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
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U.S. Patent Jul. 21, 2015 Sheet 2 of 5 US 9,084,769 B2
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U.S. Patent Jul. 21, 2015 Sheet 4 of 5 US 9,084,769 B2
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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
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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, maintaining known as “COX-2 Inhibitor’ for their ability to inhibit COX-2 blood flow and kidney function, and processing sensations. US 9,084,769 B2 3 4 Kidney Toxicity: A comprehensive review of nephro-tox particles range to enhance the dispersion of active ingredient icity of existing NSAIDs suggested that the adverse effects of and incorporation of substances that would enhance the bio NSAIDs are mediated via inhibition of prostaglandin synthe availability of the compositions. sis from arachidonic acid by non-specific blocking of the U.S. Pat. No. 4,873,231 disclosed a possible mode of enzyme cyclooxygenase leading to vasoconstriction and decreasing the toxicity of a salt of ibuprofen by combining reversible mild renal impairment in volume contracted states. with suitable amounts of bicarbonate or carbonate. (Ejaz P. Bhojani K, Joshi V R; J. Assoc. Phys. India, Vol 52, U.S. Pat. No. 5,155,118 uses substituted imidazoles for 2004, pp 632-640) This could lead to acute tubular necrosis preventing NSAID-induced renal failure by administering and acute renal failure when unopposed. In patients on long these separately or as NSAID composition. term NSAIDs without acute or chronic renal failure, subclini 10 U.S. Pat. No. 5,213,807 utilized curative property of pros cal renal dysfunction such as reduced creatinine clearance taglandin in NSAIDs formulation through a three layered and impaired urine concentrating ability has been observed. coaling having commercially available prostaglandin, miso This sub-clinical dysfunction, although reversible on with prostol in the mantle core. Similarly, U.S. Pat. No. 6,656,503 drawal of NSAIDs in most cases, some cases of persistent (EP1068867), U.S. Pat. No. 7,303,761 and also U.S. Pat. No. residual dysfunction have also bean reported. The authors 15 6,740,340 (WO99/65496) disclose similar use of prostaglan conclude that despite a wide range of NSAIDs being avail dins in NSAIDs formulations. able, a renal safe NSAID is yet to be discovered. U.S. Pat. No. 6,926,907 (EP2163241A1) provides dosage It has been determined that use of COX-2 inhibitors forms capable of releasing an agent that raises the pH of a increases the chances of having a heart attack. Further, most patient’s gastrointestinal tract prior to the release of non NSAIDs, including COX-2 inhibitors boost blood pressure 20 steroidal anti-inflammatory drug. and could counteract the effect of some blood-pressure drugs. U.S. Pat. No. 4,757,060 and U.S. Pat. No. 5,037,815 dis They have also been shown to impair blood vessels’ ability to close NSAID compositions having an H1 receptor blocker relax and may stimulate the growth of smooth muscle cells such as diphenhydramine and/or its salt, ethanolamines, eth inside arteries leading to clogging of arteries, a process ylenediamines, alkylamines and piperazines and/or their salts known as atherosclerosis. 25 and an H2 receptor blocker such as cimetidine, ranitidine, Other Toxicities: One of the othertoxicities associated with famotidine and/or their salts to reduce gastrointestinal injury. the use of NSAIDs is the “Liver toxicity’; the long term use of U.S. Pat. No. 7,488,497, U.S. Pat. No. 6,365,184, U.S. Pat. NSAIDs, especially at high doses, is reported to harm the No. 6,613,354 and US2002155153 employ proton pump liver. Ringing in the ears (tinnitus) is another malady reported inhibitors, lansoprazole, pantoprozole and S-omeprazole by many people on high doses of aspirin or other NSAIDs. 30 and/or their salts in NSAID compositions for reduction of Further, anyone who has a cardiovascular disease (i.e., coro gastric acid forbetter patient compliance which are otherwise nary artery disease or angina) may have a further increase in used most often separately while administering NSAID. risk of heart attacks when taking an NSAID other than aspirin WO2011/144994A1 uses esomeprazole magnesium dihy which is sometimes recommended in low doses to people drate as acid blocker where as US2009233970A1 uses ran with coronary artery disease to reduce the risks of developing 35 itidine as acid blocking agent with NSAIDs such as ibuprofen a blood clot. and naproxene. Regimens of NSAID therapy, therefore, include adminis U.S. Pat. No. 4,766,117 provides an improved anti-inflam tration of antacids (acid neutralization), and cimetidine, ran matory composition of piroxicam or its salt with analgesic itidine and famotidine (acid secretion inhibition) as a matter acetaminophen, antidepressant doxepin, bronchodilator pir of necessity as of now and the search for a better and safe 40 buterol, minor tranquilizer diazepam, or antihypertensive tri composition of NSAID remains a challenge particularly mazosin wherein acetaminophen has been selected for its where the therapy must be protracted for a long time, e.g., in reported property of reducing the ulcerogenicity of aspirin treatment of rheumatoid arthritis in old people. and doxepin has been used for its reported gastric antisecre tory activity. Novelty Search 45 U.S. Pat. No. 5,185,144 discloses oral compositions con taining a gastroprotective amount of zirconium-aluminum The present invention is targeted to address the problems glycinate (ZAG), aluminum chlorohydrate (ACH) or a mix associated with toxicities, particularly the gastrointestinal, ture thereof for protecting the gastric mucosa against injury cardiovascular, and renal toxicities described above. The nov caused by a gastric irritant. elty search presented below would show that effective com 50 U.S. Pat. No. 5,811,410 utilizes administration of thera positions based on the ‘triple combination’ as disclosed in this peutically effective dose of hyaluronic acid or a non-toxic salt application which precisely ameliorate the side effects asso thereof immediately following or at the same time as the ciated with renal and gastrointestinal toxicities of NSAIDs treatment with the NSAID wherein it is postulated that hyalu have not been discovered or reported before. ronic acid facilitates the transport of the agent to the site Many different researchers have therefore attempted dif 55 through membranes of the individual cells to be treated and ferent strategies to find acceptable solutions. Some research also effectively counteracts the toxic side effects such as ers designed cyclo-oxygenase-2 (COX-2) inhibitors which gastro-intestinal distress, neurological abnormalities, depres were claimed to be devoid of ulcer-promoting effects but this sion, etc. U.S. Pat. No. 5,847,002 and U.S. Pat. No. 6,159,955 premise remained unfulfilled clue to concerns about the car (WO97/03699) provide other variants of NSAID composi diovascular safety of COX-2 inhibitors. Others used a group 60 tions involving hyaluronic acid. of drugs commonly known as ‘proton-pump inhibitors’ as WO2007086931 uses synergistically effective amounts of part of NSAID composition essentially to reduce gastric acid vitamins C & E and DHA with a preferred NSAID for pre production during NSAID administration. Another group of vention of the onset and/or progression of dementia or Alzhe drugs known as ‘H2-receptor’ producing similar effects how imer’s disease in individuals at increased risk thereof. Like ever working through a different mode of action have also 65 wise WO2010.069493A1 uses quinolone antibiotic with been incorporated in NSAID compositions. Then there have NSAID for veterinary use. And WO2010069493A1 uses qui also been attempts to formulate the compositions in the nano nolone antibiotic with NSAID for veterinary use. US 9,084,769 B2 5 6 US2007093457 uses curcumin with an NSAID to effec side effects that NSAIDs produce, the gastrointestinal as well tively reduce the dose of NSAID in the treatment of cancer as renal failure constitutes a major problem. and inflammation. Accordingly, in one aspect of the present invention, there is U.S. Pat. No. 5,183,829, U.S. Pat. No. 5,518,736 and U.S. provided a triple combination of a preferred NSAID, epilac Pat. No. 5,552,160 using nano-technological concepts tose and a zinc salt, a composition based on which and com employ surface modifiers adsorbed on crystalline NSAID prising of effective amounts of each component provide a maintaining an effective average particle size of less than highly potent drug for certain indications with no or unex about 400-1000 nm which are reported to act as dispersing pectedly minimal side effects and toxicities elaborated above. agents for the active ingredients; these formulations exhibit In other embodiments, a composition based on the combi reduced gastric irritation and hasten onset of action. 10 nation of a preferred NSAID and epilactose, without the third US2007134339A1 uses zonisomide, an antiseizure drug as a component of any zinc salt as before useful for treatment of component with a preferred NSAID at nanoscale of 2000 mm certain other indications may be as effective and devoid of for a formulation stated to be effective for migraine. Likewise observable side effects. Both epilactose and the chosen zinc US200931.1335 with its family of patents, viz., EP2320893, salt indicate interaction with functional groups of the active WO2009.1521.92, JP2011524358 and CA2723998 use trip 15 ingredient of the chosen NSAID and the metabolic processes tan, a drug for migraine in combination with NSAID for during the treatment of mammals for certain indications. treatment of migraine wherein the triptan is in a controlled Thus, epilactose together with or without a suitable zinc release matrix and the NSAID is essentially in the nano salt were conceived to be ideal constituents) in the new for particulate range of 2000 nm for its enhanced bioavailability. mulations enhancing the bioavailability of the drug and Many biotechnological approaches have also been adopted 20 improving its absorption characteristics in the intestine, fur to modify the compositions and/or preventing side effects of ther enabling the inventors to hypothesize and demonstrate NSAIDs administration. WO/1998/046249A1 provides that NSAIDs compositions together with these constituents methods and compositions for administration of a pharma produce a considerable, more than additive, synergistic ceutically effective amount of vascular endothelial cell effect. growth factor (VEGF), produced in several isoforms through 25 Novel and highly synergistic triple pharmaceutical com r-DNA technology to treat various forms of ulcers including positions of NSAIDs with epilactose and zinc have thus been those induced from NSAIDs and other drugs. disclosed in this invention. Triple and double pharmaceutical U.S. Pat. No. 5,772,999 teaches a method of preventing, compositions of selected NSAIDs with different amounts of countering, or reducing NSAID-induced gastrointestinal epilactose together with a suitable zinc salt or using them damage by administering milk or egg products from animals 30 individually were prepared in the laboratory using standard hyper-immunized with an antigenic or genetic vaccine to the preparatory methods in the preferred embodiments to test the subject undergoing treatment with NSAID administration. hypothesis of synergistic efficacy. Several experimental con Analogs of somatostatin, a peptide hormone [also known ditions were tested with these compositions against single as growth hormone-inhibiting hormone (GHIH) or soma component doses of key NSAID used in the above formula totropin release-inhibiting factor (SRIF)] that regulates the 35 tions as well as other single component NSAIDs and plain endocrine system and has been shown to have potent inhibi epilactose and a relevant zinc salt far comparison purposes. In tory effects on various secretory processes in tissues such as this way, test compositions as obtained were designated as pituitary, pancreas and gastrointestinal tract have been uti Ibu-FEpi-ZnCar, Ibu-Epi-ZnCl, Ibu-HZnCar, Ibu-ZnSt, Ibu-H lized in the NSAIDs compositions reported in EP0671413. ZnCl, Ibu-FEpi where ‘Ibu' refers to ibuprofen as the selected U.S. Pat. No. 6,017,932 have reportedly achieved 40 NSAID, “Epi’ refers to epilactose which is one of the essential enhanced bio-availability of NSAIDs composition contain key component of this invention, “ZnCar’ refers to zinc car ing piperine, its metabolites, structural analogues or isomers nosine, a selected zinc salt in the preferred embodiment, which are already extensively used in Indian system of medi ‘ZnCl’ refers to zinc chloride as another selected zinc salt in cine for similar purposes in other Indian ayurvedic drugs. the preferred embodiment, “ZnSt’ refers to zinc stearate as Despite scores of inventions reported in patent and non 45 another selected zinc salt in the preferred embodiment. patent literature as described above, there still is a need for These compositions were used for pre-clinical tests on simple and effective NSAID compositions and the treatment animal models to test for their efficacy against a range of based on the same that can alleviate and prevent NSAID studies using single components of epilactose (Epi), zinc salt induced gastrointestinal damage and chronic gastrointestinal (Zn) or zinc carnosine (ZnCar), along with single components disorders as well as renal failure, without the complication of 50 of selected NSAIDs, viz., ibuprofen (Ibu), naproxen (Nap) side effects. The inventors and the applicantherein, therefore, and celecoxib (Cox). Standard GLP protocols were used in undertook this development task and adopted a radically dif carrying out pre-clinical studies and efficacy tests against ferent and novel approach to produce NSAID compositions pain, inflammation, ulcerogenicity, and hemoglobin loss. To of highly improved characteristics and minimal side effects further evaluate the role of synergistic interactions between unreported hitherto. 55 the different combinations, an isobolographic analysis was The prime objects of this invention will be realized by those conducted on the safety index from the gastrointestinal, skilled in the art from the following disclosure which refers to hemoglobin and renal studies conducted herein on all NSAID key ingredients of the compositions and their utility in the formulations. The experimental results not only demonstrate formulations and their clinical results. the gastroprotective, vascular, and renoprotective safety pro 60 files of these compositions but a remarkable synergistic prop BRIEF SUMMARY OF THE INVENTION erty of the triple combination which forms a key discovery of this invention. Histopathological investigations carried on The primary object of this invention was to develop highly these preclinical studies showed dramatic resolution of signs safe and effective compositions of non-steroidal anti-inflam with these new improved triple compositions. matory drugs, the clinical use of which continues to grow 65 All publications from patented or non-patented literature globally often on long term basis in high doses despite well mentioned in this specification under ‘Novelty Search’ or known side effects and health related risks. Of the various elsewhere are herein incorporated by reference and for the
US 9,084,769 B2 10 tive amount” or the term “therapeutically effective amount” of the appropriate base or acid in water or in an organic and refers to the amount of a compound or a combination of solvent, or in a mixture of the two; generally, non-aqueous compounds of the compositions disclosed in this invention or media like ether, ethyl acetate, ethanol, isopropanol, or aceto other similar things used for experimental purposes herein nitrile are preferred. Lists of suitable salts are found in Rem and comparison of efficacies, that, when administered to a ington Pharmaceutical Sciences, 19th ed. (Mack Publishing mammal for treating a state, disorder or condition, is suffi Company, 1995) and Remington: The Science and Practice of cient to effect such treatment. The “therapeutically/pharma Pharmacy, 20th Edition, Baltimore, Md., Lippincott Williams ceutically effective amount” will vary depending on the com & Wilkins, 2000, which are incorporated by reference herein pound, the disease and its severity and the age, weight, in their entirety. physical condition and responsiveness of the mammal to be 10 Further, in the specification, the singular forms also include treated. the plural, unless the context clearly dictates otherwise. The term ‘treat”, “treating” or “treatment” of a state, dis Unless defined otherwise, all technical and scientific terms order or condition as used herein means: (1) preventing or used herein have the same meaning as commonly understood delaying the appearance of clinical symptoms of the state, by one of ordinary skill in the art to which this invention disorder or condition developing in a mammal that may be 15 belongs, in the case of any conflict, the present specification afflicted with or predisposed to the state, disorder or condition will prevail. Also, all percentages and ratios used herein, but does not yet experience or display clinical or subclinical unless otherwise indicated, are by weight. symptoms of the state, disorder or condition, (2) inhibiting Having decided about the key ingredients of new compo the state, disorder or condition, i.e., arresting or reducing the sitions, several preferred embodiments comprising of combi development of the disease or at least one clinical or subclini 20 nations of an NSAID and epilactose with or without a phar cal symptom thereof, or (3) relieving the disease, i.e., causing maceutically acceptable zinc salt were prepared for regression of the state, disorder or condition or at least one of experimental purposes and to test the mode of enablement of its clinical or subclinical symptoms. The benefit to a subject our invention. Preparatory methods of these embodiments are to be treated is either statistically significant or at least per described below in the following examples. ceptible to the patient or to the physician. 25 The first of these pharmaceutical active moieties is NSAID For example, the term ‘treatment of pain’ as referred herein as defined above. For preferred embodiments for practical specifically means administration of therapeutically effective validation of this invention, the NSAIDs used herein included amount of a composition of this invention or an equivalent ibuprofen, naproxene, and celecoxib, and/or pharmaceuti compound to a mammal for providing relief from pain (which cally acceptable salt thereof. The average particle diameter or is further defined as unpleasant sensory and emotional expe 30 size of the active moiety of NSAID (e.g., ibuprofen) or a rience and other distressing symptoms) as a result of acute pharmaceutically acceptable salt thereof identified was not surgical conditions such as appendicitis, peritonitis etc. or less than 1 nanometer and not more than 600 micrometers. road accidents or due to chronic ailments such as rheumatoid The formulation in this inversion also comprises of the arthritis, osteoarthritis, spondylosis etc. Similarly, the term chemical compound, epilactose, also known as 2-epi-lactose; ‘treatment of inflammation’ as referred herein refers to 35 4-O-B-galactopyranosyl-D-mannopyranose or 4-o-fl-galac administration of therapeutically effective amount of a com topyranosyl-d-mannopyranose or 4-O-b-Galactopyranosyl position of this invention or an equivalent compound to a D-mannopyranoside or 4-O-SS-Galactopyranosyl-D-Man mammal for providing relief from inflammation accompany nopyranoside Or 4-O-Beta-Galactopyranosyl-D ing acute pain as well as long term persistent medical condi Mannopyranoside or 4-O-(b-D-Galactopyranosyl)-D tions, such as rheumatoid arthritis, osteoarthritis, spondylosis 40 mannopyranoside. The average particle diameter or size of etc. the epilactose used in these compositions was not less than 1 The term ‘triple composition’ or ‘triple combination’ as nanometer and not more than 600 micrometers. used herein refer to a composition containing three main The third key constituent in the formulations disclosed in components, one of which is a preferred NSAID, the other, this invention comprises of one or more pharmaceutically epilactose and the third a suitable zinc salt all in pharmaceu 45 acceptable divalent zinc salt as defined above. For validation tical acceptable doses. Likewise, a ‘double combination’ of this invention, the preferred embodiments included zinc refers to a composition containing two main components, one chloride, zinc carnosine, and zinc stearate having the average of which is a preferred NSAID and the other, epilactose. particle diameter or size not less than 1 nanometer and not The term, ‘NSAID’ or ‘non-steroidal anti-inflammatory more than 600 micrometers. drugs’ as used herein mean those medicines which have been 50 In one embodiment, the NSAID (e.g., Ibuprofen) or a phar duly approved by authorized agencies for marketing and maceutically acceptable salt thereof may be converted into clinical use in USA and/or other countries and are within the the zinc complex of NSAID (e.g., Ibuprofen) either during the scope of sound medical judgment for treatment of various manufacturing process or as an intermediate processing step. medical conditions and which belong to various sub-catego In this embodiment, the active ingredient used in the formu ries based on their chemical structures and/or functions and as 55 lation to produce the finished product will be a Zinc complex described in detail in ‘Background to the Invention’ in this of NSAID (e.g., Ibuprofen) as per the following equation: patent application. The term “mammal’ as used herein is equivalent to the terms ‘patient’ and/or ‘subject’ in need of a treatment for a where, R-COOH is NSAID (e.g., Ibuprofen); Zn” repre medical indication and could be living human or an animal 60 sents the zinc salt in its ionic form (divalent state) described such as cat, dog, cattle etc. above; (R—COO),Zn is the zinc salt of NSAID, and Hº is As used herein, “pharmaceutically acceptable salts” refer hydrogen ion as released in the reaction. In this embodiment, to derivatives of the pharmaceutical active compounds as an example, if ibuprofen and zinc chloride are used to wherein the parent compound is modified by making add or prepare the Zn complex, the chemical reaction would be as base salts thereof. Generally, such salts can be prepared, as 65 follows: known to person skilled in the art, by reacting the free acid or base forms of these compounds with a stoichiometric amount
US 9,084,769 B2 13 14 Several experimental conditions were tested with these While NSAIDs have immense therapeutic benefit, they compositions against single component doses of key NSAID also cause numerous side-effects, in particular gastro intesti used in the above formulations as well as other single com nal and renal toxicity. The gastro intestinal toxicity of ponent NSAIDs and plain epilactose and a relevant line salt. NSAIDs can be broadly characterized into dyspepsia and Thus, these included the following: 5 abdominal pain, mucosal lesions and serious gastro intestinal a) Epilactose (Epi) complications, such as perforated ulcers or bleeding requir b) Zinc Carnosine (ZnCar) ing hospitalization. Renal side-effects include fluid retention c) Ibuprofen (Ibu) and hypertension, and in severe cases NSAIDs may precipi d) Naproxen (Nap) tate congestive heart failure and renal failure. Given that all e) Celecoxib (Cox) 10 NSAIDs, including low-dose aspirin, increase the risk of f) Ibuprofen with Epilactose (Ibu-HEpi) serious complications, the present inventors performed g) Ibuprofen with Zinc Chloride (Ibu-HZnCl) elaborate investigations with the above formulations to cor h) Ibuprofen with Zinc Stearate (Ibu-HZnSt) relate adverse effect profiles when compared to conventional i) Ibuprofen with Zinc Carnosine (Ibu--ZnCar) NSAIDs. This elicited both surprising and highly interesting j) Ibuprofen with Epilactose and Zinc Chloride (Ibu-FEpi 15 novel results for gastroprotective and renoprotective syner ZnCl) gistic effects when treated with Ibu-FEpi4-ZnCar. k) Ibuprofen with Epilactose and Zinc Carnosine (Ibu-- To evaluate gastroprotective effects, ulcerogenicity was Epi-ZnCar) determined using standard protocols. Eight rats were used in C57B1/6 mice and Sprague-Dawley (SD) rats were used. each group. Ulcerogenic activity was evaluated after oral Animals were group-housed under controlled temperature 20 administration of Epi, ZnCar, Ibu, Nap, Cox, Ibu-FEpi, Ibu-H (25°C.) and photoperiods (12:12-hour light-dark cycle), and ZnCl, Ibu-ZnSt, Ibu--ZnCar, Ibu--Epi-ZnCl, and Ibu-Epi allowed unrestricted access to standard diet and tap water, ZnCar for 5 days. Animals were then sacrificed and the stom unless otherwise noted. Animals were allowed to acclimate to ach was extracted, dissected along the greater curvature, these conditions for at least 7 days before inclusion in experi washed and cleaned with distilled wafer and normal saline, ments. For each group of experiments, animals were matched 25 and fixed by intraluminal irrigation with 2% formalin. The by age, sex, and body weight. Care and experimentation of mucosal damage was examined by means of a stereoscopic mice were performed in accordance with guidelines under microscope. Mucosal damage was assessed as follows: a. 0.5 protocols approved by the Institutional Animal Care and Use for redness and erythema, b. 1 for spot ulcers, c. 1.5 for Committee. hemorrhagic streaks, d. 2 for ulcers