Title:  Proteinic drug delivery system using membrane mimetics

United States Patent:  6,193,997

Assignee:  Generex Pharmaceuticals Inc. (Toronto, CA)

Filed:  September 27, 1998

A mixed liposome pharmaceutical formulation with multilamellar vesicles, comprises a proteinic pharmaceutical agent, water, an alkali metal lauryl sulphate in a concentration of from 1 to 10 wt./wt. %, at least one membrane-mimetic amphiphile and at least one phospholipid. The membrane-mimetic amphiphile is hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, sulphosuccinates, stearamide DEA, gamma-linoleic acid, borage oil, evening of primrose oil, monoolein, 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, trihydroxy-oxo-cholanylglycine and alkali metal salts thereof, and octylphenoxypolythoxyethanol, polydecanol X-lauryl ether, polydecanol X-oleyl ether, wherein X is from 9 to 20, or combinations thereof. The phospholipid is phospolipid GLA, phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, sphingomyelin, ceramides, cephalin, triolein, lecithin, saturated lecithin and lysolecithin, or a combination thereof. The amount of each membrane mimetic amphiphile and phospholipid is present 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.

SUMMARY OF THE INVENTION

Accordingly the present invention provides a mixed liposome pharmaceutical formulation with multilamellar vesicles, comprising a proteinic pharmaceutical agent, water, an alkali metal lauryl sulphate in a concentration of from 1 to 10 wt./wt. % of the total formulation, at least one membrane-mimetic amphiphile and at least one phospholipid,

wherein the membrane-mimetic amphiphile is selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, sulphosuccinates, stearamide DEA, gamma-linoleic acid, borage oil, evening of primrose oil, monoolein, 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, trihydroxy-oxo-cholanylglycine and alkali metal salts thereof, octylphenoxypolythoxyethanol, polydecanol X-lauryl ether, polydecanol X-oleyl ether, wherein X is from 9 to 20, and cobinations thereof, and

wherein the phospholipid is selected from the group consisting of, phospholipid GLA (glycolic, lactic acid), phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, 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 7.0.

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 lauryl sulphate is sodium lauryl sulphate.

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.

In one embodiment, the membrane-mimetic amphiphile is selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid and mixtures thereof, the concentration such absorption enhancing compound being from about 1 to about 5 wt./wt. %.

In another embodiment, suitable for delivery through oral mucosal membranes, the formulation contains sodium lauryl sulphate, and combinations selected from the group consisting of:

i) sodium salt of trihydroxy-oxo-cholanyl glycine, sphingomyelin and stearamide DEA;

ii) sodium salt of trihydroxy-oxo-cholanyl glycine and phospholipid GLA;

iii) ceramide and stearamidopropyl phosphatidyl PG-diammonium chloride;

iv) borage amidopropyl phosphatidyl PG-diammonium chloride and lecithin;

v) octylphenoxypolyethoxyethanol and saturated lecithin;

vi) sodium hyaluronate, polydecanol 9-lauryl ether, lecithin and evening of primrose oil; and

vii) monoolein, saturated lecithin, sodium hyaluronate and evening of primrose oil.

In yet another embodiment, suitable for topical delivery transdermally, the formulation contains sodium lauryl sulphate and combinations selected from the group consisting of:

i) lecithin, sodium hyaluronate, glycolic acid and propylene glycol; and

ii) sodium hyaluronate, sphingomyelin, glycolic acid and propylene glycol.

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 formulation suitable for delivery through oral mucosal membranes may be in chewable form, in which case it will be necessary to add ingredients suitable for such form. Such ingredients include guar gum, powdered acacia, carrageenin, beeswax and xanthan gum.

The proteinic 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, hirudine, interferons, interleukins, cytokines, mono and polyclonal antibodies, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, growth hormones, parathyroid hormone (PTH), 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.

Claim 1 of 16 Claims

What is claimed is:

1. A mixed liposome pharmaceutical formulation with multilamellar vesicles, comprising a proteinic pharmaceutical agent, water, an alkali metal lauryl sulphate in a concentration of from 1 to 10 wt./wt. % of the total formulation, at least one membrane-mimetic amphiphile and at least one phospholipid,

wherein the membrane-mimetic amphiphile is selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, lauramidopropyl betain, lauramide monoisopropanolamide, sodium cocoamphopropionate, bishydroxypropyl dihydroxypropyl stearammonium chloride, polyoxyethylene dihydroxypropyl stearammonium chloride, dioctadecyldimethylammonium chloride, sulphosuccinates, stearamide DEA, gamma-linoleic acid, borage oil, evening of primrose oil, monoolein, 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, trihydroxy-oxo-cholanylglycine and alkali metal salts thereof, and octylphenoxypolythoxyethanol, polydecanol X-lauryl ether, polydecanol X-oleyl ether, wherein X is from 9 to 20, and combinations thereof, and

wherein the phospholipid is selected from the group consisting of phospholipid GLA, phosphatidyl serine, phosphatidylethanolamine, inositolphosphatides, dioleoylphosphatidylethanolamine, sphingomyelin, ceramides, cephalin, triolein, 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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