Exhibit 1009
`
`U.S. Patent No. 5,756,125 (“the ‘125 Patent”)
`
`

`
`United States Patent [191
`Desai
`
`USOO5756125A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,756,125
`May 26, 1998
`
`[54] CONTROLLED RELEASE NAPROXEN
`SODIUM PLUS NAPROXEN COMBINATIQN
`TABLET
`
`4
`.
`[75] Inventor‘ Subhash Desa" Gmyslakc‘ “1'
`.
`_
`.
`[73] Asslgnee' G‘ D‘ seam’ 8‘ C0" Chlcago' m‘
`
`[21] Appl. No.: 457,415
`[22] Filed:
`Jun. 1, 1995
`
`.
`.
`Related [15' Apphmm“ Data
`[63] Continuation-impart of Ser. No. 937,920, Aug. 31, 1992,
`P99 No‘ 5,609,834
`........................ .. A61K 9/22
`[51] Int. Cl.6 .
`[52] us. 01. ........................ .. 424/468; 424/464; 424/465;
`424/469; 424/457
`[58] Field of Search ................................... .. 424/468. 464.
`424/482_ 489_ 480_ 409
`References Cited
`U-S' PATENT DOCUMENTS
`2/1986 Hsiao et a1. ............................ .. 424/22
`4,571,333
`7/1986 Cooper ............ ..
`. 514/557
`4,599,359
`4,704,406 11/1937 Stanislaus et a1,
`514/570
`4,794,112 12/1988 Cooper .... ..
`.. 514/255
`4,803,079
`2/1989 Hsiao et a1, .......................... .. 424/468
`
`[56]
`
`424/468
`4,888,178 12/1989 Rotini et a].
`424/468
`4,888,179 12/1989 Rotini et a],
`514/557
`4,920,149
`4/1990 Sunshine et a1
`514/557
`4,923,898
`5/1989 Sunshine et a1.
`424/490
`5,043,167
`8/1991 Rotini et a].
`424/482
`5,055,306 10/1991 Barry et a1.
`424/468
`5,093,200
`3/1992 Watanabe et a1. ..
`424/469
`5,378,474
`1/1995 Morella et a1.
`424/480
`5,425,950
`6/1995 Dandiken et a1. ..
`5,480,650
`l/l996 Mai-chi et a1. ........................ .. 424/464
`FOREIGN PATENT DOCUMENTS
`0 274 734 A1 7/1988 European Pat. 01f. ....... .. A61K 9/24
`0 438 249 A1 7/1991 European Fat. 011, ..... .. A61K 31/19
`Primary Examiner-—'I‘hmman K. Page
`Assistant Examiner—William E. Benston. Jr.
`Attorney Agent’ 0’ Fiwnmia S‘ Kovacevic: R‘Jg?r A‘
`wllhams
`ABSTRACT
`[57]
`_
`_
`The present invention relates to controlled release dosage
`forms composed of a naproxen layer which contains a
`delayed release granulate of naproxen compressed with an
`immediate release granulate of naproxen and an immediate
`release naproxen sodium layer compressed with the
`IlaProxen lay“ dcsigned t° promptly ext" 3 th?rapcu?c
`effect Whilc also maintaining the Ihcrapeutic blood concen
`tration for a prolonged duration of 24 hours.
`
`14 Claims, 3 Drawing Sheets
`
`

`
`US. Patent
`
`May 26, 1998
`
`Sheet 1 0f 3
`
`5,756,125
`
`28
`
`32
`
`26
`
`s
`
`,
`[I
`
`7/
`
`5
`
`7/.
`“x v’
`
`a
`A FIG.2
`
`16
`\
`
`a4
`\
`
`‘O
`
`

`
`U.S. Patent
`
`May 26, 1998
`
`Sheet 2 of 3
`
`5,756,125
`
`XENARC.R.
`
`EXAMPLE3
`
`EXAMPLE2
`
`as
`$I-
`
`0E ENX
`
`cu
`
`xO0
`
`:
`a.
`
`<2 <
`
`
`
`TIME(HOURS)
`
`NAPROXEN PLASMA LEVELS
`
`

`
`US. Patent
`
`May 26, 1993
`
`Sheet 3 of 3
`
`5,756,125
`
`I101
`wmaF 0E mwm KN XOtnZZd.
`
`lmlllllll
`
`
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`
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`
`mm
`
`m.
`
`6%? NEE
`
`mm N. n._
`
`NAPROXEN PLASMA LEVELS
`
`

`
`1
`CONTROLLED RELEASE NAPROXEN
`SODIUM PLUS NAPROXEN COMBINATION
`TABLET
`This is a CONTINUATION IN PART of Application Ser.
`No. 07/937920. ?led Aug. 31. 1992. now US. Pat. No.
`5.609.884.
`BACKGROUND OF THE INVENTION
`The invention herein is directed to new controlled release
`multi-layer pharmaceutical compositions containing a com
`bination of naproxen and naproxen sodium. The ?rst layer of
`the pharmaceutical composition consists of delayed release
`granulates of naproxen compressed together with immediate
`release granulates of naproxen. A layer of immediate release
`naproxen sodium is compressed onto the ?rst layer of
`naproxen forming an adjacent layer or layers.
`Naproxen.
`[(S)-6-methoxy-or-methyl-2
`naphthaleneacetic acid. hereinafter also referred to as
`naproxen acid] is of the formula
`
`CH3
`I
`CHCOOI-l
`
`CHgO
`
`20
`
`25
`
`35
`
`5.756.125
`2
`Rotini and Marchi (U.S. Pat. No. 4.888.178) disclose
`galenic formulations made of a mixture of immediate release
`naproxen granulate and a controlled release naproxen granu
`late. Naproxen. in its acid form (naproxen acid). is used in
`both the immediate release granulate and the controlled
`release granulate.
`Although the concept of using either naproxen or
`naproxen sodium independently in controlled release dosage
`forms has been demonstrated. the art available has several
`disadvantages. First. the relevant art demonstrates that thera
`peutic blood levels. as indicated by the maximum concen
`tration (Cm) are not achieved promptly to exert a fast
`therapeutic response. Such a delay in reaching therapeutic
`blood levels is unsuitable for use as an analgesic and
`antipyretic in the treatment of mild to moderate pain such as
`dysmenorrhea or arthritis. where fast onset of action is
`necessary to obtain pain relief.
`Furthermore. utilizing naproxen sodium alone in a con
`trolled release system disclosed in the relevant art results in
`failure to maintain therapeutic blood concentration for a
`prolonged duration of 24 hours since its higher solubility
`will not delay the release of the compound from the dosage
`form at a rate comparable to naproxen.
`In addition. matrix systems described in the art are
`designed to remain intact. and since naproxen and naproxen
`sodium are known to be irritants to the gastrointestinal tract.
`such systems may not empty from the stomach due to its
`large size. The retention of such systems in the stomach may
`thereby cause gastric damage.
`It would be desirable to provide a pharmaceutical com
`position that achieves a therapeutic blood level of naproxen
`anions promptly to exert a fast therapeutic analgesic effect.
`which composition also maintains the therapeutic blood
`concentration for a prolonged duration of 24 hours being
`therefore suitable for once a day administration and which
`does not remain intact as a matrix.
`SUMMARY OF THE INVENTION
`The present invention relates to controlled release prepa
`rations containing a combination of naproxen sodium and
`naproxen acid. Speci?cally. it relates to a multilayer oral
`dosage form comprising a layer of naproxen comprised of a
`delayed release granulate of naproxen compressed with an
`immediate release granulate of naproxen. The delayed
`release naproxen is a mixture of naproxen with retarding
`agents. hydrogenated castor oil and ethyloellulose. The
`immediate release naproxen is a granulate of naproxen.
`The compressed delayed release naproxen and immediate
`release naproxen (hereinafter the naproxen layer) are then
`compressed with a layer of immediate release naproxen
`sodium granulate (hereinafter the naproxen sodium laya).
`The tablet is designed to provide prompt therapeutic plasma
`levels of naproxen in less than 1 hour and maintain these
`levels for a duration of 24 hours. thereby providing for once
`daily administration. The tablet is designed to disintegrate.
`rather than remain as a matrix in the stomach. thereby
`reducing the potential for gastric irritation and variability in
`absorption.
`The invention herein will be more fully understood with
`regard to the following brief description of the accompany
`ing drawings and the following detailed description of the
`invention.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a cross sectional representation of a tablet of the
`pharmaceutical composition described herein.
`
`Naproxen is widely used (in such an acid state) as an
`anti-in?ammatory compound in the treatment of arthritis.
`and as an analgesic and antipyretic in the treatment of mild
`to moderate pain. such as dysmenorrhea or arthritis.
`Naproxen has a low water solubility and a comparatively
`slow rate of absorption which is a disadvantage when using
`naproxen as an analgesic. This drawback is overcome by the
`use of its salt. naproxen sodium. Naproxen sodium is the
`sodium salt of naproxen acid. Naproxen sodium. due to its
`higher water solubility. has a comparatively faster rate of
`absorption leading to a prompt analgesic and antipyretic
`e?ect. Hence. naproxen sodium is the drug of choice in the
`treatment of mild to moderate pain where a prompt thera
`peutic eifect is desired. After absorption. both naproxen and
`naproxen sodium exist in the circulating blood as naproxen
`anions.
`45
`Naproxen is available in 250 mg. 375 mg and 500 mg
`tablets and is generally administered in therapeutic doses of
`500-1000 mg per day. while naproxen sodium is available
`in 275 mg and 550 mg tablets and is administered in
`therapeutic doses of 550-1100 mg per day. Both compounds
`have multiple frequencies of administration of 8-12 hours
`every day.
`Conventional dosage forms of naproxen or naproxen
`sodium are administered two to three times daily to maintain
`therapeutic blood levels which results in a large ?uctuation
`in peak and trough blood levels. Controlled release dosage
`forms for naproxen have been designed to overcome this
`drawback by reducing the ?uctuation and maintaining the
`desired therapeutic blood concentration as well as reducing
`the frequency of drug administration.
`Hsias and Kent (U.S. Pat. Nos. 4.571.333 and 4.803.079)
`disclose the use of controlled release naproxen formulations
`and disclose the use of controlled release naproxen sodium
`formulations. Therapeutic blood peak levels of naproxen are
`not achieved promptly by these formulations and take
`greater than 6 hours to be achieved. as indicated by the
`maximum concentrations (Cm) disclosed therein.
`
`50
`
`55
`
`65
`
`

`
`20
`
`30
`
`35
`
`5.756.125
`4
`3
`w/w %. more preferably from about 1 to about 5 w/W % and
`FIG. 2 is a cross sectional representation of a second
`most preferably about 4.5 w/w %. The percent of naproxen
`embodiment of a tablet of the pharmaceutical composition
`acid present in the controlled release granulate of the
`described herein.
`naproxen acid layer is from about 20 to about 50 w/w % and
`FIG. 3 is a cross sectional representation of a third
`most preferably about 35.5 w/w %.
`embodiment of a tablet of the pharmaceutical composition
`A total composition is formed from a mixture of:
`described herein.
`54.3 w/w % naproxen;
`FIG. 4 is a graphical representation of the plasma pro?les
`14.4 w/w % naproxen sodium;
`of two different naproxen and naproxen sodium controlled
`1.8 w/w % lactose;
`release formulations. of an immediate release naproxen
`18.3 w/w % hydrogenated castor oil;
`sodium formulation and of a controlled release naproxen
`5.8 w/w % ethyl cellulose;
`acid formulation. over 24 hours.
`3.6 w/W % polyvinylpyrrolidone; and
`FIG. 5 is a graphical representation of the plasma pro?les
`1.8 w/W % other pharmaceutically acceptable excipients
`of two different naproxen and naproxen sodium controlled
`and lubricating agents.
`formulations. of an immediate release naproxen sodium
`Preferably the total composition is formed from a mixture
`formulation and of a controlled release naproxen acid
`of 40.1 wlw % naproxen; 33.9 w/w % naproxen sodium; 7.1
`formulation. over the initial four hours following adminis
`w/w % lactose hydrous; 13.5 Wlw % hydrogenated castor
`tration.
`oil; 4.3 w/w % ethyl cellulose and 1.1 w/w % other phar
`maceutically acceptable excipients and lubricating agents.
`The pharmaceutical compositions of the present invention
`can be described with regard to the accompanying drawings.
`FIGS. 1. 2 and 3 schematically representing embodiments of
`the invention. the preferred embodiment being represented
`by the tablet of FIG. 1.
`FIG. 1 represents a cross sectional view of a pharmaceu
`tical composition herein. The pharmaceutical composition
`consists of a bilayer tablet (18) which can have any geo
`metric shape. although for ease of description herein. an oval
`cross section is shown. The tablet (18) includes a naproxen
`layer (20) which includes. as the pharmaceutically active
`component. naproxen acid and other pharmaceutically
`acceptable excipients. The naproxen acid in the naproxen
`layer consists of an immediate release naproxen granulate
`(23) and a delayed release naproxen granulate (24). The
`naproxen layer (20) can be formulated by compression of
`the naproxen acid granulates with any suitable tableting
`equipment. Standard compression tableting techniques can
`be employed for forming the naproxen layer. The naproxen
`layer of the present invention can be prepared according to
`the methodology of Rotini and Marchi. U.S. Pat. No. 4.888.
`178. hm'eby incorporated by reference. The ratio of the
`immediate release naproxen granulate to the delayed release
`naproxen granulate can be as described in the U.S. Pat. No.
`4.888.178 patent
`‘
`Adjacent to the naproxen layer (20) is a naproxen sodium
`layer (22) consisting of naproxen sodium and other phar
`maceutically acceptable excipients. The naproxen sodium
`layer can be applied to the naproxen layer by compression
`or spraying techniques. such as are well known in the
`tableting art. The naproxen sodium in the naproxen sodium
`layer can be present in any therapeutically acceptable
`amount.
`FIG. 2 represents an cross sectional view of an second
`embodiment of a pharmaceutical composition herein. The
`pharmaceutical composition consists of a trilayer tablet (26)
`which can have any geometric shape. although for ease of
`description herein. an oval cross section is shown. The tablet
`(26) includes a naproxen layer (30) which includes. as the
`pharmaceutically active component. naproxen acid and
`other pharmaceutically acceptable excipients. The naproxen
`acid in the layer consists of an immediate release naproxen
`granulate (31) and a delayed release naproxen granulate (32)
`as described above. The naproxen layer (30) can be formu
`lated by compression of the naproxen acid granulates with
`any suitable tableting equipment. Standard compression
`tableting techniques can be employed for forming the
`naproxen layer.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention is directed to multilayer controlled
`release preparations containing a layer of compressed
`delayed and immediate release granulates of naproxen and a
`layer of naproxen sodium. Such a dosage form. immediately
`releasing naproxen sodium. provides a fast rate of
`absorption. achieving a desired therapeutic plasma level in
`less than 1 hour. The subsequent disintegration and release
`of the immediate and delayed release granulates of naproxen
`maintains the therapeutic blood levels for a duration of 24
`hours. thereby providing once daily administration. The
`compositions achieve a therapeutic effect which is prompt
`and maintained for a longer duration while disintegration of
`the tablet reduces gastric retention time thereby reducing the
`potential for gastric irritation and damage. The compositions
`reduce variability of absorption of naproxen thereby leading
`to predictable bioavailability.
`As used herein the terms “multilayer” or “multilayered”
`encompass tablets consisting of two or more adjacent layers.
`including but not limited to. bilayer and trilayer tablets and
`compositions consisting of a coating surrounding an inner
`core. Types of multilayer pharmaceutical compositions and
`methods of manufacturing such compositions are well
`lmown in the pharmaceutical art. The terms “core” or
`“coating" are used herein synonymously with the term
`“layer" which is further described in the detailed description
`of the drawings herein.
`The precise amounts of naproxen sodium and naproxen
`needed to achieve therapeutic blood concentration are cal
`culated by means of pharmacokinetic modelling and phar
`macodynamic response. (See Thomson et al.. Clin. Phar
`macol. Then, February 1981. 29(2) p. 168-73 for plasma
`concentration pro?les.)
`More speci?cally. the present invention is a controlled
`release pharmaceutical composition containing naproxen
`sodium present in an amount from about 15 to about 70 w/w
`% of the compositions of the present invention. more
`preferably from about 20 to about 50 w/w %. more prefer
`ably from about 30 to about 35 w/w % and most preferably
`about 33 to 34% w/w %.
`Preferably. the percent of naproxen acid present in the
`pharmaceutical composition of the present invention is from
`about 20 to about 70 w/w % of the compositions of the
`present invention. more preferably from about 40—80 w/w %
`and most preferably about 40 w/w %.
`65
`The percent of naproxen acid present in the immediate
`release granulate of the naproxen acid layer is up to about 10
`
`50
`
`55
`
`

`
`15
`
`25
`
`35
`
`5.756.125
`6
`5
`Exemplary of such binding agents are
`Adjacent to the naproxen layer (30) are two layers (28)
`polyvinylpyrrolidone. carboxymethylcellulose. microcrys
`consisting of naproxen sodium and other pharmaceutically
`acceptable excipients. The naproxen sodium layers (28) can
`talline cellulose. lactose. saccharose. mannitol. gumarabic.
`be applied by compression and spraying techniques. such as
`pectin. gelatin and the like.
`are well known in the tableting art The naproxen sodium in
`Representative disintegrating agents include starch.
`the layer can be present in any therapeutically acceptable
`sodium starch glycolate. alginates. polyvinylpyrrolidone and
`amount.
`the like.
`FIG. 3 represents a cross sectional view of a third embodi~
`Examples of lubricating agents are talc. magnesium
`ment of a pharmaceutical composition herein. The pharma
`ceutical composition consists of a tablet (10) which can have
`stearate. stearic acid. silica gel and the like.
`any geometric shape. although for ease of description herein
`A delayed release naproxen granulate is prepared by wet
`an oval cross section is shown. The tablet (10) includes an
`granulating the active agent with retarding agents by means
`inner core (12) which includes. as the pharmaceutically
`of a solvent selected from an alcohol containing from 1 to 4
`active component. naproxen acid and other pharmaceuti
`carbon atoms. an aromatic hydrocarbon. a ketone containing
`cally acceptable excipients. The naproxen acid in the core
`from 3 to 6 carbon atoms. an alkyl halide containing from 1
`consists of an immediate release naproxen granulate (13)
`and a delayed release naproxen granulate (14) as described
`to 4 carbon atoms. mixtures thereof or mixtures thereof with
`above. The core (12) can be formulated by compression of
`water. then drying the granules in an oven at 50° C. and
`the naproxen acid granulates with any suitable tableting
`sifting them through a sieve having meshes of 1 mm. The
`equipment. Standard compression tableting techniques can
`preferred solvent being 95% ethyl alcohol.
`be employed for forming the core.
`Representative retarding agents are ethylcellulose.
`Surrounding the core is a coating (16) consisting of
`methylcellulose. polyvinylacetate. methacrylic acid esters.
`naproxen sodium and other pharmaceutically acceptable
`cellulose acetate. fatty alcohols containing from 12 to 32
`excipients. The coating can be applied by coating
`carbon atoms. glyceric esters of fatty acids containing from
`techniques. such as are well known in the tableting art. The
`10 to 22 carbon atoms. like the mono~ and di-stearate of
`naproxen sodium in the coating can be present in any
`glycerol. esters of fatty acids and alcohols having from 12 to
`therapeutically acceptable amount.
`31 carbon atoms. para?in. natural waxy substances like
`The naproxen acid in the naproxen layer can be present in
`any therapeutically acceptable amount. Naproxen is present
`beeswax. unbleached wax. candelilla wax. carnauba wax.
`sealing wax. sperrnaceti. ozokerite and hydrogenated veg
`in the naproxen layer in immediate and delayed release
`granulates in amounts e?’ective for maintaining therapeutic
`etable oils like hydrogenated castor oil. hydrogenated peanut
`oil. hydrogenated cotton seed oil and mixtures thereof.
`blood levels of naproxen anions over a period of 24 hours.
`Methylcellulose. ethylcellulose. hydrogenated vegetable
`Naproxen administered independently is generally adminis
`tered in therapeutic doses of about 500 to 1000 mg per day.
`oils and mixtures thereof are preferred retarding agents in
`The naproxen present in the naproxen layer of the pharma
`the present invention.
`ceutical compositions herein can therefore be present in an
`The immediate release naproxen granulate and the
`amount to accomplish such dosing regimen in combination
`delayed release naproxen granulate are mixed and com
`with the naproxen sodium of the immediate release layer.
`pressed in such weight ratios that the active principle
`For the practice of the invention herein the amount of
`contained in the ?nal naproxen layer is in the amounts
`naproxen acid in the naproxen layer is generally present in
`described supra.
`an amount from about 20 to about 70 wlw % of the
`The immediate release naproxen sodium layer granulate is
`composition. and preferably from about 40 to about 80 w/w
`prepared by solubilizing polyvinylpyrrolidone in ethyl
`% and most preferably about 40 w/w %. Various pharma
`alcohol. adding a dye. mixing in the naproxen sodium.
`ceutically acceptable excipients can be combined with the
`drying the granules in an oven and sifting them through a
`naproxen acid granulates. as is well known in the pharma
`sieve having meshes of 1 mm.
`ceutical art.
`The naproxen sodium layer particles are mixed with
`The naproxen sodium in the naproxen sodium layer can
`additional pharmaceutically acceptable excipients and com
`be present in any therapeutically acceptable amount.
`Naproxen sodium administered independently is generally
`pressed or sprayed onto the naproxen layer to form a
`naproxen sodium layer partially or entirely surrounding the
`administered in therapeutic doses of 550-1100 mg per day.
`naproxen layer. according to conventional methods well
`The naproxen sodium layer of the pharmaceutical compo
`sition herein is preferably in an amount to accomplish such
`known in the tableting art.
`dosing regimen in combination with the naproxen acid of the
`The following examples 1-5 illustrate the methods used
`naproxen layer. The amount of naproxen sodium in the
`to prepare the compositions of the invention. These
`naproxen sodium layer is generally in an amount from about
`examples are given by way of illustration only and are not
`15 to about 70 w/w % of the compositions of the present
`to be construed as limiting the invention in spirit or scope.
`invention. preferably from about 20 to about 50 w/w % and
`as many modi?cations in materials and methods will be
`more preferably from about 30 to about 35 w/w % and most
`apparent from this disclosure to one having ordinary skill in
`preferably about 33 to 34 w/w %. Various pharmaceutically
`the art.
`acceptable excipients can be combined with the naproxen
`sodium in the naproxen sodium layer as is well known in the
`pharmaceutical art.
`In the preparation of the formulations of the present
`invention. an immediate release naproxen granulate is pre
`pared by dry granulating the active agent naproxen with
`suitable adjuvant agents like binding. disintegrating and
`lubricating agents and then sifting the granules on a sieve
`having meshes of 1 mm.
`
`EXAMPLE 1
`Apharrnaoeutical composition consisting of an immediate
`and delayed release naproxen acid granulate layer and an
`immediate release naproxen sodium layer was prepared
`according to the following methodology. (This methodology
`results in a 2.000 tablet yield.)
`
`45
`
`50
`
`55
`
`

`
`5.756.125
`7
`A) Naproxen sodium granulate (for the naproxen sodium
`layer)
`
`Naproxen sodium
`PVP K30
`Dye (yellow) E 102
`Ethyl alcohol
`
`2
`
`PVP K30 was solubilized in 45 grams of ethyl alcohol. the
`dye was added and mixed with the naproxen sodium for 5
`minutes in a mixer. The mixture was granulated by extrusion
`and dried in an oven at 35° C. The dried product was sifted
`on a 1 mm size sieve.
`B) Naproxen acid granulate (immediate release)
`
`5
`
`10
`
`15
`
`-continued
`NAPROXEN LAYER
`
`Cornstarch
`Lactose
`Sodium starch glycolate
`PVP K 90
`Magnesium stearate
`Hydrogenated castor oil
`Ethyl cellulose
`WP 01..
`Naproxen Acid
`Total Weight
`
`mg 8.16
`mg 24.18
`mg 4.92
`mg 4.92
`mg 0.33
`mg 140.22
`mg 44.28
`mg 20.4
`mg 450
`mg 854.41
`
`EXAMPLE 3
`
`Naproxen acid
`Starch
`Lactose
`Sodium starch glyoolate
`PV? K90
`Magnesium stearate
`95% ethyl alcohol
`
`130 g.
`13
`38.48
`7.8
`7.8
`_ 0.52
`3.458
`
`A pharmaceutical composition was prepared consisting of
`20 an immediate and delayed release naproxen acid granulate
`layer and an immediate release naproxen sodium layer
`according to the method of example 1. The tablet had the
`following composition:
`
`The powders were mixed for 15 minutes in a granulator.
`Ethyl alcohol was sprayed onto the powder mixture and
`mixing was continued for 10 minutes. The dried granulation
`was then passed through a 1.25 mm sieve.
`C) Naproxen acid granulate (delayed release)
`
`25
`
`NAPROXEN SODIUM LAYER
`Naproxen Sodium
`mg 150
`PVP K 30
`mg 6
`Yellow Dye E 102
`mg l
`NAPROXEN LAYER
`
`Cornstarch
`Lactose
`Sodium glycolate starch
`PV? K 90
`Magnesium stearate
`Hydrogenated castor oil
`Ethylcellulose
`PV? CL.
`Naproxen Acid
`Total Weight
`
`mg 6.5
`mg 19.24
`mg 3.9
`mg 3.9
`mg 0.26
`mg 190
`mg 60
`mg 34
`mg 565
`mg 1039.80
`
`30
`
`35
`
`40
`
`Naproxen acid
`Ethyl-cellulose
`Hydrogenated castor oil
`Ethyl alcohol
`
`1000 g.
`1X)
`380
`402.24
`
`The powders were mixed for 60 minutes in a mixer and
`then mixed with ethyl alcohol for 10 minutes. Granulation
`was done by extrusion and was dried at 50° C. The dried
`product was sifted using a 1 mm sieve.
`D) Formation of the naproxen layer
`The immediate release and delayed release granulates of
`naproxen acid were mixed with PVP CL micrionized (68 g.)
`for 10 minutes. The granulation mixture was compressed
`with a suitable punch to form a layer of naproxen acid.
`E) Compression of the naproxen layer with the naproxen
`sodium layer
`The naproxen layer was compressed with naproxen
`sodium granulate using a suitable punch to form a bilayered
`tablet having separate layers of naproxen and naproxen
`sodium.
`
`45
`
`EXAMPLE 4
`A pharmaceutical composition was prepared consisting of
`an immediate and delayed release naproxen acid granulate
`layer and an immediate release naproxen sodium layer
`so according to the method of example 1. The tablet had the
`following composition:
`
`EXAMPLE 2
`A pharmaceutical composition was prepared consisting of
`an immediate and delayed release naproxen acid granulate
`layer and an immediate release naproxen sodium layer
`according to the method of Example 1. The tablet had the
`following composition:
`
`55
`
`60
`
`NAPROXEN SODIUM LAYER
`Naproxen Sodium
`mg 150
`PVP K 30
`mg 6
`Yellow Dye E 102
`mg 1
`
`65
`
`NAPROXEN SODIUM LAYER
`Naproxen Sodium
`mg 179.1
`PVP K 30
`mg 7.1
`Yellow Dye E 102
`mg 0.18
`PVP CL.
`mg 7.5
`Magiesium Stem-ate
`mg 1.9
`NAPROXEN LAYER
`
`Cornstarch
`Lactose
`Sodium glycolate starch
`PVP K 90
`Magnesium stearate
`Hydrogenated castor oil
`Ethyloelluloee
`
`mg 2.4
`mg 7.1
`mg 1.4
`mg 1.4
`mg 0.05
`mg 71.2
`mg 22.5
`
`

`
`5,756,125
`
`-continued
`
`PVP C1,.
`Naproxen Acid
`Total Weight
`
`mg 12.7
`mg 211.5
`mg 526
`
`EXAMPLE 5
`A pharmaceutical composition was prepared consisting of
`an immediate and delayed release naproxen acid granulate
`layer and an immediate release naproxen sodium layer
`according to the method of example 1. The tablet had the
`following composition:
`
`NAPROXEN SODIUM LAYER
`Naproxen Sodium
`mg 238.8
`PVP K 30
`mg 9.5
`Yellow Dye E 102
`mg 0.24
`PVP CL.
`mg 9.9
`Magnesium Stearate
`mg 2.6
`NAPROXEN LAYER
`
`Cornstarch
`Lactose
`Sodium glyoolate starch
`PVP K 90
`Magnesium stearate
`Hydrogenated castor oil
`Ethylcellulose
`PVP C.L.
`Naproxen Acid
`Total Weight
`
`mg 3.2
`mg 9.5
`mg 1.9
`mg 19
`mg 0.06
`mg 95.0
`mg 30.0
`mg 16.9
`mg 282.0
`mg 701.5
`
`25
`
`30
`
`10
`TABLE I-continued
`Hematic Levels of Napwxen
`Formulation of Exggle 3
`Hematic Levels of
`Naproxen
`(mean value meg/ml)
`13.5
`5.7
`
`Time (hrs)
`48
`72
`
`TABLE II
`Hematic Levels of Naproxen
`Formulation of Example 2
`Hematic Levels of
`Naproxen
`(mean value meg/ml)
`37.0
`49.8
`57.1
`59.7
`59.4
`50.6
`44.5
`35.7
`21.6
`7.7
`3.2
`
`Time (hrs)
`0.5
`1
`2
`3
`4
`6
`8
`12
`24
`48
`72
`
`FIG. 4 is a graphical representation of the plasma pro?le
`of two formulations of controlled release naproxen and
`naproxen sodium. of an immediate release formulation of
`naproxen sodium and a controlled release naproxen
`formulation. over 24 hours. FIG. 5 is an enlargement of the
`plasma pro?les for the same four formulations for the initial
`four hours. after administration.
`It is shown in FIGS. 4 and 5 that the compositions of the
`present invention. Examples 2 and 3 reach therapeutic blood
`plasma levels in less than one hour. FIG. 4 shows that the
`compositions of Examples 2 and 3 maintain therapeutic
`blood levels over a period of 24 hours.
`FIG. 4 shows that Anaprox®. (described in the Physi
`cian’s Desk Reference. 46th edition 1992. as an immediate
`release naproxen sodium tablet. commercially available
`from Syntex) achieves therapeutic blood levels within 0.5
`hours but as shown in FIG. 4. the therapeutic blood levels
`are not maintained over a period of 24 hours and thus that
`composition would not be useful for once daily administra
`tion. Xenar. CR (3 controlled release naproxen acid tablet.
`commercially available in Italy from Alfa Pharmaceuticals)
`as is shown in FIG. 5. does not achieve therapeutic blood
`levels for almost two hours and thus would not be useful for
`immediate relief from pain.
`A particularly bene?cial aspect of the invention herein. as
`shown in the graphs. is that the immediate release naproxen
`sodium layer allows for faster absorption thereby providing
`for pain relief within an hour. FIG. 4 shows the added bene?t
`that the controlled release layer of naproxen acid maintains
`the therapeutic blood levels for a duration of 24 hours
`thereby providing for once daily administration.
`Additionally. the design of the tablet provides for total
`disintegration of the tablet thereby reducing the potential for
`gastric irritation and damage.
`
`Phannacokinetic tests have been carried out in man to
`verify the onset and duration of naproxen plasma levels for
`the above described formulations. These pharmacokinetic
`tests have been performed on groups each consisting of six
`healthy volunteers. by examining the hematic levels of
`naproxen at various time points from 0.3 up to 72 hours after
`the administration of the compositions.
`The values reported in the following Tables I and 11 are
`calculated from the mean of the values of the single values
`of the six healthy volunteers. The naproxen was checked in
`the plasma by spectrophotometric methodology at 272 nm
`after passing through a high pressure liquid chromatography
`column (HPLC); the values are expressed in mcyrnl of
`plasma.
`
`35
`
`50
`
`55
`
`65
`
`TABLE I
`l-lernatic Levels of Naproxen
`Formulation of Example 3
`Hematic Levels of
`Naproxen
`(mean value meg/m1)
`34.2
`41.7
`50.2
`57.4
`63.0
`61.1
`56.1
`50.8
`45 .3
`33.0
`
`Tune (his)
`0.3
`0.6
`
`isonmaun?
`
`

`
`5.756.l25
`
`11
`What is claimed is:
`1. A controlled release pharmaceutical composition com
`prising:
`a layer of naproxen acid; and
`an outer layer of naproxen sodium adjacent to the
`naproxen acid layer which achieves therapeutic plasma
`levels of naproxen in less than one hour wherein the
`naproxen acid is present in an amount from about 20 to
`about 70 w/w % and the naproxen sodium is present in
`an amount from about 15 to about 70 w/w %.
`2. A controlled release pharmaceutical composition
`according to claim 1 wherein the naproxen acid layer
`comprises:
`an immediate release granulate of naproxen acid; and
`a delayed release granulate of naproxen acid.
`3. A controlled release pharmaceutical composition
`according to claim 2 wherein the naproxen sodium is present
`in an amount from about 20-50 wlw % of the composition.
`4. A controlled release pharmaceutical composition
`according to claim 3 wherein the naproxen acid is present in
`an amount from about 40-80 w/w % of the composition.
`5. A controlled release pharmaceutical composition
`according to claim 4 wherein the naproxen sodium is present
`in an amount from about 30-35 w/w % of the composition.
`6. A controlled release pharmaceutical composition
`according to claim 5 wherein the naproxen acid is present in
`an amount of about 40 w/W % of the composition.
`7. A controlled release pharmaceutical composition
`according to claim 6 wherein the naproxen sodium is present
`in an amount of about 35 wlw % of the composition.
`8. A controlled release pharmaceutical composition com
`prising:
`
`12
`a layer of naproxen acid comprised of an immediate
`release granulate of naproxen acid and a delayed
`release granulate of naproxen acid; and
`a layer of naproxen sodium adjacent to the naproxen acid
`layer;
`wherein the naproxen acid is present in an amount from
`about 20 to about 70 w/w % and the