WO2019106574A1 - Compositions et méthodes pour traiter et prévenir une douleur articulaire - Google Patents

Compositions et méthodes pour traiter et prévenir une douleur articulaire Download PDF

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Publication number
WO2019106574A1
WO2019106574A1 PCT/IB2018/059422 IB2018059422W WO2019106574A1 WO 2019106574 A1 WO2019106574 A1 WO 2019106574A1 IB 2018059422 W IB2018059422 W IB 2018059422W WO 2019106574 A1 WO2019106574 A1 WO 2019106574A1
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Prior art keywords
composition
biomarker
relative abundance
amu
subject
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PCT/IB2018/059422
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English (en)
Inventor
Joshua M. COSTIN
John M. Williams
Dan Li
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Hsrx Group, Llc
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Publication of WO2019106574A1 publication Critical patent/WO2019106574A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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

Definitions

  • the present invention relates to formulations containing a mixture of compounds capable of preventing and treating joint pain such as osteoarthritis.
  • Osteoarthritis a cause of joint pain, is a major health problem, affecting approximately 30 million Americans (Cisternas et al .). The prevalence of OA of the knee is increasing rapidly in the USA and the Center for Disease Control and Prevention (CDC) estimates that prevalence of symptomatic knee osteoarthritis may reach 50 % by age 85 (Murphy et al).
  • Pain associated with OA is caused by a wearing down of the cartilage that serves as a protective shock absorber between the joints.
  • Cartilage is important for minimizing the impact of activities on the joints, but this use also means that it is subject to high levels of wear and tear.
  • nutraceuticals like glucosamine and/or chondroitin supplements.
  • nutraceuticals are natural substances found in the joint or in joint fluid. They are thought to trigger cartilage production and reduce inflammation.
  • One of the current market leaders in OTC knee joint pain treatment is OSTEO BI-FLEX TRIPLE STRENGTH®. This product is marketed as a joint support supplement and claims to improve joint comfort within 7 days.
  • OSTEO BI-FLEX TRIPLE STRENGTH® constituents include vitamin C, glucosamine, boswellia, chondroitin, and shellfish (shrimp, crab, lobster, and crayfish). Allergies to shellfish are quite common and it is estimated that 7 million people in the U.S. alone have this allergy which would immediately exclude them from taking this supplement.
  • Topical analgesic or pain relief treatments are also commonly used OTC medication for joint pain and are available in many forms such as, creams, salves, gels and patches.
  • the active ingredients can include capsaicin (found naturally in hot peppers), camphor, menthol, eucalyptus oil, lidocaine, and salicylates.
  • Many of the active ingredients in topical pain relieving treatments work by distracting the body’s reaction to pain.
  • an OTC treatment for arthritis BENGAYTM, uses camphor, menthol and methyl salicylate to cause heating and cooling effects on the skin which distracts from the pain sensations present in that area, leading to relief from pain.
  • the present invention provides a solution to the current problems facing treatment and prevention of joint pain.
  • the inventors have surprisingly found that a combination of several compounds found in green tea can prevent and treat joint pain such as osteoarthritis.
  • a treatment regimen using biomarkers 1 through 12 and trolamine salicylate, Arnica montana extract, and peppermint oil is capable of treating osteoarthritis better than the over-the-counter topical treatment OSTEO BI-FLEX TRIPLE STRENGTH® in combination with peppermint oil with or without trolamine salicylate.
  • a composition containing biomarkers 1 through 12 is capable of treating osteoarthritis, especially in combination with Arnica montana extract with or without trolamine salicylate.
  • composition containing any one of, any combination of, or all of twelve biomarkers found in green tea.
  • the composition includes any one of, any combination of, or all of biomarker 1 having an accurate mass of 461.1470 amu, biomarker 2 having an accurate mass of 108.0205 amu, biomarker 3 having an accurate mass of 122.0493 amu, biomarker 4 having an accurate mass of 129.0472 amu, biomarker 5 having an accurate mass of 145.0747 amu, biomarker 6 having an accurate mass of 161.0718 amu, biomarker 7 having an accurate mass of 165.0775 amu, biomarker 8 having an accurate mass of 170.0243 amu, biomarker 9 having an accurate mass of 174.0992 amu, biomarker 10 having an accurate mass of 180.0673 amu, biomarker 11 having an accurate mass of 194.0804 amu, and biomarker 12 having an accurate mass of 211.0896 amu, wherein each biomarker is
  • biomarker 1 has a relative abundance of at least 2.28%
  • biomarker 2 has a relative abundance of at least 11.46%
  • biomarker 3 has a relative abundance of at least 25.67%
  • biomarker 4 has a relative abundance of at least 90.91%
  • biomarker 5 has a relative abundance of at least 41.91%
  • biomarker 6 has a relative abundance of at least 19.70%
  • biomarker 7 has a relative abundance of at least 94.69%
  • biomarker 8 has a relative abundance of at least 38.75%
  • biomarker 9 has a relative abundance of at least 1162.44%
  • biomarker 10 has a relative abundance of at least 100.06%
  • biomarker 11 has a relative abundance of at least 3234.90%
  • biomarker 12 has a relative abundance of at least 25.33%, wherein the relative abundance is relative abundance as compared to 0.01 mg
  • biomarker 1 has a relative abundance of at most 3.42%
  • biomarker 2 has a relative abundance of at most 17.19%
  • biomarker 3 has a relative abundance of at most 38.51%
  • biomarker 4 has a relative abundance of at most 136.37%
  • biomarker 5 has a relative abundance of at most 62.86%
  • biomarker 6 has a relative abundance of at most 29.56%
  • biomarker 7 has a relative abundance of at most 142.04%
  • biomarker 8 has a relative abundance of at most 58.12%
  • biomarker 9 has a relative abundance of at most 1743.66%
  • biomarker 10 has a relative abundance of at most 150.09%
  • biomarker 11 has a relative abundance of at most 4852.36%
  • biomarker 12 has a relative abundance of at most 38.00%, wherein the relative abundance is relative abundance as compared to 0.01 mg/ml curcumin spiked in 1 mg/ml of the composition.
  • the composition includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of biomarkers 1 to 12.
  • the mass of each biomarker is the mass as determined by a Direct Analysis in Real Time-TOF (DART-TOF) mass spectrometer.
  • the composition is combined with a composition containing one or more of trolamine salicylate and/or Arnica montana extract.
  • one composition contains one or more of the biomarkers disclosed herein and one or more of trolamine salicylate and/or Arnica montana extract.
  • the one or more of the biomarkers disclosed herein and one or more of trolamine salicylate and/or Arnica montana extract are separated in two or more compositions.
  • any one of the compositions further contains peppermint oil.
  • the amounts of the ingredients within the composition(s) can vary (e.g., amounts can be as low as 0.000001% to as high as 80% w/w or any range therein).
  • biomarkers 1 through 12 are synthetically obtained.
  • at least one of biomarkers 1 through 12 are obtained from an organism.
  • at least one of biomarkers 1 through 12 are obtained from green tea.
  • the composition has at least 90%, preferably at least 95%, or at least 98% batch-to-batch chemical consistency of relative abundance for the biomarkers.
  • the composition further includes a joint pain reducing agent.
  • the joint pain reducing agent is a joint pain reducing drug.
  • the joint pain reducing agent is an oral analgesic, topical analgesic, nonsteroidal anti inflammatory drug (NS AID), corticosteroid, opioid, and/or nutraceutical.
  • composition comprising one or more of biomarkers 1 to
  • the composition is one or more of a lozenge, a powder, a tablet, a capsule, a delayed release capsule, a quick release capsule, a controlled release capsule, a gel-cap, a gelatin, a liquid solution, and/or a dissolvable film.
  • any of the compositions herein are formulated for topical application.
  • the composition is one or more of an emulsion, solution, foam, spreadable solid, soap, serum, etc.
  • any of the compositions herein are formulated for intravenous administration and/or intranasal delivery.
  • the composition or regimen disclosed herein is capable of treating and/or preventing joint pain.
  • the composition or regimen is capable of treating and/or preventing osteoarthritis.
  • the composition or regimen is capable of reducing joint pain and/or increasing range of motion of a joint.
  • the compositions contain a topical, oral, nutraceutical, and/or pharmaceutically acceptable carrier.
  • the topical, oral, nutraceutical, and/or pharmaceutically acceptable carrier can be a naturally or a non-naturally occurring compound or structure.
  • the composition further contains a pH adjuster, structuring agents, inorganic salt, preservative, stabilizer, bulking agent, and/or excipient.
  • the preservative, stabilizer, bulking agent, and/or excipient can be a naturally or a non-naturally occurring compound or composition.
  • the composition is a topical composition.
  • the composition is suitable for oral administration.
  • the composition is a nutraceutical composition.
  • the composition is a pharmaceutical composition.
  • the composition is coated with a polymer.
  • the polymer is a naturally or a non-naturally occurring polymer.
  • the formulated composition can be comprised in a solid nanoparticle, a lipid-containing nanoparticle, a lipid-based carrier, a sealed conduit, a sealed bag, or any combination thereof.
  • the composition can be formulated for administration by injection. [0016] In another aspect, the composition may further comprise one or more ingredients described herein.
  • the composition may comprise one or more additional ingredients selected from one or more pH adjusters, structuring agents, inorganic salts, preserving agents, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrance, antibacterial agents, antifungal agents, lubricating agents, vitamins, polymers, siloxane containing compounds, essential oils, and dispensing agents.
  • Each carrier is acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • the carrier can include at least one hydrophilic polymeric compound selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a carbohydrate carrier, talc, lactose, mannitol, glucose, water, gelatin, a protein-derived compound, polyvinyl pyrrolidone, magnesium stearate, and any combination thereof.
  • the amounts of such ingredients can range from 0.0001% to 99.9% by weight or volume of the composition, or any integer or range in between as disclosed in other sections of this specification, which are incorporated into this paragraph by reference.
  • the composition can be stored for one month, 6 months, 12 months, 18 months, or 24 months at room temperature.
  • the composition contains a dose of the biomarkers contained therein.
  • a dose is 1 pg to 10 grams of any one or more of the biomarkers.
  • the composition contains a sub-dose of one or more of the biomarkers.
  • the composition contains 0.1 mg to 3 g, 1 mg to 1 g, 1 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 1 to 10 mg, 1 mg, 2 mg, 3 mg, or 4 mg of any one or more of the biomarkers, or any range therein.
  • the composition contains a second joint pain reducing agent. In some instances, the composition does not comprise a second joint pain reducing agent.
  • the method comprises administering any one or more of the compositions of the present invention to the subject. Further, there is disclosed a method of administering any one or more of the compositions of the present invention to a subject by administering any one or more of the compositions of the present invention to the subject.
  • the subject has been diagnosed with joint pain.
  • the subject has osteoarthritis.
  • the method is for treating osteoarthritis.
  • the method is for preventing osteoarthritis.
  • the method is for reducing joint pain and/or increasing range of motion for a joint.
  • the treatment and/or prevention regimen comprises administering any one or more of the compositions of the present invention to the subject.
  • the regimen includes oral administration of a composition containing one or more of biomarkers 1 to 12 found in green tea.
  • the regimen also includes application of additional joint pain reducing agents.
  • the regimen also includes topical application of Arnica montana extract.
  • the regimen also includes topical application of trolamine salicylate.
  • the regimen also includes topical application of Arnica montana extract and trolamine salicylate.
  • the regimen includes topical administration of a composition containing one or more of biomarkers 1 to 12 found in green tea. In some instances, the regimen includes the oral administration of a composition containing one or more of biomarkers 1 to 12 found in green tea and the topical administration of trolamine salicylate and/or Arnica montana extract. In some instances, the regimen includes the topical application of a composition containing one or more of biomarkers 1 to 12 found in green tea and the topical administration of trolamine salicylate and/or Arnica montana extract. In some instances, the regimen is for reducing joint pain and/or increasing range of motion of a joint.
  • the subject is administered a total sum of between 1 and
  • the subject is administered any one of the compositions disclosed herein at least once a day. In some instances, the subject is administered any one of the compositions disclosed more than once a day. In some instances, the subject is administered any one of the compositions disclosed herein twice a day. In yet another instance, the composition is administered at least once a day for at least three days. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least five days. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least ten days.
  • the subject is administered any one of the compositions disclosed herein daily for at least fourteen days. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least two weeks, at least a month, at least two months, at least half a year, at least a year, or at least several years. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least six days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least ten days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least fourteen days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least two weeks, at least a month, at least two months, at least half a year, at least a year, or at least several years.
  • compositions disclosed herein by producing a composition having an at least 90%, preferably at least 95% or at least 98% batch-to-batch chemical consistency of relative abundance for the biomarkers.
  • Kits that include the compositions of the present invention are also contemplated.
  • the composition is comprised in a container.
  • the container can be a bottle, dispenser, package, or a straw.
  • the container can dispense a predetermined amount of the composition.
  • the compositions are dispensed as a pill, a tablet, a capsule, a transdermal patch, an edible chew, a cream, a lotion, a gel, spray, mist, dollop, a powder, or a liquid.
  • the container can include indicia on its surface. The indicia can be a word, an abbreviation, a picture, or a symbol.
  • the product can be a nutraceutical product.
  • the nutraceutical product can be those described in other sections of this specification or those known to a person of skill in the art.
  • the product can be a pharmaceutical product.
  • the pharmaceutical and/or nutraceutical product can be those described in other sections of this specification or those known to a person of skill in the art.
  • Non-limiting examples of products include a pill, a tablet, an edible chew, a capsule, a cream, a lotion, a gel, a spray, a mist, a dissolving film, a transdermal patch, or a liquid, e/c.
  • Embodiment 1 is a composition comprising the following biomarkers: biomarker 1 having an accurate mass of 461.1470 amu and having a relative abundance of at least 2.28%; biomarker 2 having an accurate mass of 108.0205 amu and having a relative abundance of at least 11.46%; biomarker 3 having an accurate mass of 122.0493 amu and having a relative abundance of at least 25.67%; biomarker 4 having an accurate mass of 129.0472 amu and having a relative abundance of at least 90.91%; biomarker 5 having an accurate mass of 145.0747 amu and having a relative abundance of at least 41.91%; biomarker 6 having an accurate mass of 161.0718 amu and having a relative abundance of at least 19.70%; biomarker 7 having an accurate mass of 165.0775 amu and having a relative abundance of at least 94.69%; biomarker 8 having an accurate mass of 170.0243 amu and having a relative
  • Embodiment 2 is the composition of claim 1, wherein the biomarkers contained therein have a relative abundance of at most: biomarker 1 of 3.42%; biomarker 2 of 17.19%; biomarker 3 of 38.51%; biomarker 4 of 136.37%; biomarker 5 of 62.86%; biomarker 6 of 29.56%; biomarker 7 of 142.04%; biomarker 8 of 58.12%; biomarker 9 of 1743.66%; biomarker 10 of 150.09%; biomarker 11 of 4852.36%; and biomarker 12 of 38.00%, wherein the relative abundance is relative to 0.01 mg/ml curcumin spiked in 1 mg/ml of the composition.
  • Embodiment 3 is the composition of any of claims 1 to 2, wherein the mass of each biomarker is the mass as determined by a Direct Analysis in Real Time-TOF (DART- TOF) mass spectrometer.
  • Embodiment 4 is the composition of any one of claims 1 to 3, wherein at least one of the biomarker(s) are synthetically obtained.
  • Embodiment 5 is the composition of any one of claims 1 to 4, wherein at least one of the biomarker(s) are isolated from a plant.
  • Embodiment 6 is the composition of claim 5, wherein at least one of the biomarkers(s) are isolated from green tea.
  • Embodiment 7 is the composition of any one of claims 1 to 6, wherein the composition has an at least 90%, preferably at least 95%, or at least 98% batch-to-batch chemical consistency of relative abundance for the biomarkers.
  • Embodiment 8 is the composition of any one of claims 1 to 7, wherein the composition further comprises a preservative.
  • Embodiment 9 is the composition of any one of claims 1 to 8, wherein the composition further comprises at least one agent that reduce joint pain.
  • Embodiment 10 is the composition of claim 9, wherein at least one agents that reduce joint pain is an oral analgesic, topical analgesic, nonsteroidal anti-inflammatory drug (NSAID), corticosteroid, opioid, and/or nutraceutical.
  • NSAID nonsteroidal anti-inflammatory drug
  • Embodiment 11 is the composition of any one of claims 1 to 10, wherein the composition is formulated for oral administration.
  • Embodiment 12 is the composition of claim 11, wherein the composition is in a lozenge, a powder, a tablet, a gel-cap, a gelatin, a liquid solution, a syrup, an oil, and/or a dissolvable film.
  • Embodiment 13 is the composition of any one of claims 1 to 10, wherein the composition is formulated for topical administration, administration through injection, and/or intranasal administration.
  • Embodiment 14 is the composition of claim 13, wherein the composition is in a liquid solution, emulsion, powder, or patch.
  • Embodiment 15 is the composition of any of claims 1 to 14, wherein the composition further comprises trolamine salicylate and/or Arnica montana extract.
  • Embodiment 16 is the composition of any of claims 1 to 15, wherein the composition is formulated to treat and/or prevent joint pain.
  • Embodiment 17 is the composition of any of claims 1 to 16, wherein the composition is formulated to treat and/or prevent osteoarthritis.
  • Embodiment 18 is the composition of claim 17, wherein the composition is formulated to reduce pain and/or increase range of motion of a joint.
  • Embodiment 19 is a kit comprising: a first composition comprising a green tea extract formulated to be administered to a subject; and a second composition comprising trolamine salicylate formulated to be administered to a subject.
  • Embodiment 20 is the kit of claim 19, wherein the green tea extract is an aqueous extract.
  • Embodiment 21 is the kit of claim 19, wherein the first composition comprises any one of the compositions of claims 1 to 18.
  • Embodiment 22 is the kit of any of claims 19 to 21, wherein the kit further comprises Arnica montana extract.
  • Embodiment 23 is the kit of claim 22, wherein the Arnica montana extract is comprised in the second composition.
  • Embodiment 24 is a method of treating a subject at risk for or having joint pain, the method comprising administering a composition containing a green tea extract to the subject, wherein at least one symptom of the joint pain is ameliorated in the subject and/or the onset of the joint pain is delayed in comparison to the expected onset of the joint pain if the patient had not been treated.
  • Embodiment 25 is the method of claim 24, wherein the green tea extract is an aqueous extract.
  • Embodiment 26 is the method of claim 24, wherein the composition containing a green tea extract comprises the composition of any one of claims 1 to 18.
  • Embodiment 27 is the method of any of claims 24 to 26, wherein the method further comprises administering trolamine salicylate to the subject.
  • Embodiment 28 is the method of any of claims 24 to 27, wherein the method further comprises administering Arnica montana extract to the subject.
  • Embodiment 29 is the method of any of claims 24 to 28, wherein the subject is treated for osteoarthritis and/or wherein osteoarthritis is prevented.
  • Embodiment 30 is the method of any of claims 24 to 29, wherein the subject is diagnosed as having osteoarthritis.
  • Embodiment 31 is the method of any one of claims 24 to 30, wherein the subject is administered a total amount of between 1 and 10,000 mg, between 10 and 5,000 mg, between 50 and 2,500 mg, or between 100 and 1,000 mg of the green tea extract during a 24 hour period.
  • Embodiment 32 is the method of any one of claims 24 to 31, wherein the composition containing the green tea extract is administered orally.
  • Embodiment 33 is the method of any one of claims 24 to 32, wherein the composition containing the green tea extract is administered topically.
  • Embodiment 34 is the method of any one of claims 27 to 33, wherein a second composition comprises the trolamine salicylate and/or Arnica montana extract.
  • Embodiment 35 is the method of any of claims 24 to 34, wherein joint pain is reduced and/or range of motion of a joint is increased.
  • Embodiment 36 is a method of producing a composition of any of claims 1 to 18, wherein the method of producing produces a composition having an at least 90%, preferably at least 95% or at least 98% batch-to-batch chemical consistency of relative abundance for the biomarkers.
  • “Therapeutic agent” encompasses the compounds specifically claimed herein.
  • nutraceutical and/or pharmaceutically acceptable salts thereof include salts with inorganic acids, organic acids, inorganic bases, or organic bases.
  • Therapeutic agents useful in the present invention are those compounds that affect a desired, beneficial, and often pharmacological, effect upon administration to a human or an animal, whether alone or in combination with other nutraceutical and/or pharmaceutical excipients or inert ingredients.
  • biomarker refers to the compound defined as the biomarker, analogues thereof, derivatives thereof, or salt forms of any analogue or derivative thereof.
  • the term “accurate mass” refers to a measured mass of a molecule experimentally determined for an ion of known charge.
  • the units for accurate mass include atomic mass units (amu) and milli unified atomic mass units (mmu).
  • the term“molecular weight” refers to the average weight of the molecule with all of the different isotopic compositions present in a compound but weighted for their natural abundance.
  • relative abundance refers to the abundance of a compound of interest relative to the abundance of a reference compound.
  • relative abundance is the raw intensity of a mass spectrometry peak for the compound of interest over the raw intensity of a mass spectrometry peak for a reference compound.
  • the mass spectrometry peaks can be obtained by the use of DART-TOF mass spectrometry.
  • the reference compound is a compound that is spiked, or doped, into a sample containing the compound of interest.
  • the reference compound is a compound that does not exist in the sample previous to its addition to the sample for determining relative abundance.
  • the reference compound can be curcumin.
  • the accurate mass and relative abundances described herein are based on experiments using particular instruments and particular settings and can change from instrument to instrument. There is variability in each measurement.
  • the accurate mass and relative abundances are defined as being close to as understood by one of ordinary skill in the art.
  • the terms are defined to be within 20%, preferably 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.
  • the accurate mass has an error of within +/- 20 mmu, preferably 10 mmu, more preferably within 5 mmu, and most preferably within 1 mmu.
  • the relative abundance has an error of +/- 20%, preferably 10%, preferably within 5%, and more preferably within 1%, and most preferably within 0.5%.
  • “Patient,”“subject,” or“individual” refers to a mammal (e.g ., human, primate, dog, cat, bovine, ovine, porcine, equine, mouse, rat, hamster, rabbit, or guinea pig).
  • the patient, subject, or individual is a human.
  • “Inhibiting” or“reducing” or any variation of these terms includes any measurable decrease or complete inhibition to achieve a desired result.
  • Treating” or“treat” or any variation of these terms includes any measurable improvement in a disease, condition, or symptom that is being treated or is associated with the disease, condition, or symptom being treated.
  • Preventing or“prevent” or any variation of these terms means to slow, stop, or reverse progression toward a result.
  • the prevention may be any slowing of the progression toward the result.
  • “Derivative,” in relation to a parent compound, refers to a chemically modified parent compound or an analogue thereof, wherein at least one substituent is not present in the parent compound or an analogue thereof.
  • One such non-limiting example is a parent compound which has been covalently modified. Typical modifications are amides, carbohydrates, alkyl groups, acyl groups, esters, pegylations and the like.
  • Controlled release refers to the release of the therapeutic agent at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic concentrations over a period of time of about one hour or longer, preferably 12 hours or longer.
  • blood e.g., plasma
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering a drug compound of the present invention to a mammal such as an animal or human.
  • “Nutraceutical acceptable carrier” refers to a nutraceutical acceptable solvent, suspending agent or vehicle for delivering a compound of the present invention to a mammal such as an animal or human.
  • “Pharmaceutically acceptable” ingredient, excipient or component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
  • “Nutraceutical acceptable” ingredient, excipient or component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
  • the term“about” or“approximately” or“substantially unchanged” are defined as being close to as understood by one of ordinary skill in the art, and in one non-limiting embodiment the terms are defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. Further,“substantially non-aqueous” refers to less than 5%, 4%, 3%, 2%, 1%, or less by weight or volume of water. [0047] The use of the word“a” or“an” when used in conjunction with the term
  • the words“comprising” (and any form of comprising, such as“comprise” and“comprises”),“having” (and any form of having, such as“have” and“has”),“including” (and any form of including, such as“includes” and “include”) or“containing” (and any form of containing, such as“contains” and“contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • compositions and methods for their use can “comprise,” “consist essentially of,” or“consist of’ any of the ingredients or steps disclosed throughout the specification.
  • transitional phase“consisting essentially of” in one non limiting aspect, a basic and novel characteristic of the compositions and methods disclosed in this specification includes the compositions’ abilities to treat or prevent joint pain, such as osteoarthritis.
  • FIG. 1 Average Pain Reduction - ARMS A, B, and C, as measured by a 0-10 visual numerical scale.
  • FIG. 2 Speed and Magnitude of Pain Reduction - ARM A vs. ARM C.
  • FIG. 3 Average Increase in Range of Motion - ARMS A, B, and C, as measured by digital goniometer.
  • FIG. 4 Average Increase in Range of Motion - Speed and Magnitude of
  • FIG. 5 WOMAC Questionnaire Composite Score Improvement - ARMS A, B, C as measured by WOMAC questionnaire.
  • FIG. 6 WOMAC Questionnaire Composite Score Improvement - Comparison of improvement in the WOMAC questionnaire composite score between treatment ARM A vs ARM C.
  • the inventors have surprisingly found that a combination of several compounds found in green tea can prevent and treat joint pain such as osteoarthritis. Specifically, it is shown herein in clinical studies that a treatment regimen using trolamine salicylate, Arnica montana extract, and a composition containing biomarkers 1 through 12 is capable of treating osteoarthritis better than the over-the-counter (OTC) topical treatment OSTEO BI-FLEX TRIPLE STRENGTH® in combination with peppermint oil and better than a treatment regimen using OSTEO BI-FLEX TRIPLE STRENGTH® in combination with peppermint oil and trolamine salicylate.
  • OTC over-the-counter
  • a composition containing biomarkers 1 through 12 is capable of treating osteoarthritis, especially in combination with Arnica montana extract with or without trolamine salicylate. Further, it is expected that the composition containing biomarkers 1 through 12 will have synergistic effect with other joint pain treating agents to treat or prevent joint pain. It is also believed that the compounds and compositions disclosed herein are capable of treating and preventing the symptoms associated with osteoarthritis. Non-limiting examples of symptoms include pain and decreased range of motion of the joint.
  • Green tea is one of the most popular beverages worldwide and is known for its beneficial effects on health and disease, with numerous studies that support its ability to act as a powerful anti-oxidant (Higdon et al .).
  • Green tea extracts contain compounds called catechins and polyphenols that are known to be effective scavengers of reactive oxygen species (ROS) (Pham-Huy et al).
  • ROS reactive oxygen species
  • the accumulation of ROS in the body causes a phenomenon called oxidative stress that is implicated in the development of chronic and degenerative illness and in the development of osteoarthritis (Yudoh et al).
  • compositions disclosed herein are effective in treating and preventing joint pain. Specifically, it has now been shown herein that a regimen or composition containing compounds found in green tea can be used to treat and prevent joint pain and osteoarthritis. Further, the effects of these compounds may be enhanced further by administration of trolamine salicylate and/or Arnica montana extract. In some instances, the compositions or regimen can more effectively treat or prevent joint pain and osteoarthritis than a leading commercial joint pain medication and that medication in combination with trolamine salicylate.
  • composition of the present invention can include one or more of the biomarkers found in green tea defined by accurate mass of 461.1470 amu, 108.0205 amu, 122.0493 amu, 129.0472 amu, 145.0747 amu, 161.0718 amu, 165.0775 amu, 170.0243 amu, 174.0992 amu, 180.0673 amu, 194.0804 amu, and 211.0896 amu, and combinations thereof.
  • the biomarker or combination of biomarkers has a
  • the compound or combination of compounds has a 95% and/or 98% batch-to-batch chemical consistency of relative abundance for the biomarkers.
  • the compounds and derivatives and analogues can be made through known synthetic methods.
  • the compounds can be synthetically obtained by producing the compound according to methods known to one of skill in the art in chemical synthesis. In one instance, the compound is synthesized through organic chemistry methods.
  • the compounds can be isolated from extracts of an organism such as fruits, plants, animals, fungi, bacteria, and/or archaea.
  • suitable plants include green tea.
  • the compound(s) can be extracted from the organism using known extraction methods, such as contacting the extract with CO2, contacting the extract with H2O, contacting the extract with EtOH, or any combination of EtOEfEhO, and/or with any method utilizing polymer separating the extract.
  • a polymer used for polymer separation includes ADS 5 polymer (Nankai ETniversity, China), Sephadex LH-20 (GE Healthcare Life Sciences), and AMBERLITE® XAD7HP (The Dow Chemical Company).
  • the extract can include any one of or combination of compounds defined by accurate mass of 461.1470 amu, 108.0205 amu, 122.0493 amu, 129.0472 amu, 145.0747 amu, 161.0718 amu, 165.0775 amu, 170.0243 amu, 174.0992 amu, 180.0673 amu, 194.0804 amu, and/or 211.0896 amu, found in green tea and any combination thereof.
  • one or more of the compounds of the composition and derivatives and analogues thereof can be made through known synthetic methods known by one of skill in the art and one or more of the compounds of the composition and derivatives and analogues thereof may be isolated from other sources, such as, but not limited to, extracts of fruits and plants.
  • composition of the present invention can include one or more of the compounds defined by accurate mass of about 461.1470 amu, 108.0205 amu, 122.0493 amu, 129.0472 amu, 145.0747 amu, 161.0718 amu, 165.0775 amu, 170.0243 amu, 174.0992 amu, 180.0673 amu, 194.0804 amu, and/or 211.0896 amu found in green tea and any combination thereof.
  • the accurate mass and relative abundances described herein are based on experiments using particular instruments and particular settings and can change from instrument to instrument. There is variability in each measurement. Thus, the accurate mass and relative abundances are defined as being close to as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be within 20%, preferably 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. In one non-limiting embodiment, the accurate mass has an error of within +/- 20 mmu, preferably 10 mmu, more preferably within 5 mmu, and most preferably within 1 mmu. In one non-limiting embodiment, the relative abundance has an error of +/- 20%, preferably 10%, preferably within 5%, and more preferably within 1%, and most preferably within 0.5%.
  • the compounds of the present invention can be identified using Direct Analysis in Real Time (DART) Time of Flight/Mass Spectrometry (TOF/MS).
  • DART Direct Analysis in Real Time
  • TOF/MS Time of Flight/Mass Spectrometry
  • a JEOL DARTTM AccuTOF-mass spectrometer from Jeol USA of Peabody, MA (JMS-T100LC) can be used.
  • Accurate mass can be determined by subtracting the mass of a proton (1.007825 amu) from the measured mass of the ions produced from the sample.
  • the mass of compounds may be determined in a sample by directly introducing the sample to the ion stream by means of a Dip-IT sampler and a Dip-IT sampler holder (IONSENSETM).
  • a chemical doped/spiked solution can be used for quantitation relative to a known quantity.
  • curcumin is not present in green tea extract and can therefore be used to create a quantitative chemical profile of the bioactive molecules.
  • the settings for the DART ion source can be the following:
  • Samples can be analyzed in six replicates by DART-TOF MS. These six replicates can be analyzed to create a single, averaged, filtered, and statistically significant DART fingerprint of the sample. This processed fingerprint can then be used to determine the presence of the bioactive markers by comparison of masses. Due to the initial discovery and identification of these bioactive markers, a simple mass comparison is sufficient to determine their presence in any extract or mixture of chemicals.
  • the compounds of the present invention can be determined by DART TOF/MS by using a JEOL DARTTM AccuTOF-mass spectrometer from Jeol EISA of Peabody, MA (JMS-T100LC) executed in the positive ion mode ([M+H] + ) using the following settings for the DART ion source:
  • the settings for the JEOL AccuTOF MS can be the following:
  • a second joint pain reducing agent can be combined with the compounds of the compositions disclosed herein or can be administered to a subject in addition to the compounds of the compositions disclosed herein.
  • the joint pain reducing agent is a joint pain reducing drug.
  • the compositions disclosed herein further includes at least one additional joint pain reducing agent.
  • the joint pain reducing agent is an oral analgesic, topical analgesic, nonsteroidal anti-inflammatory drug (NS AID), corticosteroid, opioid, nutraceutical, etc ., or any combination thereof.
  • the joint pain reducing agent is trolamine salicylate, Arnica montana extract, acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, prednisone, betamethas
  • compositions of the present invention can include any amount of the ingredients discussed in this specification.
  • the compositions can also include any number of combinations of additional ingredients described throughout this specification (e.g ., stabilizers, fillers, pharmaceutically and/or nutraceutical acceptable salts, and/or additional pharmaceutical and/or nutraceutical ingredients).
  • additional ingredients e.g ., stabilizers, fillers, pharmaceutically and/or nutraceutical acceptable salts, and/or additional pharmaceutical and/or nutraceutical ingredients.
  • concentrations of the any ingredient within the compositions can vary.
  • the compositions can comprise, consisting essentially of, or consist of, in their final form, for example, at least about 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0011%, 0.0012%, 0.0013%, 0.0014%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%, 0.0020%, 0.0021%, 0.0022%, 0.0023%, 0.0024%, 0.0025%, 0.0026%, 0.0027%, 0.0028%, 0.0029%, 0.0030%, 0.0031%, 0.0032%, 0.0033%, 0.0034%, 0.0035%, 0.0036%, 0.0037%, 0.0038%, 0.0039%, 0.0040%, 0.0041%, 0.0042%, 0.0043%, 0.0044%, 0.0045%, 0.0046%
  • the percentage can be calculated by weight or volume of the total composition or relative abundance.
  • concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given composition.
  • the compound of the present invention can be formulated into any suitable composition form for administration to a human or non-human animal patient.
  • composition may consist of the claimed compound or compounds alone or may include the compound or compounds and any suitable additional component, such as one or more pharmaceutically and/or nutraceutical acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • suitable additional component such as one or more pharmaceutically and/or nutraceutical acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • Excipients employed in the compositions of the present invention can be solids, semi-solids, liquids or combinations thereof. Preferably, the excipients are solids.
  • Compositions of the invention containing excipients can be prepared by any known technique that comprises, for example, admixing an excipient with the claimed compounds.
  • a pharmaceutical composition of the invention contains a desired amount of the claimed compounds per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, or any other form reasonably adapted for such administration.
  • a pharmaceutical composition of the invention contains a desired amount of the claimed compounds per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, or any other form reasonably adapted for such administration.
  • If intended for topical application it can be in the form of an emulsion, solution, powder, patch, spreadable solid, etc.
  • Suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CELUTABTM and EMDEXTM), mannitol, sorbitol, xylitol, dextrose (e.g., CERELOSETM 2000) and dextrose monohydrate, dibasic calcium phosphate dihydrate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, granular calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, celluloses including microcrystalline cellulose, food grade sources of alpha- and amorphous cellulose (e.g., RexcelJ), powdered cellulose, hydroxy
  • Such carriers or diluents constitute in total about 5% to about 99.999%, about 10% to about 85%, and 20% to about 80%, of the total weight of the composition.
  • the carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • compositions of the invention optionally can include one or more pharmaceutically and/or nutraceutical acceptable disintegrants as excipients.
  • Suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate and pregelatinized corn starches, clays, celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium, alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums.
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the total weight of the composition.
  • compositions of the present invention can include binding agents or adhesives particularly for tablet formulations.
  • binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • binding agents may also prevent or inhibit crystallization or recrystallization of a co-crystal of the present invention once the salt has been dissolved in a solution.
  • Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; tragacanth, sucrose, gelatin, glucose, starches such as, but not limited to, pregelatinized starches, celluloses such as, but not limited to, methylcellulose and carmellose sodium, alginic acid and salts of alginic acid; magnesium aluminum silicate, PEG, guar gum, polysaccharide acids, bentonites, povidone, polymethacrylates, HPMC, hydroxypropylcellulose, and ethylcellulose.
  • binding agents and/or adhesives constitute in total about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about 1% to about 10%, of the total weight of the pharmaceutical composition.
  • Many of the binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, can be included in pharmaceutical compositions of the present invention.
  • Polyvinylpyrrolidones is an non-limiting example of a binder used for slow release tablets.
  • Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer.
  • Polymeric binding agents can also be copolymers, such as block co- polymers that contain mixtures of ethylene oxide and propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance.
  • wetting agents can be used in the compositions of the present invention.
  • Wetting agent can be selected to maintain the crystal in close association with water, a condition that may improve bioavailability of the composition. Such wetting agents can also be useful in solubilizing or increasing the solubility of crystals. Surfactants can be used as wetting agents.
  • Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and di glycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80, propylene glycol fatty acid esters, for example propylene
  • Lubricants can be included in the compositions of the present invention.
  • Suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behenate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils, colloidal silica, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, PEG (e.g., CARBOWAXTM 4000 and CARBOWAXTM 6000 of the Dow Chemical Company), sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total about 0.1% to about 10%, preferably about 0.2% to about 8%, and more preferably about 0.25% to about 5%, of the total weight of the composition.
  • Surfactant emulsifier, or effervescent agents can be used in the compositions.
  • Emulsifying agents can be used to help solubilize the ingredients within a soft gelatin capsule.
  • the surfactant, emulsifier, or effervescent agent include D-sorbitol, ethanol, carrageenan, carboxyvinyl polymer, carmellose sodium, guar gum, glycerol, glycerol fatty acid ester, cholesterol, white beeswax, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, stearyl alcohol, stearic acid, polyoxyl 40 stearate, sorbitan sesquioleate, cetanol, gelatin, sorbitan fatty acid ester, talc, sorbitan trioleate, paraffin, potato starch, hydroxypropyl cellulose, propylene glycol, propylene glycol fatty acid ester, pectin, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropy
  • compositions of the invention can be provided in the form of tablets, lozenges, granules, capsules, pills, ampoule, suppositories or aerosol form.
  • compositions can also be provided in the form of suspensions, solutions, and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
  • composition may, for example, be a pharmaceutical composition
  • compositions according to the present invention include formulations suitable for oral or parenteral routes.
  • routes include intradermal, subcutaneous, intramuscular, intravenous, local injection, rectal, intranasal inhalation, insufflation, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art. Such methods include the step of bringing into association the active ingredient (or ingredients) with the carrier, which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a suitable carrier, such as liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • a suitable carrier such as liquid carriers or finely divided solid carriers or both
  • Formulations of the subject invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, or as an oil-in-water liquid emulsion, water-in-oil liquid emulsion, or as a supplement within an aqueous solution, for example, a tea.
  • the active ingredient can also be presented as bolus, electuary, or paste.
  • Useful injectable preparations include sterile suspensions, solutions or emulsions of the compound compositions in aqueous or oily vehicles.
  • compositions can also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
  • the formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, and can contain added preservatives.
  • the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc ., before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc ., before use.
  • the compound compositions can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth, pastilles that include the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia, mouthwashes that include the active ingredient in a suitable liquid carrier, and chocolate comprising the active ingredients.
  • Formulations suitable for topical administration according to the subject invention can be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • a formulation can comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active ingredients, and optionally one or more excipients or diluents.
  • topical formulations preferably comprise compounds that facilitate absorption of the active ingredients through the skin and into the bloodstream.
  • Formulations suitable for intranasal administration include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for intranasal administration include aqueous or oily solutions of the agent.
  • Formulations preferably can include compounds that facilitate absorption of the active ingredients through the skin and into the bloodstream.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations can be presented in unit-dose or multi-dose or multi-dose sealed containers, such as for example, ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • sterile liquid carrier for example, water for injections
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically and/or nutraceutical acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p hydroxybenzoates or sorbic acid).
  • the preparations can also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
  • compositions can take the form of the non limiting examples of tablets or lozenges formulated in a conventional manner.
  • the compound compositions can be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compound compositions can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compound compositions can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • the compound compositions can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • transdermal delivery systems manufactured as an adhesive disc or patch, which slowly releases the compound compositions for percutaneous absorption, can be used.
  • permeation enhancers can be used to facilitate transdermal penetration of the compound compositions. Suitable transdermal patches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.
  • Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the compound compositions.
  • Certain organic solvents such as dimethylsulfoxide (DMSO) can also be employed, although usually at the cost of greater toxicity.
  • DMSO dimethylsulfoxide
  • formulations useful in the present invention can include other agents conventional in the art regarding the type of formulation in question.
  • formulations suitable for oral administration can include such further agents as sweeteners, thickeners, and flavoring agents. It also is intended that the agents, compositions, and methods of this invention be combined with other suitable compositions and therapies.
  • the pharmaceutical and/or nutraceutical compositions of the invention can be administered locally to the area in need of treatment; such local administration can be achieved, for example, by local infusion, by injection, or by means of a catheter.
  • a compound or composition of the invention is administered in a manner so as to achieve peak concentrations of the active compound at sites of the disease. Peak concentrations at disease sites can be achieved, for example, by intravenously injecting of the agent, optionally in saline, or orally administering, for example, a tablet, capsule or syrup containing the active ingredient.
  • compositions of the invention can be administered simultaneously or sequentially with other drugs or biologically active agents.
  • drugs or biologically active agents include, but are not limited to antioxidants, free radical scavenging agents, analgesics, anesthetics, anorectals, antihistamines, anti-inflammatory agents including non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antimicrobials, anti-cancer actives, antineoplastics, biologically active proteins and peptides, enzymes, hemostatics, steroids including hormones and corticosteroids, etc.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose, or an appropriate fraction thereof, of an agent.
  • Therapeutic amounts can be empirically determined and will vary with the pathology being treated, the subject being treated, and the efficacy and toxicity of the agent.
  • suitable dosage formulations and methods of administering the agents can be readily determined by those of ordinary skill in the art.
  • a therapeutic method of the present invention can include treating a disease, condition, or disorder by administering to a subject having such disease or condition a stable formulation as described herein in an amount effective to treat the disease, condition, or disorder.
  • the subject is administered a stable formulation comprising the compounds claimed herein.
  • the disease, condition, or disorder can be a joint pain disorder. Further, the disease, condition, or disorder can be osteoarthritis and related diseases, conditions, and disorders.
  • the composition can be administered to a patient at risk of developing one of the previously described conditions.
  • composition administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art. In some aspects of the invention, total dosage amounts of a compound composition will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg of patient/day to about 100 mg/kg patient/day, but may be higher or lower, depending upon, among other factors, the activity of the components, its bioavailability, the mode of administration and various factors discussed above.
  • Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds can be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • Certain embodiments provide for the administration or application of one or more secondary or additional forms of therapies or preventative interventions.
  • the type of therapy is dependent upon the type of disease that is being treated or prevented.
  • the secondary form of therapy may be administration of one or more secondary pharmacological agents that can be applied in the treatment or prevention joint pain or osteoarthritis.
  • the secondary or additional therapy is a pharmacological agent, it may be administered prior to, concurrently, or following administration of the compositions disclosed herein.
  • the interval between administration of the compositions and the secondary or additional therapy may be any interval as determined by those of ordinary skill in the art.
  • the compositions and the secondary or additional therapy may be administered simultaneously, or the interval between treatments may be minutes to weeks.
  • the agents are separately administered, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that each therapeutic agent would still be able to exert an advantageously combined effect on the subject.
  • the interval between therapeutic agents may be about 12 h to about 24 h of each other and, more preferably, within about 6 hours to about 12 h of each other.
  • the timing of administration of a secondary therapeutic agent is determined based on the response of the subject to the composition.
  • secondary treatments useful with methods disclosed herein are: joint pain reducing drugs.
  • secondary treatments can include treatments for the symptoms of a joint pain or osteoarthritis or the complications caused thereby, such as pain reducers, etc.
  • Secondary treatments can also include dietary supplements such as vitamins C, E and D, calcium, zinc, selenium, curcumin, folate, bioflavonoids, resveratrol, and plant extracts.
  • kits for treating or preventing a disease, condition or disorder as described herein can be included in a kit.
  • a kit can include a container.
  • Containers can include a bottle, a metal tube, a laminate tube, a plastic tube, a dispenser, a straw, a pressurized container, a barrier container, a package, a compartment, or other types of containers such as injection or blow-molded plastic containers into which the dispersions or compositions or desired bottles, dispensers, or packages are retained.
  • the kit and/or container can include indicia on its surface.
  • the indicia for example, can be a word, a phrase, an abbreviation, a picture, or a symbol.
  • the containers can dispense a predetermined amount of the composition.
  • the container can be squeezed (e.g ., metal, laminate, or plastic tube) to dispense a desired amount of the composition.
  • the composition can be dispensed as a spray, an aerosol, a liquid, a fluid, a semi-solid, or a solid. In a preferred embodiment, the composition is dispensed as a tablet or lozenge.
  • the containers can have spray, pump, or squeeze mechanisms.
  • a kit can also include instructions for employing the kit components as well the use of any other compositions included in the container. Instructions can include an explanation of how to apply, use, and maintain the compositions.
  • compositions can, if desired, be presented in a pack or dispenser device, which can contain one or more unit dosage forms containing the compound compositions.
  • the pack can, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the inventors have surprisingly found that a combination of several compounds found in green tea can prevent and treat joint pain.
  • the inventors have also found that specific relative concentrations of the compounds act to enhance the ability of the combined compounds to prevent and treat joint pain.
  • the inventors expect that using compounds of the present invention with additional joint pain reducing agents may enhance the ability of the combined compounds to prevent and treat joint pain.
  • the dried material was chromatographed on a column, preferably AMBERLITE® XAD7HP.
  • the fractions were eluted off by 10 - 80% ethanol or 40- 95% acetone.
  • the fraction material was then concentrated to dryness using a suitable drying method, such as rotary evaporator, at a temperature below 50°C, other suitable drying methodologies include, but are not limited to, vacuum drying and spray drying.
  • the compounds of the present invention include biomarker compounds defined by compounds found in green tea with an accurate mass of 461.1470 amu, 108.0205 amu, 122.0493 amu, 129.0472 amu, 145.0747 amu, 161.0718 amu, 165.0775 amu, 170.0243 amu, 174.0992 amu, 180.0673 amu, 194.0804 amu, and 211.0896 amu.
  • These compounds may be produced synthetically or isolated from an organism such as, but not limited to, green tea.
  • the compounds may be characterized by methods known by one of skill in the art.
  • the accurate mass and relative abundances described herein are based on experiments using particular instruments and particular settings and can change from instrument to instrument. There is variability in each measurement.
  • the accurate mass and relative abundances are defined as being close to as understood by one of ordinary skill in the art.
  • the terms are defined to be within 20%, preferably 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.
  • the accurate mass has an error of within +/- 20 mmu, preferably 10 mmu, more preferably within 5 mmu, and most preferably within 1 mmu.
  • the relative abundance has an error of +/- 20%, preferably 10%, preferably within 5%, and more preferably within 1%, and most preferably within 0.5%.
  • Extract samples were analyzed in six replicates by DART-TOF MS. These six replicates were analyzed to create a single, averaged, filtered, and statistically significant DART fingerprint of the extract. This processed fingerprint was then used to determine the presence of the bioactive markers by comparison of masses. Due to the initial discovery and identification of these bioactive markers, a simple mass comparison was sufficient to determine their presence in any extract or mixture of chemicals. For the AccuTOF, that mass tolerance is less than 20 millimass units (mmu) (predicted mass +/-10 mmu). Given the same extract and ion source, other TOF mass spectrometers may have a higher or lower mass tolerance.
  • mmu millimass units
  • samples of the disclosed compositions were doped/spiked with curcumin. Samples were then analyzed by the DART-TOF method used above.
  • Table 1 discloses the relative abundance of the biomarkers disclosed herein found in non-limiting, preferred embodiments of compositions comprising all twelve biomarkers found in green tea.
  • a dose-reliable, green tea extract comprising biomarkers 1 through 12 was produced in general according to the methods described in Example 1.
  • the green tea extract was encapsulated in a capsule for oral administration.
  • Example 1 The composition of Example 1 was tested for safety for human use. In the clinical study of Example 5 and in human pharmacokinetic studies (not shown), no adverse events were attributed to the composition of Example 1.
  • the primary aim of the study was to identify otherwise healthy individuals who had been diagnosed with mild to moderate osteoarthritis of the knee and to determine if the composition of the present invention successfully reduces joint pain and inflammation associated with arthritis, while also increasing the range of motion of the affected joint significantly better and faster than a leading competitive product, OSTEO BI-FLEX TRIPLE STRENGTH®. It was found that the composition, treatments, and regimens of the present invention treat and prevent joint pain. Specifically, treatment with the compounds of the present invention reduced joint pain and increased the range of motion of a joint better than OSTEO BI-FLEX TRIPLE STRENGTH®.
  • the Primary Study Endpoint was reduction in knee pain using a Visual Numeric Scale (0-10) measured at Baseline, 24 hours, 48 hours, 72 hours, 7 days, and 14 days.
  • ARM A treatment consisted of a topical spray, which contains trolamine salicylate and natural ingredients that include Arnica montana extract, peppermint oil, and water and a capsule, taken orally, containing an extract of organic green tea containing biomarkers 1 to 12.
  • the ARM A topical spray contained only an FDA approved analgesic (trolamine salicylate), 2 natural GRAS status products, and distilled water.
  • ARM B and ARM C received open-label OSTEO BI-FLEX TRIPLE STRENGTH® and a topical spray.
  • Topical analgesic trolamine salicylate is an organic compound which is the salt formed between triethanolamine and salicylic acid. This compound has been used for years as an ingredient in sunscreens, analgesic creams, and cosmetics.
  • the salicylic acid portion has sun protecting properties (by absorbing UVB radiation), in addition to analgesic (pain reducing) effects.
  • the triethanolamine neutralizes the acidity of the salicylic acid.
  • Trolamine salicylate not only alleviates pain, but has no common side effects reported with its use. This compound is odorless and approved by the FDA for topical analgesic use.
  • trolamine salicylate for the treatment of OA has been previously reported and was found to have mixed results in treatment efficacy. In the most relevant study involving reducing pain in the knee due to joint pain, it was reported to not be effective (Algozzine et al .). While in another study it was found to be effective at reducing pain and stiffness in subjects with joint pain of the hand (Rothacker et al).
  • Arnica montana extract is an 70% ethanol extract of dried flower heads of the plant, Arnica montana.
  • the composition of the extract can include palmitic acid, linoleic acid, myristic acid, linolenic acid, sesquiterpene actones, triterpene alcohols, phenolic acids, and/or flavonoids.
  • Study ARM A Product A contained the following ingredients:
  • Liquid Topical Spray Trolamine salicylate 10.0%, distilled water, Arnica extract, and Peppermint oil.
  • Capsule composition of Example 1 containing all twelve biomarkers 1 through 12 at relative abundances shown in Table 2.
  • Study ARM B Product B contained the following ingredients:
  • Liquid Topical Spray Trolamine salicylate 10.0%, distilled water, and Peppermint oil.
  • Capsule OSTEO BI-FLEX TRIPLE STRENGTH®: vitamin C, glucosamine, manganese, JOINT SHIELDTM 5-LOXIN® Advanced (Boswellia), chondroitin/MSM complex, crospovidone, and shellfish (shrimp, crab, lobster, crayfish).
  • Study ARM C Product C contained the following ingredients:
  • Placebo toner dextrose, distilled water, red, green, and yellow food coloring, and Peppermint oil.
  • VNS Visual Numeric Scale
  • the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index is a tested questionnaire that was used to assess symptoms and physical functional disability in patients with OA of the knee.
  • the WOMAC is a self-reported instrument that includes 24 questions divided into 3 sections; pain (5 questions), stiffness (2 questions), and physical function (17 questions).
  • the pain category assesses pain elicited during activities of daily living (ADL), while the stiffness category assesses the amount of stiffness elicited after staying in certain positions and the time of day it is experienced.
  • the physical function category measures the patient’s ability to perform certain activities including; going from sit to stand, walking, stair negotiation, putting on socks, etc.
  • Pain reduction - Pain reduction was measured by visual numeric scale (VNS), during the baseline visit (Day 1) and each subsequent visit (Days 2, 3, 4, 7, and 14). Each patient rated the severity of their knee joint pain on a scale of 0 to 10. FIGs. 1 and 2 and
  • FIGs. 1 and 2 and Table 3 also illustrate how much faster and more effective the treatment regime in ARM A was than the treatment regime in ARM C in reducing knee pain.
  • Range of Motion Another measure of efficacy tested was the ability of the treatments to increase the range of motion (ROM) of the knee joint.
  • ROM range of motion
  • FIGs. 3 and 4 show the increase in ROM for each subsequent visit compared to the baseline visit.
  • Patients in ARM A also experienced greater increase in ROM than did patients in ARM B (FIG. 3).
  • the average increase in ROM was consistently greater in ARM A versus ARM C or ARM B.
  • Table 4 shows the average ROM scores and shows that the greatest difference between ARM A and ARM C was seen at Day 4, when the average ROM scores in ARM A was 5.5 times greater than in ARM C. A similar difference between ARM A and ARM B is also shown.
  • FIGs. 3 and 4 and Table 4 also illustrate how much faster and more effective the treatment regime in ARM A was than the treatment regime in ARM C or ARM B in increasing knee ROM.
  • day 3 an average increase of ROM by greater than 6.0 degrees was seen for ARM A, while in ARM C it took more than 7 days and in ARM B it took approximately 7 days for the average increase of ROM to be greater than 6.0 degrees.
  • Table 4 Average increase in ROM data in ARM s A and C as measured by a digital goniometer, with the increase in magnitude of average ROM by Day in ARM A vs ARM C shown (i.e. ARM A/ ARM C).
  • WOMAC WOMAC
  • the questionnaire includes 24 items related to pain, stiffness and physical function that the patients rank in terms of difficulty using a scale of 0-4.
  • FIG. 5 shows the improvement in composite WOMAC score on each subsequent visit compared to the baseline visit.
  • Example 1 can quickly reduce pain and improve range of motion, at a pace significantly faster than one of the current leading joint pain product, OSTEO BI-FLEX TRIPLE STRENGTH®. The difference was not only in speed of efficacy, but also in the magnitude of efficacy. From day 3 onwards, the OSTEO BI-FLEX TRIPLE STRENGTH® with the placebo spray never reached the same level of efficacy as the treatment of ARM A on any day when testing reduction of pain or increase in range of motion.
  • ARM A increased average range of motion more quickly and to a greater extent than the OSTEO BI-FLEX TRIPLE STRENGTH® with a placebo spray and OSTEO BI-FLEX TRIPLE STRENGTH® with a trolamine salicylate spray.
  • compositions, treatments, and joint pain treatment regimens disclosed herein contain a known safe topical analgesic plus known safe natural ingredients with little chance of an allergic-reaction experienced by the patient. All of these factors may contribute to increased compliance for treatment, and greater consumer satisfaction in the treatment of joint pain.
  • compositions disclosed herein containing compounds found in green tea will act synergistically with other agents that reduce joint pain that act through a separate mechanism.
  • the compositions disclosed herein can be tested in combination with one or more agents that reduce joint pain.
  • the agents that reduce joint pain can include one or more joint pain drugs.
  • Combination studies can show competitive, additive, or synergistic interactions for treatment and/or prevention of joint pain, cell viability, cellular toxicity, side effects, etc. of the combination in cell culture, animal studies, human studies, etc. Non-limiting examples of studies can include those described above and herein as well as those known to one of skill in the art.
  • the compositions disclosed herein containing compounds found in green tea in combination with Arnica montana extract and/or trolamine salicylate may show synergistic activity against at least osteoarthritis.
  • a non-limiting example of a combination assay that can be performed to determine the competitive, additive, or synergistic interactions of a combination can utilize an interaction matrix commonly used to look at drug interactions and synergy.
  • the interaction matrix is used in a prevention and/or treatment study of osteoarthritis in an animal model. Briefly, the experiment can have 25 test subjects: 4 treated with a first test compound/composition (such as the compositions disclosed herein containing compounds found in green tea) alone, 4 treated with a second test compound/composition (such as Arnica montana extract) alone, 1 treated with placebos, and the remaining 16 can be treated with combinations of the first and second test compounds/compositions.
  • a first test compound/composition such as the compositions disclosed herein containing compounds found in green tea
  • a second test compound/composition such as Arnica montana extract
  • 1 :4 dilutions of the first test compound/composition from a starting concentration such as 1 mg/kg for the compositions disclosed herein containing compounds found in green tea
  • 1 :4 dilutions of the second test compound/composition from a starting concentration such as 1 mg/kg for Arnica montana
  • the osteoarthritis can occur in the constant presence of the inhibitory treatments. In this way, the experiment simulates a patient developing osteoarthritis while on prophylactic treatment and tests prevention of developing osteoarthritis by the first test compound/composition alone, the second test compound/composition alone, and the combination of the two at a range of administration concentrations.
  • the data can be analyzed with the methodology of Berenbaum to determine competitive, additive, or synergistic interactions. (Berenbaum 1977).
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • FDA U.S. Food and Drug Administration
  • Oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis Res Ther ., 7(2), R380-91.

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Abstract

La présente invention concerne de manière générale des régimes de traitement, des compositions et des procédés d'utilisation qui traitent et/ou préviennent une douleur articulaire telle que l'arthrose. Les compositions peuvent contenir des composés trouvés dans un extrait de thé vert.
PCT/IB2018/059422 2017-11-28 2018-11-28 Compositions et méthodes pour traiter et prévenir une douleur articulaire WO2019106574A1 (fr)

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US20240156842A1 (en) * 2022-11-15 2024-05-16 William Spivak Topical NSAID Formulation with Improved Skin Absorption

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US20060172012A1 (en) * 2005-01-28 2006-08-03 Finley John W Anti-inflammatory supplement compositions and regimens to reduce cardiovascular disease risks
US20080031979A1 (en) * 2006-08-04 2008-02-07 Claude Saliou Use of extracts for the treatment of viral disorders
US20080113044A1 (en) * 2006-03-23 2008-05-15 Alberte Randall S Extracts and Methods Comprising Green Tea Species
WO2012039745A1 (fr) * 2010-09-23 2012-03-29 Nestec S.A. Procédés et compositions pour prévenir ou traiter l'arthrose
US20130274343A1 (en) * 2011-05-16 2013-10-17 Omniactive Health Technologies Ltd Water Soluble Composition Comprising Curcumin Having Enhanced Bioavailability and Process Thereof
US20160263176A1 (en) * 2013-05-14 2016-09-15 Mars, Incorporated Joint care composition

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Publication number Priority date Publication date Assignee Title
US20060172012A1 (en) * 2005-01-28 2006-08-03 Finley John W Anti-inflammatory supplement compositions and regimens to reduce cardiovascular disease risks
US20080113044A1 (en) * 2006-03-23 2008-05-15 Alberte Randall S Extracts and Methods Comprising Green Tea Species
US20080031979A1 (en) * 2006-08-04 2008-02-07 Claude Saliou Use of extracts for the treatment of viral disorders
WO2012039745A1 (fr) * 2010-09-23 2012-03-29 Nestec S.A. Procédés et compositions pour prévenir ou traiter l'arthrose
US20130274343A1 (en) * 2011-05-16 2013-10-17 Omniactive Health Technologies Ltd Water Soluble Composition Comprising Curcumin Having Enhanced Bioavailability and Process Thereof
US20160263176A1 (en) * 2013-05-14 2016-09-15 Mars, Incorporated Joint care composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240156842A1 (en) * 2022-11-15 2024-05-16 William Spivak Topical NSAID Formulation with Improved Skin Absorption

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