The invention is directed to compositions comprising lecithin, olive oil, esterified fatty acids and mixed tocophenols for use in the treatment and prevention of various types of arthritis and other inflammatory joint conditions, periodontal diseases and psoriasis, which avoid many of the side effects associated with known treatments. The compositions of the present invention have the advantage of increased stability, a reduction of arachidonic acid in cells, a reduction in eicosanoid production and enhanced cell regulation and communication. Also disclosed are methods for using the compositions for treatment and prevention.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention is based on the discovery that the compositions of the present invention are effective in the treatment and prevention of arthritis and other inflammatory disorders but avoid certain side effects associated with known treatments, such as renal and cardiac dysfunction. These compositions have the added benefit of increased efficacy and stability, a reduction of arachidonic acid in cells, a reduction in eicosanoid production and enhanced cell regulation and communication. The present invention is also effective against psoriasis, lupus and heart/cardiovascular disease.

In one aspect, the invention is directed to a composition comprising a lecithin fatty acid, an olive oil fatty acid, an esterified fatty acid and mixed tocophenols.

The lecithin fatty acid may be about 1% to about 10% of the composition. Preferably, the lecithin fatty acid is about 1% to about 5% of the composition. More preferably, the lecithin fatty acid is about 5% of the composition. The olive oil fatty acid may be about 15% to about 25% of the composition. Preferably, the olive oil fatty acid is about 15% to about 20% of the composition. More preferably, the olive oil fatty acid is about 20% of the composition. The esterified fatty acid may be about 70% to about 80% of the composition. Preferably, the esterified fatty acid is about 70% to about 75% of the composition. More preferably, the esterified fatty acid is about 74% of the composition. The mixed tocophenols may be about 1% to about 5% of the composition. Preferably, the mixed tocophenols are about 1% to about 3% of the composition. More preferably, the mixed tocophenols are about 1% of the composition.

The lecithin fatty acid may include, but is not limited to, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid and mixtures thereof. The olive oil fatty acid may include, but is not limited to, oleic acid, palmitic acid, linoleic acid, stearic acid, arachidic acid, and mixtures thereof. The esterified fatty acid may include, but is not limited to, decanoic acid, lauric acid, myristoleic acid, myristic acid, palmitoleic acid, palmitic acid, oleic acid, stearic acid and mixtures thereof.

In a further aspect, the invention is directed to a pharmaceutical composition for treating and/or preventing an arthritis or other inflammatory joint conditions, psoriasis, lupus, periodontal diseases or heart or cardiovascular condition comprising from about 1% to about 10% of a lecithin fatty acid, from about 15% to about 25% olive oil fatty acid, from about 70% to about 80% of an esterified fatty acid, and about 1% to about 5% of a tocophenol, and pharmaceutically appropriate carriers thereof. The pharmaceutical composition may further comprises biocompatible polymers as protective colloids, suspensions or bulking agents, excipients, binders and carriers, as appropriate.

In a further aspect, the invention is directed to a method of treating and/or preventing an arthritis or other inflammatory joint conditions, psoriasis, lupus, periodontal diseases or heart or cardiovascular condition comprising the administration of an effective amount of a composition comprising a lecithin fatty acid, an olive oil fatty acid, an esterified fatty acid and mixed tocophenols to a subject in need thereof. The arthritis or other inflammatory joint condition may include, but is not limited to, osteoarthritis, ankylosing spondylitis, cervical arthritis, firbromyalgia, osteonecrosis, Paget's Disease, bursitis, psoriasis, gout, carpal tunnel syndrome, juvenile rheumatoid arthritis, lumbosacral arthritis, psoriatic arthritis and rheumatoid arthritis. The subject may be a mammal. Preferably, the mammal is a human, canine or feline.

Preferably, the composition is administered topically. When administered topically, preferably the amount of the composition administered is about 1 to 15 mg/kg of body weight of said subject per day. More preferably, the amount of the composition administered is about 3 to 10 mg/kg of body weight of said subject per day. Most preferably, the amount of the composition administered is about 5 to 8 mg/kg of body weight of said subject per day.

The composition is also preferably administered orally. When administered orally, preferably the amount of the composition administered is about 5 to 32 mg/kg of body weight of said subject per day. More preferably, the amount of the composition administered is about 10 to 30 mg/kg of body weight of said subject per day. Most preferably, the amount of the composition administered is about 15 to 25 mg/kg of body weight of said subject per day. Preferably, the composition is administered orally via a soft gel, or alternatively, a tablet or capsule.

Preferably, the composition may be administered once a day or twice a day.

In a further aspect, the invention is directed to a method wherein the composition is administered to a subject in combination with another compound or therapy effective to treat or prevent arthritis or other inflammatory joint conditions, psoriasis, periodontal diseases, lupus or cardiovascular and heart disease.

DETAILED DESCRIPTION OF THE EMBODIMENTS

In general, the terms in the present application are used consistently with the manner in which those terms are understood in the art.

By the term "arthritis and other inflammatory joint conditions," as used herein, is meant joint inflammation, and refers to more than 100 different diseases, including, but not limited to, osteoarthritis, ankylosing spondylitis, cervical arthritis, firbromyalgia, osteonecrosis, Paget's Disease, bursitis, psoriasis, gout, carpal tunnel syndrome, juvenile rheumatoid arthritis, lumbosacral arthritis, psoriatic arthritis and rheumatoid arthritis. These diseases usually affect the area in or around joints, such as muscles and tendons. Some of these diseases can also affect other parts of the body, including the skin and internal organs.

By the term "topically" is meant application over the afflicted area. For example, the present invention may be applied over the knee joint, or anywhere on the body in order to put the composition into the blood stream.

By the term "periodontal diseases" is meant any inflammatory condition resulting in the destruction of the support structure of the dentition.

A. Compositions and Methods of Treatment and Prevention Using Same

The present invention is directed to a composition that is particularly effective in the treatment and prevention of arthritis and other inflammatory joint conditions, as well as psoriasis.

The inflammation process of arthritis involves the release of pro-inflammatory cytokines (e.g., IL-1.beta. and TNF-.alpha.). Fatty acids have been shown to affect these inflammatory cytokines in patients with rheumatoid arthritis. It is likely that dietary supplements of these fatty acids reduce chronic inflammation of rheumatoid arthritis by reducing the release of leukotriene B4 from stimulated neutrophils and of interleukin-1 from monocytes.

Esterified fatty acids (EFA) are fatty acids esterified to cetyl alcohol that are found in small amounts in ruminant fat reported that rats injected with EFA showed greatly increased resistance to adjuvant-induced arthritis. Recently, osteoarthritis patients given EFA showed significant improvement in quality of life. Thus, EFA has potent physiological effects. See Curtis et al, J. Biol Chem (2000) 275:721-724; and Kremer, Lipids (1996) 31 Supp:5243-47.

Esterified fatty acids (EFA) are well absorbed when given orally or topically. Most of the EFA are metabolized, with only a small proportion remaining intact in the tissues or plasma. EFA and its metabolites distribute to various tissues, such as liver, kidney, muscle, and adipose tissue. The lipid profile of EFA and its metabolites in tissues is similar between oral and topical administration. The largest proportion of intact EFA are found in the skin tissue at the site of topical administration.

Thus, the present invention uses an esterified fatty acid formulation. The present formulations are composed of lecithin fatty acids, olive oil fatty acids and esterified fatty acids. The formulations may also contain mixed tocophenols. Preferably, the formulations comprise 5% lecithin, 20% olive oil, 74% esterified fatty acids and 1% mixed tocophenols.

In addition to being effective against arthritis and other inflammatory conditions, the ingredients of the compositions confer other advantages. Specifically, the mixed tocophenols, as a liquid antioxidant, provide the advantage of increased efficacy, stability and preservation to the fatty acid blend. The fatty acid carbons cause a reduction of arachidonic acid in cells, a reduction in eicosanoid production via lipoxygenase and cyclooxygenase and enhanced cell regulation and communication. Tables 1-3 (see Original Patent) provide preferred lecithin fatty acids, olive oil fatty acids and esterified fatty acids for use in the present invention.

The most preferred formula blend of the present invention is shown in Table 4 (see Original Patent).

The present invention, whether taken orally or topically, delivers a group of compounds that are found in limited supply in the normal diet. The primary components not consumed in large amounts are cetyl alcohol and the carbon 14 fatty esters, myristic acid and myristoleate.

These compounds are distributed within the various tissues. The resulting chylomicrons are then distributed within the circulation and made available to the entire cellular matrix. In addition, it is very likely that with both oral and topical use, there is probably some distribution within tissue spaces prior to the first pass through the liver. One likely pathway is the adipocytokine pathway recently found within the body. The primary compound in this pathway is leptin. Leptin is considered to be involved in the inflammatory process both as an initiator and as a down regulator.

Fatty acid products can induce alterations in the cellular membrane. Monounsaturated fatty acids similar to those found in the present invention have been shown to inhibit endothelial activation and to reduce tissue responsiveness to cytokines. Fatty acids have been shown to regulate a variety of enzymatic processes that regulate chronic inflammatory disease.

Arachidonic acid is one of the primary mediators for inflammation. Fatty acids from fish oil have been shown to decrease the amount of arachidonic acid in cell membranes reducing eicosanoid production via cyclooxygenase and lipoxygenase. It is the integration between arachidonic acid byproducts and their involvement with leukotriene and proglandins that lead to inflammation control. The fatty acids within the present invention work to limit eicosanoid production thereby reducing the inflammatory cascade.

There is evidence showing that fatty acids have profound impact on cellular regulation and communication. The primary organs for this process are the endoplasmic reticulum and Golgi body apparatus. These two cellular structures are the main manufacturers of the cellular signals within the body. The immediate benefit found with the present invention is such rapid cellular communication and regulation.

One area that has great potential is the interplay between the fatty acid compounds of the present invention and sphingolipids. Sphingolipids are essential for cellular function and are uniquely integrated with the endoplasmic reticulum and Golgi bodies. Sphingolipids are considered dynamic regulators of cellular processes. The variable structure of sphingolipids and glycerolipids trigger the formation of microdomains or rafts within the membrane. Spingolipids are traditionally based upon a C18 fatty acid backbone, but over 60 different species are known with chain lengths varying from 14 to 20 carbons differing in saturation and hydroxylation.

The influence of dietary manipulation of sphingolipids and glycerolipids in vitro has demonstrated that stearic acid and EPA can alter the endoplasmic reticulum to Golgi body lipid trafficking compared to oleic acid. One result was an inhibition of ER lipid synthesis and transfer of membrane lipids to luminal particles. In addition, the polyunsaturated fatty acid mediation of T cell inhibition is attributable to signal protein displacement in membranes. The alteration in lipid rafts is the primary loci.

The formulation content can be adjusted for pH and isotonicity as needed, as understood by the skilled artisan. Preferably, the pH range is 4.0 to 8.0. These formulations can also include biocompatible polymers such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or polyethylene glycol (PEG), and other polymers as protective colloids and suspension or bulking agents, excipients, binders and carriers, as appropriate.

Well known oral dosage forms that work well with the present invention include pills, tablets, including coated tablets, capsules, gel capsules, soft gels, elixirs, emulsions, micro-emulsions and pre-emulsion concentrates for controlled or immediate release. Soft gels are the most preferred oral form. Solubility plays a large role in the development of oral dosage formulations, because the formulation used to deliver the active drug will affect the amount and/or concentration of the drug that reaches the active site over a given period of time. The composition of the formulation also directly affects the solubilization of the drug compound in the gastrointestinal tract, and consequently the extent and rate of the absorption of the active drug compound into the blood stream. In addition, the therapeutic value of a drug is affected by the rate in which the drug is released from the delivery system itself, which in turn affects the rate and extent of solubilization of the active compound in the gastrointestinal tract before absorption.

In addition to effectively treating arthritis or other inflammatory joint conditions, periodontal disease, psoriasis, lupus or cardiovascular and heart disease, the compositions of the present invention are effective at preventing these conditions. In the same way that fatty acids work within the cell to reduce inflammation, they also work within the cell to prevent inflammation from reoccurring. Further, the compositions of the present invention, by reducing and preventing inflammation, prevent the onset of diseases and conditions which result from inflammation. For example, by reducing inflammation of the arteries, the compositions of the present invention prevent occurrences of heart disease and cardiovascular disease.

The appropriate dosage of the composition of the present invention will depend, for example, on the condition to be treated/prevented, the severity and course of the condition, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the composition and the discretion of the attending physician.

Preferably, the composition is administered topically. When administered topically, preferably the amount of the composition administered is about 1 to 15 mg/kg of body weight of said subject per day. More preferably, the amount of the composition administered is about 3 to 10 mg/kg of body weight of said subject per day. Most preferably, the amount of the composition administered is about 5 to 8 mg/kg of body weight of said subject per day. When administered orally, preferably the amount of the composition administered is about 5 to 32 mg/kg of body weight of said subject per day. More preferably, the amount of the composition administered is about 10 to 30 mg/kg of body weight of said subject per day. Most preferably, the amount of the composition administered is about 15 to 25 mg/kg of body weight of said subject per day.

The composition is suitably administered to the patient at one time or over a series of treatments, and may be administered to the patient at any time from diagnosis onwards. The composition may be administered as the sole treatment or in conjunction with other drugs or therapies useful in treating and preventing the condition in question.

Thus, in practicing the methods of this invention, the compounds of this invention may be used alone or in combination with other therapeutic agents. As used herein, two (or more) agents are said to be administered in combination when the two agents are administered simultaneously or are administered independently in a fashion such that the agents will act contemporaneously. In certain preferred embodiments, the compositions of this invention may be co-administered along with other treatments typically prescribed for these conditions according to generally accepted medical practice. For example, the compositions of this invention can be administered in combination with other therapeutic agents or physical therapies for the treatment and/or prevention of arthritis or related conditions. Some of the conditions contemplated for treatment with the present invention, either alone or in combination with other known therapies, are provided below. Typical therapies are also provided, which may be administered in combination with the present invention.

Rheumatoid arthritis is characterized by inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and periarticular structures, with or without generalized manifestations. Treatments include NSAIDs, salicylates, gold compounds, cytotoxic or immunosuppressive drugs and corticosteroids.

Ankylosing spondylitis (AS) is categorized as a type of seronegative spondyloarthropathies. Neurologic and cardiological signs can occasionally result. AS is characterized by mild or moderate flares of active spondylitis alternating with periods of almost or totally inactive inflammation. Treatment includes daily exercise, NSAIDs and corticosteroids, which have limited therapeutic value.

Osteoarthritis includes marked thickening and proliferation of the anterior longitudinal ligaments. Functional compromise of the vertebral arteries, infarction of the spinal cord, and esophageal compression by osteophytes occasionally occur. Treatment includes acetaminophen or NSAIDs, and may include surgeries such as laminectomy, osteotomy, and total joint replacement.

A vascular necrosis occurs in the femoral and humeral heads, the body of the talus, and the carpal scaphoid. Posttraumatic avascular necrosis develops when blood supply is impaired and is thus a function of the relative contributions of arteries to the femoral or humeral head and the extent of anastomoses between them, which varies among persons. Treatment includes analgesics, range-of-motion exercise and cortical bone grafts.

Acute infectious arthritis is caused by bacteria or viruses. Neisseria gonorrhoeae is the most common bacterial cause in adults. It spreads from infected mucosal surfaces (i.e., cervix, rectum, pharynx) to the small joints of the hands, wrists, elbows, knees and ankles. Chronic infectious arthritis is caused by mycobacteria, fungi, and some bacteria with low pathogenicity. Treatment includes antibiotics.

Acute gouty arthritis (gout) may be precipitated by minor trauma, overindulgence in purine-rich food or alcohol, surgery, fatigue, emotional stress, or medical stress (e.g., infection, vascular occlusion). The pain becomes progressively more severe and is often excruciating. Treatments include NSAIDs, colchicine, and lowering the urate concentration in extracellular body fluid.

Osteochondromatosis is characterized by numerous cartilaginous loose bodies in a swollen, painful joint. Surgery is needed to remove the loose bodies along with the synovium of the joint.

Osteoporosis occurs when the amount of bone available for mechanical support of the skeleton eventually falls below the fracture threshold, and the patient may sustain a fracture with little or no trauma. The major clinical manifestations of osteoporosis are bone fractures, which cause chronic pain. Treatment includes pharmaceuticals, maintenance of adequate body weight, increased walking and other weight-bearing exercises.

Paget's disease is characterized by increased bone density, abnormal architecture, cortical thickening, bowing, and overgrowth. Treatment may include salicylates, NSAIDs, orthotics and orthopedic surgery.

Dystonias are sustained muscle contractions that can lead to repetitive twisting movements and abnormal postures. Torticollis is a chronic, focal dystonia that is different from wryneck, an active, painful, self-limited neck spasm. Treatment includes intensive physical therapy, anticholinergics and benzodiazepines.

Boutonniere Deformity (Buttonhole Deformity) is caused by disruption of the central slip attachment base of the middle phalanx extensor tendon, creating a so-called buttonholing of the proximal phalanx between the lateral bands of the extensor tendon. Surgical reconstruction after fixed deformities develop is often found to be unsatisfactory.

Dupuytren's Contracture (Palmar Fibromatosis) is progressive contracture of the palmarfascial bands, producing flexion deformities of the fingers. Treatment includes local injection of a corticosteroid suspension into the nodule, surgery and high-dose vitamin E.

Carpal Tunnel Syndrome is the term used to describe a specific group of symptoms (tingling, numbness, weakness, or pain) in the fingers or hand and occasionally in the lower arm and elbow. These symptoms occur when there is pressure on a nerve within the wrist. Treatment often includes surgery.

Sports injuries include lateral and medial epicondylitis (tennis elbow) and patellofemoral pain (runner's knee). The most common cause of muscle or joint injury is overuse. Treatment for almost all acute athletic injuries includes ice, compression and elevation, as well as local corticosteroid injections.

Psoriasis is characterized by skin cells that multiply up to 10 times faster than normal. As underlying cells reach the skin's surface and die, their sheer volume causes raised, red patches covered with white scales. Treatment includes, salicylic acid and steroids.

Lupus is an autoimmune disease that can cause inflammation, pain, and tissue damage throughout the body. Treatment includes anti-inflammatory medications.

Cardiovascular and heart disease is often characterized by inflammatory lesions throughout the vascular system. Reducing the inflammation of the vascular system can reduce the risk and/or severity of heart/cardiovascular disease.

Periodontal diseases are comprised of a group of inflammatory conditions that result in the destruction of the supporting structure of the dentition, caused by hyperactivated inflammatory conditions. The activated condition causes the release of toxic compounds which degrade the surrounding dentition. The regulation of these toxic compounds is similar to compounds found in most inflammatory conditions derived from cell membrane oxidation and/or tissue phospholipid liberation. Fatty acids modulate the inflammatory cascade via leukotriene, prostaglandin and thromboxane pathways.

Treatments of periodontal disease includes oral rinse and gum gels containing tetracycline, chlorhexidine, doxycycline and minocycline. It is believed that antibiotic intervention reduces or eliminates the viability of gram-negative and anaerobic bacteria commonly found in the mouth cavity. Elimination of the bacterial load retards the development of periodontal disease and bone loss. Oral administration of fatty oils elicits a reduction in gingival inflammation. The topical application of the compositions and formulations of the present invention can accomplish similar reductions in bacterial load.
 

Claim 1 of 20 Claims

1. A method of treating periodontal disease comprising administering an effective amount of a composition comprising a cetylated fatty acid to a subject in need of such treatment, wherein the cetylated fatty acid is selected from the group consisting of cetylated decanoic acid, cetylated lauric acid, cetylated myristic acid, cetylated palmitoleic acid, cetylated oleic acid, and cetylated stearic acid.
 

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