Exhibit 1001
`
`U.S. Patent No. 7,332,183 (“the ‘183 Patent”)
`
`

`
`(12) United States Patent
`Plachetka et a1.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,332,183 B2
`Feb. 19, 2008
`
`US007332183B2
`
`(54)
`
`(75)
`
`(73)
`(*)
`
`(21)
`(22)
`(65)
`
`(60)
`
`(51)
`(52)
`(58)
`
`(56)
`
`MULTILAYER DOSAGE FORMS
`CONTAINING NSAIDS AND TRIPTANS
`Inventors: John R. Plachetka, Chapel Hill, NC
`(US); Venkata Markandeya
`Kothapalli, Cary, NC (US); Donna L.
`Gilbert, Chapel Hill, NC (US)
`Assignee: Pozen Inc., Chapel Hill, NC (US)
`Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC 154(b) by 650 days.
`Appl. No.: 10/741,592
`Filed:
`Dec. 22, 2003
`Prior Publication Data
`US 2004/0180089 A1
`Sep. 16, 2004
`Related US. Application Data
`Provisional application No. 60/436,000, ?led on Dec.
`26, 2002.
`Int. Cl.
`(2006.01)
`A61K 9/24
`US. Cl. .................................................... .. 424/472
`Field of Classi?cation Search .............. .. 424/472,
`424/473, 474
`See application ?le for complete search history.
`References Cited
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`
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`2/1993
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`5/1997
`0 117 164
`8/1984
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`7/1990
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`9/1991
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`2/1984
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`9/1984
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`2/1986
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`8/1996
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`11/1994
`
`CS
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`GB
`GB
`JP
`W0
`
`(Continued)
`OTHER PUBLICATIONS
`Certi?ed Translation of EP 0 117 164, Reference B9 above.
`Andersson, et al., “Double-Blind Study of NaproXen vs Placebo in
`the Treatment of Acute Migraine Attacks,” Cephalalgia 9:29-32
`(1989).
`Baumel, “Migraine: A Pharmacologic Review with Newer Options
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`Boureau, et al., “Comparison of Subcutaneous Sumatriptan with
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`(1995).
`
`(Continued)
`Primary ExamineriSharon Kennedy
`(74) Attorney, Agent, or FirmiMichael A. SanZo; Law
`Of?ce of Michael A. SanZo, LLC
`(57)
`ABSTRACT
`
`The present invention is directed to multilayer pharmaceu
`tical tablets in which an NSAID and a triptan are present in
`separate and distinct layers. The layers are in a side-by-side
`con?guration, which allows the dissolution of triptan and
`NSAID to occur independently and immediately.
`
`20 Claims, 1 Drawing Sheet
`
`

`
`US 7,332,183 B2
`Page 2
`
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`WO 97/38986
`10/1997
`WO 98/06392
`2/1998
`WO 98/15275
`4/1998
`WO 98/20870
`5/1998
`WO 99/45905
`9/1999
`WO 00/06161
`2/2000
`WO 00/25779
`5/2000
`WO 00/48583
`8/2000
`OTHER PUBLICATIONS
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`
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`
`

`
`US 7,332,183 B2
`Page 3
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`1996); 5,510,496 (Apr. 1996); 5,516,907 (May 1996); 5/521,207
`(May 1996); 5,563,165 (Oct. 1996); 5,700,816 (Dec. 1997);
`5,753,688 (May 1998); 5,760,068 (Jun. 1998); and 5,932,598 (Aug.
`1999).
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`English language abstract of JP 8-208516, Reference B7 above.
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`(1996).
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`man & Gilman, 9th Ed.
`The Merck Index, 12Lh Ed., 1996: THER-12-13.
`The Merck Index, 13Lh Ed., 2001:1480.
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`databases, following a query for “ALX-1323.”
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`Opposition papers ?led by Opponent Almirall Prodesfarma SA.
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`English language translation for CS 277 525, Reference B1 above.
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`
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`European Search Report for Application Number EP03808537.9.
`* cited by examiner
`
`

`
`U.S. Patent
`
`Feb. 19,2008
`
`US 7,332,183 B2
`
`Figure 1.
`Representative drawings of three different dosage form con?gurations.
`
`Panel A: Multi-Layer Tablet (Bilayer Tablet Shown)
`W Sumatriptan Succinate Layer
`
`Naproxen Sodium Layer
`
`Panel B: Naproxen Sodium Core Tablet with Sumatriptan
`Succinate in the Film-Coat
`
`//////
`
`/////A
`
`\\\\\\\\\\\\\\\\\\\
`
`\\\\\\\\\\\\\\\\\\\\§
`
`Naproxen Sodium core tablet with
`Sumatriptan Succinate in the ?lm-coat
`
`Panel C: Physical Admixture
`
`Single layer tablet containing a physical
`admixture of Sumatriptan Succinate and
`Naproxen Sodium
`
`

`
`1
`MULTILAYER DOSAGE FORMS
`CONTAINING NSAIDS AND TRIPTANS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`This application claims priority to US. provisional appli
`cation No. 60/436,000, ?led on Dec. 26, 2002, Which is
`incorporated in its entirety herein by reference.
`FIELD OF THE INVENTION
`The present invention is in the general ?eld of treatments
`for pain, and particularly treatments for pain associated With
`migraine headache. It encompasses solid dosage forms hav
`ing triptans and NSAIDs, particularly naproxen, in a mul
`tilayer arrangement. In addition, the invention is concerned
`With methods of treating headache using these dosage forms.
`BACKGROUND OF THE INVENTION
`
`It has been estimated that 6% of men and 18% of Women
`in the United States currently sulfer from migraine head
`aches. Often, patients experience 30 or more potentially
`debilitating attacks a year. Current treatments include a
`range of over-the-counter analgesics as Well as ergotamines
`and triptans.
`Recently, reports have indicated that combination thera
`pies in Which triptans are combined With NSAIDs greatly
`improve the relief available to migraine patients (US. Pat.
`No. 6,060,499; US. Pat. No. 5,872,145; see also US. Pat.
`No. 6,384,034; US. 2002/0099059; EP 1051993; EP
`1064967; EP 1051995; EP 10649966; and EP 1064948). In
`general, NSAIDs have been delivered orally, for example in
`the form of either single or multilayer tablets or as coated
`granules (US. Pat. No. 6,365,184; US. Pat. No. 5,637,320;
`US. Pat. No. 5,480,650; and US. Pat. No. 6,387,410).
`Triptans have been given orally, intranasally and by injec
`tion (see, e.g., US. Pat. No. 4,816,470; US. Pat. No.
`5,307,845; US. Pat. No. 5,307,953; US. Pat. No. 5,554,639;
`and US. Pat. No. 5,705,520; US. Pat. No. 6,368,627; and
`WO 00/06161).
`Although a good deal of Work has been done in the area
`of dosage forms for triptans and NSAIDs, relatively little is
`knoWn about the properties of dosage forms. in Which these
`agents are combined. The Way in Which such dosage forms
`are constructed may affect not only the stability of the
`individual therapeutic agents but also the speed at Which the
`individual agents dissolve and become available to provide
`pain relief to patients.
`SUMMARY OF THE INVENTION
`The present invention is directed to speci?c oral dosage
`forms containing a triptan and an NSAID, especially
`naproxen, in Which these therapeutic agents are segregated
`into separate layers of a multilayer tablet. Unless otherWise
`speci?ed, reference to an NSAID or a triptan Will be
`understood to include pharmaceutically acceptable salts of
`these drugs. The dosage forms of the invention have been
`found to have substantial advantages over others in terms of
`release properties, stability and pharmacokinetic pro?le.
`These advantages could not have been predicted a priori and
`make the dosage forms the selection of choice for the
`treatment of patients With migraine headache.
`In its ?rst aspect, the invention is directed to a multilayer
`pharmaceutical tablet comprising naproxen (preferably
`
`2
`naproxen sodium at a therapeutic dosage of betWeen 200 and
`600 mg) and a triptan. Most preferably, the tablet has 40 mg
`of sodium succinate, 400 mg naproxen sodium and may be
`formulated as described in Example 6B. Substantially all of
`the triptan is found in one layer of the tablet and substan
`tially all of the naproxen is found in a second, separate layer.
`These tWo layers are in a side-by-side arrangement such that
`the dissolution of the naproxen occurs independently of the
`dissolution of triptan. As discussed further beloW, this tablet
`arrangement has surprisingly better properties than other
`tablet arrangements. Without being held to any particular
`theory, it is believed that, in the stomach, naproxen forms a
`gel-like matrix that retards the dissolution of triptans (or
`other drugs) unless the tWo agents are maintained in distinct,
`side by side layers.
`Other types of NSAIDs Whose characteristics might pos
`sibly be improved by a side by side tablet con?guration
`include acidic NSAIDs, i.e., NSAIDs having a pKa of less
`than 7.0, and, long acting NSAIDs, i.e., NSAIDs having a
`half life of at least four hours and duration of action of at
`least six hours. Examples of long acting NSAIDs that might
`be used include ?urbiprofen, ketoprofen, naproxen,
`oxaproZin, etodolac, indomethacin, ketorolac, nabumetone,
`mefanamic acid, piroxicam, lomoxicam, meloxicam, and
`pharmaceutically acceptable salts thereof. Another group of
`NSAIDs that could be used is the cyclooxygenase-2 (COX
`2) inhibitors. Members of this group include: rofecoxib;
`celecoxib, valdecoxib, etoricoxib, JTE-522; L-745,337;
`NS398; and pharmaceutically acceptable salts thereof. The
`most preferred of these is rofecoxib Which has a half life of
`about 17 hours. Preferably this should be present in tablets
`in an amount of betWeen 10 and 50 mg and the total initial
`daily dose should not exceed 50 mg.
`Examples of triptans that may be used include sumatrip
`tan, eletriptan, riZatriptan, frovatriptan, almotriptan, Zolmi
`triptan, and naratriptan and pharmaceutically acceptable
`salts thereof. The most preferred of these is sumatriptan at a
`therapeutic dose of betWeen 25 and 100 mg. The other
`triptans should be administered to patients at the dosages
`knoWn in the art to be effective at relieving pain.
`As discussed above, substantially all of the triptan and
`substantially all of the NSAID in dosage forms should be in
`separate layers. The term “substantially all” indicates that at
`least 90%, and preferably greater than 95%, of the total
`therapeutic agent present in the tablet is included Within one
`distinct layer. The layers should be arranged such that the
`individual therapeutic agents dissolve independently of one
`another, i.e., dissolution should occur at approximately the
`same rate as Would occur if the drugs Were given separately.
`In this context, “approximately the same rate” indicates that
`the time for complete dissolution of agent When drugs are
`given in the combination tablet should require the same
`amount of time:10% as When the same amount of agent is
`given alone. This can be achieved by placing the individual
`layers in a side-by-side arrangement, as opposed, for
`example, in a single layer tablet matrix containing both
`agents or one layer forming a core surrounded by the other
`layer. In a preferred embodiment, the layers are arranged so
`that they are juxtaposed symmetrically along a single planar
`surface such that essentially all of the triptan-containing
`layer is on one side of the plane and essentially all of the
`NSAID-containing layer is on the other side. The term
`“essentially all” is equivalent to “substantially all” and
`means that at least 90% and preferably greater than 95% of
`the therapeutic agent is present. These layers may come into
`direct contact With one another or, alternatively, they may be
`separated by one or more additional layers, e.g., a barrier
`
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`3
`layer or coating Which prevents the therapeutic agents from
`interacting With one another. In preferred embodiments, the
`tablets are in a bilayer arrangement and may be surrounded
`With a ?lm coating.
`In an alternative aspect, the invention is directed to
`methods of treating a patient for headache, preferably
`migraine headache, by administering any of the tablets
`described above. Other types of headache that can be treated
`include tension-type headache; cluster headache and chronic
`paroxysmal hemicrania; miscellaneous headache unassoci
`ated With a structural lesion; headache associated With a
`non-vascular intracranial disorder; headache associated With
`the administration of a substance or its WithdraWal; head
`ache associated With noncephalic infection; headache asso
`ciated With a metabolic disorder; headache associated With
`a disorder of the cranium, neck, eyes, ears, nose, sinuses,
`teeth, mouth or other facial or cranial structure; cranial
`neuralgias; and nerve trunk pain and dealferentiation pain.
`(For a description of headache classes, see Olesen, et al., The
`Headaches, pp. 9-14, Raven Press; see also, “Classi?cation
`and diagnostic criteria for headache disorders, cranial neu
`ralgias and facial pain,” Headache Classi?cation Committee
`of the International Headache Society, Cephalalgia 8(supp.
`7):1-96 (1988)). In all cases, suf?cient analgesic should be
`administered to alleviate the pain associated With the con
`dition being treated.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1: FIG. 1 depicts three different con?gurations that
`may be used for a tablet containing sumatriptan succinate
`and naproxen sodium. Panel A shoWs a side-by-side type
`con?guration encompassed by the present invention. Panel
`B shoWs an arrangement in Which naproxen sodium is
`present as a core surrounded by a coating of sumatriptan
`succinate, and panel C shoWs a single layer tablet in Which
`there is an admixture of sumatriptan succinate and naproxen
`sodium.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention is directed to certain speci?c oral
`dosage forms Which contain both a triptan and an NSAID,
`preferably naproxen. The main characteristics of the dosage
`forms are that they are in the form of tablets in Which the
`triptan and NSAID are maintained in separate distinct layers
`and dissolve in an independent manner. Experiments dis
`cussed in the Examples section have shoWn that, in other
`types of tablets, the dissolution of triptan is delayed. Appli
`cants believe that naproxen and similar NSAIDs possess
`poor solubility in vivo due, in part, to the stomach’s loW pH
`environment. This poor solubility may impart sloWer drug
`release properties for a given dosage form. Because of the
`sloW eroding nature of naproxen sodium tablets and similar
`NSAIDs, triptans may become entrapped, and, as a result,
`their release may be delayed When non-segregated tablets
`are used. By maintaining the triptan and NSAID in separate
`layers, this problem is avoided. Thus, a multilayer or bilayer
`tablet provides for independent and immediate release of
`each component and has favorable biopharmaceutical
`attributes With respect to headache pain relief. In addition,
`experiments have shoWn that physiochemical stability is
`improved When NSAID and triptan are maintained in dis
`tinct layers.
`
`4
`Any method for producing multilayered tablets is com
`patible With the present invention With the only restriction
`being that the triptan and NSAID must be separated. Pre
`ferred methods for producing tablets are described in the
`Examples section. If an NSAID other than naproxen is used,
`then it is desirable that it be a long-acting NSAID because
`of the longer duration of pain relief resulting from these
`agents. Naproxen and naproxen sodium are themselves long
`acting NSAIDs With half lives of about 12 to 15 hours and
`about 12 to 13 hours, respectively. Examples of other long
`acting NSAIDs include ?urbiprofen, With a half life of about
`6 hours; ketoprofen, With a half life of about 4 hours;
`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 about
`8 to 9 hours; nabumetone, With a half life of about 22 to 30
`hours; mefanamic acid, With a half life of about 4 hours; and
`piroxicam, With a half life of about 4 to 6 hours. Any salt
`form of NSAID or triptan is compatible With the invention.
`Any of the triptans that have been reported in the literature
`may also be used in the present invention. Sumatriptan is the
`most preferred and should be administered to patients at a
`dosage ofbetWeen 1 and 300 mg With dosages of 25-100 mg
`being preferred. Effective dosages for a variety of NSAIDs
`are: indomethacinithree 25 mg doses taken at intervals
`during the day, 75 mg total; ?urbiprofenitablets of 50-100
`mg With a total daily dosage of betWeen 100 and 500 mg and
`preferably betWeen 200 and 300 mg; ketoprofenitablets of
`25-75 mg With a total daily dosage of 100-500 mg and
`preferably 100-300 mg; naproxenitablets of 250-500 mg
`and, for the sodium salt, tablets of 275-550 mg; oxaproZini
`tablets of about 600 mg With a total daily dose of about 1200
`mg; etodolacitablets of about 400 mg With a total daily
`dosage of less than 1200 mg; ketorolacitablets of 10-40
`mg; nabumetoneitablets of 500-750 mg With a total daily
`dosage of 1500-2000 mg; mefanamic aciditablets contain
`ing 100-1000 mg With about 500 mg being typical; and
`piroxicamitablets of 10-20 mg. This information concem
`ing tablets and dosages are provided merely as guidelines
`and it is expected that one of ordinary skill in the art Would
`make certain adjustments either for convenience or to better
`suit the needs of particular patients.
`The compositions described herein can be made in accor
`dance With methods that are standard in the art (see, e.g.,
`Remington ’s Pharmaceutical Sciences, 16th ed., A. Oslo
`Editor, Easton, Pa. (1980)). In addition to the active agents,
`the different layers of tablets may contain binders (e.g.,
`polyvinylpyrrolidone), disintegrants (e.g., microcrystalline
`cellulose, or croscarmellose sodium), lubricants (e.g., talc,
`or magnesium stearate) and ?llers (e.g., lactose). The tablets
`may be coated or there may be a barrier or coating layer
`betWeen layers containing active agents. Typical coating
`components that may be used include a polymer (e.g.,
`hydroxypropylmethyl cellulose), a plasticiZer (e.g., polyeth
`ylene glycol or polysorbate 80) and a coloring agent (e.g.,
`titanium dioxide). A preferred formulation for the triptan
`layer of a tablet is shoWn in Table 1 beloW and a preferred
`formulation for the NSAID layer is shoWn in Table 2. Any
`standard manufacturing method for producing tablets using
`either a Wet or dry granulation procedure is compatible With
`the invention and speci?c preferred methods are set forth in
`the Examples section beloW.
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`5
`EXAMPLES
`Example 1
`Making of Bilayer Tablets and Other Dosage
`Forms
`
`The dosage forms of this invention can be prepared by
`different manufacturing processes. The manufacture of a
`bilayer tablet dosage form comprising sumatriptan succinate
`and naproxen sodium layers With acceptable carriers is
`described beloW in subsection A and large scale methods of
`manufacturing these tablets are described in Example 5. In
`brief, the manufacturing process for the separate granula
`tions incorporates high shear granulation, ?uid-bed drying,
`milling, blending, and lubrication. The production of alter
`native dosage forms (naproxen sodium core tablets With
`sumatriptan succinate in the ?lm-coat or a physical admix
`ture of naproxen sodium and sumatriptan succinate granu
`lations) is described in subsections B and C. Representative
`draWings of the dosage forms are shoWn in FIG. 1.
`A. Bilayer Tablet Dosage For