111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`us 20030069255Al
`
`(19) United States
`(12) Patent Application Publication
`Plachetka
`
`(54) PHARMACEUTICAL COMPOSITIONS FOR
`THE COORDINATED DELIVERY OF NSAIDS
`
`(75)
`
`Inventor:
`
`John R. Plachetka, Chapel Hill, NC
`(US)
`
`Correspondence Address:
`PILLSBURY WINTHROP LLP
`1600 TYSONS BOULEVARD
`MCLEAN, VA 22102 (US)
`
`(73)
`
`Assignee: POZEN Inc.
`
`(21)
`
`Appl. No.:
`
`10/158,216
`
`(22)
`
`Filed:
`
`May 31, 2002
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/294,588, filed on Jun.
`1,2001.
`
`(10) Pub. No.: US 2003/0069255 Al
`Apr. 10,2003
`(43) Pub. Date:
`
`Publication Classification
`
`(51)
`
`Int. CI?
`
`(52) U.S. CI.
`
`A61K 31/495; A61K 31/4439;
`A61K 31/415
`514/255.04; 514/338; 514/406
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to drug dosage forms that
`release an agent that raises the pH of a patient's gastrointes(cid:173)
`tinal tract, followed by a non-steroidal anti-inflammatory
`drug. The dosage form is designed so that the NSAID is not
`released until the intragastric pH has been raised to a safe
`level. The invention also encompasses methods of treating
`patients by administering this coordinated release, gastro(cid:173)
`protective, antiarthritic/analgesic combination unit dosage
`form to achieve pain and symptom relief with a reduced risk
`of developing gastrointestinal damage such as ulcers, ero(cid:173)
`sions and hemorrhages.
`
`Dr. Reddy's Exh. 1021
`
`

`

`Patent Application Publication Apr. 10,2003 Sheet I of 2
`
`US 2003/0069255 Al
`
`BARRIER FILM
`COAT
`
`ACID INHIBITOR COAT
`
`ENTERIC FILM COAT
`
`FIG.1
`
`NAPROXEN CORE TABLEr
`
`ACID INHIBITOR COAT
`
`ENTERIC FILM COAT
`
`FIG.2
`
`Dr. Reddy's Exh. 1021
`
`

`

`Patent Application Publication Apr. 10,2003 Sheet 2 of 2
`
`US 2003/0069255 Al
`
`ENTERIC FILM
`COAT
`
`FIG.3
`
`Dr. Reddy's Exh. 1021
`
`

`

`US 2003/0069255 Al
`
`Apr. 10, 2003
`
`1
`
`PHARMACEUTICAL COMPOSITIONS FOR THE
`COORDINATED DELIVERY OF NSAIDS
`
`FIELD OF THE INVENTION
`
`[0001] 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 compositions have a reduced likelihood of
`causing unwanted side effects, especially gastrointestinal
`side effects, when administered as a treatment for pain,
`arthritis and other conditions amenable to treatment with
`NSAIDs.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Although non-steroidal anti-inflammatory drugs
`are widely accepted as effective agents for controlling pain,
`their administration can lead to the development of gas(cid:173)
`troduodenallesions, 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 inde(cid:173)
`pendent doses of acid inhibitors (Dig. Dis. 12:210-222
`(1994); Drug Safety 21:503-512 (1999); Aliment. Pharma(cid:173)
`col. Ther. 12:135-140 (1998); Am. J. Med. 104(3A):67S-74S
`(1998); Clin. Ther. 17: 1159-1173 (1995)). Other major fac(cid:173)
`tors contributing to NSAID-associated gastropathy include a
`local toxic effect of NSAIDs 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
`[0003]
`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 inhibi(cid:173)
`tors 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.
`
`[0004] 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.
`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 dur(cid:173)
`ing six months of NSAID therapy, up to 16% of patients still
`develop ulcers,
`indicating that
`there remains substantial
`(N. Eng J. Med. 338:727-734
`room for
`improvement
`(1998)). Thus, the addition of a pH sensitive enteric coating
`to an NSAID could provide additional protection against
`gastroduodenal damage not provided by the H2 blocker or
`PPI alone. In addition, although long acting acid inhibitors
`may reduce the risk of GI lesions in chronic NSAID users,
`there are questions about
`the safety of maintaining an
`abnormally elevated pH in a patient's GI tract for a pro(cid:173)
`longed period of time (Scand. J. Gastroenterol. Suppl.
`178:85-92 (1990)).
`
`[0005] Recognizing the potential benefits of PPIs for the
`prevention of NSAID-induced gastroduodenal damage, oth(cid:173)
`ers 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. Pat. Nos. 5,204,118; 5,417,980;
`5,466,436; and 5,037,815).
`In certain cases, suggested
`means of delivery would expose the gastrointestinal tract to
`NSAIDs prior
`to onset of PPI activity (U.S. Pat. No.
`6,365,184).
`
`[0006] Attempts to develop NSAIDs that are inherently
`less toxic to the gastrointestinal tract have met with only
`limited success. For example,
`the recently developed
`cyclooxygenase-2 (COX-2) inhibitors show a reduced ten(cid:173)
`dency to produce gastrointestinal ulcers and erosions, but a
`significant risk is still present, especially if the patient is
`exposed to other ulcerogens (JAMA 284:1247-1255 (2000);
`N. Eng. J. Med. 343:1520-1528 (2000)). In this regard, it
`appears that even low doses of aspirin will negate most of
`the benefit relating to lower gastrointestinal
`lesions.
`In
`addition, the COX-2 inhibitors may not be as effective as
`other NSAIDs at relieving some types of pain and have been
`associated with significant cardiovascular problems (JADA
`131:1729-1737 (2000); SCRIP 2617, pg. 19, Feb. 14,2001);
`NY Times, May 22, 2001, pg. C1)).
`
`[0007] Other attempts to produce an NSAID therapy with
`less gastrointestinal toxicity have involved the concomitant
`administration of a cytoprotective agent. In 1998, Searle
`began marketing Arthrotec™ for the treatment of arthritis in
`patients at risk for developing GI ulcers. This product
`contains misopristol (a cytoprotective prostaglandin) and the
`NSAID diclofenac. Although patients administered Arthro(cid:173)
`tec™ do have a lower risk of developing ulcers, they may
`experience a number of other serious side effects such as
`diarrhea, severe cramping and,
`in the case of pregnant
`women, potential damage to the fetus.
`
`[0008] 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.
`
`Dr. Reddy's Exh. 1021
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`

`

`US 2003/0069255 Al
`
`Apr. 10, 2003
`
`2
`
`the risk of
`it may be concluded that
`[0009] Overall,
`inducing GI ulcers is a recognized problem associated with
`the administration of NSAIDs and that, despite considerable
`effort, an ideal solution has not yet been found.
`
`SUMMARY OF THE INVENTION
`[0010] 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 mini(cid:173)
`mizes the adverse effects of the NSAID on the gastroduode(cid:173)
`nal mucosa. Either short or long acting acid inhibitors can be
`effectively used in the dosage forms. This method has the
`added benefit of being able to protect patients from other
`gastrointestinal ulcerogens whose effect may otherwise be
`enhanced by the disruption of gastroprotective prostaglan(cid:173)
`dins due to NSAID therapy.
`the invention is directed to a
`[0011]
`In its first aspect,
`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(cid:173)
`associated ulcers (N. Eng. J. Med. 340: 1888-1899 (1999)),
`these agents are preferred compounds in the current inven(cid:173)
`tion. Specific, H2 blockers that may be used include cime(cid:173)
`tidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxti(cid:173)
`dine or famotidine. The most 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, esome(cid:173)
`prazole, pantoprazole, lansoprazole or rabeprazole.
`[0012] 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 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, acetaminophen, ibuprofen, flurbi(cid:173)
`profen,
`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 prefer(cid:173)
`ably, 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
`NSAID absorption in the presence of an acid inhibitor.
`[0013] 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 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 gas(cid:173)
`trointestinal tract has risen to at least 3.5, preferably at least
`4, and more preferably at
`least 5. Thus, a time-release
`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.
`
`treating a
`[0014] The invention includes methods of
`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 rheuma(cid:173)
`toid arthritis. Other conditions that may be treated include,
`including
`limited to: all form of headache,
`but are not
`migraine headache; acute musculoskeletal pain; ankylosing
`spondylitis; dysmenorrhoea; myalgias; and neuralgias.
`
`In a more general sense, the invention includes
`[0015]
`methods of treating pain, inflammation and/or other condi(cid:173)
`tions by orally administering an acid inhibitor at a dose
`least 3.5,
`effective to raise a patient's gastric pH to at
`preferably to at least 4 or and more preferably to at least 5.
`The patient is also administered an NSAID, for example in
`a coordinated dosage form,
`that has been coated in a
`polymer that only dissolves at a pH of least 3.5, preferably
`at
`least 4 and, more preferably, 5 or greater or which
`dissolves at a rate that is slow enough to prevent NSAID
`release until after the pH has been raised. When acid
`inhibitor and NSAID are administered in separate doses,
`e.g., in two separate tablets, they should be given concomi(cid:173)
`tantly (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 famo(cid:173)
`tidine 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.
`
`[0016] The invention also provides a method for increas(cid:173)
`ing 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
`
`Dr. Reddy's Exh. 1021
`
`

`

`US 2003/0069255 Al
`
`Apr. 10, 2003
`
`3
`
`form, thereby reducing the number of individual doses to be
`administered during any given period.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`[0017] FIG. 1 is a schematic diagram of a four layer tablet
`dosage form. There is a naproxen core layer surrounded by
`a barrier layer. A third, enteric coating, layer delays the
`release of naproxen sodium until the pH is at a specific level,
`e.g., above 4. Finally, there is an outer layer that releases an
`acid inhibitor such as famotidine.
`[0018] FIG. 2 illustrates a three layer dosage form. An
`acid inhibitor, e.g., famotidine, is released immediately after
`ingestion by a patient
`in order to raise the pH of the
`gastrointestinal tract to above a specific pH, e.g., above 4.
`The innermost layer contains naproxen. Thus, the dosage
`form has a naproxen core, an enteric film coat and an acid
`inhibitor film coat.
`[0019] FIG. 3 illustrates a naproxen sodium pellet which
`contains a subcoat or barrier coat prior to the enteric film
`coat.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0020] 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 coordinated release of therapeutic agents, i.e., for the
`sequential release of acid inhibitor followed by analgesic.
`
`[0021] The NSAIDs used in preparations may be either
`short or long acting. As used herein, the term "long acting"
`refers to an NSAID having a pharmacokinetic half-life of at
`least 2 hours, preferably at least 4 hours and more preferably,
`at least 8-14 hours. In general, its duration of action will
`equal or exceed about 6-8 hours. Examples of long-acting
`NSAIDs are: fiurbiprofen with a half-life of about 6 hours;
`ketoprofen with a half-life of about 2 to 4 hours; naproxen
`or naproxen sodium with half-lives of about 12 to 15 hours
`and about 12 to 13 hours respectively; oxaprozin with a half
`life of about 42 to 50 hours; etodolac with a half-life of about
`7 hours; indomethacin with a half life of about 4 to 6 hours;
`ketorolac with a half-life of up to about 8-9 hours, nabu(cid:173)
`metone with a half-life of about 22 to 30 hours; mefenamic
`acid with a half-life of up to about 4 hours; and piroxicam
`with a half-life of about 4 to 6 hours. If an NSAID does not
`naturally have a half-life sufficient to be long acting, it can,
`if desired, be made long acting by the way in which it is
`formulated. For example, NSAIDs such as acetaminophen
`and aspirin may be formulated in a manner to increase their
`half-life or duration of action. Methods for making appro(cid:173)
`priate formulations are well known in the art (see e.g.
`Remington's Pharmaceutical Sciences, 16th ed., A. Oslo
`editor, Easton, Pa. (1980)).
`
`[0022]
`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:
`[0023]
`Indomethacin is particularly useful when con(cid:173)
`tained 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.
`
`[0024] Aspirin will typically be present in tablets or
`capsules in an amount of between about 250 mg and
`1000 mg. Typical daily dosages will be in an amount
`ranging from 500 mg to about 10 g.
`
`Ibuprofen may be provided in tablets or cap(cid:173)
`[0025]
`sules 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.
`
`[0026] 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.
`
`[0027] 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.
`
`[0028] Naproxen is particularly useful when con(cid:173)
`tained 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.
`
`[0029] Oxaprozin may be used in tablets or capsules
`in the range of roughly 200 mg to 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.
`
`[0030] 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.
`
`[0031] 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.
`
`[0032] 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.
`
`[0033] 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.
`
`[0034] Lomoxicam is provided in tablets of 4 mg or
`8 mg. Useful doses for acute pain are 8 mg or 16 mg
`daily, and for arthritis are 12 mg daily.
`
`Dr. Reddy's Exh. 1021
`
`

`

`US 2003/0069255 Al
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`Apr. 10, 2003
`
`4
`
`[0035] One particular group of long acting NSAIDs that
`may be used are the cyclooxygenase-2 inhibitors. These
`include: celecoxib, rofecoxib, meloxicam, piroxicam, val(cid:173)
`decoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,
`337, or NS398.
`JTE-522, L-745,337 and NS398 as
`described, inter alia, in Wakatani, et al. (Jpn. J. Pharmacal.
`78:365-371 (1998)) and Panara, et al. (Er. J. Pharmacal.
`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:
`[0036] 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.
`[0037] Piroxicam may be used in tablets or capsules
`containing from about 10 to 20 mg.
`[0038] 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 manage(cid:173)
`ment of acute pain is 50 mg.
`[0039] 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.
`[0040] 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.
`[0041] 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 nizati(cid:173)
`dine, 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 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; lanso(cid:173)
`prazole, 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.
`
`[0042] Making of Pharmaceutical Preparations
`
`[0043] 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, 16th ed., A
`Oslo editor, Easton, Pa. (1980)). Drugs and drug combina(cid:173)
`tions will typically be prepared in admixture with conven(cid:173)
`tional excipients. Suitable carriers include, but are not
`limited to: water; salt solutions; alcohols; gum arabic; veg(cid:173)
`etable oils; benzyl alcohols; polyethylene glycols; gelatin;
`carbohydrates such as lactose, amylose or starch; magne(cid:173)
`sium 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.
`
`[0044] 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: meth(cid:173)
`acrylic acid copolymers, shellac, hydroxypropylmethcellu(cid:173)
`lose phthalate, polyvinyl acetate phthalate, hydroxypropyl(cid:173)
`methylcellulose trimellitate, carboxymethylethylcellulose,
`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 poly(cid:173)
`mers 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, dibutyl phthalate, triace(cid:173)
`tin, polyethylene glycols, polysorbates or other plasticizers.
`Additives such as dispersants, colorants, anti-adhering and
`anti-foaming agents may also be included.
`
`[0045] The Making of Tablet Dosage Forms
`
`[0046] 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 naproxen may be granulated by methods
`such as slugging, low- or high-shear granulation, wet granu(cid:173)
`lation, or fluidized-bed granulation. Of these processes,
`slugging generally produces tablets of less hardness and
`greater friability. Low-shear granulation, high-shear granu(cid:173)
`lation, wet granulation and fluidized-bed granulation gener(cid:173)
`ally produce harder, less friable tablets.
`
`EXAMPLES
`
`EXAMPLE 1
`
`[0047] Enteric Coated Naproxen Sodium Core and Famo(cid:173)
`tidine Immediate Release
`
`[0048] A schematic diagram of a four layer tablet dosage
`form is shown in FIG. 1. The first layer contains naproxen
`sodium distributed throughout a matrix of pharmaceutically
`acceptable fillers, excipients, binding agents, disintegrants,
`and lubricants.
`
`[0049] 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-I-421OA or Opadry® YS-I-7006
`(Colorcon, West Point, Pa.). Polymer film coating ingredi(cid:173)
`ents such as hydroxypropylmethylcellulose 2910 and poly(cid:173)
`ethylene glycol 8000 in a coating suspension may also be
`used.
`
`[0050] The function 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
`
`Dr. Reddy's Exh. 1021
`
`

`

`US 2003/0069255 Al
`
`Apr. 10, 2003
`
`5
`
`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 phtha(cid:173)
`late 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.
`
`[0051] 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 famoti(cid:173)
`dine 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 absorp(cid:173)
`tion.
`
`Core Tablet Ingredients
`
`%WjW
`
`mgrrablet
`
`Naproxen sodium, USP
`Microcrystalline cellulose, NF
`(Avicel PH 200)
`Povidone (K29/32), USP
`Talc, USP
`Magnesium Stearate, NF
`
`74.074
`17.166
`
`3.450
`4.350
`0.960
`
`500.00
`115.87
`
`23.29
`29.36
`6.48
`
`Total
`
`100.00
`
`675.00
`
`Barrier Film Coating Ingredients
`
`%WjW
`
`Opadry Clear ® YS-1-7006
`Purified water USP
`
`Total
`
`Enteric Coating Dispersion
`Ingredients
`
`Methacrylic Acid Copolymer, NF
`(Eudragit L-l00-55)
`Methacrylic Acid Copolymer, NF
`(Eudragit L-l00)
`Triethyl Citrate, NF
`Dibutyl Phthalate, NF
`Ammonium Hydroxide (30%), NF
`Purified water, USP
`
`Total
`
`Famotidine Coating Dispersion
`Ingredients
`
`Famotidine, USP
`Opadry Clear ® (YS-1-7006)
`Talc, USP
`Purified Water, USP
`
`Total
`
`5.00
`95.00
`
`100.00
`
`%WjW
`
`7.30
`
`7.30
`
`2.95
`1.17
`0.87
`80.41
`
`100.00
`
`%WjW
`
`3.0
`5.0
`3.0
`89.0
`
`100.0
`
`EXAMPLE 2
`
`[0052] Enteric Coated Naproxen Core and Famotidine
`Immediate Release
`
`[0053] FIG. 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 phar(cid:173)
`maceutically acceptable excipients. These excipients per(cid:173)
`form specific functions and may serve as binders, disinte(cid:173)
`grants, or lubricants. A pharmaceutically acceptable enteric
`coating surrounds the naproxen core. 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 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.
`
`[0054] 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