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(12) United States Patent (10) Patent No.: US 9,084,769 B2 Alex Et Al

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(12) United States Patent (10) Patent No.: US 9,084,769 B2 Alex Et Al US009084769B2 (12) United States Patent (10) Patent No.: US 9,084,769 B2 Alex et al. (45) Date of Patent: Jul. 21, 2015 (54) COMPOSITIONS COMPRISING NON (2013.01); A61K31/192 (2013.01); A61 K STEROIDAL ANTI-INFLAMMLATORY DRUGS 31/415 (2013.01); A61 K3I/7016 (2013.01) AND METHODS FOR USE THEREOF (58) Field of Classification Search CPC A61K 2300/00; A61K 31/7016; A61K 33/30 (71) Applicants:Phillip Alex, Abingdon, MD (US); Ben USPC .................................. 424/641, 451, 474, 490 Johns, Scotch Plains, NJ (US) See application file for complete search history. (72) Inventors: Phillip Alex, Abingdon, MD (US); Ben (56) References Cited Johns, Scotch Plains, NJ (US) |U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 2010/0150861 A1* 6/2010 Geibel et al. ................. 424/85.2 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 13/705,552 Watanabe et al. Prebiotic Properties of Epilactose. Aug. 5, 2008. J. Dairy Sci. pp. 4518-4526.” (22) Filed: Dec. 5, 2012 Lanza et al. NSAID-induced gastric ulceration is dose related by weight: an endoscopic study with flurbiprofen. May 1993. Am J (65) Prior Publication Data Gastroenterol. Abstract.” |US 2013/0142869 A1 Jun. 6, 2013 * cited by examiner Primary Examiner – Frederick Krass Related U.S. Application Data Assistant Examiner – Tracy Liu (60) Provisional application No. 61/566,765, filed on Dec. (74) Attorney, Agent, or Firm – Christina Chamberlin 5, 2011. (57) ABSTRACT (51) Int. Cl. The invention provides analgesic, antipyretic and anti-in A6 IK 3.1/7016 (2006.01) flammatory compositions containing epilactose in combina A6 IK 33/30 (2006.01) tion with non-steroidal anti-inflammatory drugs and pharma A6 IK 31/167 (2006.01) ceutically acceptable zinc compounds. This invention relates A6 IK 31/192 (2006.01) to the use of these novel compositions for significantly A6 IK 31/415 (2006.01) improved and synergistic safety and therapeutic profiles. (52) U.S. CI. CPC ............... A61K33/30 (2013.01); A61K3I/I67 14 Claims, 5 Drawing Sheets U.S. Patent Jul. 21, 2015 Sheet 1 of 5 US 9,084,769 B2 (%) www. U.S. Patent Jul. 21, 2015 Sheet 2 of 5 US 9,084,769 B2 ; U.S. Patent Jul. 21, 2015 Sheet 3 of 5 US 9,084,769 B2 U.S. Patent Jul. 21, 2015 Sheet 4 of 5 US 9,084,769 B2 Figure 4 fiftediati-effect fºot 5: ... ZnC - Zinc Carriosirie Znºj - Ziric Ch?otide ZnSt - Zinc Stearate ~. - : s Epi. Epifactose U.S. Patent Jul. 21, 2015 Sheet 5 of 5 US 9,084,769 B2 Figure 5 Fractiona: ?ffect Fra?na ££8. : 3 US 9,084,769 B2 1 2 COMPOSITIONS COMPRISING NON enzyme selectively which was considered clinically very sig STEROIDAL ANTI-INFLAMMLATORY DRUGS nificant. Selective NSAIDs (also called COX-2 inhibitors) are AND METHODS FOR USE THEREOF as effective in relieving pain and inflammation as nonselec tive NSAIDs but are less likely to cause gastrointestinal FIELD OF THE INVENTION injury. Due to their decreased potential to cause ulcers or gastrointestinal bleeding, selective NSAIDS such as cele The present invention relates to the combination of phar coxib are sometimes recommended for people who have had maceutical compositions comprising of epilactose, a non a peptic ulcer, gastrointestinal bleeding, or gastrointestinal steroidal anti-inflammatory drug, and an appropriate zinc upset when taking other nonselective NSAIDs. However, compound, and the use thereof for the safe, effective, and 10 many of the drugs in this sub-category have been withdrawn pronounced treatment of pain, inflammation and fever. The present invention is also directed to methods of preparation of from the US market in view of other observed side effects, disclosed pharmaceutical compositions with all key ingredi which include valdecoxib, rofecoxib, parecoxib, etoricoxib. ents in different embodiments in pharmaceutically effective Lumiracoxib is known to have been put on watch list; the only amounts that maintain synergy in their efficacy for the 15 drug in this sub-category available commercially is cele intended clinical use. coxib. Numeslide, also a COX-2 inhibitor has been with drawn in many countries due to adverse effects. BACKGROUND OF THE INVENTION NSAIDs have strong anti-inflammatory, antipyretic, and analgesic properties, and are used for the treatment of a vari Non-steroidal anti-inflammatory drugs (NSAIDs) form a 20 ety of acute and chronic conditions associated with pain, fever very large category of drugs that are primarily used to reduce and inflammation. Some of the conditions that NSAIDs are fever, pain and inflammation. As the name implies, they do widely used include rheumatoid arthritis, osteoarthritis, not act via the same path as steroids that suppress the immune ankylosing spondylitis, inflammatory arthropathies, acute system from producing fever and pain. NSAIDs are also gout, dysmenorrhoea, metastatic bone pain, headache and non-narcotic and their sub-categories are based on their 25 migraine, postoperative pain, pyrexia, ileus, renal colic, and chemical structure. They differ in not only form, but also in pain associated with injuries and dental procedures. The which enzymes they inhibit and for how long. principal pharmacological effects of NSAIDs in reducing the Among the ‘Salicylates’ sub-category, the most famous pain and inflammation have been demonstrated to be due to drug is aspirin known to be an effective pain killer. It also has their potential to inhibit enzymes, called cyclooxygenase, other therapeutic uses such as effective blood thinner. Other 30 which in turn inhibit prostaglandin synthesis. Cyclooxyge known drugs in this sub-category are salicylamide, salicyl nase enzyme inhibition is also responsible for many of the salicylate, methyl salicylate, magnesium salicylate, fais side effects of NSAIDs. Two main types of NSAIDs are lamine, ethenzamide, diflunisal, choline magnesium salicy known as ‘selective’ and ‘nonselective’ depending on their late, benorylate/benorilatem and amoxiprin. ability to inhibit specific types of cyclooxygenase (COX) Another sub-category is constituted by ‘Arylalkanoic 35 enzymes. Nonselective NSAIDs are known to inhibit both acids’, which has an aryl group on one of the rings of the drug COX-1 and COX-2 enzymes whereas selective NSAIDs pref molecule. The drugs in this sub-category presently in use are erentially inhibit COX-2 enzymes found at the sites of inflam aceclofenac, acemetacin, alclofenac, bromfenac, diclofenac, mation more than the COX-1 enzymes normally found in the etodolac, indometacin, nabumetone, oxametacin, proglu stomach, blood platelets and blood vessels. metacin, sulindac, and tolmetin. 40 Most nonselective NSAIDs, such as aspirin, ibuprofen, The ‘2-Arylpropionic acids’ are an important sub-category naproxen etc. are commonly available without prescription in and tends to have an ending of ‘profen’ in their generic names. most countries and belong to ‘Over-the-counter (OTC)’ The known drugs in this sub-category are alminoprofen, group. Most people also tolerate NSAIDs without any prob benoxaprofen carprofen, dexibuprofen, dexketoprofen, fen lem when taken occasionally. However, side effects occurand bufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, 45 are frequently encountered when the drugs are necessarily ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, taken on long-term basis. naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid. The clinical utility of NSAIDs is significantly limited due Another sub-category of NSAIDs is collectively known as largely to their ability to cause a diverse array of toxicities, ‘N-Arylanthranilic acids’; the generic drugs in this sub-cat particularly of those in the gastrointestinal tract, renal, and egory tend to have ending of ‘fenamic acids’ and the well 50 cardiovascular systems. The most common side effects and known drugs are mefenamic acid, flufenamic acid, meclofe associated risks of their use due to their toxicities include the namic acid, and tolfenamic acid. following: “Oxicams’ is yet another sub-category of NSAID, which Gastrointestinal system: While short term use of NSAIDs are essentially enolic acid (e.g., a double bond between two can cause stomach upset (dyspepsia), their long term use, adjacent carbon atoms and a hydroxyl containing molecules) 55 especially at high doses, can lead to peptic ulcer and bleeding that exhibit keto-enol tautomerism. The well known drugs in of the upper gastrointestinal tract in the stomach. These side this sub-category are droxicam, lomoxicam, meloxicam, effects are caused by NSAIDs inhibiting the COX-1 enzyme piroxicam, and tenoxicam. resulting into decrease of mucous production in cells lining of Another sub-category is characterized as ‘Pyrazolidine’ the gastrointestinal tract, leaving it vulnerable to gastric acid, derivates; pyrazolidine is a five member ring with two nitro 60 bile, enzymes, and alcohol. Gastrointestinal injuries range gen atoms adjacent to each other that beardifferent functional from heartburn, nausea, erosion and abdominal pain to seri groups. The well known drugs in this sub-category are ampy ous complications such as ulcers and hemorrhage (Shoenfeld rone, azapropazone, clofezone, kebuzone, metamizole, P, M O Kimmey, J. Scheiman, D. Bjorkman, L. Laine, Ali mofebutazone, oxyphenbutazone, phenazone, phenylbuta ment Pharmacol Ther 1999; 13:1273-1285). COX-1 has been zone, sulfinpyrazone. 65 found to be responsible for protecting the stomach through Finally, another important sub-category of NSAIDs is mucous membrane and immune cell defense,
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