Pharmaceutical Compositions for the Coordinated
`Delivery of NSAIDs
`
`Cross Reference to Related Applications
`
`The present application is a continuation—in—part of U.S. application no. 10/158,216,
`
`filed on May 31, 2002. The ‘2l6 application claims the benefit of U.S. provisional
`
`application no. 60/294,588, filed on June 1, 2001.
`
`Field of the Invention
`
`The present invention is directed to pharmaceutical compositions that provide for the
`
`coordinated release of an acid inhibitor and a non—steroidal anti-inflammatory drug
`
`(NSAID). These compositionsrhave 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
`
`gastroduodenal lesions, e.g., ulcers and erosions, in susceptible individuals. 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
`
`independent doses of acid inhibitors (Dig. Dis. 122210-222 (1994); Drug Safety 211503-512
`
`(1999); Aliment. Pharmacol. Ther. 12:l35~140 (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 NSAlI)s and inhibition of protective
`
`prostaglandins (Can. J. Gastroenterol. 13:135—142 (1999) and Pract. Drug Safety 21:503-
`
`512, (1999)), which may also make some patients more susceptible 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
`
`Lupin Exh. 1003
`
`

`
`2
`
`explanation 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 damage
`
`occurs before the pH of the gastrointestinal tract can be raised and after the acid inhibiting .
`
`effect of the short acting acid inhibitor dissipates.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Although longer lasting agents, such as proton pump inhibitors (PPIS), usually
`
`maintain a consistently higher gastroduodenal pH throughout the day, their antisecretory
`
`effect may be delayed for several hours and may not take full effect for several days (Clin.
`
`Pharmacokinet. 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 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 vulnerable to NSAID-associated gastroduodenal damage (Aliment. Pharmacol. Ther.
`
`14:709-714 (2000)). Despite a significant reduction in gastroduodenal
`
`lesions with the
`
`concomitant administration of a proton pump inhibitor during 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 prolonged period of time (Scand. J. Gastroenterol. Suppl. 1 78:85-92 (1990)).
`
`Recognizing the potential benefits of PPIS for the prevention of NSAID-induced
`
`gastroduodenal damage, others have disclosed strategies for combining the two active
`
`agents for therapeutic purposes. However, these suggestions do not provide for coordinated
`
`drug release or for reducing intragastric acid levels to a non~toxic level prior to the release
`
`ofNSAID (U.S. 5,204,118; U.S. 5,417,980; U.S. 5,466,436; and U.S. 5,037,815). In certain
`
`

`
`3
`
`cases, suggested means of delivery would expose the gastrointestinal tract to NSAIDS prior
`
`to onset of PPI activity (U.S. 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 tendency 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 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:l729-1737 (2000); SCRIP 2617, pg. 19,
`
`Feb. 14, 2001); 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 ArthrotecTM for the treatment of arthritis in patients at risk for developing GI
`
`ulcers. This product contains misoprostol (a cytoprotective prostaglandin) and the NSAID
`
`diclofenac. Although patients administered ArthrotecTM do have a lower risk of developing
`
`ulcers, they may experience a number of other serious side effects such as 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
`
`studies (Scand. J. Gastroenterol. 20: 239-242 (1985) and Scand. J. Gastroenterol. 25:231—
`
`234 (1990)), there is no consistent evidence of a long term benefit during chronic treatment.
`
`10
`
`15
`
`20
`
`25
`
`Overall, it may be concluded that the risk of inducing GI ulcers is a recognized
`
`problem associated with the administration of NSAIDS and that, despite considerable effort,
`
`30
`
`an ideal solution has not yet been found.
`
`

`
`Summary of the Invention
`
`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, unit-dose product that combines: a) an agent that actively raises
`
`intragastric 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 minimizes the
`
`adverse effects of the NSAID on the gastroduodenal 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 prostaglandins due to
`
`NSAID therapy.
`
`In its first aspect, the invention is directed to a pharmaceutical 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-associated ulcers (N. Eng. J. Med. 340:1888-1899 (1999)), these
`
`agents are preferred compounds in the current invention. 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
`
`10
`
`15
`
`20
`
`25
`
`amount of between 5 mg and 100 mg.
`
`Other preferred agents that may be effectively used as acid inhibitors are the proton
`
`Pump
`
`inhibitors
`
`such
`
`as
`
`omeprazole,
`
`esomeprazole,
`
`pantoprazole,
`
`lansoprazole,
`
`rabeprazole, pariprazole, leminoprazole and tenatoprazole. Examples of particular proton
`
`30
`
`pump inhibitors include omeprazole, present in unit dosage forms in an amount of between
`
`5 mg and 50 mg; lansoprazole, present in unit dosage fonns in an amount of between 5 mg
`
`and 150 mg (and preferably at between 5 mg and 30 mg); and pantoprazole, present in unit
`
`dosage forms in an amount of between 10 mg and 200 mg. Recently, a newer class of acid
`
`

`
`5
`
`inhibitor has been developed which competes with potassium at
`
`the acid pump. The
`
`compounds in this class have been referred to as “reversible proton pump inhibitors” or
`
`“acid pump antagonists” and may also be used in the present invention. Examples include
`
`AZD-0865, AR-H047108, CS-526, pumaprazole,
`
`revaprazan and soraprazan (see
`
`WO9605177 and WO9605199). Other compounds in this group are H-335/25 (Astrazeneca,
`
`Dialog file 128, accession number 020806); Sch—28080 (Schering Plough, Dialog file 128,
`
`accession
`
`number 009663); Sch—32651 (Schering Plough, Dialog file 128, accession
`
`number 006883) and SK&F~96067 (CAS Registry no. 115607-61-9).
`
`10
`
`15
`
`The pharmaceutical composition also contains a non-steroidal anti-inflammatory
`
`drug in an amount effective to reduce or eliminate pain or inflammation. The NSAID may
`
`be celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522,
`
`L—745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of
`
`the present invention), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac,
`
`indomethacin, ketorolac,
`
`lornoxicam, meloxicam, piroxicam, droxicam,
`
`tenoxicam,
`
`nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,
`
`tolrnetin,
`
`fenoprofen,
`
`suprofen, benoxaprofen, aceclofenac,
`
`tolfenamic acid, oxyphenbutazone,
`
`azapropazone, and phenylbutazone. 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
`
`20
`
`600 mg.
`
`It will be understood that, for the purposes of the present invention, reference to an
`
`acid inhibitor, NSAID, or analgesic agent will include all of the common forms of these
`
`compounds and,
`
`in particular,
`
`their pharmaceutically acceptable salts. The amounts of
`
`NSAHDS which are therapeutically effective may be lower in the current invention than
`
`otherwise found in practice due to potential positive kinetic interaction and NSAID
`
`25
`
`absorption in the presence of an acid inhibitor.
`
`Preferably, the pharmaceutical composition of the present invention is in the form of
`
`a tablet or capsule that has: (a) the acid inhibitor present in an amount effective to raise the
`
`gastric pH of a patient to at least 3.5 upon the administration of one or more unit dosage
`
`30
`
`forms; and (b) the non—steroidal anti~inflammatory drug (NSAID) present in an amount
`
`effective to reduce or eliminate pain or inflammation in a patient upon administration of
`
`one or more of said unit dosage forms. The NSAID in the dosage form should be in a core,
`
`preferably a single core when tablets are used, that is surrounded by a coating that does not
`
`

`
`6
`
`release NSAID until the pH of the surrounding medium is 3.5 or higher. In the case of
`
`capsules, there may be several cores of NSAID, i. e., there may be multiple particles, each
`
`being surrounded by a coating that does not release NSAID until the pH of the surrounding
`
`medium is 3.5 or higher. The acid inhibitor is in one or more layers outside of the core
`
`which do not contain any NSAID. These layers are not surrounded by an enteric coating
`
`and, upon ingestion of the tablet or capsule by a patient, release the acid inhibitor into the
`
`patient’s stomach.
`
`The term “unit dosage form” as used herein refers to a single entity for drug
`
`10
`
`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 the deleterious effects of the NSAID on the gastroduodenal mucosa, i.e., the acid
`
`inhibitor is released first and the release of NSAID is delayed until after the pH in the GI
`
`15
`
`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 NSAID. In
`
`the most preferred form, coordinated delivery is accomplished by having the inner core
`
`20
`
`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 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 gastrointestinal tract has risen to at least 3.5, preferably at least 4, and more
`
`25
`
`preferably at least 5. Thus, a time-release 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.
`
`One NSAID of special interest in dosage forms is aspirin which not only provides
`
`30
`
`relief from pain and inflammation but may also be used in low doses by patients to reduce
`
`the risk of stroke, heart attack and other conditions. Thus, pharmaceutical compositions may
`
`contain an acid inhibitor in combination with aspirin in an amount effective, upon the
`
`administration of one or more unit dosage forms, to acheive any of these objectives. As with
`
`

`
`7
`
`the compositions described above the unit dosage form can be a tablet or capsule in which
`
`aspirin is present in a core and is surrounded by a coating that does not release the aspirin
`
`until the pH of the surrounding medium is 3.5 or higher. The acid inhibitor is in one or more
`
`layers outside the core, which do not include an NSAID, are not surrounded by an enteric
`
`coating; and, upon ingestion of the dosage form by a patient, release the acid inhibitor into
`
`the patient’s stomach. Any of the acid inhibitors described herein may be used in the
`
`aspirin-containing dosage forms. In dosage forms designed for providing low dose aspirin
`
`therapy to patients, the aspirin should typically be present at 207200 mg.
`
`The invention includes methods of treating a patient for pain, inflammation and/or
`
`other conditions by administering 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 limited to: all fonns of
`
`headache, including migraine headache; 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 at
`
`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 administered 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, 1'. e., NSAID is given within one hour afler 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. Proton pump inhibitors may also be used and offer
`
`advantages in terms of duration of action. 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 acid inhibitor and analgesic will be typically delivered as part of a single A
`
`unit dosage form which provides for the coordinated release of therapeutic agents. The most
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`
`8
`
`preferred dosage form is a multilayer tablet having an outer layer comprising an H2 blocker
`
`or a proton pump inhibitor and an inner core comprising an NSAID.
`
`The invention also provides a method for increasing compliance in 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.
`
`10
`
`15
`
`20
`
`Brief Description of the Drawings
`
`Figure 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.
`
`Figure 2 illustrates a three layer dosage form. An acid inhibitor, e.g., farnotidine, 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 form has a naproxen core, an enteric film coat and an acid
`
`inhibitor film coat.
`
`Figure 3 illustrates a naproxen sodium pellet which contains a subcoat or barrier coat
`
`prior to the enteric fihn coat.
`
`Detailed Description of the Invention
`The present invention is based upon the discovery of improved pharmaceutical.
`
`25
`
`compositions for administering NSAIDS to patients. In addition to containing one or more
`
`NSAIDS, the compositions include acid inhibitors that are 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
`
`30
`
`followed by analgesic.
`
`The NSAlDs 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
`
`

`
`9
`
`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: flurbiprofen with a half—life of about 6 hours; ketoprofen with a half~1ife 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, nabumetone 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 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 appropriate formulations
`
`are well known in the art (see e.g. Remington’s Pharmaceutical Sciences, 16"‘ 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 administered to a patient based upon standard techniques.
`
`well known in the art. Nevertheless, the following general guidelines 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 usefiil 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. However, low dose aspirin present at 20—200 mg
`
`(and preferably 40-100 mg) per tablet or capsule may also be used.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Ibuprofen may be provided in tablets or capsules of 50, 100, 200, 300, 400, 600,
`
`or 800 mg. Daily doses should not exceed 3200 mg. 200 mg — 800 mg may be
`
`particularly useful when given 3 or 4 times daily.
`
`

`
`10
`
`Flurbiprofen is usefiil when in tablets at about from 50 to 100 mg. Daily doses
`
`of about 100 to 500 mg, and particularly from about 200 to 300 mg, are usually
`
`effective.
`
`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 usefiil 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`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.
`
`

`
`ll
`
`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. US6fll1 doses for acute pain
`
`are 8 mg or 16 mg daily, and for arthritis are 12 mg daily.
`
`Other NSAIDS that may be used include: celecoxib,
`
`rofecoxib, meloxicam,
`
`piroxicam, droxicam, tenoxicam, valdecoxib, 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. Pharmacol. 78:365-371 (1998)) and Panara, et al. (Br. J. Pharmacol. 1I6:2429- '
`
`2434 (1995)). The amount present in a tablet or administered to a patient will depend upon
`
`the particular NSAID being used. For example:
`
`10
`
`15
`
`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
`
`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.
`
`25
`
`30
`
`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"
`
`

`
`12
`
`dose; ranitidine, 50-300 mg/unit dose; famotidine, 5-100 mg/unit dose; ebrotidine 400 — 800
`
`mg/unit dose; pabutidine 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 5 to 50 mg, with about 10 or 20 mg being preferred.
`
`Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg being preferred;
`
`lansoprazole, 5-150 mg (preferably 5-50 mg), with about 7.5, 15 or 30 mg being most
`
`preferred; pantoprazole, 10-200 mg, with about 40 mg being preferred; and rabeprazole, 5-
`
`100 mg, with about 20 mg being preferred.
`
`Making of Pharmaceutical Preparations
`
`The pharmaceutical compositions of the invention include 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"‘ ed., A Oslo editor, Easton, Pa. (1980)).
`
`Drugs and drug combinations will typically be prepared in admixture with conventional
`
`excipients. Suitable carriers include, but are not limited to: water; salt solutions; alcohols;
`
`gum arabic; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates
`
`such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume
`
`oil;
`
`fatty
`
`acid
`
`esters;
`
`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; 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 one or more of the following
`
`materials: methacrylic acid copolymers, shellac, hydroxypropylmethcellulose phthalate,
`
`polyvinyl acetate phthalate, hydroxypropylmethylcellulose trimellitate, carboxy1nethylethyl-
`
`cellulose, cellulose acetate phthalate or other suitable enteric coating poly1ner(s). The 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 characteristics of
`
`the polymer film can be altered by the ratio of free carboxyl groups to ester groups. Enteric
`
`coating layers also contain pharmaceutically acceptable plasticizers such as triethyl citrate,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`
`13
`
`dibutyl phthalate,
`
`triacetin, polyethylene glycols, polysorbates or other plasticizers.
`
`Additives such as dispersants, colorants, anti-adhering and anti~foaming agents may also be
`
`included.
`
`The Making of Tablet Dosage Forms
`
`Preferably, the combination of an acid inhibitor and an NSAID will be in the form of
`
`a bi- or multi-layer tablet. In a bilayer configuration, one portion of the tablet contains the
`
`acid inhibitor in the required dose along with appropriate excipients, agents to aid
`
`dissolution, lubricants, fillers, etc. The second portion of the tablet will contain the NSAID,
`
`preferably naproxen, in the required dose along with other excipients, dissolution agents,
`
`lubricants, fillers, etc. In the most preferred embodiment, the NSAID layer is surrounded by
`
`a polymeric coating which does not dissolve at a pH of less than 4. The NSAID may be
`
`granulated by methods such as slugging, low- or high— shear granulation, wet granulation, or
`
`fluidized—bed granulation. Of these processes, slugging generally produces tablets of less
`
`hardness and greater
`
`friability. Low—shear granulation, high-shear granulation, wet
`
`granulation and fluidized-bed granulation generally produce harder, less friable tablets.
`
`Example 1: Enteric Coated Naproxen Sodium Core and Famotidine
`Immediate Release
`
`Examples
`
`A schematic diagram of a four layer tablet dosage form is shown in Figure 1. The
`
`first layer contains naproxen sodium distributed throughout a matrix of pharmaceutically
`
`acceptable fillers, excipients, binding agents, disintegrants, and lubricants.
`
`The second layer is a barrier layer which protects the first layer containing naproxen
`
`sodium. The barrier film coat is applied by conventional pan coating technology and the
`
`weight of the barrier coat may vary from 1% to 3% of the core tablet weight. In particular
`
`embodiments, the core naproxen sodium tablet is coated with coating ingredients such as
`
`Opaspray® K-1-4210A or Opadry® YS—1—7006 (Colorcon, West Point, PA). Polymer film
`
`coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol
`
`8000 in a coating suspension may also be used.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`
`14
`
`The function of the third layer is to prevent the release of naproxen sodium until the 5
`
`dosage form reaches an environment where the pH is above about 4 or 5. The enteric
`
`coating does not dissolve in areas of the GI tract where the pH may be below about 4 or S
`
`such as in an unprotected stomach. Methacrylic acid copolymers are used as the enteric
`
`coating ingredient, triethyl citrate and dibutyl phthalate are plasticizers, and ammonium
`
`hydroxide is used to adjust the pH of the dispersion. The coating dissolves only when the
`
`local pH is above, for example, 5.5 and, as a result, naproxen sodium is released.
`
`The outermost layer contains an “acid inhibitor” in an effective amount which is
`
`released from the dosage form immediately after administration to the patient. The acid
`
`inhibitor in the present example is a proton pump inhibitor or, preferably the H2 blocker '
`
`famotidine, which raises the pH of the gastrointestinal tract to above 4. The typical effective
`
`amount of famotidine in the dosage form will vary from 5 mg to 100 mg. A typical film
`
`coating formulation contains Opadry Clear® YS—1—7006 which helps in the formation of the
`
`film and in uniformly distributing famotidine within the fourth layer without tablets sticking
`
`to the coating pan or to each other during application of the film coat. Other ingredients may
`
`include: plasticizers such as triethyl citrate, dibutyl phthalate, and polyethylene glycol; anti-
`
`adhering agents such as talc;
`
`lubricating ingredients such as magnesium stearate; and
`
`opacifiers such as titanium dioxide.
`
`In addition, the pH of the film coating solution can be
`
`adjusted to aid in dissolution of the famotidine. The film coating is thin and rapidly releases
`
`famotidine for absorption.
`
`Core Tablet Ingredients
`
`% W/W
`
`mg/Tablet
`
`Naproxen sodium, USP
`
`74.074
`
`500.00
`
`Microcrystalline cellulose, NF
`(Avicel PH 200)
`
`Povidone (K29/32), USP
`
`Talc, USP
`
`Magnesium Stearate, NF
`
`17.166
`
`115.87
`
`3.450
`
`4.350
`
`0.960
`
`23.29
`
`29.36
`
`6.48
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Total
`
`100.00
`
`675.00
`
`

`
`15
`
`Barrier Film Coating Ingredien