Pharmaceutical Compositions for the Coordinated
`Delivery of NSAIDS
`
`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-inflamrnatory drug (NSAID).
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`These compositions have a reduced likelihood of causing unwanted side effects, especially
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`gastrointestinal side effects, when administered as a treatment for pain, arthritis and other
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`conditions amenable to treatment with NSAIDS.
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`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
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`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
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`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. 12:210-222 (1994); Drug Safety 21:503-512
`
`(1999); Aliment. Pharmacol. Ther. I2:135-140 (1998); Am. J. Med. I04(3A):67S-74S (1998);
`
`Clin. Ther. 1721159-1173 (1995)). Other major factors contributing to NSAID-associated
`
`gastropathy include a local toxic effect of NSAIDS and inhibition of protective prostaglandins
`
`(Can.
`
`.1. Gastroenterol. 13:
`
`135-142 (1999) and Pract. Drug Safety 212503-512, (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 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
`
`I).
`
`10
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`25
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`30
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`Lupin Exh. 1005
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`Lupin Exh. 1005
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`

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`administered simultaneously, NSAID-related mucosal damage occurs before the pH of the
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`gastrointestinal tract can be raised and after the acid inhibiting effect of the short acting acid
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`inhibitor dissipates.
`
`Although longer lasting agents, such as proton pump inhibitors (PPIS), usually
`
`maintain a consistently higher gastroduodenal pH throughout the day, after several days
`
`dosing, their antisecretory effect may be delayed for several hours and may not take full
`
`effect for several days (Clin. Pharmacokinet. 20:38-49 (1991)). Their effect may be
`
`diminished toward the end of the usual dosing interval. lntragastric pH rises particularly
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`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
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`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 gastroduo-
`
`denaldamage (Aliment. Pharmacol. Ther. I4:709-714 (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
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`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
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`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)).
`
`
`
`25
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`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 of
`
`NSAID (U.S. 5,204,118; U.S. 5,417,980; U.S. 5,466,436; and U.S. 5,037,815). In certain
`
`30
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`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
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`

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`

`
`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
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`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
`
`9 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.
`
`.1 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
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`preferred acid inhibitor is famotidine present in dosage forms in an amount of between 5 mg
`
`and 100 mg. Other agents that may be effectively used include proton pump inhibitors such
`
`as omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole.
`
`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 a
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`COX-2 inhibitor such as celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib, parecoxib,
`
`etoricoxib, CS-502, JTE-522, L-745,337 or NS398. Alternatively, the NSAID may be aspirin,
`
`
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`25
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`30
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`acetaminophen,
`
`ibuprofen,
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`flurbiprofen, ketoprofen, naproxen,
`
`oxaprozin,
`
`etodolac,
`
`indomethacin, ketorolac, lornoxicam, nabumetone, or diclofenac. The most preferred NSAID
`
`is naproxen in an amount of between 50 mg and 1500 mg, and more preferably, in an amount
`
`of between 200 mg and 600 mg.
`
`It will be understood that, for the purposes of the present
`
`invention, reference to an acid inhibitor, NSAID, or analgesic agent will include all of the
`
`common forms of these compounds and, in particular, their pharmaceutically acceptable salts.
`
`The amounts of NSAIDS which are therapeutically effective may be lower in the current
`
`invention than otherwise found in practice due to potential positive kinetic interaction and
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`NSAID absorption in the presence of an acid inhibitor.
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`

`
`Iv
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`10
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`
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`The term “unit dosage form” as used herein refers to a single entity for drug
`
`administration. For example, a single tablet or capsule combining both an acid inhibitor and
`
`an NSAID would be a unit dosage form. A unit dosage form of the present invention
`
`preferably provides for coordinated drug release, in a way that elevates gastric pH and
`
`reduces 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 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
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`the most preferred form, coordinated delivery is accomplished by having the inner core
`
`surrounded by a polymeric barrier coating that does not dissolve unless the surrounding
`
`medium is at a pH of at least 3.5, preferably at least 4 and more preferably, at least 5.
`
`Alternatively, a barrier 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 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.
`
`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 usefiil in patients with osteoarthritis or rheumatoid
`
`arthritis. Other conditions that may be treated include, but are not limited to: all form of
`
`headache, including migraine headache; acute musculoskeletal pain; ankylosing spondylitis;
`
`25
`
`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
`
`30
`
`preferably to at
`
`least 5. The patient is also administered an NSAID, for example in a
`
`coordinated dosage form, that has been coated in a polymer that only dissolves at a pH of
`
`least 3.5, preferably at least 4 and, more preferably, 5 or greater or which dissolves at a rate
`
`that is slow enough to prevent NSAID release until after the pH has been raised. When acid
`
`inhibitor and NSAID are administered in separate doses, e. g., in two separate tablets, they
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`

`
`should be given concomitantly (i. e. , so that their biological effects overlap) and may be given
`
`concurrently, i. e., NSAID is given within one hour after the acid inhibitor. Preferably, the
`
`acid inhibitor is an H2 blocker and, in the most preferred embodiment, it is famotidine at a
`
`dosage of between 5 mg and 100 mg. Any of the NSAIDS described above may be used in
`
`the method but naproxen at a dosage of between 200 and 600 mg is most preferred. It is
`
`expected that the inhibitor and analgesic will be typically delivered as part of a single unit
`
`dosage form which provides for the coordinated release of therapeutic agents. The most
`
`preferred dosage form is a multilayer tablet having an outer layer comprising an H2 blocker
`
`and an inner core comprising an NSAID.
`
`The 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.
`
`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., famotidine, is
`
`released immediately after
`
`ingestion by a patient
`
`in order
`
`to raise the pH of the
`
`gastrointestinal tract to above a specific pH, e.g., above 4. The innermost layer contains
`
`naproxen. Thus, the dosage 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 film coat.
`
`Detailed Description of the Invention
`
`The present
`
`invention is based upon the discovery of improved pharmaceutical
`
`compositions for administering NSAIDS to patients. In addition to containing one or more
`
`NSAIDS, the compositions include acid inhibitors that are 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
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`25
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`35
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`

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`coordinated release of therapeutic agents,
`
`i.e., for the sequential release of acid inhibitor
`
`followed by analgesic.
`
`The NSAIDS used in preparations may be either short or long acting. As used herein,
`
`the term “long acting” refers to an NSAID having a pharmacokinetic half-life of at least 2
`
`hours, preferably at least 4 hours and more preferably, at least 8-14 hours. In general, its
`
`duration of action will equal or exceed about 6-8 hours. Examples of long-acting NSAIDS
`
`are:
`
`flurbiprofen with a half—life of about 6 hours; ketoprofen with a half—life of about 2 to 4
`
`hours; naproxen or naproxen sodium with half~lives of about 12 to 15 hours and about 12 to
`
`13 hours respectively; oxaprozin with a half life of about 42 to 50 hours; etodolac with a half-
`
`life of about 7 hours; indomethacin with a half life of about 4 to 6 hours; ketorolac with a
`
`half—life of up to about 8-9 hours, 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. Reming1on’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 useful in some patients.
`
`Aspirin will typically be present in tablets or capsules in an amount of between
`
`about 250 mg and 1000 mg. Typical daily dosages will be in an amount ranging
`
`from 500 mg to about 10 g.
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`10
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`25
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`30
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`

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`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.
`
`Flurbiprofen is useful 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.
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`Ketoprofen is usefiil 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
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`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
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`amount of from 250 to 500 mg. For naproxen sodium, tablets of about 275 or
`
`about 550 mg are typically used.
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`Initial doses of from 100 to 1250 mg, and
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`particularly 350 to 800 mg are also used, with doses of about 550 mg being
`
`generally preferred.
`
`Oxaprozin may be used in tablets or capsules in the range of roughly 200 mg to
`
`1200 mg, with about 600 mg being preferred. Daily doses of 1200 mg have been
`
`found to be particularly useful and daily doses should not exceed 1800 mg or 26
`
`mg/kg.
`
`Etodolac is useful when provided in capsules of 200 mg to 300 mg or in tablets of
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`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.
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`25
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`30
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`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.
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`5
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`Mefenarnic 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.
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`10
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`Lornoxicam is provided in tablets of 4 mg or 8 mg. Useful doses for acute pain
`
`are 8 mg or 16 mg daily, and for arthritis are 12 mg daily.
`
`
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`25
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`One particular group of
`
`long acting NSAIDS that may be used are the
`
`cyclooxygenase-2 inhibitors. These include: celecoxib, rofecoxib, meloxicam, piroxicam,
`
`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-
`
`37l
`
`(1998)) and Panara, et al.
`
`(Br. J. Pharmacol. 116:2429-2434 (1995)). The amount
`
`present in a tablet or administered to a patient will depend upon the particular COX-2
`
`inhibitor being used. For example:
`
`Celecoxib may be administered in a tablet or capsule containing from about 100
`
`mg to about 500 mg or, preferably, from about 100 mg to about 200 mg.
`
`Piroxicam may be used in tablets or capsules containing from about 10 to 20 mg.
`
`Rofecoxib will typically be provided in tablets or capsules in an amount of 12.5,
`
`25 or 50 mg. The recommended initial daily dosage for the management of acute
`
`pain is 50 mg.
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`30
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`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.
`
`

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`,
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`_
`
`10
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`With respect to acid inhibitors, tablets or capsules may contain anywhere from 1 mg
`
`to as much as 1 g. Typical amounts for H2 blockers are: cimetidine, 100 to 800 mg/unit dose;
`
`ranitidine, 50-300 mg/unit dose; famotidine, 5-100 mg/unit dose; ebrotidine 400 — 800
`
`mg/unit dose; pabutidine 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 close. For example, the proton pump inhibitor omeprazole should be present in tablets
`
`or capsules in an amount from 5 to 50 mg, with about 20 mg per unit dosage form being
`
`preferred. Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg per unit
`
`dosage form being preferred; lansoprazole, 15-150 mg, with about 30 mg per unit dosage
`
`form being preferred; pantoprazole, 10-200 mg, with about 40 mg per unit dosage form being
`
`preferred; and rabeprazole, 5-100 mg, with about 20 mg per unit dosage form being
`
`preferred.
`
`Making of Pharmaceutical Preparations
`
`The pharmaceutical compositions of the invention include 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, carboxymethylethyl-
`
`cellulose, cellulose acetate phthalate or other suitable enteric coating polymer(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
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`30
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`ll
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`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,
`
`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
`
`10
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`acid inhibitor in the required close 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 naproxen 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 l. The first
`
`25
`
`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
`
`30
`
`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-l-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.
`
`

`
`12
`
`The fitnction of the third layer is to prevent the release of naproxen sodium until the
`
`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 5 such as in
`
`an unprotected stomach. Methacrylic acid copolymers are used as the enteric coating
`
`ingredient, triethyl citrate and dibutyl phthalate are plasticisers, 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 C1ear® 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: plasticisers 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
`
`25
`
`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
`
`30
`
`Total
`
`100.00
`
`675.00
`
`

`
`13
`
`Barrier Film Coating Ingredients
`
`% W/W
`
`Opadry Clear® YS-1-7006
`
`Purified water USP
`
`Total
`
`5.00
`
`95.00
`
`1 00.00
`
`Enteric Coating Dispersion
`
`Ingredients
`
`% W/W
`
`10
`
`Methacrylic Acid Copolymer, NF
`(Eudragit L—100-55)
`
`Methacrylic Acid Copolyrner, NF
`(Eudragit L-100)
`
`Triethyl Citrate, NF
`
`Dibutyl Phthalate, NF
`
`Ammonium Hydroxide (3 0%), NF
`
`Purified water, USP
`
`Total
`
`Famotidine Coating Dispersion
`
`Ingredients
`
`Famotidine, USP
`
`Opadry Clear® (YS-1-7006)
`
`Talc, USP
`
`Purified Water, USP
`
`Total
`
`7.30
`
`7.30
`
`2.95
`
`1 . 1 7
`
`0.87
`
`80.41
`
`100.00
`
`% W/W
`
`3.0
`
`5.0
`
`3.0
`
`89.0
`
`100.0
`
`
`
`25
`
`30
`
`35
`
`Example 2: Enteric Coated Naproxen Core and Famotidine
`Immediate Release
`
`Figure 2 illustrates a three layered dosage form which releases
`
`famotidine
`
`immediately after ingestion by the patient in order to raise the pH of the gastrointestinal tract
`
`to above about 4. The innermost layer contains naproxen uniformly distributed throughout a
`
`matrix of pharmaceutically acceptable excipients. These excipients perform specific functions
`
`and may serve as binders, disintegrants, or lubricants. A pharmaceutically acceptable enteric
`
`coating surrounds the naproxen core. The fimction of the enteric coat is to delay the release of
`
`naproxen until the dosage form reaches an environment where the pH is above about 4. The
`
`

`
`14
`
`coating does not dissolve in the harshly acidic pH of the unprotected stomach. It contains
`
`methacrylic acid copolymers which prevent the release of naproxen in the unprotected
`stomach. Also included are:
`triethyl citrate, a plasticiser; simethicone emulsion, an anti-
`
`foaming agent; and sodium hydroxide which is used to adjust the pH of the dispersion.
`
`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 this example is a proton pump inhibitor or, preferably, the H2 blocker famotidine
`
`which raises the pH of the stomach to above 4. A typical film coating formulation contains
`Opadry Clear® YS-1-7006 which helps in the formation of the film and in uniformly
`distributing famotidine in the fourth layer without tablets sticking to the coating pan or
`sticking to each other during application of the film coat. Other ingredients are: plasticisers
`such as polyethylene glycol 8000; 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, USP
`
`Povidone K-90, USP
`
`Starch, USP
`
`Croscarmellose Sodium, USP
`
`Magnesium Stearate, NF
`
`90.91
`
`2.00
`
`2.59
`
`4.00
`
`0.50
`
`100.00
`
`500.00
`
`11.00
`
`14.25
`
`22.00
`
`2.75
`
`550.00
`
`
`
`
`25
`
`Total
`Purified Water, USP qs
`
`Enteric Coating Dispersion Ingredients
`
`% W/W
`
`Methacrylic Acid Copolymer Type C, NF
`
`Giudragit L- 1 00-5 5)
`
`30
`
`Talc, USP
`
`Sodium Hydroxide, NF
`
`Triethyl Citrate, NF
`
`14.5
`
`3.8
`
`0.2
`
`1.7
`
`

`
`Simethicone Emulsion, USP
`
`Purified Water, USP
`
`Total
`
`Famotidine Coating Dispersion
`Ingredients
`
`Famotidine, USP
`
`Opadry Clear® (YS-1-7006)
`
`10
`
`Talc, USP
`
`Purified Water, USP
`
`Total
`
`15
`
`0.02
`
`79.78
`
`100.00
`
`% W/W
`
`3.0
`
`5.0
`
`3.0
`
`89.0
`
`100.0
`
`
`
`25
`
`30
`
`35
`
`Example 3: Naproxen Controlled Release Core and Famotidine
`Immediate Release
`
`A trilayer tablet which separates famotidine contained in the film coat
`
`from
`
`controlled-release naproxen may be used in the present invention. The core tablet of naproxen
`
`is formulated using excipients which control the drug release for therapeutic relief from pain
`
`and inflammation for 24 hours. Figure 2 shows an example of an appropriate trilayer tablet.
`
`In this particular example, naproxen is mixed with a polymeric material, hydroxypropyl—
`
`methylcellulose and granulated with water. The granules are dried, milled, and blended with a
`
`lubricant, such as magnesium stearate. They are then compacted into tablets.
`
`The controlled-release core tablet of naproxen is film coated with a pharmaceutically
`
`acceptable enteric coating. The function of the enteric coat is to delay the release of naproxen
`
`until the dosage form reaches an environment where the pH is above about 4. The coating
`
`does not dissolve in the extremely acidic pH of the unprotected stomach. The function of
`
`methacrylic acid copolymers is to prevent the release of naproxen until the pH of the stomach
`
`rises. Triethyl citrate is a plasticiser, simethicone emulsion is a anti-foaming agent, and
`
`sodium hydroxide is used to adjust the pH of the dispersion.
`
`The outermost layer contains an “acid inhibitor” 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
`
`consistently raises the pH of the stomach to above 4. The typical effective amount of
`
`

`
`.
`
`16
`
`famotidine in the dosage will Vary from 5 mg to 100 mg. A typical film coating formulation
`
`contains Opadry B1ue® YS-1-4215 which is essential for film formation and for the uniform
`
`application of
`
`famotidine
`
`to the
`
`core
`
`tablet. Polymer
`
`film coating ingredients,
`
`hydroxypropylmethylcellulose or Opaspray® K-1-4210A (Colorcon, West Point, PA) may
`
`also be used. Other ingredients which help in the formation of the film and in the uniform
`
`application of famotidine to the core tablet are: plasticisers such as triethyl citrate and dibutyl
`
`phthalate; 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
`
`10
`
`rapidly releases famotidine for absorption.
`
`
`
`
`
`Core Tablet Ingredients
`
`% W/W
`
`mg/Tablet
`
`Naproxen, USP
`
`Hydroxypropyl methylcellulose
`2208, USP (Viscosity 15000 cps)
`
`Magnesium Stearate, NF
`
`94.00
`
`5.00
`
`1.00
`
`750
`
`39.9
`
`7.95
`
`Total
`
`100.00
`
`797.85
`
`Enteric Coating Dispersion Ingredients
`
`% W/W
`
`Methacrylic Acid Copolymer Type C, NF
`(Eudragit L-1 00-5 5)
`
`14.5
`
`3.8
`
`0.2
`
`1.7
`
`0.02
`
`79.78
`
`l00.00
`
`Talc, USP
`
`Sodium Hydroxide, NF
`
`Triethyl Citrate, NF
`
`25
`
`Simethicone Emulsion, USP
`
`Purified Water, USP
`
`Total
`
`30
`
`35
`
`Famotidine Coating Dispersion Ingredients
`
`% W/W
`
`Famotidine, USP
`
`Opadry B1ue® (YS-l-4215)
`
`Talc, USP
`
`Purified Water, USP
`
`Total
`
`2.0
`
`10.0
`
`9.0
`
`79.0
`
`100.0
`
`

`
`.
`
`17
`
`Example 4: Naproxen and Famotidine Controlled Release Core and
`Famotidine Immediate Release
`
`A trilayer tablet which separates famotidine contained in the film