US 6,544,556 B1
`(10) Patent N0.:
`(12) United States Patent
`
`Chen et al.
`(45) Date of Patent:
`Apr. 8, 2003
`
`U5006544556B1
`
`(54) PHARMACEUTICAL FORMULATIONS
`CONTAINING ANON-STEROIDAL
`ANTIINFLAMMATORY DRUG AND A
`
`4,508,905 A
`4,628,098 A
`4,738,975 A
`
`4/1985 Junggren et a1.
`12/1986 Nohara et a1.
`4/1988 Nohara et al.
`
`........ 546/2737
`
`546/2737
`.............. 514/338
`
`PROTON PUMP INHIBITOR
`
`(List continued on next page.)
`
`(75)
`
`Inventors: Chih-Ming Chen; Unchalee
`K051tprapa> bOth 0f Dam” FL (Us)
`.
`.
`.
`(73) A551gnee: Andrx C0rp0rat10n, Dav1e, FL (US)
`
`( * ) Notice:
`
`Subject. to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`.
`(21) Appl. No.. 09/659,222
`
`(22)
`
`Filed:
`
`Sep. 11,2000
`
`(51)
`
`Int. Cl.7 ............................ A61K 9/20; A61K 9/22;
`A61K 9/24; A61K 9/26; A61K 9/54
`....................... 424/469; 424/451, 424/452,
`(52) us. Cl.
`424/457; 424/458; 424/464; 424/465; 424/470;
`424/472
`_
`(58) Fleld of Search ................................. 424/451, 455,
`424/456, 464, 468, 469, 470, 477, 480,
`481, 482, 489, 493, 494, 495, 496, 497,
`452’ 472’ 457’ 458
`
`(56)
`
`-
`References Clted
`U.S. PATENT DOCUMENTS
`
`3,161,654 A
`3,228,831 A
`3,385,886 A
`3,558,690 A
`3,591,584 A
`3,600,437 A
`3,766,263 A
`3,843,681 A
`3,845,215 A
`3,904,682 A
`4,009,197 A
`4,045,563 A
`4,255,431 A
`4,359,465 A
`4,472,409 A
`
`
`
`12/1964 Shen .......................... 548/500
`1/1966 Nicholson et a1.
`.. 514/568
`5/1968 Nicholson et a1.
`.. 562/492
`1/1971 Sallman et a1.
`560/47
`7/1971 Lombardino
`544/49
`8/1971 Marshall ........
`562/465
`10/1973 Godfrey ............
`562/465
`10/1974 Demerson et a1.
`.
`.. 548/432
`10/1974 Godfrey ..................... 514/557
`9/1975 Fried et al.
`................. 562/466
`2/1977 Fried et al.
`...........
`560/56
`8/1977 Berntsson et a1.
`.. 514/338
`.....
`3/1981 Junggren et a1.
`.. 514/338
`11/1982 Ruwart ....................... 514/314
`9/1984 Senn—Bilfinger
`............ 514/338
`
`
`
`EP
`EP
`EP
`EP
`EP
`GB
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`0005129
`4/1979
`......... C07D/403/12
`0166287
`6/1985
`......... C07D/401/12
`0174726
`7/1985
`......... C07D/401/12
`0295603
`6/1988
`C07D/401/12
`
`...... A61K/9/20
`0519365
`6/1992
`
`2163747
`3/1986
`C07D/235/28
`
`......... C07D/401/12
`9427988
`12/1994
`9501977
`1/1995
`C07D/401/12
`
`.......... A61K/45/06
`9725064
`7/1997
`
`OTHER PUBLICATIONS
`Hawkey, Christopher J., et al., Omeprazole Compared With
`Mis0pr0st01 for Ulcers Associated with Nonsteroidal Anti-
`inflammatory Drugs, New England Journal of Medicine
`(Mar. 12, 1988), 338:727—734.
`Primary Examiner—James M. Spear
`(74) Attorney, Agent, or Firm—Davidson, Davidson &
`Kappel, LLC
`
`ABSTRACT
`(57)
`An oral solid dosage form includes a therapeutically effec-
`tive amount of an NSAID and a
`roton um inhibitor in an
`p
`p
`p
`amount effective to inhibit or prevent gastrointestinal side
`effects normally associated With the NSAID. Also disclosed
`is a method of treating a human patient
`in need of
`antiinflammatory, analgesic and/or antipyretic therapy, com-
`prising orally administering to the patient an oral pharma-
`ceutical dosage form Which includes a therapeutically effec-
`tive amount of an NSAID and an amount of a proton pump
`inhibitor effective to substantially inhibit gastrointestinal
`side effects of the NSAID. The invention is further related to
`
`a method of prophylactically treating a human patient Who
`is on a therapy known to have significant gastrointestinal
`side effects or is about to begin such a therapy, via concur-
`rent administration of an NSAID and a proton pump inhibi-
`tor in a combination (single) oral dosage form.
`
`34 Claims, 4 Drawing Sheets
`
`DICLOFENAC Nu ER/OMEPRAZOLE DR TABLET
`
`
`r;
`
`D(“/cOMEPRAZOLE]
`
`AMOUNTDISSOLV
`
`
`
`
`
`
`DISSOLUTION TIME (mm)
`
`O INITIAL
`[:1 ZWEEKS
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 1
`
`

`

`US 6,544,556 B1
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`272233;?) 2
`5,006,547 A
`5,008,283 A
`5,039,806 A
`5,045,321 A
`5,045,552 A
`5,068,458 A
`
`1313:: Egg: :: :1 ““““““ 454/422
`
`4/1991 L00:
`.
`N
`514/414
`4/1991 Blackburn et a1.
`.......... 514/414
`8/1991 Brandstram et a1.
`........ 546/271
`9/1991 Makino et a1.
`............. 424/475
`9/1991 Souda et a1.
`................ 514/338
`11/1991 Dales et a1.
`................ 568/634
`
`5,204,118 A
`5,312,824 A
`5,417,980 A
`5,510,382 A
`5,629,305 A
`5,708,017 A
`5,798,120 A
`5,817,338 A
`5,877,192 A
`
`424/489
`4/1993 Goldman et a1.
`
`514/338
`5/1994 Sohda et a1.
`........... 424/464
`5/1995 Goldman et a1.
`4/1996 Stjernschantz et a1.
`..... 514/530
`5/1997 Eek et a1.
`................... 514/199
`1/1998 Dave et a1.
`................. 514/393
`8/1998 Tomohisa et a1.
`~~
`424/482
`
`10/1998 Bergstrand et a1.
`424/468
`............ 514/338
`3/1999 Lindberg et a1.
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 2
`
`

`

`US. Patent
`
`1B
`
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`
`333.memJOqummEOEmm2qumnfiSEwka
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 3
`
`

`

`US. Patent
`
`Apr. 8, 2003
`
`Sheet 2 0f 4
`
`US 6,544,556 B1
`
`$4kammm4ON§amEDEmm2QizmufijowaNmink
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 4
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 4
`
`
`

`

`US. Patent
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`8,
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 5
`
`
`

`

`US. Patent
`
`Apr. 8, 2003
`
`Sheet 4 0f 4
`
`US 6,544,556 B1
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 6
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`

`

`US 6,544,556 B1
`
`1
`PHARMACEUTICAL FORMULATIONS
`CONTAINING A NON-STEROIDAL
`ANTIINFLAMMATORY DRUG AND A
`PROTON PUMP INHIBITOR
`
`FIELD OF THE INVENTION
`
`The present invention is related to the combination of a
`non-steroidal antiinflammatory drug (“NSAID”) or one of
`its single enantiomers or salt of the NSAID, and a proton
`pump inhibitor or one of its single enantiomers, or an
`alkaline salt of the proton pump inhibitor or one of its single
`enantiomers, in a single oral pharmaceutical dosage form.
`BACKGROUND
`
`their
`Although NSAIDs are often used for
`antiinflammatory, analgesic, and/or antipyretic effects, it is
`well known that NSAIDs have the potential to cause gas-
`trointestinal (GI) bleeding through a variety of mechanisms
`related to their topical and systemic effects. The GI bleeding
`may depend on the length of the treatment and on the
`particular drug. This problem is important in cases where the
`therapy must be continued for a long period of time. For
`example, osteoarthritis and rheumatoid arthritis in the eld-
`erly is often treated with long-term NSAID therapy, as
`chronic treatment is needed to control pain and inflammation
`and to improve quality of life.
`Additionally it is well known that because of their side-
`effects on the GI tract, NSAIDs are invariably administered
`after meals or, generally, when the stomach is not empty.
`This pharmacological principle is confirmed by the recom-
`mendations found in the labeling of these medications.
`Patients who have an ulcer or who are susceptible to
`developing ulcers are commonly advised to avoid taking
`NSAIDs for pain, inflammation, and/or fever.
`Other measures which can be taken to decrease GI side
`
`affects associated with NSAID therapy is to coadminister an
`H2 blocker e.g. ranitidine, or a prostaglandin analogue, e.g.
`misoprostol, with the NSAID. In fact, a combination tablet
`containing diclofenac sodium and misoprostol (Arthrotec®,
`Pharmacia Corp.) has had FDA approval since 1988.
`There is a continuing need for analgesic medications able
`to provide high efficacy pain relief while reducing the
`possibility of undesirable effects. Non-steroidal anti-
`inflammatory drugs,
`including compounds such as
`ibuprofen, ketoprofen and diclofenac, have anti-
`inflammatory actions and are effective on pain associated
`with the release of prostaglandins and other mediators of
`inflammation. For example, diclofenac and pharmaceuti-
`cally acceptable salts thereof, e.g. diclofenac sodium, are
`considered to be extremely potent and effective as an anal-
`gesic and anti-inflammatory agent. Diclofenac is approved
`in the United States for the long-term symptomatic treatnent
`of rheumatoid arthritis, osteoarthritis and ankylosing
`spondylitis. It is also considered to be useful for the short-
`term treatment of acute musculoskeletal injury, acute shoul-
`der pain, postoperative pain and dysmenorrhea. However,
`NSAIDs such as diclofenac produce side effects in about
`20% of patients that require cessation of medication. Side
`effects include, for example, gastrointestinal bleeding and
`the abnormal elevation of liver enzymes.
`Non-steroidal anti-inflammatory drugs (NSAIDs) exert
`most of their anti-inflammatory, analgesic and antipyretic
`activity and inhibit hormone-induced uterine contractions
`and certain types of cancer growth through inhibition of
`prostaglandin G/H synthase, also known as cyclooxygenase.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`Inhibition of COX-1 causes a number of side effects includ-
`ing inhibition of platelet aggregation associated with disor-
`ders of coagulation, and gastrointestinal side effects with the
`possibility of ulcerations and of hemorrhage. It is believed
`that the gastrointestinal side effects are due to a decrease in
`the biosynthesis of prostaglandins which are cytoprotective
`of the gastric mucosa.
`A high incidence of side effects has historically been
`associated with chronic use of classic cyclooxygenase
`inhibitors, all of which are about equipotent for COX-1 or
`COX-2, or which are COX-1-selective. While renal toxicity
`occurs, it usuallybecomes evident in patients who already
`exhibit renal insufficiency (D. Kleinknecht, Sem. Nephrol.
`15: 228, 1995). By far,
`the most prevalent and morbid
`toxicity is gastrointestinal. Even with relatively nontoxic
`drugs such as piroxicam, up to 4% of patients experience
`gross bleeding and ulceration (M .J .S. Langman et al, Lancet
`343: 1075, 1994). In the United States, it is estimated that
`some 2000 patients with rheumatoid arthritis and 20,000
`patients with osteoarthritis die each year due to gastrointes-
`tinal side effects related to the use of COX inhibitors. In the
`
`UK, about 30% of the annual 4000 peptic ulcer-related
`deaths are attributable to COX inhibitors (Scrip 2162, p.17).
`COX inhibitors cause gastrointestinal and renal toxicity due
`to the inhibition of synthesis of homeostatic prostaglandins
`responsible for epithelial mucus production and renal blood
`flow, respectively.
`The second form of cyclooxygenase, COX-2, is rapidly
`and readily inducible by a number of agents including
`mitogens, endotoxins, hormones, cytokines and growth fac-
`tors. It has been proposed that COX-2 is mainly responsible
`for the pathological effects of prostaglandins, which arise
`when rapid induction of COX-2 occurs in response to such
`agents as inflanmmatory agents, hormones, growth factors,
`and cytokines. Selective inhibitors of COX-2 have anti-
`inflammatory, antipyretic and analgesic properties similar to
`those of a conventional non-steroidal anti-inflammatory
`drug (NSAID), but COX-2 inhibitors have been touted as
`providing a reduced potential for gastrointestinal toxicity,
`among other side effects. Nevertheless, experience with
`selective COX-2 inhibitors is limited relative to experience
`with non-selective COX inhibitors (which non-selectively
`inhibit COX-1 and COX-2). Non-selective COX inhibitors
`are widely used, and it is expected that these drugs will
`continue to be widely used. Further, there has been recent
`suggestions that COX-2 inhibitors have serious but previ-
`ously unrecognized side effects,
`including increased
`intraocular pressure and the risk of glaucoma, as well as
`possible effects on the central nervous system.
`For years, neutralization of gastric acid with antacids was
`the only relief from the pain of ulcers. However, more
`recently, a class of antisecretory agents that do not exhibit
`anticholinergic or H2 histamine antagonistic properties, but
`that suppress gastric acid secretion by the specific inhibition
`of the H+, K+—ATPase enzyme system at the secretory
`surface of the gastric parietal cell, has been developed.
`These agents (hereinafter “proton pump inhibitors”) provide
`a more specific class of inhibitors of gastric acid secretion in
`mammals and man by blocking the final step of acid
`production.
`Generally, proton pump inhibitors, their single enanti-
`omers or alkaline salts thereof, are used for the prevention
`and treatment of gastric acid related diseases including, but
`not limited to, reflux esophagitis, gastritis, duodenitis, gas-
`tric ulcer and duodenal ulcer. These proton pump inhibitors
`may also be used in patients in intensive care situations, in
`patients with acute upper gastrointestinal bleeding, pre- and
`
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`

`US 6,544,556 B1
`
`3
`postoperatively to prevent acid aspiration of gastric acid and
`to prevent and treat stress ulceration. Also, they may be
`useful in the treatment of psoriasis as well as in the treatment
`of Helicobacter infections and diseases related to these.
`
`Additionally, these proton pump inhibitors may be used for
`the treatment of other gastrointestinal disorders where gas-
`tric acid inhibitory effect is desirable, such as patients with
`Non Ulcer Dyspepsia, in patients with symptomatic gastro-
`esophageal reflux disease, in patients with gastrinomas, and
`in particular in patients on NSAID therapy.
`US. Pat. No. 5,817,338 (Bergstrand, et al.) describes
`multiple unit tableted dosage forms of omeprazole, a proton
`pump inhibitor commercially available for inhibiting gastric
`acid secretion in humans. Therein,
`it
`is suggested that
`omeprazole may be used for treatment of other gastrointes-
`tinal disorders where gastric acid inhibitory effect
`is
`desirable, e.g., in patients on NSAID therapy. However, this
`patent does not describe pharmaceutical formulations com-
`bining a proton pump inhibitor such as omeprazole with an
`NSAID.
`
`10
`
`15
`
`20
`
`SUMMARY OF THE INVENTION
`
`It is an object of this invention to provide a method for the
`treatment of pain, inflammation, and/or fever with the use of
`a NSAID without the undesirable stomach discomfort and
`
`25
`
`other side effects typically associated with NSAID therapy.
`It is a further object of the invention to decrease the risk
`of the development and/or exacerbation of ulcers which may
`occur during NSAID therapy.
`It is a further object of the invention to promote patient
`compliance and thereby increase efficacy of NSAID treat-
`ment in patients who are being chronically treated with
`NSAIDs.
`
`It is a further object of the invention to provide prophy-
`lactic treatment
`to a human patient who is on NSAID
`therapy or is about to begin NSAID therapy, in order to
`avoid or minimize gastrointestinal side-effects.
`It is a further object of the invention to provide prophy-
`lactic treatment to a human patient who is on a therapy
`known to have significant gastrointestinal side effects or is
`about to begin such a therapy, in order to avoid or e such side
`effects.
`
`It is a further object of the invention to provide cost
`effective therapy to decrease the risk of the development
`and/or exacerbation of ulcers which may occur during
`NSAID therapy.
`In view of the above-mentioned objects and others, the
`invention is directed to an oral solid dosage form comprising
`a therapeutically effective amount of an NSAID and a proton
`pump inhibitor in an amount effective to inhibit or prevent
`gastrointestinal side effects normally associated with the
`NSAID treatment.
`
`The invention is further directed to a solid oral dosage
`form comprising
`a) an NSAID (e.g. diclofenac or a pharmaceutically
`acceptable salt thereof) extended release tablet and
`b) an enterically coated proton-pump inhibitor without a
`separating layer between the proton pump inhibitor and
`the enteric coat.
`
`The invention is further directed to a (non-steroidal)
`antiinflammatory, analgesic, and antipyretic oral
`therapy
`which does not possess any substantial gastrointestinal side-
`effects, comprising an orally administrable dosage form
`comprising a therapeutically effective amount of an NSAID
`and an amount of a proton pump inhibitor effective to
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`substantially inhibit gastrointestinal side effects of the
`NSAID, together with one or more pharmaceutically accept-
`able excipients.
`The invention is further directed to a dosage form com-
`prising a therapeutically effective amount of an NSAID and
`an amount of a proton pump inhibitor effective to substan-
`tially inhibit gastrointestinal side effects of the NSAID,
`wherein said proton pump inhibitor is coated with a material
`suitable to prevent contact of said proton pump inhibitor
`with acidic gastric juice (e.g. an enteric coating). In pre-
`ferred embodiments, the material is directly coated onto the
`proton pump inhibitor without a separating layer between
`the material and the proton pump inhibitor.
`The invention is further directed to the prophylactic
`treatment of a human patient who is on NSAID therapy or
`is about to begin NSAID therapy, via the concurrent admin-
`istration of a proton pump inhibitor.
`The invention is further directed to the prophylactic
`treatment of a human patient who is on a therapy known to
`have significant gastrointestinal side effects or is about to
`begin such a therapy, via the concurrent administration of a
`proton pump inhibitor.
`The invention is further related to a method of treating a
`human patient in need of antiinflammatory, analgesic and/or
`antipyretic therapy, comprising orally administering to the
`patient an oral pharmaceutical dosage form comprising a
`therapeutically effective amount of an NSAID and an
`amount of a proton pump inhibitor effective to substantially
`inhibit gastrointestinal side effects of the NSAID.
`In certain preferred embodiments, the dosage form is an
`oral
`tablet comprising the NSAID,
`the proton pump
`inhibitor, and one or more pharmaceutically acceptable
`excipients. In other preferred embodiments, the NSAID and
`the proton pump inhibitor comprise a mixture of tablets,
`powders, pellets, granules, or inert nonpareil beads coated
`with the drugs, contained within a gelatin capsule.
`The inventive formulations and methods described herein
`
`promote patient compliance and thereby increase efficacy of
`NSAID treatment in patients who are being chronically
`treated with NSAIDs. In other words, the inventive formu-
`lations increase the likelihood that a patient on NSAID
`therapy who is noncompliant due to gastrointestinal side
`effects, or who forgets or refuses to take both medications
`separately will be more accepting of a single composition
`combining the NSAID and proton pump inhibitor, particu-
`larly due to the avoidance of gastrointestinal side effects.
`Proton pump inhibitors are known to be highly acid labile,
`and therefore it is preferred that the proton pump inhibitor(s)
`contained in the dosage forms of the invention be protected
`from contact with acidic gastric juice.
`In certain preferred embodiments,
`inhibitor is omeprazole.
`the NSAID is
`In certain preferred embodiments,
`diclofenac, more preferably diclofenac sodium.
`For purposes of this disclosure, all references to proton
`pump inhibitors and NSAIDs include their single enanti-
`omers and their pharmaceutically acceptable salts.
`For purposes of this disclosure, the phrase “substrates” is
`meant
`to encompass inert pharmaceutically acceptable
`beads, particles, granules or pellets.
`For purposes of this disclosure, the phrase “combination
`pharmaceutical” shall be understood to include any drug
`composition containing at least two therapeutically active
`components of which at least one is a non-steroidal antiin-
`flammatory drug. The term “pain-alleviating” shall be
`understood herein to include the expressions “pain-
`suppressing” and “pain-inhibiting” as the invention is appli-
`
`the proton pump
`
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`

`US 6,544,556 B1
`
`5
`cable to the alleviation of existing pain as well as the
`suppression or inhibition of pain which would otherwise
`ensue from an imminent pain-causing event.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph of in vitro dissolution data which shows
`the dissolution profile of omeprazole from the initial for-
`mulation of Example 1 and the formulation of Example 1
`after exposure to accelerated storage conditions of 40° C.
`and 75% relative humidity for 2 weeks. The dissolution
`medium is a 0.5 M Phosphate buffer at a pH 6.8.
`FIG. 2 is a graph of in vitro dissolution data which shows
`the dissolution profile of diclofenac from the initial formu-
`lation of Example 1 and the formulation of Example 1 after
`exposure to accelerated storage conditions of 40° C. and
`75 % relative humidity for 2 weeks. The dissolution medium
`is a 0.5 M Phosphate buffer at a pH 6.8.
`FIG. 3 is a graph of in vitro dissolution data which shows
`the dissolution profile of diclofenac from the initial formu-
`lation of Example 2, the formulation of Example 2 after
`exposure to accelerated storage conditions of 40° C. and
`75% relative humidity for 2 weeks and the formulation of
`Example 2 after exposure to accelerated storage conditions
`of 40° C. and 75% relative humidity for 1 month. The
`dissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.
`FIG. 4 is a graph of in vitro dissolution data which shows
`the dissolution profile of omeprazole from the initial for-
`mulation of Example 2, the formulation of Example 2 after
`exposure to accelerated storage conditions of 40° C. and
`75% relative humidity for 2 weeks and the formulation of
`Example 2 after exposure to accelerated storage conditions
`of 40° C. and 75% relative humidity for 1 month. The
`dissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The term “NSAID,” as used herein, refers to any com-
`pound acting as a non-steroidal anti-inflammatory agent
`identifiable as such by one of ordinary skill in the art. For
`many years NSAIDs have been used for treating pain and/or
`inflammation. “Treating” includes prophylaxis of a physical
`and/or mental condition or amelioration or elimination of the
`developed condition once it has been established, or alle-
`viation of the characteristic symptoms of such condition.
`The term “pain” includes all types of pain. Pain includes, but
`is not limited to, chronic pains, such as arthritis pain (e.g.
`pain associated with osteoarthritis and rheumatoid arthritis),
`neuropathic pain, and post-operative pain, chronic lower
`back pain, cluster headaches, herpes neuralgia, phantom
`limb pain, central pain, dental pain, neuropathic pain,
`opioid-resistant pain, visceral pain, surgical pain, bone
`injury pain, pain during labor and delivery, pain resulting
`from bums, including sunburn, post partum pain, migraine,
`angina pain, and genitourinary tract-related pain including
`cystitis, the term also refers to nociceptive pain or nocice-
`ption.
`The Merck Manual, 16th Edition, Merck Research Labo-
`ratories (1990) pp 1308—1309 provide well known examples
`of NSAIDs. The term NSAID includes, but is not limited to,
`the group consisting of salicylates,
`indomethacin,
`flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,
`tebufelone,
`ibuprofen, etodolac, nabumetone,
`tenidap,
`alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone,
`phenylbutazone, clofezone, oxyphenbutazone, prexazone,
`apazone, benzydamine, bucolome, cinchopen, clonixin,
`ditrazol, epirizole, fenoprofen, fioctafeninl, fiufenamic acid,
`
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`indoprofen, ketoprofen, meclofenamic acid,
`glaphenine,
`mefenamic acid, nifiumic acid, phenacetin, salidifamides,
`sulindac, suprofen and tolmetin. The salicylates may include
`acetylsalicylic acid, sodium acetylsalicylic acid, calcium
`acetylsalicylic acid, salicylic acid, and sodium salicylate.
`NSAIDs have been widely used in arthritis therapy for
`several years. The following references, hereby incorporated
`by reference, describe various NSAIDs suitable for use in
`the invention described herein, and processes for
`their
`manufacture: US. Pat. No. 3,558,690 to Sallmann and
`Pfister, (assigned to Ciba Geigy), issued 1971; US. Pat. No.
`3,843,681 (assigned to American Home Products), issued
`1974; US. Pat. No. 3,766,263 to Godfrey, (assigned to
`Reckitt and Colman) issued 1973; US. Pat. No. 3,845,215
`to Godfrey (assigned to Reckitt and Colman) issued 1974;
`US. Pat. No. 3,600,437 to Marshall (assigned to Eli Lilly),
`issued 1971; US. Pat. No. 3,228,831 to Nicholson and
`Adams, (assigned to Boots Pure Drug), issued 1966; (US.
`Pat. No. 3,385,886 to Nicholson and Adams, (assigned to
`Boots Pure Drug) issued 1968; US. Pat. No. 3,161,654 to
`Shen, (assigned to Merck & Co.), issued 1964; US. Pat. No.
`3,904,682 to Fried and Harrison, (assigned to Syntex),
`issued 1975; US. Pat. No. 4,009,197 to Fried and Harrison,
`(assigned to Syntex), issued 1977; US. Pat. No. 3,591,584
`to Lombardino (assigned to Pfizer) issued 1971; US. Pat.
`No. 5,068,458 to Dales et al., (assigned to Beecham Group,
`PLC.), issued Nov. 26, 1991; US. Pat. No. 5,008,283 to
`Blackburn et al. (assigned to Pfizer, Inc.), issued Apr. 16,
`1991; and US. Pat. No. 5,006,547 to Loose (assigned to
`Pfizer), issued Apr. 9, 1991, All of the above patents are
`hereby incorporated by reference.
`inhibitors of
`Proton pump inhibitors (PPI) are potent
`gastric acid secretion,
`inhibiting H+, K+—ATPase,
`the
`enzyme involved in the final step of hydrogen ion produc-
`tion in the parietal cells. The term proton pump inhibitor
`includes, but is not limited to, omeprazole, lansoprazole,
`rabeprazole, pantoprazole and leminoprazole,
`including
`isomers, enantiomers and tautomers thereof, and alkaline
`salts thereof Proton pump inhibitors typically include ben-
`zimidazole compounds. The following patents describe vari-
`ous benzimidazole compounds suitable for use in the inven-
`tion described herein: US. Pat. No. 4,045,563, US. Pat. No.
`4,255,431, US. Pat. No. 4,359,465, US. Pat. No. 4,472,409,
`US. Pat. No. 4,508,905, JP-A-59181277, US. Pat. No.
`4,628,098, US. Pat. No. 4,738,975, US. Pat. No. 5,045,321,
`US. Pat. No. 4,786,505, US. Pat. No. 4,853,230, US. Pat.
`No. 5,045,552, EP-A-295603, US. Pat. No. 5,312,824,
`EP-A-166287, EP-A-519365, EP5129, EP 174,726, EP 166,
`287 and GB 2,163,747, All of the above patents are hereby
`incorporated by reference. Proton pump inhibitors, e.g.
`omeprazole and its pharmaceutically acceptable salts, which
`are used in accordance with the invention are known com-
`
`pounds and can be produced by known processes. In certain
`preferred embodiments,
`the proton pump inhibitor is
`omeprazole, either in racernic mixture or only the
`(—)enantiomer of omeprazole (i.e. esomeprazole), as set
`forth in US. Pat. No. 5,877,192, hereby incorporated by
`reference.
`
`Omeprazole is typically administered in a 20 mg dose/day
`for active duodenal ulcer for 4—8 weeks; in a 20 mg dose/day
`for gastro-esophageal reflux disease (GERD) or severe ero-
`sive esophagitis for 4—8 weeks; in a 20 mg dose/twice a day
`for treatment of Helicobacter pylori (in combination with
`other agents); in a 60 mg dose/day for active duodenal ulcer
`for 4—8 weeks and up to 120 mg three times/day, and in a 40
`mg dose/day for gastric ulcer for 4—8 weeks. Such dosages
`are contemplated to be within the scope of the invention.
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 9
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 9
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 9
`
`

`

`US 6,544,556 B1
`
`7
`Thus, in certain embodiments of the invention, the amount
`of proton pump inhibitor which is included in the dosage
`form is an amount which is considered to be therapeutically
`effective, in accordance with the dosages set forth above for
`a variety of disease states. In other preferred embodiments
`of the invention,
`the dose of proton pump inhibitor is
`sub-therapeutic. For example, when the drug is omeprazole,
`the dosage form may contain from about 0.1 mg to about 120
`mg omeprazole.
`Lansoprazole is typically administered about 15—30
`mg/day; rabeprazole is typically administered 20 mg/day
`and pantoprazole is typically administered 40 mg/day.
`However, any therapeutic or sub-therapeutic dose of these
`agents is considered within the scope of the present inven-
`tion.
`
`The proton pump inhibitor(s) included in the dosage
`forms of the invention are preferably protected from contact
`with acidic gastric juice, and preferably is transferred with-
`out exposure to gastric fluid until the dosage form reaches a
`part of the gastrointestinal tract where the pH is near neutral
`and where rapid absorption of omeprazole can occur.
`In preferred embodiments of the invention, the pharma-
`ceutical compositions containing the proton pump inhibitors
`and NSAIDs set forth herein are administered orally. Such
`oral dosage forms may contain one or both of the drugs in
`immediate or sustained release form. The oral dosage forms
`may be in the form of tablets, capsules, troches, lozenges,
`aqueous or oily suspensions, dispersible powders or
`granules, emulsions, multiparticulate formulations, syrups,
`elixirs, and the like.
`The combination of proton pump inhibitor and a NSAID
`can be employed in admixtures with conventional
`excipients, i.e., pharmaceutically acceptable organic or inor-
`ganic carrier substances suitable for oral, parenteral, nasal,
`intravenous, subcutaneous, enteral, or any other suitable
`mode of administration, known to the art. Suitable pharma-
`ceutically acceptable carriers include but are not limited to
`water, salt solutions, alcohols, gum arabic, vegetable oils,
`benzyl alcohols, polyethylene glycols, gelate, carbohydrates
`such as lactose, amylose or starch, magnesium stearate talc,
`silicic acid, viscous paraffin, perfume oil,
`fatty acid
`monoglycerides and diglycerides, pentaerythritol fatty acid
`esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
`The pharmaceutical preparations can be sterilized and if
`desired mixed with auxiliary agents, e.g.,
`lubricants,
`preservatives, stabilizers, wetting agents, emulsifiers, salts
`for influencing osmotic pressure buffers, coloring, flavoring
`and/or aromatic substances and the like. They can also be
`combined where desired with other active agents, e.g., other
`analgesic agents. For oral application, particularly suitable
`are tablets, dragees,
`liquids, drops, suppositories, or
`capsules, caplets and gelcaps. The compositions intended for
`oral use may be prepared according to any method known in
`the art and such compositions may contain one or more
`agents selected from the group consisting of inert, non-toxic
`pharmaceutically excipients which are suitable for the
`manufacture of tablets. Such excipients include, for example
`an inert diluent such as lactose; granulating and disintegrat-
`ing agents such as cornstarch; binding agents such as starch;
`and lubricating agents such as magnesium stearate. The
`tablets may be uncoated or they may be coated by known
`techniques for elegance or to delay the release of the active
`ingredients. Formulations for oral use may also be presented
`as hard gelatin capsules wherein the active ingredient is
`mixed with an inert diluent.
`
`Aqueous suspensions containing the above-identified
`combination of drugs and that mixture have one or more
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`excipients suitable as suspending agents, for example phar-
`maceutically acceptable synthetic gums such as hydroxypro-
`pylmethylcellulose or natural gums. Oily suspensions may
`be formulated by suspending the above-identified combina-
`tion of drugs in a vegetable oil or mineral oil. The oily
`suspensions may contain a thickening agent such as beeswax
`or cetyl alcohol. A syrup, elixir, or the like can be used
`wherein a sweetened vehicle is employed.
`As is well known in the art, proton pump inhibitors are
`susceptible to degradation and/or transformation in acidic
`and neutral media. For example, the half-life of degradation
`of omeprazole in water solutions at pH-values less than three
`is shorter than ten minutes. The degradation of proton pump
`inhibitors is catalyzed by acidic compounds and is stabilized
`in mixtures wit