United States Patent:  5,994,318

Assignee:  Albany Medical College (Albany, NY); University of Medicine and Dentistry of New Jersey (Newark, NJ)

Filed:  February 21, 1997

The instant disclosure relates to cochleates comprising a) a biologically relevant molecule component b) a negatively charged lipid component, and c) a divalent cation component. The cochleate has an extended shelf life, even in a desiccated state. Advantageously, the cochleate can be ingested. The biologically relevant molecule can be a topical application and an in vitro treatment, a polypeptide a drug, a nutrient, or a flavor.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the instant invention to provide a means for stabilizing biologic molecules to yield a formulation with prolonged shelf life, which can be made into powder form and which later can be rehydrated to yield a biologically active molecule.

It also is an object of the instant invention to provide a formulation suitable for use as a vehicle to administer a biologically active molecule to a host. The formulation can be used to deliver a biologic molecule to the gut for absorption or to a targeted organ, tissue or cell. A suitable biologic molecule is a polynucleotide or a bioactive compound such as a lipophilic drug.

Other suitable biologic molecules are polypeptides such as hormones and cytokines or nutrients such as vitamins, minerals, and fatty acids.

Yet other suitable biologic molecules are essential oils which impart flavor.

Those and other objects have been obtained by providing a cochleate formulation comprising the following components:

a) at least one biologically relevant molecule component to be stabilized or delivered,

b) at least one negatively charged lipid component, and

c) at least one divalent cation component.

In a preferred embodiment, the cochleate formulation is administered orally.

The instant invention further provides a cochleate formulation containing a polynucleotide wherein said polynucleotide-cochleate comprises the following components:

a) at least one polynucleotide component,

b) at least one negatively charged lipid component, and

c) at least one divalent cation component.

The polynucleotide can be one which is expressed to yield a biologically active polypeptide or polynucleotide. Thus, the polypeptide may serve as an immunogen or, for example, have enzymatic activity. The polynucleotide may have catalytic activity, for example, be a ribozyme, or may serve as an inhibitor of transcription or translation, that is, be an antisense molecule If expressed, the polynucleotide would include the necessary regulatory elements, such as a promoter, as known in the art.

The instant invention further provides a cochleate formulation containing a polypeptide, wherein said polypeptide-cochleate comprises the following components:

a) a polypeptide component

b) a negatively charged lipid component, and

c) a divalent cation component.

A specific example is an insulin cochleate.

The instant invention also provides a cochleate formulation containing a lipophilic drug, wherein said drug-cochleate comprises the following components:

a) at least one drug,

b) at least one negatively charged lipid component, and

c) at least one divalent cation component.

Thus, the drug may be an inhibitor of viral replication such as that used in the treatment of HERPES (acyclovir), or one prescribed for it's antifungal effect on mycotic infections (miconazole nitrate). The drugs may also be those with specific targeted effects on different physiological systems such as anesthetics (propofol) which effect the nervous system, or immunosuppressants, such as cyclosporin A, which inhibit immune cell function. Other lipophilic drugs may also be selected from the groups of anti-infectious, anti-cancer, steroidal anti-inflammatory, non-steroidal anti-inflammatory, tranquilizer, or vasodilatory agents.

The instant invention further provides a cochleate formulation containing a nutrient, wherein said nutrient-cochleate comprises the following components:

a) at least one nutrient,

b) at least one negatively charged lipid component, and

c) at least one divalent cation component.

Specific examples include vitamin A-, polyunsaturated fatty acids- and mineral-cochleates.

The instant invention further provides a cochleate formulation containing a flavor, wherein said flavor-cochleate comprises the following components:

a) at least one essential oil or extract,

b) at least one negatively charged lipid component, and

c) at least one divalent cation component.

Examples include flavor substances generally associated with essential oils and extracts obtained from botanical sources such as herbs, citrus, spices and seeds. Oils/extracts are sensitive to degradation by oxidation, and because the processing of the natural oils and extracts often involves multistep operations, costs are generally considered to be higher. The advantage of an oil/extract-cochleate would be in the stabilization of these otherwise volatile and expensive flavor substances. Flavor-cochleates can also be incorporated into consumable food preparations as flavor enhancers.

The advantages of cochleates are numerous. The cochleates have a nonaqueous structure while not having an internal aqueous space, and therefore cochleates:

(a) are more stable than liposomes because the lipids in cochleates are less susceptible to oxidation;

(b) can be stored lyophilized which provides the potential to be stored for long periods of time at room temperatures, which would be advantageous for worldwide shipping and storage prior to administration;

(c) maintain structure even after lyophilization, whereas liposome structures are destroyed by lyophilization;

(d) exhibit efficient incorporation of biological molecules, particularly with hydrophobic moieties into the lipid bilayer of the cochleate structure;

(e) have the potential for slow or timed release of the biologic molecule in vivo as cochleates slowly unwind or otherwise dissociate;

(f) have a lipid bilayer matrix which serves as a carrier and is composed of simple lipids which are found in animal and plant cell membranes, so that the lipids are non-toxic, non-immunogenic and non-inflammatory;

(g) contain high concentration of divalent cation, such as, calcium, an essential mineral;

(h) are safe, the cochleates are non-living subunit formulations, and as a result the cochleates have none of the risks associated with use of live vaccines, or with vectors containing transforming sequences, such as life threatening infections in immunocompromised individuals or reversion to wild type infectivity which poses a danger to even healthy people;

(i) are produced easily and safely; and

(j) can be produced as defined formulations composed of predetermined amounts and ratios of biologically relevant molecules, including polypeptides, carbohydrates and polynucleotides, such as DNA, lipophilic drugs, and nutrients such as vitamins, minerals and fatty acids.

The advantages of oral administration also are numerous. An oral route has been chosen by the WHO Children's Vaccine Initiative because of ease of administration. Oral vaccines are less expensive and much safer to administer than parenterally (intramuscular or subcutaneous) administered vaccines. The use of needles adds to the cost, and also, unfortunately, in the field, needles are often reused.

Claim 1 of 59 Claims

1. A nutrient-cochleate formulation comprising:

a) a nutrient component and

b) a cochleate further comprising a negatively charged lipid component and a divalent cation component.

____________________________________________
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.