(12) United States Patent
`Chen et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,544,556 B1
`Apr. 8, 2003
`
`US006544556B1
`
`(54) PHARMACEUTICAL FORMULATIONS
`CONTAINING A N()N-STER()II)AL
`ANTHNFLAMMATORY DRUG AND A
`PROTON PUMP INHIBITOR
`
`(75)
`
`Inventors: Chih-Ming Chen; Unchalee
`Kositprapa, both of Davie, FL (US)
`
`(73)
`(*)
`
`(21)
`(22)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Assignee: AndrX Corporation, Davie, FL (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC 154(b) by 0 days.
`
`Appl. No.: 09/659,222
`Filed:
`Sep. 11, 2000
`
`Int. Cl.7 .......................... .. A61K 9/20; A61K 9/22;
`A61K 9/24; A61K 9/26; A61K 9/54
`US. Cl. ..................... .. 424/469; 424/451; 424/452;
`424/457; 424/458; 424/464; 424/465; 424/470;
`424/472
`Field 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
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,161,654 A 12/1964 Shen ........................ .. 548/500
`3,228,831 A
`1/1966 Nicholson et a1.
`514/568
`3,385,886 A
`5/1968 Nicholson et a1. ........ .. 562/492
`3,558,690 A
`1/1971 Sallman et a1. ............. .. 560/47
`3,591,584 A
`7/1971 Lombardino ..
`544/49
`3,600,437 A
`8/1971 Marshall ..... ..
`562/465
`3,766,263 A 10/1973 Godfrey ......... ..
`562/465
`3,843,681 A 10/1974 Demerson et a1.
`548/432
`3,845,215 A 10/1974 Godfrey ......... ..
`514/557
`3,904,682 A
`9/1975 Fried et al.
`.. 562/466
`
`4,009,197 A
`
`2/1977 Fried et al. . . . . . . .
`
`. . . .. 560/56
`
`514/338
`8/1977 Berntsson et a1.
`4,045,563 A
`514/338
`3/1981 Junggren et a1.
`4,255,431 A
`514/314
`4,359,465 A 11/1982 RuWart ........... ..
`4,472,409 A
`9/1984 Senn-Bil?nger .......... .. 514/338
`
`4/1985 Junggren et a1. ...... .. 546/273.7
`4,508,905 A
`4,628,098 A 12/1986 Nohara et a1. ......... .. 546/2737
`4,738,975 A
`4/1988 Nohara et a1. ............ .. 514/338
`(List continued on next page.)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`GB
`WO
`WO
`WO
`
`0005129
`0166287
`0174726
`0295603
`0519365
`2163747
`9427988
`9501977
`9725064
`
`4/1979
`6/1985
`7/1985
`6/1988
`6/1992
`3/1986
`12/1994
`1/1995
`7/1997
`
`....... .. C07D/403/12
`....... .. C07D/401/12
`....... .. C07D/401/12
`....... .. C07D/401/12
`.......... .. A61K/9/20
`....... .. C07D/235/28
`....... .. C07D/401/12
`....... .. C07D/401/12
`........ .. A61K/45/06
`
`OTHER PUBLICATIONS
`
`HaWkey, Christopher J ., et al., OmepraZole Compared With
`Misoprostol for Ulcers Associated With Nonsteroidal Anti
`in?ammatory 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
`(57)
`
`ABSTRACT
`
`An oral solid dosage form includes a therapeutically effec
`tive 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. Also disclosed
`is a method of treating a human patient in need of
`antiin?ammatory, 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 signi?cant 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
`
`DlCLOFENAC Na ER/OMEPRAZOLE DR TABLET
`
`AMOUNT D! SSOLVED (% OMEPRAZOL'E]
`
`DISSOLUTION TIME (mm)
`
`O INITIAL
`[:1 ZWEEKS
`
`Lupin Exh. 1007
`
`

`
`US 6,544,556 B1
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,204,118 A
`
`4/1993 Goldman et a1. ......... .. 424/489
`
`424/468
`4 786 505 A 11/1988 Lovgren et al
`4’853’230 A
`8/1989 Lovgren et a1: """"" " 424/466
`5:006:54” A
`4/1991 Loose """"""" "
`514/414
`
`5,312,824 A
`5,417,980 A
`5,510,382 A
`
`5/1994 Sohda et a1. .............. .. 514/338
`5/1995 Goldman et a1. ......... .. 424/464
`4/1996 Stjernschantz et a1.
`514/530
`
`
`
`5,008,283 A 5,039,806 A
`
`
`
`4/1991 Blackburn et al' N 8/1991 Brandstram et a1
`
`546/271
`
`
`
`5,629,305 A 5,708,017 A
`
`
`
`Eek 618.1. ................. .. 1/1998 Dave et a1. ..... ..
`
`514/393
`
`424/475
`9/1991 Makino et a1_ __
`5,045,321 A
`__ 514/338
`9/1991 SOuda et a1, __
`5,045,552 A
`5,068,458 A 11/1991 Dales et a1. .............. .. 568/634
`
`424/482
`8/1998 Tomohisa et a1.
`5,798,120 A
`5,817,338 A 10/1998 Bergstrand et a1. ....... .. 424/468
`5,877,192 A
`3/1999 Lindberg et a1. .......... .. 514/338
`
`

`
`U.S. Patent
`
`Apr. 8, 2003
`
`Sheet 1 of 4
`
`US 6,544,556 B1
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`
`U.S. Patent
`
`Apr. 8, 2003
`
`Sheet 3 of 4
`
`US 6,544,556 B1
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`

`
`U.S. Patent
`
`Apr. 8,2003
`
`Sheet 4 0f 4
`
`US 6,544,556 B1
`
`P1‘
`
`w 5 , - l s i a i ,
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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 antiin?ammatory 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
`
`Although NSAIDs are often used for their
`antiin?ammatory, 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 in?ammation
`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 con?rmed 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, in?ammation, 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 ef?cacy pain relief While reducing the
`possibility of undesirable effects. Non-steroidal anti
`in?ammatory drugs, including compounds such as
`ibuprofen, ketoprofen and diclofenac, have anti
`in?ammatory actions and are effective on pain associated
`With the release of prostaglandins and other mediators of
`in?ammation. For example, diclofenac and pharmaceuti
`cally acceptable salts thereof, eg diclofenac sodium, are
`considered to be extremely potent and effective as an anal
`gesic and anti-in?ammatory 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-in?ammatory drugs (NSAIDs) exert
`most of their anti-in?ammatory, 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
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`15
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`20
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`25
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`30
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`35
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`40
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`45
`
`50
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`60
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`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 insuf?ciency (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
`?oW, 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 in?anmmatory agents, hormones, groWth factors,
`and cytokines. Selective inhibitors of COX-2 have anti
`in?ammatory, antipyretic and analgesic properties similar to
`those of a conventional non-steroidal anti-in?ammatory
`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 speci?c 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 speci?c class of inhibitors of gastric acid secretion in
`mammals and man by blocking the ?nal 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, re?ux 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
`
`

`
`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 re?ux 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.
`
`SUMMARY OF THE INVENTION
`
`It is an object of this invention to provide a method for the
`treatment of pain, in?ammation, and/or fever With the use of
`a NSAID Without the undesirable stomach discomfort and
`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 signi?cant 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)
`antiin?ammatory, 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
`
`10
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`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 (eg 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 signi?cant 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 antiin?ammatory, 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 ef?cacy 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, the proton pump
`inhibitor is omepraZole.
`In certain preferred embodiments, the NSAID is
`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
`?ammatory drug. The term “pain-alleviating” shall be
`understood herein to include the expressions “pain
`suppressing” and “pain-inhibiting” as the invention is appli
`
`

`
`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 pro?le 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 pro?le 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 pro?le 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 pro?le 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-in?ammatory agent
`identi?able as such by one of ordinary skill in the art. For
`many years NSAIDs have been used for treating pain and/or
`in?ammation. “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,
`?urbiprofen, 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, ?octafeninl, ?ufenamic acid,
`
`10
`
`15
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`glaphenine, indoprofen, ketoprofen, meclofenamic acid,
`mefenamic acid, ni?umic 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
`P?ster, (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 P?Zer) 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 P?Zer, Inc.), issued Apr. 16,
`1991; and US. Pat. No. 5,006,547 to Loose (assigned to
`P?Zer), issued Apr. 9, 1991, All of the above patents are
`hereby incorporated by reference.
`Proton pump inhibitors (PPI) are potent inhibitors of
`gastric acid secretion, inhibiting H", K+—ATPase, the
`enZyme involved in the ?nal 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 re?ux 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.
`
`

`
`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 ?uid 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 paraf?n, 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, emulsi?ers, salts
`for in?uencing osmotic pressure buffers, coloring, ?avoring
`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-identi?ed
`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-identi?ed 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 With alkaline compounds. The stability of this
`class of antisecretory compounds is also affected by
`moisture, heat, organic solvents and to some degree by light.
`With respect to the stability properties of the proton pump
`inhibitors, it is preferable that in an oral solid dosage form
`they be protected from contact With the acidic gastric juice
`and the active substance must be transferred in intact form
`to that part of the gastrointestinal tract Where pH is near
`neutral and Where rapid absorption of the medicatio