WO2014022816A2 - Pharmaceutical compositions comprising 15-hetre and methods of treating or preventing arthritis using same - Google Patents
Pharmaceutical compositions comprising 15-hetre and methods of treating or preventing arthritis using same Download PDFInfo
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- WO2014022816A2 WO2014022816A2 PCT/US2013/053498 US2013053498W WO2014022816A2 WO 2014022816 A2 WO2014022816 A2 WO 2014022816A2 US 2013053498 W US2013053498 W US 2013053498W WO 2014022816 A2 WO2014022816 A2 WO 2014022816A2
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- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- 15-Hydroxy-eicosa-8(Z),l l(Z),13(E)-trienoic acid (“15-HETrE”) is a derivative of DGLA.
- 15-HETrE refers to 15-HETrE in its free acid form (e.g., 15-hydroxy-eicosa-8(Z), l l(Z),13(E)-trienoic acid) and/or an acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing.
- 15-HETrE can be derived by exposing DGLA to the enzyme 15 -lipoxygenase according to methods known to those skilled in the art.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The disclosure generally relates to compositions comprising fatty acids, or derivatives thereof (e.g., C1-C4 esters) including, for example, 15-HETrE for the treatment and/or prevention of arthritis.
Description
TITLE
PHARMACEUTICAL COMPOSITIONS COMPRISING 15-HETRE AND METHODS OF TREATING OR PREVENTING ARTHRITIS USING SAME
PRIORITY CLAIM
[0001] This application claims priority to U.S. provisional patent application serial no. 61/679,234, filed August 3, 2012, the entire contents of which is incorporated herein and relied upon.
FIELD
[0002] The disclosure generally relates to compositions comprising fatty acids, or derivatives thereof (e.g., C 1-C4 esters) including, for example, 15-HETrE for the treatment and/or prevention of arthritis.
BACKGROUND
[0003] Arthritis— often divided into two categories referred to as osteoarthritis (OA) and rheumatoid arthritis (RA)— is a painful condition resulting in a lower quality of life. OA, also commonly referred to as degenerative joint disease, is characterized by an imbalance between the synthesis and degradation of articular cartilage. The breakdown of joint cartilage often results in joint pain and loss of mobility. OA commonly affects the hands, feet, spine, and large weight-bearing joints, such as the hips and knees. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion. A variety of causes, including from hereditary, developmental, metabolic, and mechanical sources, may initiate processes leading to loss of cartilage. RA is a chronic inflammatory disorder that typically affects the small joints of the hands and feet. Unlike the wear-and-tear damage of OA, rheumatoid arthritis affects the lining the joints, causing a painful swelling that can eventually result in bone erosion and joint deformity. RA occurs when the immune system attacks the synovium, the lining of the membranes that surround the joints. The resulting inflammation thickens the synovium, which can eventually invade and destroy the cartilage and bone within the joint. The tendons and ligaments that hold
the joint together weaken and stretch. Gradually, the joint loses its shape and alignment. Treatment of arthritis is generally limited to symptomatic pain relief, although steroids are occasionally prescribed. Steroid use is associated with serious side effects, especially when taken orally and used long-term. Disease-modifying antirheumatic drugs (DMARDs) are believed to interfere with the immune system and thus are sometimes prescribed to combat certain types of inflammatory arthritis. DMARD use is also associated with serious side effects. Accordingly, there exists a need for compositions that are more effective in the treatment and prevention of arthritis, especially compositions that lead to fewer and/or less severe side effects when taken orally and/or long-term.
SUMMARY
[0004] The present disclosure provides compositions comprising fatty acids agents including, for example, 15-HETrE, used singly, in combination and/or in combination with a second active agent for treatment of arthritis.
[0005] The present disclosure also provides methods for treating a disease or disorder mediated by 15-HETrE in a subject in need thereof comprising administering to a subject a composition comprising a therapeutically effective amount of 15-HETrE. In some embodiments, the method comprises administering about 0.01 mg per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day of 15-HETrE.
[0006] In some embodiments, the compositions are in the form of an oral dosage form. In some embodiments, compositions of the invention are in the form of solid dosage forms. Non- limiting examples of suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, melt tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule filled with solid and/or liquids), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
[0007] In one embodiment, the 15-HETrE is in the form of an ester. In another embodiment, the compositions comprise a Ci - C5 alkyl ester of 15-HETrE. In another embodiment, the compositions comprise a methyl ester, propyl ester, or butyl ester of 15- HETrE. In another embodiment the 15-HETrE comprises 15-hydroxy-eicosa- 8(Z),1 l(Z), 13(E)-trienoic acid ethyl ester.
[0008] In another embodiment, the 15-HETrE comprises lithium, mono, di- or triglyceride or any other ester or salt of 15-HETrE, or the free acid form of 15-HETrE.
[0009] In one embodiment, 15-HETrE present in a composition of the invention comprises at least 90% by weight 15-HETrE (as the term "15-HETrE" is defined and exemplified herein). In one embodiment, 15-HETrE present in a composition of the invention comprises at least 90% by weight of all fatty acids present therein. 15-HETrE compositions can comprise even higher purity compositions, for example at least 95% by weight of the composition or of all fatty acids, or at least 97% by weight of the composition or of all fatty acids, wherein the 15-HETrE is any form of 15-HETrE as set forth herein. The purity of 15-HETrE can further be defined (e.g. impurity profile) by any of the descriptions of 15-HETrE provided herein, 95% by weight of the composition or of all fatty acids 15-HETrE or at least 97% by weight 15-HETrE of the composition or of all fatty acids, wherein the 15-HETrE is any form of 15-HETrE as set forth herein. The purity of 15-HETrE can further be defined (e.g. impurity profile) by any of the descriptions of 15-HETrE provided herein.
[0010] In another embodiment, 15-HETrE is present in a composition of the present invention in an amount of about 25 mg to about 7500mg, about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 25mg, about 50mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775
mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg,
about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, about 5000 mg.
[0011] In one embodiment, a composition of the invention contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1%, or not more than about 0.5%, by weight of the composition or of all fatty acids, of other omega-6 fatty acids such as linoleic acid, gamma linolenic acid, dihomo gamma linolenic acid or derivatives thereof.
[0012] In another embodiment, 15-HETrE represents at least about 60%, at least about 70%), at least about 80%>, at least about 90%>, at least about 95%, at least about 97%, at least about 98%>, at least about 99%, or 100%, by weight, of all fatty acids present in a composition of the invention.
[0013] These and other embodiments of the invention are described in further detail below.
DETAILED DESCRIPTION
[0014] The present disclosure provides compositions (e.g., dietary supplements) and formulations that comprise fatty acid agents including, for example, 15-HETrE. Such agents have been found to positively modulate arthritis markers. Given this capacity, the compositions and formulations disclosed herein may be used in the treatment and/or prevention of arthritis.
[0015] While the present disclosure is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the disclosure, and is not intended to limit the disclosure to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the disclosure in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0016] The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about." Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a disclosed numeric value into any other disclosed numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present disclosure.
[0017] Dihomo-gamma-linolenic acid, also known as czs-8,1 1 , 14-eicosatrienoic acid or C 20:3co6 ("DGLA"), is the elongation product of gamma-linolenic acid, also referred to as gamoleic acid or C 18:3ω6 ("GLA"). GLA is a component of natural oils from a variety of plants such as Echium, blackcurrant, borage, evening primrose, hackelia, trichodesma, and buglossoides, to name a few. As used herein, the term "DGLA" refers to DGLA free acid (e.g., cz's-8, 1 1 ,14-eicosatrienoic acid) and/or an acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing. In some embodiments, DGLA is in the form of a Ci_4 alkyl ester such as methyl ester or ethyl ester form. While there are very few natural sources of DGLA, it can be derived from elongating gamma linolenic acid by 2 carbons using the enzyme elongase. Due to the recent progress in fermentation technology, DGLA can also be derived from organisms such as microalgae, fungi, bacteria and yeast according to known methods.
[0018] 15-Hydroxy-eicosa-8(Z),l l(Z),13(E)-trienoic acid ("15-HETrE") is a derivative of DGLA. As used herein, the term "15-HETrE" refers to 15-HETrE in its free acid form (e.g., 15-hydroxy-eicosa-8(Z), l l(Z),13(E)-trienoic acid) and/or an acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing. 15-HETrE can be derived by exposing DGLA to the enzyme 15 -lipoxygenase according to methods known to those skilled in the art.
[0019] As used herein, the terms "DGLA derivative" and "derivative of DGLA" refer to compounds formed from the chemical conversion of DGLA including, without limitation, 15-HETrE, and esters, derivatives, conjugates or salts thereof, or mixtures of any of the foregoing. One of skill in the art will readily recognize from the chemical structure and other properties whether a given compound is a DGLA derivative.
[0020] As used herein, the term "animal" means any animal that has a need for preventing or treating arthritis and maintaining joint health in an animal, including human, avian, bovine, canine, equine, feline, lupine, murine, ovine, or porcine animals.
[0021] As used herein, the term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
[0022] As used herein, the terms "treating", "treat", and "treatment" embrace both preventative, i.e., prophylactic, and palliative treatment.
[0023] As used herein, the terms "pharmaceutically acceptable" and "nutraceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicoiogically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith,
[0024] As used herein, the term "health and/or wellness of an animal" means the complete physical, mental, and social well being of the animal, not merely the absence of disease or infirmity.
[0025] As used herein, the term "degenerative joint disorder" refers to any etiological or pathological symptom affecting a joint. Such symptoms and etiology include swelling, pain and/or stiffness of a joint such that complete or partial loss of function and/or damage to the joint and/or a reduction of the joint mobility. The term also includes chronic inflammation, primarily of the synovial tissue, pannus formation, destruction of articular
cartilage and release of various enzymes, for example, collagenase and lysosomal enzymes, in an affected joint, osteoarthritis, rheumatic disorders with cartilage breakdown, rheumatoid arthritis, chondrolysis after joint trauma, for example, after meniscus or patella injuries or torn ligaments, or chondrolysis associated with prolonged immobilization of joints. By way of example, degenerative joint disorder includes osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, tendonitis, ankylosing spondylitis, bursitis, spinal disc injuries, and temporomandibular joint disorder.
[0026] As used herein, the term "unsaturated fatty acids" or "UFA" means polyunsaturated fatty acids or monounsaturated fatty acids, including monocarboxyiic acids having at least one double bond. UFAs include omega-6 (ω-6) fatty acids such as linoleic acid (LA), gamma-linolenic, dihomo-gamma linolenic and arachidonic acid (AA) and omega-3 (ω-3) fatty acids such as eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), docosapentaenoic acid (DPA) and docosahexaenoie acid (DHA).
[0027] As used herein, the term "fish oil" means a fatty or oily extract, relatively rich in UFA, whether crude or purified, obtained from a sea animal, preferably a cold-water fish such as, but not limited to, salmon, tuna, mackerel, herring, sea bass, striped bass, halibut, catfish, and sardines, as well as shark, shrimp, and clams, or any combination thereof. Fish oil is generally a term of art used by ingredient suppliers and encompasses a range of products of varying UFA content and purity.
[0028] As used herein, the term "in conjunction" means that 15-HETrE or other compounds or other compositions of the invention are administered to an animal (1) together in a food composition, (2) together with another pharmaceutical ingredient or (3) separately at the same or different frequency using the same or different administration routes at about the same time or periodically. "Periodically" means that 15-HETrE or other compounds or other compositions are administered on a schedule acceptable for specific compounds or compositions. "About the same time" generally means that 15-
HETrE or other compounds or compositions are administered at the same time or within about 72 hours of each other.
[0029] As used herein, the term "dietary supplement" means a product that is intended to be ingested in addition to a normal animal diet. Dietary supplements may be in any form, e.g., solid, liquid, gel, tablet, capsule, powder, and the tike. Preferably they are provided in convenient dosage forms, e.g., in sachets. Dietary supplements can be provided in bulk consumer packages such as bulk powders, liquids, gels, or oils. Similarly such supplements can be provided in bulk quantities to be included in other food items such as snacks, treats, supplement bars, beverages, and the like.
[0030] As used herein, the term "aging" means being of an advanced age such that an animal has reached or exceeded 50% of the average life expectancy for the animal's species and/or breed within such species. For example, if the average life expectancy for a given breed of dog is 12 years, then an "aging animal" within that breed is 6 years old or older.
[0031] As used herein, the term "food" or "food product" or "food composition" means a product or composition that is intended for ingestion by an animal, including a human, and provides nutrition to the animal.
[0032] As used herein, the term "regular basis" means at least monthly dosing with 15- HETrE and more preferably weekly dosing. More frequent dosing or consumption, such as twice or three times weekly, is preferred in certain embodiments. Still more preferred are regimens that comprise at least once daily consumption, e.g., when 15-HETrE is a component of a pharmaceutical composition or food composition that is consumed at least once daily.
[0033] As used herein, the term "single package" means that the components of a kit are physically associated in or with one or more containers and considered a unit for manufacture, distribution, sale, or use. Containers include, but are not limited to, bags, boxes, cartons, bottles, packages such as shrink wrap packages, stapled or otherwise
affixed components, or combinations thereof. A single package may be containers of individual 15-HETrE and food compositions physically associated such that they are considered a unit for manufacture, distribution, sale, or use.
[0034] In one embodiment, 15-HETrE is deodorized prior to use in a method or composition as disclosed herein. In one embodiment, crude 15-HETrE is mixed with silica and charcoal. In one embodiment, the silica and charcoal are in a ratio of about 1 : 1 to about 50:1, for example about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 14:1, about 15:1, about 16:1, about 18:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, or about 50:1. In one embodiment, the ratio of 15-HETrE to silica/charcoal is about 1:1 to about 50:1, for example about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 14:1, about 15:1, about 16:1, about 18:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, or about 50:1. In one embodiment, crude 15-HETrE has been deodorized by filtering over a CELITE filter. In another embodiment, lecithin is used in the deodorizing of the fatty acids.
[0035] In a first aspect, the invention provides methods for preventing and/or treating arthritis in a subject (e.g., a human or an animal). The methods comprise administering to the subject a therapeutically effective amount of 15-HETrE.
[0036] In a second aspect, the invention provides methods for preventing and/or treating the degradation of articular cartilage in a subject. The methods comprise administering to the subject a therapeutically effective amount of 15-HETrE.
[0037] In a third aspect, the invention provides methods for promoting and maintaining joint health in a subject. The methods comprise administering to the subject a therapeutically effective amount of 15-HETrE.
[0038] In a fourth aspect, the invention provides methods for promoting the health and wellness of a subject. The methods comprise administering to the subject a therapeutically effective amount of 15-HETrE.
[0039] In the methods of the invention, 15-HETrE is administered to a subject in amounts of about 0.01 mg per kilogram of body weight per day ("mg/kg/day") to about 100 mg/kg/day, preferably about 0.05 mg/kg/day to about 50 mg/kg/day, most preferably about 0.1 mg/kg/day to about 10 mg/kg/day. For example, methods according to the present invention comprise administering 15-HETrE to the subject in an amount of about 0.01 mg/kg/day, about 0.05 mg/kg/day, about 0.1 mg/kg/day, about 0.2 mg/kg/day, about 0.3 mg/kg/day, about 0.4 mg/kg/day, about 0.5 mg/kg/day, about 1 mg/kg/day, about 1.5 mg/kg/day, about 2 mg/kg/day, about 2.5 mg/kg/day, about 3 mg/kg/day, about 3.5 mg/kg/day, about 4 mg/kg/day, about 4.5 mg/kg/day, about 5 mg/kg/day, about 5.5 mg/kg/day, about 6 mg/kg/day, about 6.5 mg/kg/day, about 7 mg/kg/day, about 7.5 mg/kg/day, about 8 mg/kg/day, about 8.5 mg/kg/day, about 9 mg/kg/day, about 9.5 mg/kg/day, about 10 mg/kg/day, about 10.5 mg/kg/day, about 11 mg/kg/day, about 11.5 mg/kg/day, about 12 mg/kg/day, about 12.5 mg/kg/day, about 13 mg/kg/day, about 13.5 mg/kg/day, about 14 mg/kg/day, about 14.5 mg/kg/day, about 15 mg/kg/day, about 15.5 mg/kg/day, about 16 mg/kg/day, about 16.5 mg/kg/day, about 17 mg/kg/day, about 17.5 mg/kg/day, about 18 mg/kg/day, about 18.5 mg/kg/day, about 19 mg/kg/day, about 19.5 mg/kg/day, about 20 mg/kg/day, about 25 mg/kg/day, about 30 mg/kg/day, about 35 mg/kg/day, about 40 mg/kg/day, about 45 mg/kg/day, about 50 mg/kg/day, about 55 mg/kg/day, about 60 mg/kg/day, about 65 mg/kg/day, about 70 mg/kg/day, about 75 mg/kg/day, about 80 mg/kg/day, about 85 mg/kg/day, about 90 mg/kg/day, about 95 mg/kg/day, or about 100 mg/kg/day. In various embodiments, the 15-HETrE is administered to the subject in amounts of from about 0.5 to about 5 mg/kg/day, for example about 0.5 mg/kg/day, about 1 mg/kg/day, about 1.5 mg/kg/day, about 2 mg/kg/day, about 2.5 mg/kg/day, about 3 mg/kg/day, about 3.5 mg/kg/day, about 4 mg/kg/day, about 4.5 mg/kg/day, or about 5 mg/kg/day.
[0040] Compositions comprising 15-HETrE according to the present invention can be administered in any suitable form according to any suitable route of administration. For example and without limitation, 15-HETrE can be administered in a food composition, in a dietary supplement, in a pharmaceutical composition, in a nutraceutical composition, or as a medicament. As used herein, the term "composition" refers broadly to any type of composition (or combination thereof), including without limitation the aforementioned exemplary list. Similarly, 15-HETrE can be administered using a variety of administration routes, including oral, intranasal, intravenous, intramuscular, intragastric, transpyloric, subcutaneous, rectal, topical and the like. In one preferred embodiment, 15- HETrE is administered to a subject orally. In another preferred embodiment, 15-HETrE is administered orally to a subject as a dietary supplement or as an ingredient in a food composition.
[0041] In another preferred embodiment, 15-HETrE is administered to a subject as a pharmaceutically appropriate active ingredient. In various embodiments, the invention provides pharmaceutical compositions, for example a capsule, comprising 15-HETrE. In another embodiment, 15-HETrE is administered to a subject in a pharmaceutical or a nutraceutical composition. The pharmaceutical or nutraceutical composition comprises 15-HETrE and optionally one or more pharmaceutically or nutraceutically acceptable carriers, diluents, or excipients. Generally, pharmaceutical compositions are prepared by admixing a compound or composition with excipients, buffers, binders, plasticizers, colorants, diluents, compressing agents, lubricants, flavorants, moistening agents, and the like, including other ingredients known to skilled artisans to be useful for producing pharmaceuticals and formulating compositions that are suitable for administration to an animal as pharmaceuticals. When administered in a pharmaceutical or nutraceutical composition, 15-HETrE comprises from about 0.001% by weight to about 90%> by weight of the composition, preferably from about 0.0025%) by weight to about 70%> by weight of the composition, more preferably from about 0.005%) by weight to about 60%> by weight of the composition.
[0042] In one embodiment, the present disclosure provides compositions comprising, for example, an amount (e.g., a therapeutically effective amount) of 15-HETrE. In one embodiment, the composition comprises about 0.5 mg to 5,000 mg of 15-HETrE.
[0043] In another embodiment, 15-HETrE is administered as a dietary supplement. The dietary supplement can have any suitable form such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, sachet, or any other suitable delivery form. The dietary supplement comprise 15- HETrE and optionally additional beneficial components such as, but not limited to, vitamins, preservatives, probiotics, prebiotics and antioxidants. The dietary supplement may be administered in small amounts, or in the alternative, can be diluted before administration. The dietary supplement may be admixed with a food composition or with water or other diluent prior to administration. When administered as a dietary supplement, 15-HETrE comprises about 0.001% by weight to about 90% by weight of the dietary supplement, preferably about 0.0025%) by weight to about 70%> by weight of the dietary supplement, more preferably about 0.005%) by weight to about 60%>%> by weight of the dietary supplement.
[0044] A composition for use in accordance with the disclosure can be formulated as one or more dosage units. The terms "dose unit" and "dosage unit" herein refer to a portion of a composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 8, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
[0045] In one embodiment, a composition including, for example, a composition, as disclosed herein is formulated as a capsule, a tablet or other oral dosage form.
[0046] In some embodiments, compositions comprising 15-HETrE further comprise one or more substances such as vitamins, minerals, probiotics, prebiotics, salts, and functional additives such as palatants, colorants, emulsifiers, and antimicrobial or other preservatives. Minerals that may be useful in such compositions include, for example,
calcium, phosphorous, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, and the like. Examples of additional vitamins useful herein include such fat soluble vitamins as A, D, E, and K. Insulin, amino acids, enzymes, coenzymes, and the like may be useful to include in various embodiments.
[0047] Compositions comprising 15-HETrE according to the present invention may further comprise one or more additional unsaturated fatty acids. In some embodiments, the additional unsaturated fatty acid is one or more of: eicosapentaenoic acid, alpha-linolenic acid, docosapentaenoic acid, docosahexaenoic acid, an ester of one or more of the foregoing, a salt of one or more of the foregoing, and combinations thereof. In a preferred embodiment, the additional unsaturated fatty acid is eicosapentaenoic acid, an ester thereof, and/or a salt thereof.
[0048] A skilled artisan can determine the appropriate amount of 15-HETrE, food ingredients, vitamins, minerals, probiotics, prebiotics, antioxidants, or other ingredients to be use to make a particular composition to be administered to a particular subject (e.g., a human or an animal). Such artisan can consider the subject's species, age, size, weight, health, and the like in determining how best to formulate a particular composition comprising 15-HETrE and other ingredients. Other factors that may be considered include the type of composition (e.g., pet food composition versus dietary supplement), the desired dosage of each component, the average consumption of specific types of compositions by different subjects (e.g., based on species, body weight, activity/energy demands, and the like), and the manufacturing requirements for the composition.
[0049] In some embodiments, the invention provides for use of 15-HETrE to prepare a medicament for one or more of preventing and treating arthritis; preventing and treating the degradation of articular cartilage; promoting and maintaining joint health; improving the quality of life; and promoting the health and wellness in an animal. Generally, medicaments are prepared by admixing a compound or composition, i.e., 15-HETrE or a composition comprising 15-HETrE, with excipients, buffers, binders, plasticizers, colorants, diluents, compressing agents, lubricants, flavorants, moistening agents, and
other ingredients known to skilled artisans to be useful for producing medicaments and formulating medicaments that are suitable for administration to a subject.
[0050] 15-HETrE can be administered to the subject on an as-needed, on an as-desired basis, or on a regular basis. A goal of administration on a regular basis is to provide the subject with a regular and consistent dose of 15-HETrE or the direct or indirect metabolites that result from such ingestion. Such regular and consistent dosing will tend to create constant blood levels of 15-HETrE and its direct or indirect metabolites. Accordingly, in some embodiments a composition comprising 15-HETrE is administered to a subject on a regular basis, such as once monthly, once weekly, once daily, more than once daily (e.g., twice daily, thrice daily, q.i.d., etc.), every other day, week, or month, every third day, week, or month, every fourth day, week, or month, and the like. When utilized as a supplement to ordinary dietetic requirements, 15-HETrE may be administered directly to the subject, e.g., orally or otherwise. 15-HETrE can alternatively be contacted with, or admixed with, daily feed or food, including a fluid, such as drinking water, or an intravenous connection for an animal that is receiving such treatment. Administration can also be carried out as part of a dietary regimen for the subject. For example, a dietary regimen may comprise causing the regular ingestion by the subject of 15-HETrE in an amount effective to accomplish the methods of the invention.
[0051] According to the methods of the invention, 15-HETrE administration, including administration as part of a dietary regimen, can span a period ranging from parturition through the adult life of the subject. In various embodiments, the subject is a human or an animal (e.g., a mammal) such as a dog or cat. in certain embodiments, the human or animal is a young or growing human or animal, in more preferred embodiments, the human or animal is an aging human or animal, in other embodiments administration begins, for example, on a regular or extended regular basis, when the human or animal has reached more than about 30%, 40%, or 50%> of its projected or anticipated lifespan, in some embodiments, the human or animal has attained 40, 45, or 50% of its anticipated lifespan. In yet other embodiments, the human or animal is older having reached 60, 66, 70, 75, or 80% of its likely lifespan. A determination of lifespan may be based on actuarial
tables, calculations, estimates, or the like, and may consider past, present, and future influences or factors that are known to positively or negatively affect lifespan. Consideration of species, gender, size, genetic factors, environmental factors and stressors, present and past health status, past and present nutritional status, stressors, and the like may also influence or be taken into consideration when determining lifespan.
[0052] 15-HETrE is administered to a subject (e.g., a human or an animal) for a time required to accomplish one or more objectives of the invention, e.g., preventing and treating arthritis in the subject; preventing and treating the degradation of articular cartilage in the subject; promoting and maintaining joint health of the subject; improving the quality of life of the subject; and/or promoting the health and wellness in the subject. Preferably, 15-HETrE is administered to the subject on a regular basis.
[0053] In another aspect, the invention provides compositions comprising 15-HETrE in a therapeutically effective amount for one or more of preventing and treating arthritis in a subject (e.g., a human or an animal); preventing and treating the degradation of articular cartilage in a subject; promoting and maintaining joint health in a subject; improving the quality of life in a subject; and promoting the health and wellness in a subject. The compositions contain 15-HETrE in amounts sufficient to administer 15-HETrE to a subject in amounts of about 0.01 mg/kg/day to about 100 mg/kg/day, preferably about 0.01 mg/kg/day to about 50 mg/kg/day, most preferably about 0.05 mg/kg/day to about 1.0 mg/kg/day, when the compositions are administered as anticipated or recommended for a particular composition. Typically, 15-HETrE comprises about 0.001% by weight to about 90%) by weight of the composition, preferably about 0.005%> by weight to about 70%) by weight of the composition, more preferably about 0.01% by weight to about 60%> by weight of the composition. In various embodiments, food compositions comprise about 1%) by weight, about 2% by weight, about 4% by weight, about 6%> by weight, about 8% by weight, about 10%. 12% by weight, about 14% by weight, about 16% by weight, about 18%o by weight, about 20% by weight, about 22% by weight, about 24% by weight, about 26%o by weight, about 28% by weight, about 30% by weight, about 32% by weight, about 34%o by weight, about 36% by weight, about 38% by weight, about 40% by weight, about
45% by weight, about 50%> by weight, about 55% by weight, about 60% by weight, about 70%) by weight, about or 80%> by weight, or more than about 80%> by weight of the food composition.
[0054] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the disclosure being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.
Claims
1. A method for treating or preventing arthritis in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising 15-HETrE.
2. The method of claim 1, wherein the composition comprises about 0.5 mg to about 5 g of 15-HETrE.
3. The method of claim 1 or 2, wherein the composition is administered to the subject in an amount sufficient to deliver about 0.01 mg to about 100 mg of 15-HETrE per kilogram of body weight of the subject per day
4. The method of any one of claims 1 to 3, wherein the composition is a pharmaceutical composition, a nutraceutical composition, a food composition, a dietary supplement, or a medicament.
5. The method of any one of claims 1 to 4, wherein the composition is administered orally.
6. The method of any one of claims 1 to 4, wherein the composition is administered intranasally, intravenously, intramuscularly, intragastrically, transpylorically, subcutaneously, rectally, or topically.
7. The method of any one of claims 1 to 6, wherein upon administration the subject experiences a reduction, including remission, of one or more symptoms associated with arthritis.
8. The method of claim 7, wherein the one or more symptoms is selected from the group consisting of: joint pain, loss of mobility, joint tenderness, joint stiffness, joint locking, effusion, joint swelling, bone erosion, joint deformity, inflammation of the synovium, weakening of tendons, and joint misalignment.
9. A dietary supplement comprising about 0.001% by weight to about 90%> by weight 15-HETrE.
10. The dietary supplement of claim 9, wherein the 15-HETrE is present in an amount of about 0.0025%) by weight to about 70%> by weight.
11. The dietary supplement of claim 9, wherein the 15-HETrE is present in an amount of about 0.005%) by weight to about 60%> by weight.
12. The dietary supplement of any one of claims 9 to 11, wherein the dietary supplement is administered to a subject for the treatment or prevention of arthritis.
13. A nutraceutical composition comprising about 0.001% by weight to about 90%> by weight 15-HETrE.
14. The nutraceutical composition of claim 13, wherein the 15-HETrE is present in an amount of about 0.0025%) by weight to about 70%> by weight.
15. The nutraceutical composition of claim 14, wherein the 15-HETrE is present in an amount of about 0.005%> by weight to about 60%> by weight.
16. The nutraceutical composition of any one of claims 13 to 15, wherein the nutraceutical composition is administered to a subject for the treatment or prevention of arthritis.
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US201261679234P | 2012-08-03 | 2012-08-03 | |
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