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WO2010124392A1 - Procédés, compositions et coffrets pour le traitement d'états inflammatoires - Google Patents

Procédés, compositions et coffrets pour le traitement d'états inflammatoires Download PDF

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Publication number
WO2010124392A1
WO2010124392A1 PCT/CA2010/000672 CA2010000672W WO2010124392A1 WO 2010124392 A1 WO2010124392 A1 WO 2010124392A1 CA 2010000672 W CA2010000672 W CA 2010000672W WO 2010124392 A1 WO2010124392 A1 WO 2010124392A1
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Prior art keywords
inflammatory
composition
subject
condition
colitis
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English (en)
Inventor
James Johnston
James Gary Nickerson
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National Research Council of Canada
Chemaphor Inc
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National Research Council of Canada
Chemaphor Inc
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    • 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
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the use of carotenoid oxidation products for treating inflammatory conditions.
  • Inflammation occurs when tissues are injured by viruses, bacteria, trauma, chemicals, heat, cold or any other harmful stimulus. Chemicals including bradykinin, histamine, serotonin and others are released, attracting tissue macrophages and white blood cells to localize in an area to engulf and destroy foreign substances.
  • Leukocytes neutrils, eosinophils, basophils, monocytes, and macrophages
  • Leukocytes and some affected tissue cells are activated by the pathogens to synthesize and release proinflammatory cytokines such as IL-I -beta, IL-3, IL-5, IL-6, IL-8, TNF-alpha (tumor necrosis factor- ⁇ ), GM-CSF (granulocyte-macrophage colony- stimulating factor), and MCP-I (monocyte chemotactic protein- 1).
  • proinflammatory cytokines such as IL-I -beta, IL-3, IL-5, IL-6, IL-8, TNF-alpha (tumor necrosis factor- ⁇ ), GM-CSF (granulocyte-macrophage colony- stimulating factor), and MCP-I (monocyte chemotactic protein- 1).
  • IL-8 and MCP-I are potent chemoattractants for, and activators of, neutrophils and monocytes, respectively, while GM-CSF prolongs the survival of these cells and increases their response to other proinflammatory agonists.
  • TNF-alpha can activate both neutrophils and monocytes and can stimulate further release of IL-8 and MCP-I from them.
  • IL- 1 and TNF-alpha are potent chemoattractants for T and B lymphocytes, which are activated to produce antibodies against the foreign pathogen.
  • ATTORNEY DOCKET NO. V83221WO damaging to the surrounding tissues.
  • inflammation causes the blood vessels at the infected site to dilate to increase blood flow to the site.
  • these dilated vessels become leaky.
  • the leaky vessels can produce serious edema in, and impair the proper functioning of, the surrounding tissues (see; e.g., V. W. M. van Hinsbergh, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 17, 1018 (1997)).
  • toxins such as reactive oxygen species
  • matrix-degrading enzymes such as matrix metalloproteinases
  • Inflammatory disorders are those in which the inflammation is sustained or chronic. Immunoinflammatory disorders are characterized by dysregulation of the immune system and inappropriate mobilization of the body's defenses against its own healthy tissue.
  • An inflammatory disorder is osteoarthritis.
  • rheumatoid arthritis a relentless, progressive disease causing severe swelling, pain, and eventual deformity and destruction of joints.
  • the invention provides compositions, methods, and kits for the administration of oxidatively transformed carotenoid and components thereof.
  • the compositions can be useful for treating inflammatory conditions.
  • the invention features a method of treating a subject having, or at risk of, an inflammatory condition, by administering to the subject a composition including oxidatively transformed carotenoid, or a fractionated component thereof, in an amount sufficient to treat the PATENT
  • ATTORNEY DOCKET NO. V83221WO inflammatory condition In certain embodiments the inflammatory condition is not a proliferative skin disease.
  • the inflammatory condition is a nondermal inflammatory disorder, such as a musculoskeletal disorder (e.g., gout, arthritis, osteoarthritis, or rheumatoid arthritis); an inflammation of the gut (e.g., an inflammatory bowel disease selected from Crohn's disease, ulcerative colitis, ileitis, ileocolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis, Crohn's colitis, Crohn's enteritis, Crohn's terminal ileitis, Crohn's entero-colitis, and ileo- colitis); an inflammatory respiratory condition (e.g., asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, sinusitis, or rhinosinusitis); an inflammation of the lung; an inflammatory ocular condition (e.g., uveitis, anterior uveitis, cor
  • the inflammatory condition is a nonproliferative dermal inflammatory disorder (e.g., acne, erythema multiforme, rash, or rosacea).
  • the inflammatory condition is an allergic reaction (e.g., asthma, graft versus host disease, contact dermatitis, urticaria, or allergic rhinitis).
  • the inflammatory condition is a heritable inflammatory condition (e.g., familial Mediterranean fever (FMF), TNF receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), or a cryopyrin-associated periodic syndrome (CAPS)).
  • FMF familial Mediterranean fever
  • TRAPS TNF receptor-associated periodic fever syndrome
  • HIDS hyperimmunoglobulinaemia D and periodic fever syndrome
  • CAS cryopyrin-associated periodic syndrome
  • the inflammatory condition can be any heritable inflammatory condition described herein.
  • the invention further features a method of treating a subject having, or at risk of, mastitis by administering to the subject a composition including oxidatively transformed carotenoid, or a fractionated component thereof, in an amount sufficient to treat the mastitis.
  • the invention also features a method of reducing the number the incidents or severity of mastitis in a subject at risk thereof by administering to the subject a composition including oxidatively transformed carotenoid, or a fractionated component thereof, in an amount sufficient to reduce the incidents or severity of mastitis.
  • the methods for treating mastitis can be used, for example, to treat a lactating beef cow or a dairy cow.
  • the oxidatively transformed carotenoid, or a fractionated component thereof is administered to the dairy cow while the cow is in a lactation period.
  • the oxidatively transformed carotenoid, or a fractionated component thereof is administered to the dairy cow while the cow is in a dry period.
  • the oxidatively transformed carotenoid, or a fractionated component thereof can, for example, be administered systemically, injected into the teat of the subject as part of a teat seal composition, or externally applied to the teat of the subject as part of a teat dip composition.
  • the invention further features a method for reducing the somatic cell count in the milk of a lactating subject by administering to the subject a composition including oxidatively transformed carotenoid, or a fractionated component thereof, in an amount sufficient to reduce the somatic cell count in the milk.
  • the invention features a method for improving the quality of milk produced by a lactating subject by administering to the subject a composition including oxidatively transformed carotenoid, or a fractionated component thereof, in an amount sufficient to improve the quality of the milk.
  • the subject is a dairy cow.
  • the invention features a kit, including (i) a composition including oxidatively transformed carotenoid or a fractionated component thereof; and (ii) instructions for administering the composition for the treatment of a subject having, or at risk of, an inflammatory condition, PATENT
  • the kit includes a composition formulated for inhalation or intranasal administration and the inflammatory condition is an inflammatory respiratory condition.
  • the kit includes a composition formulated for topical administration and the inflammatory condition is a nonproliferative dermal inflammatory disorder.
  • the kit includes a composition formulated for oral administration and the inflammatory condition is a musculoskeletal disorder or an inflammatory bowel disease.
  • the kit includes a composition formulated for ocular administration and the inflammatory condition is an inflammatory ocular condition.
  • the invention further features a kit, including (i) a composition including oxidatively transformed carotenoid or a fractionated component thereof; and (ii) instructions for administering the composition for the treatment of a subject having, or at risk of, mastitis.
  • the composition is formulated for injection into the teat of the subject as part of a teat seal composition.
  • the composition is formulated for external application to the teat of the subject as part of a teat dip composition.
  • the composition includes fractionated oxidatively transformed carotenoid.
  • the composition includes unfractionated oxidatively transformed carotenoid.
  • compositions, and kits the oxidatively transformed carotenoid, or a fractionated component thereof, can be administered orally, intravenously, intramuscularly, ocularly, topically, subcutaneously, intranasally, or by any other route of administration described herein.
  • compositions, and kits can be a human, a domesticated pet (e.g., a dog, cat, horse, or bird), or an agricultural animal, including, for example, sheep, swine, cattle (e.g., dairy cattle or beef PATENT).
  • a domesticated pet e.g., a dog, cat, horse, or bird
  • an agricultural animal including, for example, sheep, swine, cattle (e.g., dairy cattle or beef PATENT
  • ATTORNEY DOCKET NO. V83221WO cattle poultry (e.g., turkey or chicken), or fish (e.g., tilapia, catfish, trout, or salmon).
  • poultry e.g., turkey or chicken
  • fish e.g., tilapia, catfish, trout, or salmon.
  • compositions, and kits the inflammatory condition is not a proliferative skin condition. In other embodiments of any of the above methods, compositions, and kits the inflammatory condition is not the result of an infection.
  • composition can be a pharmaceutical composition.
  • Acne is a general term to denote inflammatory disorders of the pilosebaceous unit.
  • Acne is a group of disorders whose initial pathology is the comedo and includes acne vulgaris (common acne), neonatal acne, infantile acne, and pomade acne.
  • an “amount sufficient” is meant the amount of oxidatively transformed carotenoid, or a fractionated component thereof, required to treat or prevent inflammation or a disease associated with inflammation.
  • the effective amount oxidatively transformed carotenoid, or a fractionated component thereof, used to practice the invention for therapeutic or prophylactic treatment of conditions resulting in or contributed to inflammation varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "amount sufficient.”
  • carotenoid refers to naturally-occurring pigments of the terpenoid group that can be found in plants, algae, bacteria, and certain animals, such as birds and shellfish.
  • Carotenoids include carotenes, which are hydrocarbons (i.e., without oxygen), and their oxygenated derivatives (i.e., xanthophylls).
  • carotenoids examples include lycopene; ⁇ -carotene; zeaxanthin; echinenone; isozeaxanthin; astaxanthin; canthaxanthin; lutein; citranaxanthin; ⁇ -apo-8'-carotenic acid ethyl ester; hydroxy carotenoids, such as alloxanthin, apocarotenol, astacene, astaxanthin, capsanthin, capsorubin, PATENT
  • ATTORNEY DOCKET NO. V83221WO carotenediols, carotenetriols, carotenols, cryptoxanthin, decaprenoxanthin, epilutein, fucoxanthin, hydroxycarotenones, hydroxyechinenones, hydroxylycopene, lutein, lycoxanthin, neurosporine, phytoene, phytofluoene, rhodopin, spheroidene, torulene, violaxanthin, and zeaxanthin; and carboxylic carotenoids, such as apocarotenoic acid, ⁇ -apo-8'-carotenoic acid, azafrin, bixin, carboxylcarotenes, crocetin, diapocarotenoic acid, neurosporaxanthin, norbixin, and lycopenoic acid.
  • carboxylic carotenoids such as apocarotenoic acid, ⁇ -apo-8'-
  • erythema multiforme refers to an inflammatory eruption characterized by symmetric erythematous, edematous, or bullous lesions of the skin or mucous membranes.
  • the mechanism by which erythema multiforme is caused is unknown, but it is generally considered a hypersensitivity reaction.
  • fractionated refers to a composition containing the oligomeric material formed in the production of the oxidatively transformed carotenoid mixture. Methods of fractionating oxidatively transformed carotenoid mixtures into components are described in U.S. Patent No.
  • heritable inflammatory condition refers to hereditary conditions characterized by recurrent unprovoked inflammation.
  • Heritable inflammatory conditions include, without limitation, familial
  • Cryopyrin-associated periodic syndromes are autosomal-dominant autoinflammatory disorders, and include, without limitation, chronic infantile neurological cutaneous articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), Muckle- Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS).
  • CINCA chronic infantile neurological cutaneous articular
  • NOMID neonatal-onset multisystem inflammatory disease
  • MWS Muckle- Wells syndrome
  • FCAS familial cold autoinflammatory syndrome
  • improving milk quality refers to the changing levels of certain milk components for an animal undergoing a therapy of the invention in PATENT
  • An animal that gives improved milk quality according to the methods of the invention is one that produces milk having increased milk fat, increased milk protein, increased lactose content, decreased somatic cell counts, or decreased ketone body levels.
  • mastitis is meant an inflammation of the mammary gland.
  • the mastitis can be caused by an infectious agent (e.g., Staphylococcus aureus, Streptococcus agalactiae, or Escherichia coli) or can be non infectious mastitis.
  • infectious agent e.g., Staphylococcus aureus, Streptococcus agalactiae, or Escherichia coli
  • musculoskeletal disorder is meant an immune system-related disorder of the muscles, ligaments, bones, joints, cartilage, or other connective tissue.
  • Among the most commonly-occurring musculoskeletal disorders are various forms of arthritis, e.g., osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and gout.
  • nondermal inflammatory disorder refers to an autoimmune condition (e.g., musculoskeletal disorders, autoimmune diseases of the GI tract, and ocular autoimmune diseases), but specifically excludes inflammatory dermatoses.
  • Nondermal inflammatory disorders include, without limitation, musculoskeletal disorders, such as arthritis, osteoarthritis, and rheumatoid arthritis; inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis, ileocolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis, Crohn's colitis, Crohn's enteritis, Crohn's terminal ileitis, Crohn's entero-colitis, and ileo-colitis; inflammatory respiratory conditions, such as asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, sinusitis, and rhinosinusitis; and inflammatory respiratory conditions,
  • nonproliferative dermal inflammatory disorders or “nonproliferative inflammatory dermatoses” is meant an inflammatory disorder of the skin which is not also a proliferative skin disease. Inflammatory skin PATENT
  • ATTORNEY DOCKET NO. V83221WO conditions are those conditions of the skin in which inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrate the skin with no overt or known infectious etiology.
  • inflammatory cells e.g., polymorphonuclear neutrophils and lymphocytes
  • Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function.
  • Nonproliferative dermal inflammatory disorders include acne, erythema multiforme, rash, and rosacea.
  • oxidatively transformed carotenoid refers to a carotenoid which has been reacted with up to 6 to 8 molar equivalents of oxygen, or an equivalent amount of oxygen from another oxidizing agent, resulting in a mixture of very low molecular weight oxidative cleavage products and a large proportion of oligomeric material (i.e., that component of the oxidatively transformed carotenoid having a median molecular weight of about 900 Daltons).
  • the resulting reaction produces a mixture that includes molecular species having molecular weights ranging from about 100 to 8,000 Daltons.
  • the oligomeric material is believed to be formed by the many possible chemical recombinations of the various oxidative fragments that are formed.
  • OxBC refers specifically to oxidatively transformed carotenoid derived from ⁇ -carotene.
  • composition a composition containing oxidatively transformed carotenoid, or a fractionated component thereof, and formulated with one or more pharmaceutical-grade excipients in a manner that conforms with the requirements of a governmental agency regulating the manufacture and sale of pharmaceuticals as part of a therapeutic regimen for the treatment or prevention of disease in a mammal (e.g., manufactured according to GMP regulations and suitable for administration to a human).
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for PATENT
  • ATTORNEY DOCKET NO. V83221WO intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or any other formulation described herein.
  • proliferative skin disease is meant a benign or malignant disease that is characterized by accelerated cell division in the epidermis or dermis.
  • proliferative skin diseases are psoriasis, eczema, dandruff, actinic keratosis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, mycosis fungoides, lichen planus, and other skin diseases characterized by rapid proliferation of skin cells.
  • rosacea refers to a chronic inflammatory skin disorder characterized by prominent cutaneous blood vessels, erythema, papules, and pustules primarily in the central areas of the face. Tissue hypertrophy, particularly of the nose, may result. Rarely, rosacea occurs on the trunk and extremities. The cause is unknown, but the disease is most common in persons with a fair complexion.
  • subject any animal including, without limitation, humans, dogs, cats, horses, sheep, swine, cattle, poultry, and fish.
  • treating refers to administering oxidatively transformed carotenoid, or a fractionated component thereof, for prophylactic and/or therapeutic purposes.
  • prevent disease refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease.
  • Prophylactic use can be used to treat a subject not yet ill to reduce the likelihood of disease, reduce the severity of disease, or to ameliorate one or more symptoms of a disease.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease to improve or stabilize the subject's condition.
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • "at risk of refers to subjects prone to inflammation or infection.
  • Subjects can be prone to inflammation or infection, for example, by virtue of (i) having an autoimmune PATENT
  • compositions and methods of the invention can be used to treat an inflammatory condition in a subject.
  • the inflammatory condition can be any inflammatory condition described herein.
  • Figure 1 is a graph showing the suppressive effects of OxBC on chemokine levels in na ⁇ ve and challenged human primary fibroblasts.
  • Fibroblasts CCD- 1079SK were pre-treated with various concentrations of OxBC for 24 hours. Following OxBC pre-treatment cells were challenged by exposure to bacterial lipopolysaccharide (LPS) in combination with OxBC treatment or were treated with OxBC alone for an additional 24 hours. Results show that in the context of an LPS challenge (dark bars) OxBC has a significant suppressive effect on the level of certain chemokines such as IL-8 ( Figure IA), IP-IO ( Figure IB), and RANTES ( Figure 1C). Vehicle controls (DMSO) showed no significant effect on chemokine levels (results not shown).
  • LPS bacterial lipopolysaccharide
  • OxBC treatment of naive fibroblasts resulted in a trend towards decreased IL-8 levels but did not further reduce the levels of IP-IO or RANTES, which were already at low levels near detectable limits.
  • the effects of OxBC on chemokine release in na ⁇ ve cells were evaluated relative to untreated control cells using a one-way analysis of variance with Dunnett's test for multiple comparisons.
  • FIG. 2 is a graph showing the suppressive effects of OxBC on chemokine levels in na ⁇ ve and challenged THP-I monocytes.
  • Human monocytic cells THP-I
  • PATENT PATENT
  • OxBC treatment of na ⁇ ve TFIP-I cells resulted in a trend towards decreased RANTES levels while no effect on IL-8 was observed compared to untreated control cells (light hatched bars).
  • IL-8 is present at low levels, near detectable limits, in na ⁇ ve control cells and it is unlikely that OxBC could reduce IL-8 below these background levels.
  • the effects of OxBC on chemokine release in na ⁇ ve cells were evaluated relative to untreated control cells using a one-way analysis of variance with Dunnett's test for multiple comparisons.
  • Figures 3 A and 3B are graphs showing the suppressive effect of OxBC on chemokine expression in na ⁇ ve and challenged canine primary fibroblasts.
  • Fibroblasts were pre-treated with OxBC or vehicle control (DMSO) for 24 hours.
  • DMSO vehicle control
  • LPS bacterial lipopolysaccharide
  • Chemokine expression was measured using quantitative real-time PCR with total RNA. Results show that in the context of an LPS challenge (dark bars) OxBC has a significant suppressive effect on the level of MCP-I ( Figure 3A) and RANTES ( Figure 3B) gene- expression.
  • Vehicle control (DMSO) showed no significant effect on chemokine expression.
  • OxBC treatment of na ⁇ ve fibroblasts resulted in a trend towards decreased MCP-I and RANTES expression.
  • the effects of OxBC on chemokine expression in na ⁇ ve cells were evaluated relative PATENT
  • Figure 4 is a graph depicting the suppressive effect of OxBC on expression of chemokine and chemokine receptors in rat intestinal epithelial cells (IEC- 18).
  • IEC- 18 cells were incubated in the presence of OxBC (5 ⁇ M) or equivalent DMSO (control) for 24 hours. Following treatment chemokine and chemokine-receptor gene expression levels were measured using quantitative real-time PCR with total RNA. Effects of OxBC are shown relative to control cells treated with DMSO vehicle. Results show that 24-hour treatment with OxBC (5 ⁇ M) leads to reduced expression of pro-inflammatory genes including CCL-6, Cmklr-1, and IL8RA.
  • CCL-6 is a chemokine that acts to recruit immune cells to sites of infection or injury;
  • Cmklrl and IL8RA are chemokine receptors responsible for transducing the cellular effects of the inflammatory chemokines chemerin and IL 8.
  • the invention provides compositions, methods, and kits for the administration of oxidatively transformed carotenoid and fractionated components thereof.
  • the compositions can be useful for treating inflammation in a subject.
  • Therapy according to the invention may be performed alone or in conjunction with another therapy and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital.
  • the duration of the therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment.
  • the inflammation to be treated can be any condition described herein, including, without limitation, nondermal inflammatory disorders (e.g., musculoskeletal disorders, such as gout, arthritis, osteoarthritis, or rheumatoid PATENT), musculoskeletal disorders, such as gout, arthritis, osteoarthritis, or rheumatoid PATENT
  • nondermal inflammatory disorders e.g., musculoskeletal disorders, such as gout, arthritis, osteoarthritis, or rheumatoid PATENT
  • ATTORNEY DOCKET NO. V83221WO arthritis inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, ileitis, ileocolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis, Crohn's colitis, Crohn's enteritis, Crohn's terminal ileitis, Crohn's entero-colitis, or ileo-colitis; inflammatory respiratory conditions, such as asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, sinusitis, or rhinosinusitis; inflammatory ocular conditions, such as uveitis, anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, ulceris, or giant papillary conjunctivitis;
  • Mastitis inflammation of a mammary gland
  • dairy herds is one of the most costly and difficult diseases encountered by dairy producers.
  • Somatic cell count is used as an indication of mastitis.
  • the bacteria damage the duct system and establish deep-seated pockets of infection in the PATENT
  • somatic cell count of milk is commonly used as a measure of milk quality. Somatic cells are simply animal body cells present at low levels in normal milk. However, high levels of these cells in milk can indicate abnormal, reduced-quality milk that is usually associated with intramammary bacterial infection (mastitis). Milk markets routinely rely on somatic cell counts to help ensure a quality product. Somatic cell count levels are monitored to assure compliance with state and federal milk quality standards. Because most markets pay a premium for low somatic cell count, good-quality milk, reducing somatic cell count levels can result in greater revenues for milk producers.
  • the oxidatively transformed carotenoid, or a fractionated component thereof can be administered to an animal for the therapeutic or prophylactic treatment of mastitis.
  • the methods can be used to reduce the occurrence and severity of mastitis and/or reduce somatic cell count in sub-clinical infected cows, or to treat mastitis in clinically infected cows.
  • Local administration can be performed at one or more infected mammary glands of a dry cow or lactating cow suffering from mastitis.
  • the oxidatively transformed carotenoid, or a fractionated component thereof is administered systemically.
  • the method of the invention can be part of a dry cow therapy when used in combination with an internal teat sealant (i.e., a teal seal composition) or an external teat sealant (i.e., a teat dip composition).
  • an internal teat sealant i.e., a teal seal composition
  • an external teat sealant i.e., a teat dip composition
  • External sealants for use as teat dips are known in the art (see, e.g., U.S. Patent No. 6,440,442 and U.S. Publication No. 20080233074). These products are often adjuncts to antimicrobial infusion. As long as the teat end remains covered, protection from bacteria entering the gland is provided. Thus, for continuous protection, they may require visual inspection and reapplication (if required) PATENT
  • Intra-mammary teat sealant i.e., a teat seal
  • An intra-mammary sealant can be advantageous as few, if any, reapplications of treated teats are required during the dry period.
  • Therapy according to the invention may be administered, for example, orally, intravenously, intramuscularly, ocularly, topically, subcutaneously, intranasally, or by inhalation.
  • the therapy can be applied as part of a teat seal composition or teat dip composition.
  • the invention features compositions, kits, and methods for treating inflammation in a subject.
  • typical dose ranges are from about 5 ⁇ g/kg to about 50 mg/kg of body weight per day. Desirably, a dose of between 5 ⁇ g/kg and 5 mg/kg of body weight, or 5 ⁇ g/kg and 0.5 mg/kg of body weight, is administered.
  • typical dose ranges are from about 0.05 ⁇ g/kg to about 500 ⁇ g/kg of body weight per day. Desirably, a dose of between 0.05 ⁇ g/kg and 50 ⁇ g/kg of body weight, or 0.05 ⁇ g/kg and 5 ⁇ g/kg of body weight, is administered.
  • the dosage of oxidatively transformed carotenoid, or a fractionated component thereof, to be administered is likely to depend on such variables as the species, diet, and age of the animal. Standard trials, such as those described in Example 1 may be used to optimize the dose and dosing frequency of the oxidatively transformed carotenoid or a fractionated component thereof.
  • Oxidatively transformed carotenoid, or a fractionated component thereof may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.
  • Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ocular, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.
  • the oxidatively transformed carotenoid, or a fractionated component thereof is provided in unit dosage form.
  • Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, ear drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Nanoparticulate formulations may be used to control the biodistribution of the compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
  • Administration of compounds in controlled release formulations is useful where the active ingredient has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level. Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)
  • LD50 median lethal dose
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings.
  • appropriate controlled release compositions and coatings examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
  • inert diluents or fillers e.g., sucrose and sorbitol
  • lubricating agents e.g., sucrose and sorbitol
  • glidants e.g., glidants
  • antiadhesives e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc.
  • Formulations for oral use may also be provided in unit dosage form as chewable tablets, tablets, caplets, or capsules (i.e., as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium).
  • Oxidatively transformed carotenoid, or a fractionated component thereof may be formulated with a pharmaceutically acceptable diluent, carrier, or excipient as described in U.S.S.N. 10/196,695, published May 22, 2003. PATENT
  • the ophthalmic pharmaceutical compositions of the invention can be prepared by addition of oxidatively transformed carotenoid, or a fractionated component thereof, to an existing ophthalmic formulation.
  • the ophthalmic pharmaceutical composition includes buffers, surfactants, stabilizers, preservatives, ophthalmic wetting agents, and/or ophthalmic diluting agents.
  • Wetting agents commonly used in ophthalmic solutions include carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol or hydroxyethylcellulose and the diluting agent may be water, distilled water, sterile water, or artificial tears, wherein the wetting agent is present in an amount of about 0.001% to about 10%.
  • the concentration of the oxidatively transformed carotenoid, or a fractionated component thereof, can be from 0.0001 to 1 w/w %, more preferably from 0.001 to 0.1 w/w %.
  • the ophthalmic composition can be used for treatment of an inflammatory condition of the eye.
  • ophthalmic solutions and ophthalmic ointments can be formulated into such preparations utilizing a number of widely-used methods well known to those of ordinary skill in the art.
  • ophthalmic solutions for example, they can be prepared using distilled water, an aqueous base, or any other acceptable base; tonicity agents such as sodium chloride and concentrated glycerol; buffers such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, stearic polyoxyl 40, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride, thimerosal, chlorobutanol, sodium chloride, boric acid, parahydroxybenzoic acid esters (sorbate, benzoate, propionate), chlorobutanol, benzyl alcohol, mercurials, paraben; etc., and mixtures thereof, if necessary.
  • tonicity agents such
  • Benzalkonium chloride and thimerosal are the preferred preservatives.
  • the ophthalmic formulation may be varied to include acids and bases to adjust the pH; tonicity imparting agents such as sorbitol, glycerin and dextrose; other viscosity imparting agents such as PATENT
  • suitable absorption enhancers such as surfactants, bile acids
  • stabilizing agents such as antioxidants, like bisulfites and ascorbates
  • metal chelating agents such as sodium edetate
  • drug solubility enhancers such as polyethylene glycols.
  • the ophthalmic formulation of the invention can be a sterile aqueous carrier, a salve, or an ointment.
  • Salves and ointments typically include oxidative Iy transformed carotenoid, or a fractionated component thereof, dissolved or suspended in a sterile pharmaceutically acceptable salve or ointment base, such as a mineral oil-white petrolatum base.
  • a sterile pharmaceutically acceptable salve or ointment base such as a mineral oil-white petrolatum base.
  • anhydrous lanolin may also be included in the formulation.
  • Thimerosal or chlorobutanol can be added to the formulation as antimicrobial agents.
  • compositions of the invention are, desirably, formulated for topical administration.
  • Topical formulations which can be used include, without limitation, creams, foams, lotions, gels, sticks, sprays, solutions (e.g., for soaking, as with a bath salt), and ointments.
  • any conventional pharmacologically and cosmetically acceptable vehicles may be used.
  • the compounds may also be administered in liposomal formulations that allow compounds to enter the skin.
  • liposomal formulations are described in U.S. Patent Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213; and PCT Publication No. WO 96/40061.
  • Examples of other appropriate vehicles are described in U.S. Patent No. 4,877,805 and EP Publication No. 0586106A1. Suitable vehicles of the PATENT
  • ATTORNEY DOCKET NO. V83221WO invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil.
  • the formulations can include various conventional colorants, fragrances, thickeners (e.g., xanthan gum), preservatives, emollients (e.g., hydrocarbon oils, waxes, or silicones), demulcents, solubilizing excipients, dispersants, penetration enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, emulsifiers, moisturizers, astringents, deodorants, and the like can be added to provide additional benefits and improve the feel and/or appearance of the topical preparation.
  • One or more solubilizing excipients may be a necessary component in the topical formulations.
  • Solubilization is taken to mean an improvement in the solubility by virtue of surface-active compounds that can convert substances that are insoluble or virtually insoluble in water into clear, or opalescent, aqueous solutions without changing the chemical structure of these substances in the process.
  • the solubilizates formed are notable for the fact that the OxBC, or a fractionated component thereof, is present in dissolved form in the molecular associations, micelles, of the surface-active compounds, which form in aqueous solution.
  • the resulting solutions appear optically clear to opalescent.
  • Solubilizing excipients that may be used in the formulations of the invention include, without limitation, compounds belonging to the following classes: polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants, tocopherol esters, and sterol esters.
  • PATENT polyethoxyl
  • ATTORNEY DOCKET NO. V83221WO excipient are commercially available and well known to those in the field of formulations.
  • Example 1 Evaluation of antiinflammatory activity of oxidatively transformed carotenoid (OxBC) in response to LPS challenge.
  • OxBC oxidatively transformed carotenoid
  • OxBC was prepared from ⁇ -carotene (see U.S. Patent No. 5,475,006) and stored at -20°C prior to use.
  • Stock solutions 50 mM of carotene equivalents
  • Working 200 ⁇ M solutions of OxBC were prepared by dilution in the appropriate culture media and sterilized by filtration (0.22 ⁇ m pore size).
  • the equivalent values of OxBC tested and the associated amount of DMSO in both test and control samples are indicated in Table 1. Equivalent amounts of DMSO vehicle were used as controls.
  • Chemokine levels in conditioned media from na ⁇ ve and LPS-challenged cells were measured using the multiplex technology of the FACS Array Bioanalyzer. Briefly, the multiplex system employs antibodies against specific cheniokines that are conjugated to dyed beads labeled with a unique fluorescence signature to allow separation and quantitation of multiple proteins in a single sample simultaneously.
  • OxBC has the ability to reduce the level of certain inflammatory chemokines in cells that have been challenged by bacterial lipopolysaccharide (LPS) treatment. More specifically, OxBC treatment of LPS challenged human primary dermal fibroblasts resulted in an approximate 23% reduction in IL-8, 27% reduction in IP-IO, and a 75% reduction in RANTES levels (see Figures 1A-1C). While in challenged THP-I monocytic cells OxBC treatment reduced IL-8 and RANTES levels by approximately 44% and 19% respectively (see Figures 2 A and 2B).
  • LPS bacterial lipopolysaccharide
  • chemokines play an important role in directing the inflammatory response by serving as chemoattractants to recruit various immune cells including macrophages and lymphocytes to sites of injury or infection.
  • An appropriate inflammatory response is a vital component of immune defense, however dysregulation of the inflammatory response, leading to over- activation, is associated with several chronic diseases such as rheumatoid arthritis and psoriasis. Therefore, the ability of OxBC to reduce the levels of chemokines such as IL-8, IP-IO, and RANTES suggests that the compound would limit infiltration of inflammatory cells and thus highlights a potential anti-inflammatory activity.
  • OxBC treatment does not completely ablate the chemokine response of cells challenged with LPS is also noteworthy because it indicates that OxBC does not completely prevent an inflammatory response.
  • the results from these chemokine studies together with previous work showing an immune boosting effect of OxBC argue that the compound has the rare properties of a self-limiting immune boosting product.
  • OxBC appears to balance its immune enhancing activities, which include increased innate surveillance and reactivity, with an anti-inflammatory ability to limit the extent of an inflammatory response thus reducing the possibility of unregulated/over-active inflammation.
  • Example 2 Evaluation of antiinflammatory activity of oxidatively transformed carotenoid (OxBC) in canine primary tracheal fibroblasts (CF52.Tr).
  • OxBC oxidatively transformed carotenoid
  • Canine fibroblasts were seeded (l ⁇ l ⁇ 6 cells/well) onto a 6 well plate and were pre-treated with OxBC (5 ⁇ M) or vehicle control (DMSO) for 24 hours. Following pre-treatment culture media was removed and replaced with fresh media. Under the naive treatment model the fresh media contained OxBC (5 ⁇ M) or equivalent concentration of DMSO. Under the challenge treatment model fresh media contained OxBC (5 ⁇ M) or equivalent concentration of DMSO combined with LPS (30 ⁇ g). Cells were incubated for an additional 4 hours and were then processed for total RNA isolation.
  • OxBC 5 ⁇ M
  • DMSO vehicle control
  • RNA (0.5 ⁇ g) was reverse transcribed to cDNA in a 20 ⁇ L reaction volume and 1 ⁇ L of cDNA was used as template for quantitative real-time PCR (QRT-PCR) analysis of gene-expression using SYBR-green chemistry. Relative gene expression levels were calculated using ⁇ -actin as an internal control with correction for different PCR efficiencies. Treatment effects on gene-expression are shown relative to untreated control cells and OxBCs ability to reduce expression of proinflammatory chemokines was evaluated by comparison to cells treated with LPS alone (see Figures 3A and 3B).
  • Example 3 Evaluation of antiinflammatory activity of oxidatively transformed carotenoid (OxBC) in the rat intestinal epithelial cell line (IEC-18).
  • OxBC oxidatively transformed carotenoid
  • IEC-18 cells were seeded (1 x 10 6 cel Is/well) onto a 6 well plate and were treated with OxBC (5 ⁇ M) or vehicle control (DMSO) for 24 hours. Following treatment cells were processed for total RNA isolation. RNA (0.5 ⁇ g) was reverse transcribed to cDNA in a 20 ⁇ L reaction volume and 1 ⁇ L of cDNA was used as template for quantitative real-time PCR (QRT-PCR) analysis of gene-expression using SYBR-green chemistry. Relative gene expression levels were calculated using the ribosomal gene, RpI 13 a, as an internal control with correction for different PCR efficiencies. OxBC effects are shown relative to control cells treated with DMSO (see Figure 4).

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Abstract

L'invention porte sur des compositions, des procédés et des coffrets pour l'administration d'un caroténoïde transformé par oxydation ou d'un composant fractionné de celui-ci, pour traiter des états inflammatoires.
PCT/CA2010/000672 2009-04-30 2010-04-30 Procédés, compositions et coffrets pour le traitement d'états inflammatoires Ceased WO2010124392A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8211461B2 (en) 2004-09-28 2012-07-03 Chemaphor Inc. Compositions and methods for promoting weight gain and feed conversion
US10449247B2 (en) 2007-10-26 2019-10-22 Avivagen Inc. Compositions and methods for enhancing immune response
US10456369B2 (en) 2009-04-30 2019-10-29 Avivagen Inc. Methods and compositions for improving the health of animals
WO2021163786A1 (fr) * 2020-02-18 2021-08-26 Avivagen Inc. Aliments pour animaux supplémentés pour mammifères
CN116327744A (zh) * 2015-04-28 2023-06-27 阿维沃根公司 用于预防坏死性肠炎的氧化的类胡萝卜素及其组分
CN119656153A (zh) * 2024-11-19 2025-03-21 南通大学 一种上皮细胞铁死亡抑制剂及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999030701A1 (fr) * 1997-12-16 1999-06-24 Astacarotene Ab Procede de traitement prophylactique de la mastite
WO2001024787A1 (fr) * 1999-10-07 2001-04-12 Astacarotene Ab Methode de traitement et utilisation
WO2005079143A2 (fr) * 2004-02-19 2005-09-01 Occell Inc. Formulations topiques pour le traitement d'etats dermatologiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999030701A1 (fr) * 1997-12-16 1999-06-24 Astacarotene Ab Procede de traitement prophylactique de la mastite
WO2001024787A1 (fr) * 1999-10-07 2001-04-12 Astacarotene Ab Methode de traitement et utilisation
WO2005079143A2 (fr) * 2004-02-19 2005-09-01 Occell Inc. Formulations topiques pour le traitement d'etats dermatologiques

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8211461B2 (en) 2004-09-28 2012-07-03 Chemaphor Inc. Compositions and methods for promoting weight gain and feed conversion
US10449247B2 (en) 2007-10-26 2019-10-22 Avivagen Inc. Compositions and methods for enhancing immune response
US10456369B2 (en) 2009-04-30 2019-10-29 Avivagen Inc. Methods and compositions for improving the health of animals
CN116327744A (zh) * 2015-04-28 2023-06-27 阿维沃根公司 用于预防坏死性肠炎的氧化的类胡萝卜素及其组分
WO2021163786A1 (fr) * 2020-02-18 2021-08-26 Avivagen Inc. Aliments pour animaux supplémentés pour mammifères
CN115397251A (zh) * 2020-02-18 2022-11-25 阿维沃根公司 用于哺乳动物的补充动物饲料
US20230079333A1 (en) * 2020-02-18 2023-03-16 Avivagen Inc. Supplemented animal feeds for mammals
CN119656153A (zh) * 2024-11-19 2025-03-21 南通大学 一种上皮细胞铁死亡抑制剂及其应用

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