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Composition for Use in Treating and Preventing Inflammation Related Disorder

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Composition for Use in Treating and Preventing Inflammation Related Disorder (19) TZZ 54¥¥7A_T (11) EP 2 543 357 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 09.01.2013 Bulletin 2013/02 A61K 9/00 (2006.01) A61K 47/36 (2006.01) (21) Application number: 11173000.8 (22) Date of filing: 07.07.2011 (84) Designated Contracting States: (72) Inventor: Lin, Shyh-Shyan AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Taipei (TW) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Becker Kurig Straus Designated Extension States: Bavariastrasse 7 BA ME 80336 München (DE) (71) Applicant: Holy Stone Healthcare Co.,Ltd. Taipei City (TW) (54) Composition for use in treating and preventing inflammation related disorder (57) The presentinvention isrelated to ause fortreat- ease, coeliac disease, conjunctivitis, otitis, allergic rhin- ing and preventing inflammation related disorder of a itis, gingivitis, aphthous ulcer, bronchitis, gastroesopha- composition containing a drug and hyaluronic acid (HA) geal reflux disease (GERD), esophagitis, gastritis, en- or HA mixture, whereas the HA or the HA mixture as a teritis, peptic ulcer, inflammatory bowel disease (IBD), delivery vehicle can be a formulation including at least Crohn’s Disease, irritable bowel syndrome (IBS), intes- two HAs having different average molecular weights. The tinal inflammation or allergy, urethritis, cystitis, vaginitis, composition has been demonstrated to be capable of proctitis, eosinophilic gastroenteritis, or rheumatoid ar- reducing the therapeutic dose of a drug on the treatment thritis. and prevention of inflammation related disorders is acute inflammatory disease, chronic obstructed pulmonary dis- EP 2 543 357 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 543 357 A1 2 Description alleviate pain by counteracting the cyclooxygenase (COX) enzyme. On its own, COX enzyme synthe- [0001] The present invention provides a composition sizes prostaglandins, creating inflammation. In of hyaluronic acids in combination with a drug for treating whole, the NSAIDs prevent the prostaglandins from and preventing an inflammation related disorder, espe- 5 ever being synthesized, which reduces or eliminates cially where the onset of the disorder mainly occurs in the pain. Some common examples of NSAIDs are: mucosal tissue. aspirin, ibuprofen, and naproxen. The newer specific [0002] Hyaluronic acid, also known as hyaluronan, hy- COX-inhibitors, although it is presumed, sharing a aluronate and sodium hyaluronate, is generally referred similar mode of action, are not classified together to as HA, which is a natural glycosaminoglycan macro- 10 with the traditional NSAIDs. molecule including disaccharides composed of the alter- 3. ImSAIDs were discovered to have diverse biolog- native N-acetyl-D-glucosamine and D-glucuronic acid ical properties, including anti-inflammatory proper- linked via alternative β -1,3 and β -1,4 glycosidic bonds. ties. ImSAIDs work by altering the activation and mi- HA found in nature with a molecular weight (Mw) between gration of inflammatory cells, which are immune cells 50,000 Dalton (Da) and a few millions Dalton usually has 15 responsible for amplifying the inflammatory re- high viscosity. sponse (Bao F, John SM, Chen Y, Mathison RD, [0003] HA found in nature is the extra- cellular material Weaver LC. The tripeptide phenylalanine-(D) gluta- with elasticity, filling between the cells and the collagen- mate-(D)glycine modulates leukocyte infiltration and ous fibers and covering onto some epidermal tissues, oxidative damage in rat injured spinal cord. Neuro- mainly for protecting and lubricanting cells, for providing 20 science., 2006, 140(3):1011-22; Epub on 2006 Apr a platform for transporting the regulatory T cell, and also 3). The ImSAIDs represent a new category of anti- for stabilizing collagen network and protecting collagen inflammatory drugs and are unrelated to steroid hor- network from the mechanical damage. HA is also a major mones or non-steroidal anti-inflammatory drugs. lubricant in the tendon and the tendon sheath and on the surface of the synovial membrane due to the lubricant 25 [0006] US patent 6,159,955 discloses a method of feature and the high shock absorber, and HA is helpful treating aphthous ulcers comprising administration of an for the tissue rheological mechanics, motion and the cell effective amount of a composition comprising a NSAID proliferation (referring to Delpech, B. et al., 1997. Hy- and a formulation of hyaluronic acid selected from hy- aluronan: fundamental principles and applications in can- aluronic acid, pharmaceutically acceptable salts thereof, cer. J. Intern. Med. 242, 41-48), and participates in the 30 fragments thereof and/or subunits thereof. However, it receptor interaction on the surface of some cells, partic- did not emphasize the less dose of the NSAID being ularly to be the major receptor of CD44. CD44 is widely used, whereas mesalamine does not belong to NSAID. accepted as a marker of the activated lymphocyte (refer- [0007] The mucous membranes (or mucosae; singular ring to Teder P, et al., 2002, Resolution of lung inflam- mucosa) are linings of mostly endodermal origin, covered mation by CD44. Science). 35 in epithelium, and involved in absorption (gastrointestinal [0004] Recently, HA is applied in clinical treatment in tract) and secretion (gastrointestinal and respiratory the sodium salt form mainly in eye, skin, orthopedics, tract). They line cavities that are exposed to the external surgery, arthritis, artery treatment and in cosmetic fields. environment and internal organs and contiguous with The HA with alkali metal ion, alkaline earth metal ion (for skin at several body areas: at the nostrils, the mouth, the example, the magnesium ion), aluminum ion, ammonium 40 lips, the eyelids, the ears, the genital area, and the anus. ion, and salt form of the replacement of the ammonium The sticky, thick fluid secreted by the mucous mem- ion can be the carrier for assisting drug absorption (re- branes and glands is termed mucus. The term mucous ferring to Belgium Patent 904,547). The silver salt is used membrane refers to where they are found in the body as the mycocide and the gold salt is used for treating the and not every mucous membrane secretes mucus. rheumatoid arthritis among the heavy metal salt of the 45 [0008] Conjunctivitis refers to inflammation of the con- HA (referring to WO 87/05517). junctiva (the outermost layer of the eye and the inner [0005] Anti-inflammatory refers to the property of a surface of the eyelids). substance or treatment that reduces inflammation. Anti- [0009] Otitis is a general term for inflammation or in- inflammatory drugs make up about half of analgesics, fection of the ear, in both humans and other animals. remedying pain by reducing inflammation as opposed to 50 [0010] Rhinitis is defined as inflammation of the nasal opioids, which affect the central nervous system. The membranes and is characterized by a symptom complex related drugs are described as follows: that consists of any combination of the following: sneez- ing, nasal congestion, nasal itching, and rhinorrhea. The 1. Steroids, specifically glucocorticoids, reduce in- eyes, ears, sinuses, and throat can also be involved. US flammation or swelling by binding to glucocorticoid 55 patentapplication 20050107330 discloseda pharmaceu- receptors. These drugs are often referred to as cor- tical composition for curative topical treatment of rhinitis ticosteroids. comprising at least one acidic glycosaminoglycan. But 2. Non-steroidal anti-inflammatory drugs (NSAIDs) this invention also contains at least one sympathomimet- 2 3 EP 2 543 357 A1 4 ic suitable for topical application and having vasocon- to 6 weeks (Colasa®). For the treatment of mildly to mod- strictor action or detumescent action on the mucous erately active ulcerative colitis: The usual dosage in membrane or its physiologically acceptable salts or de- adults is two 400-mg tablets to be taken three times a rivatives. It did not disclose the technical concept that day for a total daily dose of 2.4 grams for a duration of 6 less dose of drug can be used in need by combining with 5 weeks (Asacol®). The recommended dosage for the in- HA. duction of remission and the symptomatic treatment of [0011] Oral mucosa is the mucous membrane epithe- mildly to moderately active ulcerative colitis is 1 g (4 PEN- lium of the mouth. An oral ulcer is an open sore inside TASA 250 mg capsules or 2 PENTASA 500 mg capsules) the mouth, or rarely a break in the mucous membrane or 4 times a day for a total daily dosage of 4 g. Treatment the epithelium on the lips or surrounding the mouth. Once 10 duration in controlled trials was up to 8 weeks. (PENTA- formed, the ulcer may be maintained by inflammation SA®). In a preferred embodiment, the drug is a steroid, and/or secondary infection. prednisolone. The initial dose of prednisone varies de- [0012] Bronchitis is inflammation of the mucous mem- pending on the condition being treated and the age of branes of the bronchi, the airways that carry airflow from the patient. The starting dose may be from 5 to 60 mg the trachea into the lungs. Bronchitis can be divided into 15 per day and often is adjusted based on the response of two categories, acute and chronic, each of which has the condition being treated (Prednesol q). In a preferred unique etiologies, pathologies, and therapies. US patent embodiment, the drug is a NSAID, Naproxen. For Rheu- application 20030171332 discloses a method of treating matoid arthritis, osteoarthritis, and ankylosing spondyli- respiratory conditions by a polysaccharide capable of tis: 250-500 mg Naproxen is administered orally twice binding CD44. However, only one single species of HA 20 daily and may be increased to 1.5 g/day of naproxen could be involved and the prior art did not disclose a base for limited time period.
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