EP1853281A1 - Préparation analgésique et anti-inflammatoire - Google Patents

Préparation analgésique et anti-inflammatoire

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Publication number
EP1853281A1
EP1853281A1 EP06704862A EP06704862A EP1853281A1 EP 1853281 A1 EP1853281 A1 EP 1853281A1 EP 06704862 A EP06704862 A EP 06704862A EP 06704862 A EP06704862 A EP 06704862A EP 1853281 A1 EP1853281 A1 EP 1853281A1
Authority
EP
European Patent Office
Prior art keywords
mixture
metal
composition
plasma
inflammatory
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06704862A
Other languages
German (de)
English (en)
Other versions
EP1853281A4 (fr
Inventor
Jeffrey D. Edwards
John Palermo
Maud Louisa Johanna Maria Eijkenboom
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cambridge Scientific Pty Ltd
Original Assignee
Cambridge Scientific Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2005900638A external-priority patent/AU2005900638A0/en
Priority claimed from US11/059,580 external-priority patent/US7510732B2/en
Application filed by Cambridge Scientific Pty Ltd filed Critical Cambridge Scientific Pty Ltd
Publication of EP1853281A1 publication Critical patent/EP1853281A1/fr
Publication of EP1853281A4 publication Critical patent/EP1853281A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/28—Mercury; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4826—Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 present invention relates to an agent having analgesic and anti-inflammatory activity.
  • the present invention relates to a composition comprising an effective amount of an analgesically and anti-inflammatory active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured.
  • Pain can be defined as an unpleasant sensation ranging from mild discomfort to agonizing distress , associated with real or potential tissue damage , or a disorder of the nervous system. Pain is a response to impulses from the peripheral nerves in damaged tissue, which pass to nerves in the spinal cord. All animals experience some degree of pain during life , whether through injury or disease . As such, one of the maj or areas of drug research is the development of analgesics to be used in pain management .
  • Pain associated with inflammation can be caused by pathologic processes in somatic structures or viscera or by prolonged dysfunction of parts the peripheral nervous system . Pain associated with inflammation may be the result of recurrent injuries , trauma, headache , arthritis including osteoarthritis , chronic obstructive pulmonary disease, psoriasis , or other pathologies . Pain associated with inflammation may be acute or chronic depending on the duration, level and extent of the inflammation .
  • Therapeutic management of pain includes four steps : 1) . peripheral level pain is treated with ice packs , heat pads , massage or non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin or ibuprofen to inhibit local responses to trauma and prevent stimulation of nociceptors ; 2 ) . mild pain is treated with non-opioid analgesics such as paracetamol ;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • aspirin can cause irreversible inhibition of platelet function and cause gastric irritation. It can precipitate hypersensitivity reactions including asthma, and there may be cross sensitivity with other NSAIDs . It also interacts with a number of other drugs and is especially hazardous with warfarin. Paracetamol does not have the haematological or GI adverse effects associated with aspirin and side effects are rare ; however, overdosage is particularly dangerous as it may cause severe or sometimes fatal hepatic damage .
  • Mild NSAIDs such as ibuprofen have weaker antiinflammatory properties than aspirin, but a much lower risk of GI side effects than aspirin and other NSAIDs .
  • Dihydrocodeine is a weak opioid which is effective for the relief of moderate pain of visceral origin. However, it is known to cause nausea, vomiting and constipation.
  • Co-dydramol and co-codamol are compound analgesic preparations which combine paracetamol with a low dose of an opioid analgesic eg . dihydrocodeine or codeine .
  • NSAIDs used regularly in full dosage have a lasting analgesic and anti-inflammatory effect which makes them particularly useful for treatment of continuous regular pain associated with inflammation, musculoskeletal and soft tissue disorders .
  • Diclofenac combines good efficacy with relatively low incidence of side effects . It is stronger than ibuprofen but has more side effects than ibuprofen. It is associated with intermediate risk of serious upper gastro-intestinal side effects .
  • analgesics have associated side effects include dyspepsia, gastric or small bowel bleeding, ulceration, renal insufficiency, confusion, rash, headache , hepatic toxicity.
  • NSAIDs also reversibly inhibit platelet aggregation and prolong bleeding time . Therefore , the use of analgesic compositions must be considered within the treatment context .
  • the treatment context is a factor that must be taken into account when considering the pharmacology and physiology of analgesic ingredients .
  • the present invention provides a composition comprising an effective amount of an analgesically and/or anti-inflammatory active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured.
  • the plasma or serum may be obtained from any animal source .
  • the plasma or serum is isolated from an animal selected from the group consisting of human, equine, bovine , ovine , murine , caprine and canine .
  • the plasma and/or serum is dried and lyophilised before use .
  • the metal , metal ion or metal salt thereof can be any metal .
  • the metal is selected from the group consisting of nickel , sodium, copper, zinc , cobalt, iron, magnesium, manganese , potassium, silver and mercury, ions or salts thereof and mixtures thereof .
  • the metal , metal ion or metal salt thereof is preferably heated to at least 50°C .
  • the mixture is heated to about 65 0 C .
  • a protease such as trypsin is preferably added before heating or after heating . At which point the resultant mixture is again heated then allowed to cool to produce an analgesic and/or anti-inflammatory mixture .
  • the second heating step is preferably carried out between about 80°C and about 15O 0 C, more preferably between about 9O 0 C and about 13O 0 C and most preferably, about 120 0 C to produce said analgesic and/or anti-inflammatory mixture .
  • the analgesic and/or anti-inflammatory mixture can be used directly or further separated to produce an analgesically and/or anti-inflammatory fraction.
  • the composition of present invention comprises at least a fraction of an analgesically and/or antiinflammatory mixture as described above . More preferably, the composition of present invention is optionally admixed with a pharmaceutical carrier . Any pharmaceutical carrier known in the art may be used.
  • an analgesic and/or anti-inflammatory composition obtained by:
  • the step of separating the analgesically active and/or anti-inflammatory fraction is by chromatography such as affinity chromatography, column chromatography, partition chromatography, gel-filtration chromatography with a suitable solvent or solvent mixture .
  • the method further comprises the steps of incubating said mixture in the presence of a protease to produce a digested mixture; and heating said digested mixture . These steps can be undertaken before or after addition of the at least one metal, metal ion or metal salt .
  • an analgesic and/or anti-inflammatory composition obtained by:
  • the step of separating the analgesically active and/or anti-inflammatory fraction is by chromatography such as affinity chromatography, column chromatography, partition chromatography, gel-filtration chromatography with a suitable solvent or solvent mixture .
  • steps (b) and (c) are performed before the addition of at least one metal, metal ion or metal salt thereof .
  • step (a) further comprises the addition of NaHCO 3 .
  • the step of denaturing the mixture by heat is preferably carried out at a temperature greater than 65°C.
  • the fractionation step (d) is preferably performed by chromatography on a polyamide column; however, any other method of fractionation may be used.
  • the present invention provides a method for providing analgesia and reduction of inflammation to a subj ect, said method comprising administering to the subj ect an effective amount of a composition comprising an effective amount of an analgesically and/or anti-inflammatory active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured.
  • the method of administration may be any method known in the art .
  • the composition is administered topically, systemically, intramuscularly, subcutaneousIy, intraperitoneally, intrapleurally, intraarticularly, intrathecally, rectally, vaginally, or by inhalation .
  • the composition is administered topically.
  • the present invention provides a composition for reducing inflammation and/or pain in a subj ect comprising a pharmaceutically acceptable carrier and an effective amount of an anti-inflammatory or analgesically active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured .
  • the present invention provides a physiologically active substance which is extracted from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured.
  • the physiologically active substance is further admixed with a pharmaceutically acceptable carrier .
  • the carrier is at least one member selected from the group consisting of distilled water, physiologically saline solution, Ringer ' s solution, plant oil , synthetic fatty acid glycerides , higher fatty acid esters , propylene glycol , lactose , mannitol , corn starch, crystalline cellulose, gum arabicum, gelatin, potato starch, carmerose , carmerose calcium, talc , and magnesium stearate .
  • the present invention provides a method for treating a subj ect afflicted with inflammation and/or pain comprising administering an effective amount of an active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or salt thereof , wherein said mixture has been denatured and wherein said fraction is admixed with a pharmaceutically acceptable carrier .
  • Figure 1 shows the effect of one form of the composition of the present invention (TL-B) comprising zinc chloride , glycine and trypsinised protein on the TNF- ⁇ production by LPS-stimulated human monocytes .
  • T-B composition of the present invention
  • Figure 2 shows the effect of the composition of the present invention, containing copper as the metal- containing solution, on the TNF- ⁇ production by LPS- stimulated human monocytes .
  • FIG. 3 shows the effect of reduced concentrations of one form of the composition of the present invention (TL-B) comprising zinc chloride, glycine and trypsinised protein on the TNF- ⁇ production by LPS-stimulated human monocytes .
  • T-B composition of the present invention
  • Figure 4 shows the titration of the effect of different concentrations of the composition of the present invention. The purpose was to demonstrate that TL-B does not compete with the FCS which is being used in the culture medium .
  • Figure 5 shows the effect of the composition on the metabolism of cells in vitro, with or without LPS challenge, on a non—radioactive proliferation assay (CellTiter 96 ® AQ ueO us Assay) , The purpose was to demonstrate that the test composition does not reduce the metabolism of the cells .
  • the present invention provides a composition useful as an analgesic and/or antiinflammatory agent .
  • anti-inflammatory is intended to include an inflammatory response modifier, including all inflammatory responses such as production of stress proteins , white blood cell infiltration, fever, pain, swelling and so forth. Furthermore , the terms
  • analgesic , "analgesia, “ and “analgesically” as used herein interchangeably are intended to include a pain reliever that is capable of reducing pain sensation or nociception, whether the pain incurred is a result of disease , inflammation, trauma or psychosomatic reaction.
  • composition of the present invention will therefore be administered as an effective amount to a subj ect in need of analgesia or anti-inflammatory treatment .
  • the phrase "in need of analgesia" as applied to a subj ect herein embraces a subj ect suffering mild to intense pain at the time of administration of the composition of the present invention, as well as a subj ect that can reasonably be expected to have an imminent onset of mild to intense pain, eg . , within about 1 to about 2 hours and especially within about 30 minutes , if no analgesic is administered.
  • an effective amount refers to that amount which is sufficient to induce or maintain an analgesic effect or analgesia when administered to a subj ect ; i . e . , an analgesic-producing amount .
  • an effective amount when used with reference to the compositions antiinflammatory activity means the amount sufficient to induce or maintain an anti-inflammatory effect .
  • What constitutes an effective pain-relieving or inflammatory amount , or dose, of the composition of the present invention depends , among other factors , on the body weight of the subj ect and the intensity of the pain and/or inflammation being treated. Normally an effective dose will be found in the range of about 1 to about 6 mg/kg body weight . For an average 75 kg subj ect , this range equates to a dose of about 75 to about 450 mg.
  • Proportionately smaller or larger doses can be appropriate for subj ects having lesser or greater body weight .
  • Such a dose can be administered as needed, but typically administration 1 to about 4 times per day, in most cases 1 or 2 times a day, provides adequate continuing relief of pain .
  • an "effective pain-relieving concentration” or “effective pain-relieving plasma concentration” as used herein is intended to mean a plasma level in a subj ect which when tested in a standardized test involving subj ect scoring of the severity of pain, achieves a mean score indicating pain relief .
  • patients score pain on a scale of from 0 (no reduction in severity of pain) to 4 (complete relief of pain) and a mean score equal to or greater than a given value is deemed to constitute effective pain-relief .
  • a mean score of 0.5 or greater and, more preferably, 1.0 or greater in such a test, as exemplified herein, is deemed to constitute effective pain relief .
  • the skilled artisan will appreciate , however, that other approaches can be used to assess the severity of pain and relief from such pain.
  • one aspect of the present invention involves a therapeutic method for analgesia in which a composition comprising the composition of the present invention is administered to a subj ect , in a formulation which provides detectable pain relief .
  • detectable pain relief it is meant that the formulation produces effective pain relief which is measurable by a standard method such as described above .
  • a formulation which achieves a mean score of 0.5 or greater and, more preferably, 1.0 or greater on a scale of from 0 to 4 in a testing system as described above, is deemed to provide detectable pain relief .
  • the invention is not limited to use of any particular type of formulation, so long as it exhibits the pharmacokinetic profile defined herein. Examples of suitable formulation types are described below.
  • composition of the present invention essentially comprises a mixture of plasma and/or serum and at least one metal , metal ion or metal salt .
  • plasma and “serum” are used herein interchangeably; however, the term “plasma” typically refers to the straw-coloured fluid in which the blood cells are suspended. It consists of various inorganic salts of sodium, potassium, calcium etc . with a high concentration of protein (approximately 70g/l) and a variety of trace elements .
  • serum refers to the fluid that separates from clotted blood or blood plasma that is allowed to stand . Serum is essentially similar in composition to plasma, but generally lacks fibrinogen and others substances that are used in the coagulation process .
  • the plasma or serum used in the present invention may be obtained from any animal source .
  • the plasma and/or serum is isolated from blood taken from an animal selected from the group consisting of human, equine , bovine, ovine, murine , caprine and canine .
  • the animal source for the plasma or serum is bovine .
  • the plasma or serum may be freshly isolated or alternatively lyophilised .
  • blood is isolated from cattle and the haemoglobin is removed by standard procedures .
  • the plasma is then preferably mixed with sodium bicarbonate (approx. 2Og per litre) and heated to about 80°C .
  • the coagulated plasma protein is then removed and lyophilised by standard procedures for further use .
  • the lyophilised plasma or serum is resuspended in water (approximately 5Og per litre) and mixed with at least one metal .
  • metals and/or metal ions are useful in the composition of the present invention and as such the present invention embraces all such metals or metal ions .
  • the metals are selected from the group consisting of nickel , sodium, copper, zinc , cobalt, iron, magnesium, manganese, potassium, silver and mercury.
  • the use of the metals as salts can be appropriate .
  • acceptable metal salts include acetate, ascorbate, benzoate, bicarbonate, chloride, citrate, carbonate, ⁇ - glycerophosphate, ⁇ -ketoglutarate , malonate , methanesulfonate, nitrate , succinate , sulfate, tartarate and tosylate salts .
  • Metal salts can be obtained using standard procedures well known in the art , for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion .
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion .
  • Alkali metal (for example , sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts can be made .
  • the metal is silver (I) , wherein the nitrate salt provides adequate free silver (I) ion to provide the necessary metal requirement .
  • the chloride salt on the other hand provides less silver, being less soluble and with a low dissociation constant and therefore is less useful in the present invention .
  • the skilled artisan will be able to readily determine the suitable salt form of the metal ion that provides the necessary properties for the present invention.
  • the metals used in the composition comprise a mixture of a number of metals .
  • the mixture of metals could consist essentially of NiSO 4 .7H 2 O, NH 4 VO 3 , NaF, CuSO 4 .5H 2 O, ZnCl 2 , (NH 4 ) 6 MO 7 O 24 .4H 2 O, COCl 2 .6H 2 O, FeSO 4 .7H 2 O, MgSO 4 .7H 2 O, H 3 BO 3 , MnCl 2 .4H 2 O and K 2 CrO 4 .
  • the metal , metal ion or metal salt thereof has been mixed with the plasma and/or serum, it is preferably- heated to at least 5O 0 C .
  • the mixture is heated to about 65°C .
  • a protease selected from the group consisting of trypsin, chymotrypsin, factor Xa, venom- protease , thrombin, plasmin and a serine-protease of the subtilisin family is preferably added before heating or after heating .
  • the protease is trypsin.
  • the protease can indeed be added before the metal , metal ion or metal salt is added . Whichever, once the protease has been added the resulting mixture of plasma/serum and protease, with or without metal , metal ion or metal salt is incubated between about 30°C and 45°C for at least 30 minutes . The mixture is then heated again. The second heating step is preferably carried out between about 80°C and about 150°C, more preferably between about 9O 0 C and about 130 0 C and most preferably, about 120°C to produce said analgesic and/or anti-inflammatory mixture .
  • analgesic and/or anti-inflammatory mixture can be either used directly or fractionated to obtain an analgesically and/or anti- inflammatory active fraction.
  • Techniques for fractionating protein-containing mixtures are well known in the art . See , for example , "Plasma Protein Fractionation” Heide K, Haupt H & Schwick H; in The Plasma Proteins , 2nd Edition VoI 3 (1977) Putnam F . (Ed) ; US Pat . No . 4 , 351 , 710 and US Pat . No . 4 , 322 , 275 both entitled "Fractionation of protein mixtures" ; US Pat . No . 5 , 138 , 034 entitled “Method of fractionating plasma proteins” all incorporated herein by reference .
  • the present invention provides a method of relieving pain and/or inflammation in a subj ect, the method comprising administering to the subj ect an effective pain- and/or inflammation-relieving amount of a composition of the present invention.
  • the method of the invention can be used to relieve mild to severe , acute or chronic pain.
  • the method of the invention is useful for treatment of non-human mammalian subj ects or patients , including domestic , farm and exotic animals , such as for example dogs horses , zoo animals and the like , but is primarily useful for treatment of human subj ects or patients .
  • the terms “treating, " “treatment” and the like are used herein to mean affecting an individual or subj ect , their tissue or cells to obtain a desired pharmacological and/or physiological effect .
  • the effect may be prophylactic in terms of completely or partially preventing the pain or inflammation or sign or symptom thereof , and/or may be therapeutic in terms of a partial or complete cure of the pain or inflammation.
  • Treating covers any treatment of , or prevention of pain or inflammation in a vertebrate , a mammal , particularly a human, and includes : (a) preventing the pain or inflammation from occurring in a subj ect that may be predisposed to the pain or inflammation, but has not yet occurred; (b) inhibiting the pain or inflammation, i . e . , arresting its development ; or (c) relieving or ameliorating the symptoms of the pain or inflammation, i . e . , cause regression of the symptoms of the pain or inflammation .
  • compositions of the present invention are also useful in the treatment and/or prevention of a wide range of conditions and disorders mediated by COX-2 , including but not restricted to disorders characterized by inflammation, pain and/or fever .
  • Such compositions are especially useful as antiinflammatory agents , such as in treatment of arthritis , with the additional benefit of having significantly less harmful side effects than compositions of conventional non-steroidal anti-inflammatory drugs (NSAIDs) that lack selectivity for COX-2 over COX-I .
  • NSAIDs non-steroidal anti-inflammatory drugs
  • compositions have reduced potential for gastrointestinal toxicity and gastrointestinal irritation including upper gastrointestinal ulceration and bleeding, reduced potential for renal side effects such as reduction in renal function leading to fluid retention and exacerbation of hypertension, reduced effect on bleeding times including inhibition of platelet function, and possibly a lessened ability to induce asthma attacks in aspirin- sensitive asthmatic subjects , by comparison with compositions of conventional NSAIDs .
  • compositions useful in methods of the invention are particularly useful as an alternative to conventional NSAIDs where such NSAIDs are contraindicated, for example in patients with peptic ulcers , gastritis , regional enteritis , ulcerative colitis , diverticulitis or with a recurrent history of gastrointestinal lesions ; gastrointestinal bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems ; kidney disease ; or in patients prior to surgery or patients taking anticoagulants .
  • compositions are useful to treat a variety of arthritic disorders , including but not limited to rheumatoid arthritis , spondyloarthropathies , gouty arthritis , osteoarthritis , systemic lupus erythematosus and juvenile arthritis .
  • compositions are useful in treating inflammation in such diseases as migraine headaches , periarteritis nodosa, thyroiditis , aplastic anemia, Hodgkin ' s disease, sclerodoma, rheumatic fever, type I diabetes , neuromuscular junction disease including myasthenia gravis , white matter disease including multiple sclerosis , sarcoidosis , nephrotic syndrome, Behcet ' s syndrome, polymyositis , gingivitis , nephritis , hypersensitivity, swelling occurring after injury including brain edema, myocardial ischemia, and the like .
  • diseases as migraine headaches , periarteritis nodosa, thyroiditis , aplastic anemia, Hodgkin ' s disease, sclerodoma, rheumatic fever, type I diabetes , neuromuscular junction disease including myasthenia gravis , white matter disease including multiple sclerosis
  • compositions are useful in treatment of pain, including but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer .
  • such compositions are useful for relief of pain, fever and inflammation in a variety of conditions including rheumatic fever, influenza and other viral infections including common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains , myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis , degenerative joint diseases (osteoarthritis) , gout and ankylosing spondylitis , bursitis , burns , and trauma following surgical and dental procedures .
  • compositions of the present invention can also be used in combination therapies with opioids and other analgesics , including narcotic analgesics , Mu receptor antagonists , Kappa receptor antagonists , non-narcotic ( i . e . , non- addictive) analgesics , monoamine uptake inhibitors , adenosine regulating agents , cannabinoid derivatives , Substance P antagonists , neurokinin-1 receptor antagonists and sodium channel blockers , among others .
  • opioids and other analgesics including narcotic analgesics , Mu receptor antagonists , Kappa receptor antagonists , non-narcotic ( i . e . , non- addictive) analgesics , monoamine uptake inhibitors , adenosine regulating agents , cannabinoid derivatives , Substance P antagonists , neurokinin-1 receptor antagonists and sodium channel blockers , among others .
  • Preferred combination therapies comprise a composition useful in methods of the invention with one or more compounds selected from aceclofenac , acemetacin, ⁇ -acetamidocaproic acid, acetaminophen, acetaminosalol , acetanilide , acetylsalicylic acid (aspirin) , S-adenosylmethionine , alclofenac , alfentanil , allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis (acetylsalicylate) , amfenac , aminochlorthenoxazin, 3 -amino-4-hydroxybutyric acid, 2-atnino-4-picoline , aminopropylon, aminopyrine , amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, antrafenine,
  • the terms “administration, " administering, “ and “administered” are used herein interchangeably .
  • the analgesic and/or anti-inflammatory composition of the present invention may be administered orally including sublingual , topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers , adjuvants , and vehicles .
  • parenteral as used herein includes subcutaneous inj ections , aerosol , intravenous , intramuscular, intrathecal , intracranial , inj ection or infusion techniques or rectal or vaginally.
  • the analgesic and/or anti-inflammatory composition of the present invention is administered together with a pharmaceutically acceptable carrier or diluent compatible with the composition .
  • any conventional pharmaceutically acceptable carrier can be utilised.
  • the carrier material can be organic or inorganic inert carrier material suitable for oral administration .
  • Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc , vegetable oils , polyalkylene-glycols , petroleum j elly and the like .
  • the pharmaceutically active preparations may contain other pharmaceutically active agents .
  • additives such as flavouring agents , preservatives , stabilisers , emulsifying agents , buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding .
  • analgesic and/or anti-inflammatory composition of the present invention When the analgesic and/or anti-inflammatory composition of the present invention is administered orally, it is generally administered at regular intervals , conveniently at meal times or once daily.
  • the analgesic and/or antiinflammatory composition of the present invention can be made up in any conventional form including : (a) solid form for oral , rectal or vaginal administration such as tablets , capsules (eg .
  • compositions for intravenous administrated may also be prepared.
  • Pharmaceutical preparations may be sterilised and/or may contain preservatives , stabilisers , wetting agents , emulsifiers , salts for varying the osmotic pressure and/or buffers .
  • analgesic and/or anti-inflammatory composition of the present invention is preferably prepared as an ointment , tincture , cream, gel , solution, lotion, spray; aerosol and dry powder for inhalation, suspension and the like .
  • any conventional methods of preparing topical compositions can be utilised in this invention .
  • the preferred methods of applying the analgesic and/or anti-inflammatory composition of the present invention is in the form of an ointment, gel , cream, lotion, spray; aerosol or dry powder for inhalation.
  • a pharmaceutical preparation for topical administration to the skin can be prepared by mixing the analgesic and/or anti-inflammatory composition of the present invention with non-toxic , therapeutically inert , solid or liquid carriers customarily used in such preparation. These preparations generally contain 0.01 to 5.0 percent by weight , preferably 0.1 to 1.0 percent by weight, of the analgesic and/or anti-inflammatory composition of the present invention, based on the total weight of the peptide preparation.
  • additives such as preservatives , thickeners , perfumes and the like conventional in the art of pharmaceutical compounding of topical preparation can be used.
  • conventional antioxidants or mixtures of conventional antioxidants can be incorporated into the topical preparations containing the afore-mentioned active agent .
  • the conventional antioxidants which can be utilised in these preparations are included N-methyl-D- tocopherolamine , tocopherols , butylated hydroxyanisole , butylated hydroxytoluene, ethoxyquin and the like .
  • Cream- base pharmaceutical formulations containing the antigen preparation are composed of aqueous emulsions containing a fatty acid alcohol , semi-solid petroleum hydrocarbon, ethylene glycol and an emulsifying agent .
  • Ointment formulations containing the analgesic and/or anti-inflammatory composition of the present invention comprise admixtures of a semi-solid petroleum hydrocarbon with a solvent dispersion of the analgesic and/or anti- inflammatory composition.
  • Cream compositions containing the analgesic and/or anti- inflammatory composition of this invention preferably comprise emulsions formed from a water phase of a humectant , a viscosity stabiliser and water, an oil phase of a fatty acid alcohol , a semi-solid petroleum hydrocarbon and an emulsifying agent and a phase containing analgesic and/or anti-inflammatory composition dispersed in an aqueous stabiliser-buffer solution .
  • Stabilisers may be added to the topical preparation.
  • fatty acid alcohol components function as a stabiliser .
  • These fatty acid alcohol components function as a stabiliser .
  • These fatty acid alcohol components are derived from the reduction of a long-chain saturated fatty acid containing at least 14 carbon atoms .
  • Formulations for aerosols are described in Drugs and Pharmaceutical Sciences , Marcel Dekker, New York, 72 : 547- 574 (1996) .
  • the analgesic and/or antiinflammatory composition of the present invention can be delivered by dry powder inhalation. Such formulations and devices are described in Pharmaceutical Technology, June 1997 , pp .117-125.
  • the treatment regime will vary. However, typically an individual is monitored hourly or daily, depending on the above factors , and the status of pain/inflammation is determined. Administration of the analgesic and/or anti-inflammatory composition of the present invention continue until the pain and/or inflammation is reduced or alleviated.
  • Protocols for conducting human pharmacokinetic studies are well known in the art and any standard protocol can be used to determine whether a particular composition of the present invention satisfies the pharmacokinetic criteria set out herein .
  • An example of a suitable protocol is described below.
  • the compositions of the present invention upon administration, reduce the amount of TNF- ⁇ present in an individual ' s tissue as compared to untreated tissue .
  • the present invention encompasses a method of reducing the amount of TNF- ⁇ in an individual ' s tissue comprising the step of administering an effective amount of a composition comprising an effective amount of an analgesically and/or anti-inflammatory active fraction separated from a mixture of plasma and/or serum and at least one metal , metal ion or metal salt thereof , wherein said mixture has been denatured, wherein the composition reduces the amount of TNF- ⁇ in the individual ' s tissue compared to untreated tissue .
  • a solution was then prepared comprising 152 litres of water, 8kg dried plasma-protein as prepared above and 200ml of a metal-containing solution.
  • the constituents of the metal-containing solution are shown in Table 1.
  • the mixture was then heated up to 12O 0 C and maintained for two hours with constant mixing . During this time the plasma-protein dissolved and was sterilized. The resulting material was then held at a temperature of about 35 0 C and 0.125g/l of trypsin was added. The material was then allowed to incubate for approximately 2 hours . The digested material was then autoclaved and cooled to produce the analgesic/anti-inflammatory composition of the present invention.
  • a composition comprising the ingredients shown in Table 2 were mixed at 75 -8O 0 C in a 250 litre vacuum homogenizer equipped with anchor and turbo mixers . Then the ingredients shown in Table 3 were added and the mixing was continued at 80-83 0 C for 10 minutes with the aid of the turbo mixer .
  • step 5 Add the water phase (step 5) to the oil phase (step 3 ) and mix using a short shaft air mixer . Then add step 4 to this using a plastic sieve to ensure that no lumps are incorporated;
  • Group A - work or injury induced conditions either acute or sub-acute eg repetitive strain injury (RSI) , tennis elbow, joint and musculo-tendinous injury;
  • RSSI repetitive strain injury
  • Group B Arthritic and aging conditions - sub-acute and chronic eg osteoarthritis .
  • Table 5 shows the effect of using the topical composition over a three (3 ) month period .
  • compositions of the present invention are metallo-peptide complexes .
  • this preparation has been shown to be as effective as orally administered indocid (Indomethacin) , a NSAID which reduces pain, swelling, and inflammation or phenylbutazone, a
  • NSAID used in the treatment of pain, lameness , laminitis and osteoarthritis , in an animal model of inflammatory arthritis .
  • the animal model was inflammation caused by an inj ection of mycobacteria into the foot pads of Long-Evans rats (data not shown) .
  • composition described in Example 2 possessed inhibitory activity against the serine proteinases-trypsin and human granulocyte elastase (HGE) . Since HGE has been implicated in the destruction of cartilage in inflammatory arthritis the inhibitory properties of the composition in Example 2 against this or similar enzymes may contribute to its overall biological activity. Apart from these direct effects it is postulated that the compositions of the present invention might also work indirectly by acting as an agent for specific transdermal transport essential metals into the affected j oints .
  • HGE serine proteinases-trypsin and human granulocyte elastase
  • the treated group When asked to assess the efficacy of the treatment composition, the treated group scored a 75% approval for product , while the placebo group only had a 45% approval rate .
  • Rottweiler B only No response and withdrew 2 Rottweiler B only Possible skin reaction to cream and withdrew 3 Rottweiler B then A Some improvement with B, no change with A 4 Rottweiler A then B Improved with A, then worse with B 5 Rottweiler A then B No response to either 6 Rottweiler A then B No response to either 7 Rottweiler B only Lost to follow up 8 Rottweiler A then B No response to either 9 Rottweiler B then A Improved on B, then worse with A 10 Labrador B then A Marked improvement on B, sustained while on A.
  • Rottweiler B only Chronic problem in elbows, complicated by sesamoid fragmentation during treatment. B used on L elbow and R sesamoid and dog became sound and has remained so. 22 Rottweiler B then A No response. Very severe case, both legs treated. Dog was destroyed.
  • compositions of the present invention are anti- inflammatory.
  • TNF- ⁇ is a cytokine known to be released as a result of early inflammatory responses .
  • the aim was to demonstrate that the compositions of the invention were capable of regulating or affecting the presence of TNF- ⁇ . It was hypothesised that if the TNF- ⁇ levels were reduced in the assay then this demonstrated that the compositions of the invention were anti-inflammatory.
  • Monocytes were isolated by elutriation by centrifugation standard procedure (Brahmi et al . , 1983 , Ann Immunol
  • test composition was that described in Example 1 , except that the metal-containing solution was a simplified version of the metal-containing solution described in Table 1 in that it only contained zinc chloride and glycine .
  • TNF- ⁇ levels in the culture supernatants were measured by ELISA Opti EIA, BD Bioscience following the manufacturer' s instructions .
  • the concentrations of test composition used were 40% (200 ⁇ L) ; 20% (lOO ⁇ L) ; 10% (50 ⁇ L) ; and 0% .
  • the control was LPS (500ng/mL) and there were 3 repeats .
  • test sample decreases LPS-induced TNF-alpha secretion in human monocytes , indicating efficacy in inhibiting inflammatory responses .
  • Example 6 This experiment was essentially a repeat of the experiment described in Example 6 , with the only difference being the metal-containing solution.
  • the test composition was that described in Example 1 , except that the metal-containing solution contained only copper sulphate .
  • test sample inhibits the inflammatory response of human monocytes to an LPS challenge .
  • Example 6 Test of the composition used in Example 6 on TNF- ⁇ production by LPS-stimulated human monocytes was undertaken, but at lower concentrations .
  • test sample does not compete in inhibiting TNF- alpha secretion with the FCS .
  • compositions of the present invention do not disturb the metabolism of cells in vitro and, thus, the TNF-alpha suppressive effect is not due to a metabolism problem of the cells a non—radioactive proliferation assay was conducted.
  • the specific assay used was the CellTiter 96 ® AQ ueOus Non- Radioactive Cell Proliferation Assay from Promega .
  • This method is a non-radioactive alternative to the [ 3 H] thymidine incorporation cell proliferation assay.
  • the manufacturer' s instructions were followed, but briefly, lOO ⁇ L of 5 x 10 6 K562 (human chronic myelogenous leukaemia) cells in RPMI supplemented with 5% fetal bovine serum (FBS) were added to the wells of a 96- well plate . Cells were then incubated for 20 hours at 37 0 C in a humidified, 5% CO 2 atmosphere .
  • the medium was then exchanged and allowed to equilibrate for 1 hour, then 20 ⁇ L of a solution comprising (3 - (4 , 5-dimethylthiazol-2-yl) -5- (3 -carboxymethoxyphenyl) -2- (4 -sulfophenyl) -2H-tetrazolium, inner salt ; (MTS) and phenazine methosulfate (PMS) was added to each well . A Ohr absorbance reading at 490nm was taken immediately and then absorbance was measured every hour thereafter . Readings at 21 and 45 hours after the addition of the MTS/PMS solution were also taken.

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Abstract

La présente invention concerne un agent présentant une activité analgésique et anti-inflammatoire. La présente invention concerne en particulier une préparation comprenant une quantité significative du point de vue thérapeutique d'une fraction active analgésique et/ou anti-inflammatoire séparée d'un mélange de plasma et/ou de sérum, et d’au moins un métal, ion métallique ou sel métallique dudit métal, ledit mélange ayant été dénaturé.
EP06704862A 2005-02-11 2006-02-10 Préparation analgésique et anti-inflammatoire Withdrawn EP1853281A4 (fr)

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AU2005900638A AU2005900638A0 (en) 2005-02-11 Analgesic and anti-inflammatory composition
US11/059,580 US7510732B2 (en) 2005-02-16 2005-02-16 Analgesic and anti-inflammatory composition
PCT/AU2006/000185 WO2006084334A1 (fr) 2005-02-11 2006-02-10 Préparation analgésique et anti-inflammatoire

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US20070048387A1 (en) * 2005-09-01 2007-03-01 Edwards Jeffrey D Tissue disruption treatment and composition for use thereof
AU2007246167B2 (en) * 2006-04-28 2012-08-16 Cambridge Scientific Pty Ltd COX-2 inhibitor
EP2019682A4 (fr) * 2006-04-28 2011-02-02 Cambridge Scient Pty Ltd Composition de médiation de la cytokine
AU2008294074B2 (en) 2007-08-30 2015-01-22 Walter And Eliza Hall Institute Of Medical Research Dendritic cell marker and uses thereof
CA3115308A1 (fr) * 2018-10-26 2020-04-30 Alkahest, Inc. Utilisation de plasma et de fractions de plasma pour attenuer la douleur, ameliorer la cicatrisation des plaies et la recuperation post-operatoire

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EP0061556A1 (fr) * 1979-11-16 1982-10-06 AB Pripps Bryggerier Préparation d'acides aminés enrichie en fer hématinique et procédé pour la confection de préparations d'acides aminés enrichies en fer hématinique à partir d'hémoprotéines
EP0417002A1 (fr) * 1989-09-08 1991-03-13 Imedex Societe Anonyme Application d'hydrolysats de globines pour la stimulation cellulaire, procédé de test de l'activité de ces substances, produits pharmaceutiques et cosmétiques obtenus et procédé de préparation d'hydrolysats de globines
EP0956869A2 (fr) * 1998-05-15 1999-11-17 Hogy Medical Co., Ltd. Agent de scellement tissulaire

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US2579367A (en) * 1950-11-24 1951-12-18 Hynson Westcott & Dunning Inc Bandage
US3152955A (en) * 1960-12-22 1964-10-13 Distillers Co Yeast Ltd Amino acids concentrate
US3672954A (en) * 1968-11-02 1972-06-27 Inst Nazionale Chimico Biolog Process for preparing deprotenized blood extracts having a healing action and product obtained thereby
EP0061556A1 (fr) * 1979-11-16 1982-10-06 AB Pripps Bryggerier Préparation d'acides aminés enrichie en fer hématinique et procédé pour la confection de préparations d'acides aminés enrichies en fer hématinique à partir d'hémoprotéines
EP0417002A1 (fr) * 1989-09-08 1991-03-13 Imedex Societe Anonyme Application d'hydrolysats de globines pour la stimulation cellulaire, procédé de test de l'activité de ces substances, produits pharmaceutiques et cosmétiques obtenus et procédé de préparation d'hydrolysats de globines
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See also references of WO2006084334A1 *

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WO2006084334A1 (fr) 2006-08-17

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