`

`US 6,926,907 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`12/1985 Hirata et a!. ................ 548/184
`4,562,261 A
`10/1986 Sunshine eta!. ........... 514/277
`4,619,934 A
`................... 424/157
`6/1987 Wu et a!.
`4,676,984 A
`11/1987 Wu et a!.
`................... 424/157
`4,704,278 A
`7/1988 Lukacsko eta!. ........... 514/160
`4,757,060 A
`8/1988 Crawford eta!. ........... 514/219
`4,766,117 A
`11/1988 Lovgren et a!.
`............ 424/468
`4,786,505 A
`10/1990 Lukacsko et a!. ............. 424/10
`4,965,065 A
`8/1991 Lukacsko eta!. ........... 514/162
`5,037,815 A
`8/1991 Lukacsko eta!. ........... 514/653
`5,043,358 A
`4/1993 Goldman et a!.
`........... 424/489
`5,204,118 A
`11/1993 Lukacsko eta!. ........... 514/471
`5,260,333 A
`................. 424/52
`11/1994 Singer et a!.
`5,364,616 A
`12/1994 Fawzi eta!. ................ 514/570
`5,373,022 A
`........... 424/464
`5/1995 Goldman et a!.
`5,417,980 A
`11/1995 Stables ....................... 514/161
`5,466,436 A
`5/1996 Mandel ....................... 514/33
`5,514,663 A
`5/1997 Mandel et a!. .............. 424/456
`5,631,022 A
`7/1997 Breitner eta!. ............. 514/570
`5,643,960 A
`11/1997 Keirn et a!. ................. 424/452
`5,686,105 A
`2/1998 Halskov et a!. ............. 424/682
`5,716,648 A
`9/1999 Lichtenberger eta!. ....... 514/78
`5,955,451 A
`1!2000 Lundberg et a!. ........... 424/468
`6,013,281 A
`2/2000 Breitner eta!. ............. 514/570
`6,025,395 A
`12/2000 Ohannesian eta!. ........ 514/629
`6,160,020 A
`12/2000 Bohlin eta!. ............... 514/338
`6,162,816 A
`3/2001 Gustavsson et a!. ........ 424/464
`6,207,188 B1
`4/2002 Depui et a!. ................ 424/469
`6,365,184 B1
`5!2002 Flanagan et a!.
`........... 424/479
`6,395,298 B1
`11/2002 Flanagan et a!.
`........... 424/479
`6,485,747 B1
`4/2003 Chen et a!. ................. 424/469
`6,544,556 B1
`9/2001 Barbe rich et a!.
`. ... ... 546/273.7
`2001!0025107 A1
`11/2001 Scott et a!.
`................. 424/463
`2001!0036473 A1
`11/2001 Gelber eta!. ................. 514/27
`2001!0044410 A1
`......... 424/400
`1!2002 Lunde berg et a!.
`2002/0012676 A1
`4/2002 Yelle eta!. ................. 514/338
`2002/0042433 A1
`4/2002 Cherukuri et a!. .......... 424/459
`2002/0044962 A1
`4/2002 Chen . ... ... ... .. ... ... ... ... .. ... 435/6
`2002/0045184 A1
`7/2002 Lundberg eta!. ........ 424/184.1
`2002/0086029 A1
`8/2002 Bergman eta!. ............ 514/338
`2002/0111370 A1
`10/2002 Depui et a!. ................ 424/452
`2002/0155153 A1
`1!2003 Barbe rich et a!.
`. . . . . . . . . . 514/338
`2003/0008903 A1
`6/2003 Lundberg et a!. ........... 424/474
`2003/0113375 A1
`7/2003 Chen et a!. ................. 424/470
`2003/0129235 A1
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`GB
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`0 426 479 A1
`5/1991
`0 550 083 B1
`7/1993
`2 105 193
`3/1983
`wo 85/03443
`8/1985
`wo 93/12817
`7/1993
`wo 94/07541
`4/1994
`wo 98/22117
`5/1998
`wo 99/00380
`1!1999
`wo 99/12524
`3/1999
`wo 00/71122
`11/2000
`WO 00/72838 A1
`12/2000
`WO 03/017980 A1
`3/2003
`01HER PUBLICATIONS
`
`......... A61K/31!415
`A61K/31!34
`A61K/31!34
`A61K/45/06
`A61K/45/06
`A61K/49/00
`A61K/33/24
`. .. ... ... C07D/401!12
`............ A61K/9/20
`.......... A61K/31!44
`.......... A61K/31!04
`A61K/9/16
`
`Bigard, et al., "Complete Prevention by Omeprazole of
`Aspirin Induced Gastric Lesions in Healthy Subjects," GUT
`29(5):A712, T49 (1988).
`Bombardier, et al., "Comparison of Upper Gastrointestinal
`Toxicity of Rofecoxib and Naproxen in Patients with Rheu(cid:173)
`matoid Arthritis," N. Engl. J. Med. 343:1520-1528 (2000).
`Brown, et al., "Prevention of the Gastrointestinal Adverse
`Effects of Nonsteroidal Anti-Inflammatory Drugs," Pract.
`Drug Safety 21:503-512 (1999).
`Cullen, et al., "Primary Gastroduodenal Prophylaxis with
`Omeprazole for Non-Steroidal Anti-Inflammatory Drug
`Users," Aliment. Pharmacal. Ther. 12:135-140 (1998).
`
`Hawkey, "Progress in Prophylaxis Against Nonsteroidal
`Anti-Inflammatory Drug-Associated Ulcers and Erosions,"
`Am. J. Med. 104:67S-74S (1998).
`Hawkey, et al., "Omeprazole Compared with Misoprostol
`for Ulcers Associated with Nonsteroidal Anti-Inflammatory
`Drugs," N. Engl. J. Med. 338:727-734 (1998).
`Katz, et al., "Gastric Acidity and Acid Breakthrough with
`Twice-Daily Omeprazole or Iansoprazole," Aliment. Phar(cid:173)
`macal. Ther 14:709-714 (2000).
`Kephart, et al., "Coprescribing of Nonsteroidal Anti-Inflam(cid:173)
`matory Drugs and Cytoprotective and Antiulcer Drugs in
`Nova Scotia's Senior Population," Clin. Ther. 17:1159-1173
`(1995).
`Lad, et al., "Management of Nonsteroidal Anti-Inflamma(cid:173)
`tory Drug-Induced Gastroduodenal Disease by Acid Sup(cid:173)
`pression," Can. J. Gastroenterol13:135-142 (1999).
`Mattsson, et al., "Omeprazole Provides Protection Against
`Experimentally Induced Gastric Mucosal Lesions," Eur. J.
`Pharmacal. 91:111-114 (1983).
`Oddsson, et al., "Endoscopic Findings in the Stomach and
`Duodenum after Treatment with Enteric-Coated and Plain
`Naproxen Tablets in Healthy Subjects," Scand. J. Castro(cid:173)
`enteral. 25:231-234 (1990).
`Scheiman, "NSAlD-Induced Peptic Ulcer Disease: A Criti(cid:173)
`cal Rview of Pathogenesis and Management," Dig. Dis.
`12:210-222 (1994).
`Selway, "Potential Hazards of Long-Term Acid Suppres(cid:173)
`sion," Scand. J. Gasatroenterol. 25(Supp. 178):85-92
`(1990).
`Silverstein, et al., "Gastrointestinal Toxicity with Celecoxib
`vs. Nonsteroidal Anti-Inflammatory Drugs for Osteoarthri(cid:173)
`tis and Rheumatoid Arthritis; The CLASS Study: A Ran(cid:173)
`domized Controlled Trial," JAMA 284:1247-1255 (2000).
`Tronstad, et al., "Gastroscopic Findings after Treatment with
`Enteric-Coated and Plain Naproxen Tablets in Healthy
`Subjects," Scand. J. Gastroenterol. 20:239-242 (1985).
`Wolfe, et al., "Gastrointestinal Toxicity of Nonsteroidal
`Anti-Inflammatory Drugs,"
`N.
`Engl.
`J. Med.
`340:1888-1899 (1999).
`Yeomans, et al., "A Comparison of Omeprazole with Ran(cid:173)
`itidine for Ulcers Associated with Nonsteroidal Anti-In(cid:173)
`flammatory Drugs," N. Engl. J. Med. 338:719-726 (1998).
`Yeomans, et al., "New Data on Healing of Nonsteroidal
`Anti-Inflammatory Drug-Associated Ulcers and Erosions,"
`Am. J. Med. 104:56S-61S (1998).
`English language abstract for DE 198 01811, Reference B13
`above.
`Dent, "Why Proton Pump Inhibition Should Heal and Pro(cid:173)
`tect Against Nonsteroidal Anti-Inflammatory Drug Ulcers,"
`Am. J. Med. 104:52S-55S (1998) .
`Kimmey, et al., "Role of H2-Receptor Blockers in the
`Prevention of Gastric Injury Resulting from Nonsteroidal
`Anti-inflammatory Agents," Am. J. Med. 84:49-52 (1988) .
`Lee, et al., "Omeprazole Prevents Indomethacin-Induced
`Gastric Ulcers in Rabbits," Aliment. Pharmacal. Ther.
`10:571-576 (1996).
`Lichtenbergetr, et al., "Nonsteroidal Anti-inflammatory
`Drug and Phospholipid Prodrugs: Combination Therapy
`with Antisecretory Agents in Rats," Gastroenterology
`111:990-995 (1996).
`Savarino, et al., "Effect of One-Month Treatment with
`Nonsteroidal Antiinflammatory Drugs (NSAlDs) on Gastric
`pH of Rheumatoid Arthritis Patients," Digestive Diseases
`and Sciences 43:459-463 (1998).
`Wagner, et al., "Effects of Nonsteroidal Antiinflammatory
`Drugs on Ulcerogenesis and Gastric Secretion in Pylorus(cid:173)
`Ligated Rat," Digestive Diseases and Sciences 40:134--140
`(1995).
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 2
`
`

`

`

`

`U.S. Patent
`
`Aug. 9, 2005
`
`Sheet 2 of 2
`
`US 6,926,907 B2
`
`NAPROXEN
`SODIUM
`PELLET
`
`ENTERIC FILM
`COAT
`FIG.3
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 4
`
`

`

`US 6,926,907 B2
`
`1
`PHARMACEUTICAL COMPOSITIONS FOR
`THE COORDINATED DELIVERY OF NSAIDS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application claims priority to U.S. provisional
`application No. 60/294,588, filed on Jun. 1, 2001.
`
`FIELD OF THE INVENTION
`
`The present invention is directed to pharmaceutical com(cid:173)
`positions that provide for the coordinated release of an acid
`inhibitor and a non-steroidal anti-inflammatory drug
`(NSAID). These compositions have a reduced likelihood of
`causing unwanted side effects, especially gastrointestinal
`side effects, when administered as a treatment for pain,
`arthritis and other conditions amenable to treatment with
`NSAIDs.
`
`BACKGROUND OF THE INVENTION
`
`Although non-steroidal anti-inflammatory drugs are
`widely accepted as effective agents for controlling pain, their
`administration can lead to the development of gastroduode(cid:173)
`nal lesions, e.g., ulcers and erosions, in susceptible indi(cid:173)
`viduals. It appears that a major factor contributing to the
`development of these lesions is the presence of acid in the
`stomach and upper small intestine of patients. This view is
`supported by clinical studies demonstrating an improvement
`in NSAID tolerability when patients are also taking inde(cid:173)
`pendent doses of acid inhibitors (Dig. Dis. 12:210--222
`(1994); Drug Safety 21:503-512 (1999); Aliment. Pharma(cid:173)
`cal. Ther. 12:135-140 (1998); Am. J. Med. 104(3A)
`:67S-74S (1998); Clin. Ther. 17:1159-1173 (1995)). Other
`major factors contributing to NSAID-associated gastropathy
`include a local toxic effect of NSAIDs and inhibition of
`protective prostaglandins (Can. J. Gastraenteral. 13:
`135-142 (1999) and Pract. Drug Safety 21:503-512,
`(1999)), which may also make some patients more suscep(cid:173)
`tible to the ulcerogenic effects of other noxious stimuli.
`In general, more potent and longer lasting acid inhibitors,
`such as proton pump inhibitors, are thought to be more
`protective during chronic administration of NSAIDs than
`shorter acting agents, e.g., histamine H2 receptor antagonists
`(H-2 blockers) (N. Eng. J. Med. 338:719-726 (1998);Am. J.
`Med. 104(3A):56S-61S (1998)). The most likely explana(cid:173)
`tion for this is that gastric pH fluctuates widely throughout
`the dosing interval with short acting acid inhibitors leaving
`the mucosa vulnerable for significant periods of time. In
`particular, the pH is at its lowest point, and hence the mucosa
`is most vulnerable, at the end of the dosing interval (least
`amount of acid inhibition) and for some time after the
`subsequent dose of acid inhibitor. In general, it appears that
`when a short acting acid inhibitor and an NSAID are
`administered simultaneously, NSAID-related mucosal dam(cid:173)
`age occurs before the pH of the gastrointestinal tract can be
`raised and after the acid inhibiting effect of the short acting
`acid inhibitor dissipates.
`Although longer lasting agents, such as proton pump
`inhibitors (PPis), usually maintain a consistently higher
`gastroduodenal pH throughout the day, after several days
`dosing, their antisecretory effect may be delayed for several
`hours and may not take full effect for several days (Clin.
`Pharmacakinet. 20:38-49 (1991)). Their effect may be
`diminished toward the end of the usual dosing interval.
`Intragastric pH rises particularly slowly with the first dose in
`a course of treatment since this class of drugs is enteric
`
`10
`
`15
`
`2
`coated to avoid destruction by stomach acid. As a result,
`absorption is delayed for several hours. Even then, some
`patients fail to respond consistently to drugs of this type and
`suffer from "acid breakthrough" which again leaves them
`5 vulnerable to NSAID-associated gastroduodenaldamage
`(Aliment. Pharmacal. Ther. 14:709-714 (2000)). Despite a
`significant reduction in gastroduodenal lesions with the
`concomitant administration of a proton pump inhibitor dur(cid:173)
`ing six months of NSAID therapy, up to 16% of patients still
`develop ulcers, indicating that there remains substantial
`room for improvement (N. Eng. J. Med. 338:727-734
`(1998)). Thus, the addition of a pH sensitive enteric coating
`to an NSAID could provide additional protection against
`gastroduodenal damage not provided by the H2 blocker or
`PPI alone. In addition, although long acting acid inhibitors
`may reduce the risk of GI lesions in chronic NSAID users,
`there are questions about the safety of maintaining an
`abnormally elevated pH in a patient's GI tract for a pro(cid:173)
`longed period of time (Scand. J. Gastraenteral. Suppl.
`20 178:85-92 (1990)).
`Recognizing the potential benefits of PPis for the preven(cid:173)
`tion of NSAID-induced gastroduodenal damage, others have
`disclosed strategies for combining the two active agents for
`therapeutic purposes. However, these suggestions do not
`25 provide for coordinated drug release or for reducing intra(cid:173)
`gastric acid levels to a non-toxic level prior to the release of
`NSAID (U.S. Pat. Nos. 5,204,118; 5,417,980; 5,466,436;
`and 5,037,815). In certain cases, suggested means of deliv(cid:173)
`ery would expose the gastrointestinal tract to NSAIDs prior
`30 to onset of PPI activity (U.S. Pat. No. 6,365,184).
`Attempts to develop NSAIDs that are inherently less toxic
`to the gastrointestinal tract have met with only limited
`success. For example, the recently developed
`cyclooxygenase-2 (COX-2) inhibitors show a reduced ten-
`35 dency to produce gastrointestinal ulcers and erosions, but a
`significant risk is still present, especially if the patient is
`exposed to other ulcerogens (JAMA 284:1247-1255 (2000);
`N. Eng. J. Med. 343:1520-1528 (2000)). In this regard, it
`appears that even low doses of aspirin will negate most of
`40 the benefit relating to lower gastrointestinal lesions. In
`addition, the COX-2 inhibitors may not be as effective as
`other NSAIDs at relieving some types of pain and have been
`associated with significant cardiovascular problems (JADA
`131:1729-1737 (2000); SCRIP2617, pg. 19, Feb. 14, 2001);
`45 NY Times, May 22, 2001, pg. C1)).
`Other attempts to produce an NSAID therapy with less
`gastrointestinal toxicity have involved the concomitant
`administration of a cytoprotective agent. In 1998, Searle
`began marketing Arthrotec™ for the treatment of arthritis in
`50 patients at risk for developing GI ulcers. This product
`contains misopristol (a cytoprotective prostaglandin) and the
`NSAID diclofenac. Although patients administered Arthro(cid:173)
`tec™ do have a lower risk of developing ulcers, they may
`experience a number of other serious side effects such as
`55 diarrhea, severe cramping and, in the case of pregnant
`women, potential damage to the fetus.
`Another approach has been to produce enteric coated
`NSAID products. However, even though these have shown
`modest reductions in gastroduodenal damage in short term
`60 studies (Scand. J. Gastraenteral. 20: 239-242 (1985) and
`Scand. J. Gastraenteral. 25:231-234 (1990)), there is no
`consistent evidence of a long term benefit during chronic
`treatment.
`Overall, it may be concluded that the risk of inducing GI
`65 ulcers is a recognized problem associated with the admin(cid:173)
`istration of NSAIDs and that, despite considerable effort, an
`ideal solution has not yet been found.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 5
`
`

`

`3
`SUMMARY OF THE INVENTION
`
`US 6,926,907 B2
`
`4
`release of NSAID is delayed until after the pH in the GI tract
`has risen. In a preferred embodiment, the unit dosage form
`is a multilayer tablet, having an outer layer comprising the
`acid inhibitor and an inner core which comprises the
`5 NSAID. In the most preferred form, coordinated delivery is
`accomplished by having the inner core surrounded by a
`polymeric barrier coating that does not dissolve unless the
`surrounding medium is at a pH of at least 3.5, preferably at
`least 4 and more preferably, at least 5. Alternatively, a barrier
`10 coating may be employed which controls the release of
`NSAID by time, as opposed to pH, with the rate adjusted so
`that NSAID is not released until after the pH of the gas(cid:173)
`trointestinal tract has risen to at least 3.5, preferably at least
`4, and more preferably at least 5. Thus, a time-release
`15 formulation may be used to prevent the gastric presence of
`NSAID until mucosal tissue is no longer exposed to the
`damage enhancing effect of very low pH.
`The invention includes methods of treating a patient for
`pain, inflammation and/or other conditions by administering
`20 the pharmaceutical compositions described above. Although
`the method may be used for any condition in which an
`NSAID is effective, it is expected that it will be particularly
`useful in patients with osteoarthritis or rheumatoid arthritis.
`Other conditions that may be treated include, but are not
`25 limited to: all form of headache, including migraine head(cid:173)
`ache; acute musculoskeletal pain; ankylosing spondylitis;
`dysmenorrhoea; myalgias; and neuralgias.
`In a more general sense, the invention includes methods
`of treating pain, inflammation and/or other conditions by
`orally administering an acid inhibitor at a dose effective to
`raise a patient's gastric pH to at least 3.5, preferably to at
`least 4 or and more preferably to at least 5. The patient is also
`administered an NSAID, for example in a coordinated
`dosage form, that has been coated in a polymer that only
`dissolves at a pH of least 3.5, preferably at least 4 and, more
`preferably, 5 or greater or which dissolves at a rate that is
`slow enough to prevent NSAID release until after the pH has
`been raised. When acid inhibitor and NSAID are adminis-
`40 tered in separate doses, e.g., in two separate tablets, they
`should be given concomitantly (i.e., so that their biological
`effects overlap) and may be given concurrently, i.e., NSAID
`is given within one hour after the acid inhibitor. Preferably,
`the acid inhibitor is an H2 blocker and, in the most preferred
`embodiment, it is famotidine at a dosage of between 5 mg
`and 100 mg. Any of the NSAIDs described above may be
`used in the method but naproxen at a dosage of between 200
`and 600 mg is most preferred. It is expected that the inhibitor
`an~ analgesic will be typically delivered as part of a single
`umt dosage form which provides for the coordinated release
`50 of therapeutic agents. The most preferred dosage form is a
`multilayer tablet having an outer layer comprising an H2
`blocker and an inner core comprising an NSAID.
`The. inve~tion al~o provides a method for increasing
`55 compliance m a patient requiring frequent daily dosing of
`NSAIDs by providing both an acid inhibitor and NSAID in
`a single convenient, preferably coordinated, unit dosage
`form, thereby reducing the number of individual doses to be
`administered during any given period.
`
`30
`
`35
`
`The present invention is based upon the discovery of a
`new method for reducing the risk of gastrointestinal side
`effects in people taking NSAIDs for pain relief and for other
`conditions, particularly during chronic treatment. The
`method involves the administration of a single, coordinated,
`u~it-d~se produ~t that combines: a) an agent that actively
`raises mtragastnc pH to levels associated with less risk of
`NSAID-induced ulcers; and b) an NSAID that is specially
`formulated to be released in a coordinated way that mini(cid:173)
`mizes the adverse effects of the NSAID on the gastroduode(cid:173)
`nal mucosa. Either short or long acting acid inhibitors can be
`effectively used in the dosage forms. This method has the
`added benefit of being able to protect patients from other
`gastrointestinal ulcerogens whose effect may otherwise be
`enhanced by the disruption of gastroprotective prostaglan(cid:173)
`dins due to NSAID therapy.
`In. its first aspect, the invention is directed to a ph arm a(cid:173)
`ceutlcal composition in unit dosage form suitable for oral
`administration to a patient. The composition contains an acid
`inhibitor present in an amount effective to raise the gastric
`pH of a patient to at least 3.5, preferably to at least 4, and
`more preferably to at least 5, when one or more unit dosage
`forms are administered. The gastric pH should not exceed
`7.5 and preferably should not exceed 7.0. The term "acid
`inhibitor" refers to agents that inhibit gastric acid secretion
`and increase gastric pH. In contrast to art teaching against
`the use of H2 blockers for the prevention of NSAID(cid:173)
`associated ulcers (N. Eng. J. Med. 340: 1888-1899 (1999)),
`these agents are preferred compounds in the current inven(cid:173)
`tion. Specific, H2 blockers that may be used include
`cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine,
`loxtidine or famotidine. The most preferred acid inhibitor is
`famotidine present in dosage forms in an amount of between
`? mg and 100 mg. Other agents that may be effectively used
`mclude proton pump inhibitors such as omeprazole,
`esomeprazole, pantoprazole, lansoprazole or rabeprazole.
`The pharmaceutical composition also contains a non(cid:173)
`steroidal anti-inflammatory drug in an amount effective to
`reduce or eliminate pain or inflammation. The NSAID may
`be a COX-2 inhibitor such as celecoxib
`rofecoxib
`meloxicam, piroxicam, valdecoxib, parecoxib, etoricoxib:
`CS-502, JTE-522, L-745,337 or NS398. Alternatively, the
`NS~ID may be aspirin, acetaminophen, ibuprofen,
`flurb1profen, ketoprofen, naproxen, oxaprozin, etodolac,
`indomethacin, ketorolac, lornoxicam, nabumetone, or
`diclofenac. The most preferred NSAID is naproxen in an
`amount of between 50 mg and 1500 mg, and more
`preferably, in an amount of between 200 mg and 600 mg. It
`will be understood that, for the purposes of the present
`invention, reference to an acid inhibitor, NSAID, or anal(cid:173)
`gesic agent will include all of the common forms of these
`compounds and, in particular, their pharmaceutically accept(cid:173)
`able salts. The amounts of NSAIDs which are therapeuti(cid:173)
`cally effective may be lower in the current invention than
`otherwise found in practice due to potential positive kinetic
`interaction and NSAID absorption in the presence of an acid
`inhibitor.
`The term "unit dosage form" as used herein refers to a 60
`single entity for drug administration. For example, a single
`tablet or capsule combining both an acid inhibitor and an
`NSAID would be a unit dosage form. A unit dosage form of
`the present invention preferably provides for coordinated
`drug release, in a way that elevates gastric pH and reduces 65
`the deleterious effects of the NSAID on the gastroduodenal
`mucosa, i.e., the acid inhibitor is released first and the
`
`45
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a schematic diagram of a four layer tablet dosage
`form. There is a naproxen core layer surrounded by a barrier
`layer. A third, enteric coating, layer delays the release of
`naproxen sodium until the pH is at a specific level, e.g.,
`above 4. Finally, there is an outer layer that releases an acid
`inhibitor such as famotidine.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 6
`
`

`

`US 6,926,907 B2
`
`10
`
`20
`
`25
`
`5
`FIG. 2 illustrates a three layer dosage form. An acid
`inhibitor, e.g., famotidine, is released immediately after
`ingestion by a patient in order to raise the pH of the
`gastrointestinal tract to above a specific pH, e.g., above 4.
`The innermost layer contains naproxen. Thus, the dosage 5
`form has a naproxen core, an enteric film coat and an acid
`inhibitor film coat.
`FIG. 3 illustrates a naproxen sodium pellet which contains
`a subcoat or barrier coat prior to the enteric film coat.
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention is based upon the discovery of
`improved pharmaceutical compositions for administering
`NSAIDs to patients. In addition to containing one or more
`NSAIDs, the compositions include acid inhibitors that are 15
`capable of raising the pH of the GI tract of patients. All of
`the dosage forms are designed for oral delivery and provide
`for the coordinated release of therapeutic agents, i.e., for the
`sequential release of acid inhibitor followed by analgesic.
`The NSAIDs used in preparations may be either short or
`long acting. As used herein, the term "long acting" refers to
`an NSAID having a pharmacokinetic half-life of at least 2
`hours, preferably at least 4 hours and more preferably, at
`least 8-14 hours. In general, its duration of action will equal
`or exceed about 6-8 hours. Examples of long-acting
`NSAIDs are: fiurbiprofen with a half-life of about 6 hours;
`ketoprofen with a half-life of about 2 to 4 hours; naproxen
`or naproxen sodium with half-lives of about 12 to 15 hours
`and about 12 to 13 hours respectively; oxaprozin with a half
`life of about 42 to 50 hours; etodolac with a half-life of about
`7 hours; indomethacin with a half life of about 4 to 6 hours;
`ketorolac with a half-life of up to about 8-9 hours, nabu(cid:173)
`metone with a half-life of about 22 to 30 hours; mefenamic
`acid with a half-life of up to about 4 hours; and piroxicam
`with a half-life of about 4 to 6 hours. If an NSAID does not 35
`naturally have a half-life sufficient to be long acting, it can,
`if desired, be made long acting by the way in which it is
`formulated. For example, NSAIDs such as acetaminophen
`and aspirin may be formulated in a manner to increase their
`half-life or duration of action. Methods for making appro(cid:173)
`priate formulations are well known in the art (see e.g.
`Remington's Pharmaceutical Sciences, 16'h ed., A. Oslo
`editor, Easton, Pa. (1980)).
`It is expected that a skilled pharmacologist may adjust the
`amount of drug in a pharmaceutical composition or admin(cid:173)
`istered to a patient based upon standard techniques well
`known in the art. Nevertheless, the following general guide(cid:173)
`lines are provided:
`Indomethacin is particularly useful when contained in
`tablets or capsules in an amount from about 25 to 75
`mg. A typical daily oral dosage of indomethacin is three
`25 mg doses taken at intervals during the day. However,
`daily dosages of up to about 150 mg are useful in some
`patients.
`Aspirin will typically be present in tablets or capsules in
`an amount of between about 250 mg and 1000 mg.
`Typical daily dosages will be in an amount ranging
`from 500 mg to about 10 g.
`Ibuprofen may be provided in tablets or capsules of 50, 60
`100, 200, 300, 400, 600, or 800 mg. Daily doses should
`not exceed 3200 mg. 200 mg-800 mg may be particu(cid:173)
`larly useful when given 3 or 4 times daily.
`Flurbiprofen is useful when in tablets at about from 50 to
`100 mg. Daily doses of about 100 to 500 mg, and 65
`particularly from about 200 to 300 mg, are usually
`effective.
`
`6
`Ketoprofen is useful when contained in tablets or capsules
`in an amount of about 25 to 75 mg. Daily doses of from
`100 to 500 mg and particularly of about 100 to 300 mg
`are typical as is about 25 to 50 mg every six to eight
`hours.
`Naproxen is particularly useful when contained in tablets
`or capsules in an amount of from 250 to 500 mg. For
`naproxen sodium, tablets of about 275 or about 550 mg
`are typically used. Initial doses of from 100 to 1250 mg,
`and particularly 350 to 800 mg are also used, with
`doses of about 550 mg being generally preferred.
`Oxaprozin may be used in tablets or capsules in the range
`of roughly 200 mg to 1200 mg, with about 600 mg
`being preferred. Daily doses of 1200 mg have been
`found to be particularly useful and daily doses should
`not exceed 1800 mg or 26 mg/kg.
`Etodolac is useful when provided in capsules of 200 mg
`to 300 mg or in tablets of about 400 mg. Useful doses
`for acute pain are 200--400 mg every six-eight hours,
`not to exceed 1200 mg/day. Patients weighing less than
`60 kg are advised not to exceed doses of 20 mg/kg.
`Doses for other uses are also limited to 1200 mg/day in
`divided doses, particularly 2, 3 or 4 times daily.
`Ketorolac is usefully provided in tablets of 1-50 mg, with
`about 10 mg being typical. Oral doses of up to 40 mg,
`and particularly 10-30 mg/day have been useful in the
`alleviation of pain.
`Nabumetone may be provided in tablets or capsules of
`between 500 mg and 750 mg. Daily doses of
`1500-2000 mg, after an initial dose of 100 mg, are of
`particular use.
`Mefenamic acid is particularly useful when contained in
`tablets or capsules of 50 mg to 500 mg, with 250 mg
`being typical. For acute pain, an initial dosage of
`1-1000 mg, and particularly about 500 mg, is useful,
`although other doses may be required for certain
`patients.
`Lomoxicam is provided in tablets of 4 mg or 8 mg. Useful
`doses for acute pain are 8 mg or 16 mg daily, and for
`arthritis are 12 mg daily.
`One particular group of long acting NSAIDs that may be
`used are the cyclooxygenase-2 inhibitors. These include:
`celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib,
`45 parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, or
`NS398. JTE-522, L-745,337 and NS398 as described, inter
`alia, in Wakatani, et al. (Jpn. J. Pharmacal. 78:365-371
`(1998)) and Panara, et al. (Br. J. Pharmacal. 116:2429-2434
`(1995)). The amount present in a tablet or administered to a
`50 patient will depend upon the particular COX-2 inhibitor
`being used. For example:
`Celecoxib may be administered in a tablet or capsule
`containing from about 100 mg to about 500 mg or,
`preferably, from about 100 mg to about 200 mg.
`Piroxicam may be used in tablets or capsules containing
`from about 10 to 20 mg.
`Rofecoxib will typically be provided in tablets or capsules
`in an amount of 12.5, 25 or 50 mg. The recommended
`initial daily dosage for the management of acute pain is
`50 mg.
`Meloxicam is provided in tablets of 7.5 mg, with a
`recommended daily dose of 7.5 or 15 mg for the
`management of osteoarthritis.
`Valdecoxib is provided in tablets of 10 or 20 mg, with a
`recommended daily dose of 10 mg for arthritis or 40 mg
`for dysmenorrhea.
`
`30
`
`40
`
`55
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 7
`
`

`

`US 6,926,907 B2
`
`7
`With respect to acid inhibitors, tablets or capsules may
`contain anywhere from 1 mg to as much as 1 g. Typical
`amounts for H2 blockers are: cimetidine, 100 to 800 mg/unit
`dose; ranitidine, 50-300 mg/unit dose; famotidine, 5-100
`mg/unit dose; ebrotidine 400-800 mg/unit dose; pabutidine 5
`40 mg/unit dose; lafutidine 5-20 mg/unit dose; and
`nizatidine, 50-600 mg/unit dose. Proton pump inhibitors
`will typically be present at about 5 mg to 600 mg per unit
`dose. For example, the proton pump inhibitor omeprazole
`should be present in tablets or capsules in an amount from 10
`5 to 50 mg, with about 20 mg per unit dosage form being
`preferred. Other typical amounts are: esomeprazole, 5-100
`mg, with about 40 mg per unit dosage form being preferred;
`lansoprazole, 15-150 mg, with about 30 mg per unit dosage
`form being preferred; pantoprazole, 10--200 mg, with about 15
`40 mg per unit dosage form being preferred; and
`rabeprazole, 5-100 mg, with about 20 mg per unit dosage
`form being preferred.
`Making of Pharmaceutical Preparations
`The pharmaceutical compositions of the invention include 20
`tablets, dragees, liquids and capsules and can be made in
`accordance with methods that are standard in the art (see,
`e.g., Remington's Pharmaceutical Sciences, 16'h ed., A Oslo
`editor, Easton, Pa. (1980)). Drugs and drug combinations
`will typically be prepared in admixture with conventional 25
`excipients. Suitable carriers include, but are not limited to:
`water; salt solutions; alcohols; gum arabic; vegetable oils;
`benzyl alcohols; polyethylene glycols; gelatin; carbohy(cid:173)
`drates such as lactose, amylose or starch; magnesium stear(cid:173)
`ate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; 30
`hydroxymethylcellulose; polyvinyl pyrrolidone; etc. The
`pharmaceutical preparations can be sterilized and, if desired,
`mixed with auxiliary agents such as: lubricants,
`preservatives, disintegrants; stabilizers; wetting agents;
`emulsifiers; salts; buffers; coloring agents; flavoring agents; 35
`or aromatic substances.
`Enteric coating layer(s) may be applied onto the core or
`onto the barrier layer of the core using standard coating
`techniques. The enteric coating materials may be dissolved
`or dispersed in organic or aqueous solvents and may include 40
`one or more of the following materials: methacrylic acid
`copolymers, shellac, hydroxypropylmethcellulose phthalate,
`polyvinyl acetate phthalate, hydroxypropylmethylcellulose
`trimellitate, carboxymethylethylcellulose, cellulose acetate
`phthalate or other suitable enteric coating polymer(s). The 45
`pH at which the enteric coat will dissolve can be controlled
`by the polymer or combination of polymers selected and/or
`ratio of pendant groups. For example, dissolution charac(cid:173)
`teristics of the polymer film can be altered by the ratio of free
`carboxyl groups to ester groups. Enteric coating layers also 50
`contain pharmaceutically acceptable plasticizers such as
`triethyl citrate, dibutyl phthalate, triacetin, polyethylene
`glycols, polysorbates or other plasticizers. Additives such as
`dispersants, colorants, anti-adhering and anti-f