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Title:  Oral or intranasal vaccines using hydrophobic complexes having proteosomes and lipopolysaccharides

United States Patent:  6,803,042

Issued:  October 12, 2004

Inventors:  Lowell; George H. (Hampstead, CA)

Assignee:  U.S. Army Medical Research Materiel Command (Fort Detrick, MD)

Appl. No.:  407327

Filed:  September 28, 1999


An immunogenic complex, essentially consisting of neisserial outer membrane protein proteosomes hydrophobically complexed to native purified bacterial lipopolysaccharide and formulated in accordance with the current invention for mucosal delivery such as via the oral or intranasal route is used as a vaccine. Specifically, a vaccine using shigella lipopolysaccharides complexed to proteosomes for such mucosal administration induces IgG and IgA antibodies in sera and in respiratory and intestinal fluids. Furthermore, such antibodies are associated with protection against shigella infection and these vaccines are herein demonstrated to protect against mucosal infection with shigella.


The present invention provides emulsions comprising a plurality of submicron oil-in-water droplets of a particle size in the range of 50 nm to 500 nm that effect enhanced immunogenicity of antigens incorporated intrinsically or extrinsically into the particles. Therefore the submicron emulsion (SME) particles of the present invention can be used as vaccine adjuvants.

In marked contrast to the aforementioned disclosures, as will be described, the present invention does not require use of any immunostimulatory mycobacteria or muramyl peptide-like additives for its submicron emulsion to be effective. Moreover, as will be seen, a preferred embodiment of the present invention consists of intrinsically incorporating the antigen into the emulsion at the time of formation of the emulsion; this is in distinct contrast to mixing the antigen with the emulsion after the emulsion has been independently extrinsically formed. It will be appreciated that intrinsic formulation will be effective even in situations and conditions and species where extrinsic formulation is not. In this regard as well, the present invention is uniquely different and not at all implied by the previously mentioned applications which indeed teaches away from the present invention in stating that it is sufficient to simply mix the antigen with the extrinsically previously formed emulsion.

The vaccine formulations of this invention also do not include any polyoxypropylene-polyoxyethylene block polymer, trehalose dimycolate, or cell wall skeleton, as are found in prior art compositions.

Another aspect of this invention is to provide compositions and methods for the preparation of submicron emulsions containing antigens, incorporated either intrinsically (emulsified together with the oil and surfactant) or extrinsically (added externally to prepared SME).

In some cases, the submicron emulsion of the present invention can be administered in combination with other vaccine delivery systems, such as proteosomes, as indicated in the examples.

The size, concentration and specific formulation of SMEs may be varied to suit the particular antigen used. Moreover, such adjuvant preparations may enhance both humoral and cell-mediated immunity (CMI) as do Freund's adjuvants. The SMEs here described have been developed for human use and since the oily droplets of the emulsions are of submicron size and contain no added pyrogenic moieties such as mycobacteria or MDP derivatives they have, unlike Freund's adjuvants, great safety potential. They may be especially applicable to antigens that are vaccine candidates to protect against biologic toxins or infectious agents which have natural hydrophobic moieties as a component including transmembrane viral, bacterial or parasite proteins, membrane proteins such as proteosomes, lipopolysaccharides, glycolipids such as gangliosides, or a variety of proteins or peptides to which hydrophobic anchors have been chemically or genetically added.

Another aspect of the invention provides compositions and methods to achieve mucosal immunity by using an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, immunogenic peptide or antigen, and an aqueous continuous phase, which induces mucosal immunity by achieving mucoadhesion of the emulsion particles to mucosal surfaces. Mucous surfaces suitable for application of the emulsions of the present invention may include ocular (corneal, conjunctival), oral (buccal, sublingual), nasal, vaginal and rectal routes of administration.

The emulsion particles have a hydrophobic core comprising a lipid or lipid-like composition and are stabilized with amphiphilic and/or non-ionic surfactants.

A wide variety of immunogens, including both water-soluble and water-insoluble peptides or polysaccharides, may be accommodated in the present emulsions. The hydrophobic core and surfactant provide a microenvironment which accommodates lipophilic immunogens such as lipid A or lipopolysaccharides as well as membrane-associated peptide antigen domains, while the aqueous continuous phase accommodates water-soluble peptide domains, or oligosaccharides.

The term "peptide" herein includes both oligopeptides and proteins. To facilitate intestinal uptake, the emulsions may be encapsulated in gelatin capsules or otherwise enterocoated to prevent their exposure to gastric fluids when the oral route of administration is selected. Furthermore, the emulsions may be lyophilized as disclosed previously (Pharmos, PCT/US 93 01415) prior to their encapsulation in order to achieve added stability of the antigen.

Another invention is a desirable vaccine using lipopolysaccharide (LPS), e.g. Shigella flexneri 2a, Shigella sonnei or other shigella lipopolysaccharide (LPS), complexed with proteosomes to induce anti-LPS antibodies in the aforementioned fluids in the absence of SME particles which protects against homologous shigella infection in a well-known animal model of shigellosis. The data disclosed herein shows that the instant invention can be used as an oral or intranasal non-living sub-unit vaccine to protect against mucosal diseases of the gastrointestinal tract such as shigellosis. In addition, since high antibody levels are induced in either the respiratory or gastrointestinal tracts following either oral or intranasal immunization, and since protection is shown against either conjunctival or respiratory challenge, these proteosome-based vaccines and there associated methodologies can also be used to protect against diseases that enter the body via respiratory, ocular or gastro-intestinal routes. These vaccines should also result in protection against mucosal diseases of the urogenital and auditory tracts.


This invention is directed to pharmaceutical compositions comprising submicron emulsions as vaccine adjuvants, and to methods for preparing and using such compositions.

5.1 Features of the Submicron Emulsion (SME) Particles

The submicron emulsion vaccine adjuvants of the present invention comprise an aqueous continuous phase suspending a colloidal phase of submicron particles. The particles have a weighted average diameter of 50 to 500 nm, more preferably 70 to 300 nm. In many embodiments, the weighted average diameter be less than 460 nm, 400 nm, 300 nm, or 200 nm.

Usually the diameter will be greater than 40 nm or 50 nm, and frequently is greater than 70 nm. Often, the above-stated upper and lower diameter ranges will include both the weighted average and at least one standard deviation of particle diameter.

The emulsion particle comprises a hydrophobic core, often including or even consisting essentially of a metabolizable and non-toxic oil such as MCT (medium chain triglycerides) oil of the type extensively used in parenteral emulsions like Intralipid.RTM. or a vegetable oil.

Optionally, other hydrophobic lipids may be used, including cholesterol or cholesteryl esters and fatty acids. In many embodiments, the core of the particles will be substantially free of protein other than the antigen to be delivered, i.e. less than 1% (w/w), and in most cases less than 0.1% of other protein.

The emulsion usually further comprises at least one surfactant, which may be a natural biologically compatible surfactant such as phospholipid (e.g., lecithin) or a pharmaceutically acceptable non-natural surfactant such as Tween-80. The surfactant assists in maintaining particles within the desired size range and preventing their aggregation.

In many embodiments the emulsion may be formed and stabilized in the substantial absence of one or more cosurfactants selected from the group, consisting of an unhalogenated aliphatic C3-C6 alcohol, a free fatty acid, a mono- or di-glyceride, a polyglycerol fatty acid ester, or a lysophosphatidyl choline. One or all of the above-named cosurfactants may comprise less than 5%, commonly less than 1%, and frequently less than 0.1% (w/w) relative to the weight of the hydrophobic core.

The emulsion also contains an immunogen. The antigen may be hydrophilic, hydrophobic, or amphiphilic since the emulsion provides a biphasic lipophilic-hydrophilic microenvironment.

The continuous phase of the emulsion is aqueous, and may contain salts, sugars, antioxidants, preservatives, microbicides, buffers, osmoticants, cryoprotectants, and other pharmaceutically useful additives or solutes.

Bioadhesive polymers, such as those currently used in pharmaceutical preparations optionally may be added to the emulsion to further enhance the immunogenicity through mucous membranes achieving mucosal immunity.

The concentrations indicated by % in the following description denote the concentration by weight of the component per 100 units volume of the entire composition.

All indicated concentrations should be understood as standing each by itself, and not cumulative. It should be appreciated by the artisan, however, that there is some dependency between the concentrations of the components, e.g. higher concentrations of the oil will generally require higher concentrations of the emulsifier and surfactant.

The emulsion used in the vaccine compositions of the present invention may comprise about 0.5 to 50% oil, about 0.1 to 10% emulsifier and about 0.05 to 5% of the non-aqueous phase, i.e. the combined concentration of the oily and the amphiphilic phase, increases viscosity of the composition. In order to obtain a non-viscous composition, the concentration of the non-aqueous phase should generally not exceed about 25%.

Preferred concentrations of the components are as follows: about 1 to 20% oil, most preferably about 1 to 10% for a composition intended to be fluid, about 0.2 to 5% of the emulsifier, with about 0.2 to 5% for the surfactant, with about 0.2 to 1% being particularly preferred.

The antigen is present in an amount of about 0.001 to 5% by weight of the composition, preferably about 0.1 to 2.5%. Depending upon whether the antigen is hydrophilic or hydrophobic, it will be physically present in the oily phase at the oil-water interface, or the aqueous component. Also, the pH of these compositions should be in a range which is suitable for the stability of the antigen.

The submicron emulsion adjuvant formulations of this invention differ from the emulsion adjuvant composition of Patent Application WO 90/14837 in the following features:

(i) all the compositions described in the above mentioned application are prepared extrinsically, namely the antigens are added externally to the previously prepared emulsion by mixing, while in the present invention the antigen can be added either extrinsically or more preferably intrinsically, together with all the emulsion components before emulsification and prior to the mixture of oil and water phases as detailed in the examples;

(ii) all the examples in the above mentioned disclosure contain an immunopotentiating amount of an immuno-stimulating glycopeptide of the type of muramyl peptides or their lipophilic derivatives, such as MTP-PE, while in the present invention all the SME adjuvant compositions are prepared in the absence of any muramyl peptide immunostimulating agent.

5.2 Composition of the Hydrophobic Core

A hydrophobic compound which is suitably non-toxic may be used as a component of the core. Examples include triglycerides, preferably of food grade purity or better, which may be produced by synthesis or by isolation from natural sources. Natural sources may include animal fat or vegetable oil, e.g., soya oil, a source of long chain triglycerides (LCT). Other triglycerides of interest are composed predominantly of medium length fatty acids, denoted medium chain triglycerides (MCT). A medium chain triglyceride (MCT) oil, is a triglyceride in which the carbohydrate chain has 8-12 carbons. Although MCT oil can be considered as a component of vegetable oil, it is separately identified herein because of its particular utility as a preferred oil for use in the present emulsions. In addition, MCT oil is available commercially. Examples of such MCT oils include TCR (trade name of Societe Industrielle des Oleagineuax, France, for a mixture of triglycerides wherein about 95% of the fatty acid chains have 8 or 10 carbons) and MIGLYOL 812 (trade name of Dynamit Nobel, Sweden for a mixed triester of glycerine and of caprylic and capric acids). The fatty acid moieties of such triglycerides may be unsaturated, monounsaturated or polyunsaturated; mixtures of triglycerides having various fatty acid moieties are acceptable. The core may comprise a single hydrophobic compound or a mixture of compounds.

Examples of vegetable oils include soybean oil, cotton seed oil, olive oil, sesame oil and castor oil. Oily fatty acids, such as oleic acid and linoleic acid, fatty alcohols, such as oleyl alcohol, and fatty esters, such as sorbitan monooleate and sucrose mono-, di- or tripalmitate, can be used as the oil component, although these are not as preferred as the other oils mentioned above.

Optionally, the core may contain cholesterol or cholesteryl esters. In many embodiments, cholesteryl esters or cholesterol comprise less than 10%, 5%, 1%, or even 0.1% (w/w) of the total hydrophobic components of the core.

Considerations in choice of core material include low toxicity and irritancy, biocompatibility, safety, metabolizability, stability and high loading capacity for antigens. Preferred hydrophobic core components have molecular weights below about 5,000 Da, more preferably below about 2,000 Da, and most preferably below about 1,500 Da.

5.3 Composition of Surfactant Component

The amphiphilic phase comprises the emulsifiers and surfactants. Preferred emulsifiers include a phospholipid compound or a mixture of phospholipids. Suitable components include lecithin; EPICURON 120 (Lucas Meyer, Germany) which is a mixture of about 70% of phosphatidylcholine, 12% phosphatidylethanol-amine and about 15% other phospholipids; OVOTHIN 160 (Lucas Meyer, Germany) which is a mixture comprising about 60% phosphatidylcholine, 18% phosphatidylethanol-amine and 12% other phospholipids; a purified phospholipid mixture; LIPOID E-75 or LIPOID E-80 (Lipoid, Germany) which is a phospholipid mixture comprising

about 80% phosphatidyl-choline, 8% phosphatidylethanol-amine, 3.6% non-polar lipids and about 2% sphingomyelin. Purified egg yolk phospholipids, soybean oil phospholipids or other purified phospholipid mixtures are useful as this component. This listing is representative and not limiting, as other phospholipid materials which are known to those skilled in the art can be used.

Some embodiments of the invention provide an improved bioadhesive emulsion comprising incorporation of an amphiphilic and/or nonionic surfactant such as phosphatidylcholine, Tween, etc., together with a mucoadhesive polymer macromolecule as described in Section 5.6.

Particularly suitable emulsifiers include phospholipids, which are highly biocompatible. Especially preferable phospholipids are phosphatidyl-cholines (lecithins), such as soy or egg lecithin. Other suitable phospholipids include phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, cardiolipin, and phosphatidyl-ethanolamine. The phospholipids may be isolated from natural sources or prepared by synthesis. Phospholipid surfactants are believed usually to form a single monolayer coating of the hydrophobic core.

The surfactant is believed in many embodiments to interact with the bioadhesive polymer to form a hydrated polymer film coating associated with the surfactant at the stabilized lipid/water interface surrounding the particle core.

Preferred compositions contain a surfactant component. The surfactant stabilizes the outer surface of the hydrophobic core component of the emulsion particles, thereby promoting a more uniform and manipulatable particle size. Usually the surfactant is present in a proportion of 0.01% to 5% (w/w) of the emulsion, preferably 0.05% to 2%.

Typically, the weight percentage of surfactant relative to hydrophobic (oil or other lipid) component is from 0.2% to 50%, more preferably from 5% to 20%. Higher ratios of surfactant to core lipid tend to promote smaller particle core diameters.

Surfactants may be either natural compounds, such as phospholipids and cholates, or non-natural compounds such as: polysorbates, which are fatty acid esters of polyethoxylated sorbitol (Tween); polyethylene glycol esters of fatty acids from sources such as castor oil (Emulfor); polyethoxylated fatty acid, e.g. stearic acid (Simulsol M-53); Nonidet; polyethoxylated isooctylphenol/formaldehyde polymer (Tyloxapol); polyoxyethylene fatty alcohol ethers (Brij); polyoxyethylene nonphenyl ethers (Triton N); polyoxyethylene isooctylphenyl ethers (Triton X). Mixtures of surfactant molecules, including mixtures of surfactants of different chemical types, are acceptable. Surfactants should be suitable for pharmaceutical administration and compatible with the peptide to be delivered.

In certain embodiments, the emulsion may be limited in or substantially free of one or more cosurfactants selected from the group consisting of free fatty acids, mono- or diglycerides (fatty acid mono- or diesters of glycerol), aliphatic C3-C6 monoalcohols (exclusive of e.g. chlorobutanol or other haloalkyl alcohol preservative), polyglycerol fatty acid esters, or lysophosphatidyl choline. In many embodiments, the particular limited cosurfactant from the above group may constitute less than 5%, usually less than 1%, often less than 0.1%, relative to the weight of hydrophobic core component. In some embodiments, one or more cosurfactants may be present.

5.4 Continuous Aqueous Phase

The aqueous component will be the continuous phase of the emulsion and may be water, saline or any other suitable aqueous solution which can yield an isotonic and pH controlled preparation.

In addition, the compositions of the invention may also comprise conventional additives such as preservatives, osmotic agents or pressure regulators and antioxidants. Typical preservatives include Thimerosal, chlorbutanol, and methyl, ethyl, propyl or butyl parabens. Typical osmotic pressure regulators include glycerol and mannitol, with glycerol being preferred. The preferred oil phase antioxidant is .alpha.-tocopherol or .alpha.-tocopherol succinate. The aqueous phase may also include an antioxidant of a polyamine carboxylic acid such as ethylene diamino tetraacetic acid, or a pharmaceutically acceptable salt thereof.

5.5 Antigens

Since the SME particles provide a hydrophilic-lipophilic microenvironment, either water-soluble or lipid-soluble immunogens can be incorporated in the SME vaccines of the present invention. Examples of peptide antigens are: hydrophilic natural or synthetic peptides and proteins derived from bacteria, viruses and parasites, such as the recombinant gp160 envelope protein of the HIV virus; natural or synthetic glycoproteins derived from parasites, bacteria or viruses such as the native surface glycoprotein of Leishmania strain or subunit vaccines containing part of the glycopeptides alone or covalently conjugated to lipopeptides like lauryl-cystein hydrophobic foot; protein toxoids such as the Staphylococcus enterotoxin B toxoid, either chemically or physically inactivated; non-toxic bacterial surface structures (fimbrial adhesions) of Escherichia coli strains such as the Shiga-like Toxin B Subunit (SLT-B) and AF-R1, a pilus adhesion which is a virulence factor for RDEC-1 E. coli strain; outer membrane proteins of Neisseria meningitidis; Hepatitis B surface antigen; native or synthetic malaria antigens derived from different portions of Plasmodium falciparum, etc.

Examples of lipophilic or hydrophobic immunogens are lipopolysaccharides (LPS), such as detoxified LPS obtained from E. coli (Sigma Chemical Co., St. Louis, USA); Lipid A, the terminal portion of LPS, such as the one isolated from Salmonella minnesota R595 from List Biological Laboratories (CA, USA).

In some embodiments, the emulsion particles will be free or substantially free of the above or other nonbioactive proteins, i.e. less than 5%, usually less than 1%, and frequently less than 0.1% (w/w) protein relative to other particle components.

5.5.1 Shigella Antigens

LPS preparation. LPS was extracted from single isolates of S. flexneri 2a or S. sonnei by hot phenol by established methods (29). Alkaline-detoxified LPS (LPSad) was prepared by mild alkaline treatment as previously described.

5.6 Bioadhesive SME Vaccine Adjuvants

Submicron emulsion vaccine adjuvants of the present invention optionally may contain a bioadhesive macromolecule or polymer in an amount sufficient to confer bioadhesive properties. The bioadhesive macromolecule enhances the delivery and attachment of antigens on or through the target mucous surface conferring mucosal immunity. The bioadhesive macromolecule may be selected from acidic non-naturally occurring polymers, preferably having at least one acidic group per four repeating or monomeric subunit moieties, such as polyacrylic acid and/or polymethacrylic acid (e.g., Carbopol, Carbomer), poly(methylvinyl ether/maleic anhydride) copolymer, and their mixtures and copolymers; acidic synthetically modified natural polymers, such as carboxymethylcellulose (CMC); neutral synthetically modified natural polymers, such as (hydroxypropyl) methylcellulose; basic amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth, and karaya gum; and neutral non-naturally occurring polymers, such as polyvinylalcohol; or their mixtures.

The ionizable polymers may be present as free acids, bases, or salts, usually in a final concentration of 0.01-0.5% (w/v).

As used herein, a polymer of an indicated monomeric subunit contains at least 75%, preferably at least 90%, and up to 100% of the indicated type of monomer subunit; a copolymer of an indicated type of monomeric subunit contains at least 10%, preferably at least 25% of that monomeric subunit.

A preferred bioadhesive macromolecule is the family of acrylic acid polymers and copolymers (e.g. CARBOPOL). These contain the general structure:

One preferred group of polymers of acrylic acid is commercially available under the tradename CARBOPOL. CARBOPOL 934 is available in a pharmaceutical grade.

Preferred bioadhesive or mucoadhesive macromolecules have a molecular weight of at least 50 kDa, preferably at least 300 kDA, and most preferably at least 1,000 kDa. Favored polymeric ionizable mucoadhesive macromolecules have not less than 2 mole percent acidic groups (e.g. COOH, SO3 H) or basic groups (NH2, NRH, NR2), relative to the number of monomeric units. More preferably, the acidic or basic groups constitute at least 5 mole percent, more preferably 25 or even 50, up to 100 mole % relative to the number of monomeric units of the macromolecule.

Preferred macromolecules also are soluble in water throughout their relevant concentration range (0.01-0.5% w/v).

5.7 Methods of Preparation

A further embodiment of the invention relates to methods for preparation of submicron emulsion vaccine adjuvants intrinsically and extrinsically as extensively detailed in the examples. In general, SME intrinsic formulations are prepared by emulsifying the antigen together with the SME components, while SME extrinsic formulations are prepared by adding externally the antigen to previously prepared plain SME.

5.8 Dehydrated SME Adjuvants

A further aspect of the invention provides dehydrated emulsions, made by dehydrating the submicron emulsion of the types described herein. Dehydrated submicron emulsions may be stored for prolonged periods with minimal degradation, then reconstituted with water shortly before use. Residual water content in the dehydrated emulsion is usually less than 5% (w/w), commonly less than 2%, and often less than 1%.

Dehydration may be performed by standard methods, such as drying under reduced pressure; when the emulsion is frozen prior to dehydration, this low pressure evaporation is known as lyophilization. Freezing may be performed conveniently in a dry ice-acetone or ethyl alcohol bath. The pressure reduction may be achieved conveniently with a mechanical vacuum pump, usually fitted with a liquid nitrogen cold trap to protect the pump from contamination. Pressures in the low millitorr range, e.g. 10-50 millitorr, are routinely achievable but higher or lower pressures are sufficient.

A cryoprotectant or anticoalescent compound may be added to the emulsion prior to dehydration to inhibit flocculation and coalescence upon rehydration. The cryoprotectant may be of any type known in the art, including sugars and polysaccharides such as sucrose or trehalose, and non-natural polymers such as polyvinylpyrrolidone. Cryoprotectants are usually present at less than 25%, commonly 10%, more commonly 5%, 4% (w/v) or less in the emulsion before lyophilization.

A preferred category of cryoprotectants is amino acids and oligopeptides. Preferred amino acids include valine, leucine, isoleucine, lysine, methionine, threonine, serine, arginine, alanine, glycine, histidine, proline, phenylalanine, taurine, and carnitine, although any of the other natural amino acids may also be present. Amino acids may be of either D or L configuration, or a mixture; the natural L form is preferred. Amino acids may be present as their salts or esters, and as mixtures of amino acids or as pure species.

A particularly preferred amino acid is glycine, which may be present either in pure form or as a component of a mixture, e.g., in an hydrolyzate of collagen or other glycine-rich protein.

Mixtures of oligopeptides, especially di- and tripeptides, are another preferred type of cryoprotectant.

These may be prepared conveniently as partial protein hydrolyzates or enzymatic digests.

The cryoprotective amino acids or oligopeptides are generally present in the emulsion at a concentration of about 0.25 to 25% (w/w), preferably about 0.5 to 12% (w/w), more preferably about 1 to 10% (w/w) and commonly 3-6% (w/w).

Cryoprotectants and methods of making lyophilized submicron emulsions are taught in more detail in copending application "Dry Compositions for Preparing Submicron Emulsions", PCT US Application No. 93/01415, which is herein incorporated by reference.

5.5.1 Shigella Antigen Proteosome Complex

Proteosomes are preparations of neisserial outer membrane protein vesicles that have previously been shown to enhance the parenteral immunogenicit of peptides and other antigens hydrophobivcally complexed to them. Moreover, large-scale vaccine trials with such meningoccal outer membrane protein preparations noncovalently complexed to meningococcal polysaccharides have demonstrated that such vaccines are safe for human use. In the present study, we evaluated an acellular approach to induce type-specific anti-Shigella immunity using purified Shigella LPS. In particular, we evaluated the mucosal immunogenicity and efficacy in animal models of S. flexneri 2a and S. sonnei LPS hydrophobically complexed to proteosomes (prot-LPS). These Shigella vaccine candidates were designed for oral or intranasal administration in order to achieve direct sensitization of targeted mucosal tissues and thereby stimulate mucosal lg production and local immunity.

Proteosome preparation. Outer membrane proteins from group B serotype 2b Neisseria meningitidis were extracted with detergent as described previously.

Claim 1 of 4 Claims

What is claimed is:

1. An immunogenic composition comprising a hydrophobic complex consisting essentially of proteosomes, at least one glycolipid and a pharmaceutically acceptable carrier.

If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.



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