United States Patent:   6,007,826

Assignee:  Yisum Research Development Company of the Hebrew University of Jerusalem (Jerusalem, IL)

Filed:  October 15, 1996

An oil-in-water emulsion useful as a delivery vehicle of hydrophobic ingredients such as pharmaceutical drugs and cosmetic active agent; wherein the emulsion particles have a net positive charge (i.e. a positive zeta potential).

GENERAL DESCRIPTION OP THE INVENTION

The present invention provides a novel oil-in-water type emulsion useful as a delivery vehicle of pharmaceutically or cosmetically active hydrophobic substances for various pharmaceutical or cosmetic applications. The pharmaceutically or cosmetically active substances in the emulsions will be referred to herein at times by the term "active ingredient". Where the active ingredient is pharmaceutically active it will at times be referred to herein as "drug".

An oil-in-water type emulsion generally comprises tiny colloid particles suspended in an aqueous solution.

Each colloid particle has an oily core comprising the oily carrier of the emulsion and an external layer comprising the emulsifiers and the surface active substances. In the description below, the following terms will at times be used: "aqueous phase" to denote the aqueous solution of the emulsion; "oily phase" to denote the oily cores of the particles; and "interfacial film" to denote the layer surrounding the cores of the particles.

Depending on the nature of the film substances, the external surface of the colloid particles may be charged. This charge is known in the art as the "zeta potential".

The present invention provides an oil-in-water type emulsion which comprises colloid particles having an oily core surrounded by an interfacial film, the film comprising surface active agents, lipids or both, said emulsions being characterized in that at least part of the surface active agents or lipids in the interfacial film have positively charged polar groups and further in that the colloid particles have a positive zeta potential.

In addition to surface active agents and/or lipids with positively charged polar groups (hereinafter: "cationic surfactants") the interfacial film may also comprise non-ionic surfactants or lipids and also surface active agents having a negatively charged polar group (hereinafter: anionic surfactants"). In order to have a positive zeta potential the total charge of the cationic surfactants should be in excess to the total charge of the anionic surfactants.

Example of cationic lipids are, C₁₀ -C₂₄ -alkylamines and C₁₂ -C₂₄ -alkanolamines, C₁₂ -C₁₈ -alkylamines and C₁₂ -C₁₈ -alkanolamines being preferred. Specific examples of cationic lipids are stearylamine, oleylamine and cholesteryl betainate and various cationic cholesterol esters and derivatives.

Examples of anionic lipids particularly in emulsions intended for pharmaceutical use are phospholipids. Examples of phospholipids which may be used in the emulsions of the invention are lecithins; Epikuron 120.TM. (Lucas Meyer, Germany) which is a mixture of about 70% phosphatidylcholine and 12% phosphatidylethanolamine and about 15% other phospholipids; Ovothin 160.TM. or Ovothin 200.TM. (Lucas Meyer, phosphatidylcholine, 18% phosphatidylethanolamine and 12% other phospholipids; a purified phospholipid mixture, e.g. such which is obtained from egg yolk; Lipoid E-80.TM. (Lipoid AG, Ludwigshafen, Germany) which is a phospholipid mixture comprising about 80% phosphatidylcholine, 8% phosphatidylethanolamine, 3.6% non-polar lipids and about 2% sphingomyeline.

Examples of anionic surfactants which may be included particularly in emulsions intended for various cosmetic uses such as in hair shampoo and other body-care preparations are sodium lauryl sulphate and alkylpolyoxyethelene sulphate and sulfonate.

Examples of non-ionic surfactants which may be included in the emulsion of the invention are poloxamers such as Pluronic F-68LF.TM., Pluronic L-62LF.TM. and Pluronic L62D.TM. (BASF Wyandotte Corp., Parsippany, N.J., USA), tyloxapol, polysorbate such as polysorbate 80, polyoxyethylene fatty acid esters such as EMULPHOR.TM. (GAF Corp., Wayne, N.J., USA).

The oily phase of the emulsion may comprise one or more members selected from the group consisting of vegetable oil, mineral oil, medium chain triglyceride (MCT) oil (i.e. a triglyceride oil in which the carbohydrate chain has about 8-12 carbon atoms), oily fatty acid, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, and in general any oily substance which is physiologically tolerated.

The major component of the oily phase will generally be either vegetable oil and/or MCT. Fatty acids or fatty alcohols may be included in cases where the hydrophobic substance to be carried by the emulsion is not sufficiently soluble in the oily phase such as in the case of the drug Diazapam.

MCT oil has many advantages over vegetable oil, amongst which are the following: lower disceptability to oxidation; having a specific density of about 0.94-0.95 which oxidation; having a specific density of about 0.94-0.95 which is higher than that of vegetable oil and which is closer to that of water, thus facilitating the obtaining of a stable emulsion; being less hydrophobic than vegetable oil and therefore allowing achieving of higher concentrations of substances dissolved therein; having a low viscosity which again allows increase in concentration of the oily phase in the emulsion while still having the viscosity within a reasonable range.

On the other hand, vegetable oil has the advantage over MCT oil in its lower price. Thus, although the use of MCT as the major component of the oily phase is generally preferred, it may at times be practical to substitute some of it with vegetable oil.

Examples of MCT oil which may be used in emulsions of the present invention are TCM.TM. (Societe des Oleagineux, France), Miglyol 812.TM. (Dynamit Novel, Sweden). Examples of vegetable oil which may be used in emulsions of the present invention are soybean oil, cottonseed oil, olive oil and sesame oil.

Examples of oily fatty acids which may be used in emulsions of the invention are oleic acid, linoleic acid, lauric acid and others. Examples of fatty alcohols which may be used are oleyl alcohol, cetyl alcohol and others. Examples of esters of sorbitol and fatty acids are sorbitan monooleate and sorbiton mono-palmitate. Examples of oily sucrose esters are sucrose mono-, di-or tri-palmitate.

As is known, the emulsion may also comprise various additives such as osmotic pressure regulators, e.g. sucrose or glycerine; anti-oxidants, e.g. .alpha.-tocopherol and ascorbic acid; or preservatives, e.g. methyl-, ethyl-, and butyl paraben.

Emulsions in accordance with the present invention may be formulated with various hydrophobic active ingredients for a large number of pharmaceutical and cosmetic applications. The emulsions may be formulated for topical, parenteral, ocular and oral administration of said active ingredients. Where an emulsion of the present invention is to be used for parenteral administration, it must be sterile, which sterility is preferably achieved by autoclaving, although other forms of sterilization such as filtration may also in principle be used. The constituents of emulsions intended for parenteral administration have to be of injection grade and medically approved for such administration.

Where the emulsion is formulated for topical or ocular application, particularly for topical cosmetic application, it is suitably supplemented with gel forming polymers, which are known per se, in order to increase the viscosity of the formulation.

In the following, concentrations of the ingredients of the emulsion will be given as "%", meaning weight of ingredient in hundred weight units of total composition ("w/w").

An injectable emulsion should not be too viscous. As a rule, the viscosity of an emulsion increases with an increase in the proportion of the non-aqueous phase, which comprises the oily carrier, the surface active agents or lipids and the hydrophobic active ingredient. It is accordingly preferred in accordance with the present invention that the proportion of the non-aqueous phase in injectable emulsions should not exceed about 30%. It is even more preferred in accordance with the present invention that the relative proportion of the non-aqueous phase in injectable emulsions be below about 25%.

On the other hand, compositions for topical administration should preferably be viscous, and to this end the relative proportion of the non-aqueous phase should preferably be above about 30%.

The preferred ranges of ingredients in injectable emulsion according to the invention are: oily carrier--about 3-20%, 6-10% being particularly preferred; phospholipids--about 0.5-3%, 0.75-2% being particularly preferred; cationic surfactants or lipids--0.05-2%, 0.1-0.4% being particularly preferred. Where the emulsion comprises a non-ionic surfactant its preferred range is about 0.5-3%. These preferred ranges are to be understood as standing each by itself and not cumulative.

A preferred pH in the aqueous phase of the emulsion of the invention is about 5.0-8.5, 6.0-8.0 being particularly preferred especially for parenteral administration.

The present invention also provides a pharmaceutical or a cosmetic composition which comprises an effective amount of a hydrophobic active ingredient, having pharmaceutical or cosmetic activity, as the case may be, and a carrier, being the above oil-in-water type emulsion.

Cosmetic compositions of the invention include various hair and body-care preparations, e.g. shampoos, body creams, sun-tan lotions, and the like. Such compositions may at times be supplemented with gel-forming polymers, in order to increase viscosity, as already pointed out above.

Cosmetically active hydrophobic active ingredients which may be incorporated into emulsions of the invention are, for example, anti-oxidants and anti-free radicals such as .alpha.-tocopherol; essential acids such as Complex Omega 6.TM. (manufactured by Seporga, Nice, France); sunscreen agents such as Parsol MCX.TM. or Parsol 1789.TM. (Givaudan, Switzerland).

Pharmaceutical compositions of the invention include parenteral, oral, ocular and topical composition. In parenteral and ocular compositions the aqueous phase is suitably saline or another isotonic solution. In oral compositions the aqueous phase may suitably be supplemented with flavouring agents to increase their platability. Ocular or topical compositions may in some cases be supplemented compositions of the invention.

Pharmaceutically active hydrophobic drugs which may be incorporated into emulsions of the invention include drugs for the treatment of glaucoma, anti-inflammatory drugs, antibiotic drugs, anti-cancer drugs, anti-fungal drugs and anti-viral drugs.

Examples of anti-glaucoma drugs are .beta.-blockers such as timolol-base, betaxolol, atenolol, livobunolol, epinephrine, dipivalyl, oxonolol, acetazolamide-base and methzolamide.

Examples of anti-inflammatory drugs are steroidal drugs such as cortisone and dexamethasone and non-steroidal anti-inflammatory drugs (NSAID) such as piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen and diclofenac acid.

An example of an antibiotic drug is chloramphenicol. Examples of anti-fungal drugs are nystatin and miconazole. Examples of an anti-viral drug is Acyclovir.TM. (Boroughs-Welcome, U.K.). Examples of anti-allergic drugs are pheniramide derivatives.

It is generally preferred, in particular in emulsions intended for parenteral use, that the particles in the emulsion will have a diameter below about 1 .mu.m, a diameter less than 0.5 .mu.m being particularly preferred. Even more preferred are emulsions having a droplet size of below about 0.3 .mu.m and even below about 0.2 .mu.m. Small droplets are preferred also since submicron emulsions have a higher degree of stability, particularly during steam autoclaving. Furthermore, small droplets enable sterilization by filtration. However, emulsions with larger droplet size, above 1 .mu.m, may at times be very useful for various purposes, such as in emulsions intended for topical or ocular applications and particularly for topical cosmetic applications.

The emulsion of the present invention may be prepared in a number of ways. By one way of preparation, an aqueous solution and an oily solution are first separately prepared. The non-ionic surfactant, the osmotic pressure regulator and the preservative (if present) are included in the aqueous solution, and the oil, the phospholipid, the hydrophobic drug, the cationic surfactant and, if present, also the antioxidant, in the oily solution. The phospholipids may also be dissolved in another, alcohol solution, which is mixed with the aqueous solution. The resulting aqueous-alcohol mixture is then heated until the alcohol evaporates and the phospholipids become dispersed in the aqueous solution.

The aqueous solution and the oily solution are then mixed with one another, preferably after each has been separately heated. However, the mixture thus obtained does not yet consist of sufficiently small droplets, the size of which (obtained after mixing, e.g. with a magnetic stirrer) is about 10 .mu.m. The droplet size may then be decreased by the use of emulsification equipment, such as Ultra Turrax.TM. (Jenkle and Kunkel, Stauffen, Germany) which yields droplets having an average diameter of about 1.1 .mu.m, or of a high shear mixer, e.g., Polytron.TM. (Kinematica, Lucerns, Switzerland) which yields droplets having an average diameter of about 06 .mu.m.

Small droplets may be obtained when utilizing a two-stage pressure homogenizer, in which the crude dispersion is forced under high pressure through the annular space between a spring-loaded valve and then through the valve seat, the second stage being in tandem with the first so that the emulsion is subjected to two very rapid dispersion processes. Example of such an apparatus is the Gaulin.TM. homogenizer (A.P.V. Gaulin, Hilversum, The Netherlands or A.P.V. Rannie, Albertsland, Denmark). After homogenization in such an apparatus, the emulsion droplets have an average diameter of less than 0.3 .mu.m, with a high degree of uniformity in droplet size. Even smaller droplets may be obtained when the emulsification process combines the use of a polytron-type high shear mixer followed by homogenization. The droplets which are obtained in such a combination have an average diameter of about 0.1-0.15 .mu.m.

Claim 1 of 18 Claims

1. A pharmaceutical or cosmetic composition comprising:

a pharmaceutically or cosmetically active effective amount of a hydrophobic active ingredient and a carrier, the carrier being an oil-in-water type emulsion which comprises colloid particles having an oily core surrounded by an interfacial film, said active ingredient being incorporated into said oily core, wherein said interfacial film comprises a cationic lipid, nonionic surfactant and an anionic surfactant or anionic lipid,

said cationic lipid is in a concentration of 0.05-2% by weight and being selected from the group consisting of a C₁₀ -C₂₄ primary alkylamine, a C₁₀ -C₂₄ primary alkanolamine and a cholesterol ester,

said nonionic surfactant is in a concentration of 0.05-3% by weight and being selected from the group consisting of poloxamers, tyloxapol, polysorbate, and polyoxyethylene fatty acid esters,

said anionic surfactant or anionic lipid are phospholipids in a concentration of 0.5-3% by weight,

wherein said colloidal particles have a positive zeta potential and an average particle size of about 0.1 to 1 micron.

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