapeutics, RNA and antisense oligonucleotides and small molecule drugs.

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

The present invention also provides a method for administering an aerosol pharmaceutical formulations of the present invention, by spraying a predetermined amount of the formulation 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 with multilamellar vesicles, comprising i) a pharmaceutical agent, ii) water, iii) an alkali metal C8 to C22 alkyl sulphate in a concentration of from 1 to 10 wt./wt. % of the total formulation, iv) at least one membrane-mimetic amphiphile, v) at least one phospholipid, vi) 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 vi) a propellant selected from the group consisting of C1 to C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof,

wherein the membrane-mimetic amphiphile is selected from the group consisting of lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, sulphosuccinates, stearamide DEA, sodium tauro dihydro fusidate, fusidic acid, alkali metal isostearyl lactylates, alkaline earth metal isostearyl lactylates, panthenyl triacetate, cocamidopropyl phosphatidyl PG-diammonium chloride, stearamidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidylcholine, polysiloxy pyrrolidone linoleyl phospholipid, octylphenoxypolythoxyethanol, and combinations thereof, and

wherein the phospholipid is selected from the group consisting of, phospholipid GLA (glycolic, lactic acid), phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, polysiloxy pyrrolidone linoleyl phospholipid, sphingomyelin, ceramides, cephalin, triolein, unsaturated lecithin, saturated lecithin and lysolecithin, and combinations thereof, and

wherein the amount of each membrane-mimetic amphiphile and phospholipid is present in a concentration of from 1 to 10 wt./wt. % of the total formulation, and the total concentration of membrane-mimetic amphiphiles and phospholipids is less than 50 wt./wt. % of the formulation.

Claim 1 of 27 Claims

What is claimed is:

1. An aerosol pharmaceutical formulation with multilamellar vesicles, comprising i) a pharmaceutical agent, ii) water, iii) an alkali metal C8 to C22 alkyl sulphate in a concentration of from 1 to 10 wt./wt. % of the total formulation, iv) at least one membrane-mimetic amphiphile, v) at least one phospholipid, vi) 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 vii) a propellant selected from the group consisting of C1 to C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof,

wherein the membrane-mimetic amphiphile is selected from the group consisting of lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, sulphosuccinates, stearamide DEA, sodium tauro dihydro fusidate, fusidic acid, alkali metal isostearyl lactylates, alkaline earth metal isostearyl lactylates, panthenyl triacetate, cocamidopropyl phosphatidyl PG-diammonium chloride, stearamidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidyl PG-diammonium chloride, borage amidopropyl phosphatidylcholine, polysiloxy pyrrolidone linoleyl phospholipid, octylphenoxypolythoxyethanol, and combinations thereof, and

wherein the phospholipid is selected from the group consisting of, phospholipid GLA (glycolic, lactic acid), phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, polysiloxy pyrrolidone linoleyl phospholipid, sphingomyelin, ceramides, cephalin, triolein, unsaturated lecithin, saturated lecithin and lysolecithin, and combinations thereof, and

wherein each membrane-mimetic amphiphile and phospholipid is present in a concentration of from 1 to 10 wt./wt. % of the total formulation, and the total concentration of membrane-mimetic amphiphiles and phospholipids is less than 50 wt./wt. % of the formulation.

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