EP 0 381 194 81
`
`Figure 2
`
`100
`
`80
`
`60
`
`40
`
`dP
`
`Q)
`IJ)
`C1j
`Q)
`.....-i
`Q)
`~
`
`t::
`......
`0
`C1j
`+J
`
`H
`
`Q) e
`0
`'0 s::
`e
`~ ......
`'0
`0
`en
`'+-<
`0
`
`Q)
`+J
`C1j
`ll::
`
`0
`
`6
`
`12
`Time (hour)
`
`18
`
`24
`
`DRL - EXHIBIT 1002
`DRL462
`
`

`
`Europaisches Patentamt
`
`European Patent Office
`
`Office european des brevets
`
`@ Publication number:
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`0 440 462 81
`
`EUROPEAN PATENT SPECIFICATION
`
`@ Date of publication of patent specification: 28.12.94 @ Int. Cl.5: A61 K 9/22
`
`@ Application number: 91300745.6
`
`@ Date of filing: 30.01.91
`
`The file contains technical information submitted
`after the application was filed and not included in
`this specification
`
`<§) Sustained release with high and low viscosity HPMC.
`
`@) Proprietor: MERCK & CO. INC.
`126, East Lincoln Avenue
`P.O. Box 2000
`Rahway
`New Jersey 07065-0900 (US)
`
`@ Inventor: Lui, Chung Yuen
`423 Shoemaker Way
`Lansdale,
`PA 19446 (US)
`
`@ Representative: Thompson, John Dr. et al
`Merck & Co., Inc.
`European Patent Department
`Terlings Park
`Eastwick Road
`Harlow, Essex CM20 2QR (GB)
`
`@ Priority: 02.02.90 US 473801
`
`@ Date of publication of application:
`07.08.91 Bulletin 91/32
`
`@ Publication of the grant of the patent:
`28.12.94 Bulletin 94/52
`
`@ Designated Contracting States:
`CH DE FR GB IT Ll NL
`
`@ References cited:
`WO-A-87/00044
`FR-A- 2 555 901
`US-A- 4 259 314
`US-A- 4 389 393
`US-A- 4 871 548
`
`CHEMICAL ABSTRACTS, vol. 111, no. 16, 16th
`october 1989, page 393, abstract no.140370f,
`Columbus, Ohio, US; G. GEISSLINGER et al.:
`"Therapeutically relevant differences in the
`pharmacokinetic and pharmaceutical behav(cid:173)
`ior of ibuprofen lysinate as compared to
`ibuprofen acid", & INT. J.CLIN. PHARMACOL.,
`THER. TOXICOL 1989, 27(7), 324-8
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person
`may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
`shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
`has been paid (Art. 99(1) European patent convention).
`
`Rank Xerox (UK) Business Services
`13.10/3.09/3.3.3}
`
`DRL - EXHIBIT 1002
`DRL463
`
`

`
`EP 0 440 462 81
`
`Description
`
`BACKGROUND OF THE INVENTION
`
`5
`
`15
`
`20
`
`Sustained release formulations containing a pharmacologically active agent and exhibiting a zero order
`release rate are particularly useful.
`Ibuprofen is a well-known analgesic which has been used to treat chronic pain such as that associated
`with arthritic and rheumatic conditions. In such cases the analgesic is best administered so as to sustain its
`action over a period of time and to have a uniform level of analgesic action over this extended time period.
`10 This objective can partly be achieved by the repeated administration of a rapid release dosage. However,
`this procedure clearly has patient acceptability problems as well as a repeated raising and lowering of the
`blood levels of analgesic.
`Generally, the release profiles in controlled release formulations follow a classical square root of time
`relationship, i.e., the release rate decreases with time. In a zero order composition a plot of the rate of
`release of drug vs. time shows a straight horizontal line, i.e., the release rate is independent of time. Zero
`order sustained release compositions provide a more uniform delivery of the therapeutic agent over long
`periods of time.
`Sustained release formulations for ibuprofen have been disclosed in EP publication 255,404, however
`the formulations disclosed do not provide for a zero order release rate. In WO 87/00044 a sustained release
`formulation, exhibiting a bimodal controlled release, is disclosed. The carrier base is composed of a
`bimodal hydroxypropylmethylcellulose (HPMC) and the medicament selected from an antiflammatory group
`such as flurbiprofen. The publication is silent on the formulation of zero order release compositions. The
`Boots Company PLC, EP 234,670 has disclosed a sustained release composition containing xanthan gum
`wherein the medicament may be ibuprofen. The Boots formulation does not solve the problem of a zero
`25 order release rate.
`In FR-A-25555901 a controlled long acting dry pharmaceutical formulation comprised of at least three
`components selected from (a) 5.5 - 98.5% by weight of hydroxypropyl methylcellulose; (b) 0.25 - 4.5% by
`weight of hydroxy components selected from (1) 5.5 - 98.5% by weight of hydroxypropyl methylcellulose or
`(2) 0.25 - 4.5% by weight of hydroxypropyl cellulose; and (c) 1-90% by weight of a carboxyvinyl polymer.
`This reference discloses that it is the combination of these 3 elements which is critical to the disclosed
`invention and it does not disclose that varying the ratio of the high density HPMC to the low density HPMC
`will affect the delivery characteristics of the system but rather suggests that varying the relative amount of
`the hydroxypropyl methyl cellulose and hydroxypropyl cellulose and carboxyvinyl polymer elements will
`affect the delivery rate. Nowhere does this reference disclose a mixture comprising a HPMC having a
`35 molecular weight of 60,000 or greater together with a HPMC having a molecular weight of 50,000 or less.
`US-A-4389393 discloses a sustained release rate formulation wherein the ratio between high molecular
`weight HPMC and low molecular weight HPMC is 45.5:19.5 or 1 :0.4. Furthermore, the formulation of this
`reference shows a significant % drop of released medicant after only 8 hours. US-A-4259314 discloses a
`method of producing a controlled long acting pharmaceutical composition wherein hydroxypropyl cellulose
`is considered an essential ingredient. In fact, the reference specifically discloses that the inadequacy of
`hydroxypropyl methylcellulose for use in long lasting troches is known. WO-A-8700044 discloses non-zero
`order formulations which can be achieved only by using the disclosed highly unusual biomodal HPMCs (B(cid:173)
`HPMCs). US-A-4871548 discloses particular combinations comprising a "low number average molecular
`weight hydroxypropy methyl cellulose ether" having an average molecular weight of from about 9,000 to
`45 30,000 and viscosities ranging from 3-106 and a "high number average molecular weight hydroxypropyl
`methyl cellulose" having an average molecular weight of 30,000 to 350,000 and viscosities ranging from
`1 ,500 to 220,000. The ratio of the high and low molecular weight MPCs disclosed in the formulations of this
`reference is 1:1. Furthermore, these formulations employ an additional ingredient - lactose.
`
`30
`
`40
`
`50 DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention is directed to a carrier base material for therapeutically active medicaments in a
`solid dosage formulation wherein
`the carrier base comprises:
`a) a high viscosity HPMC; and
`b) a low viscosity HPMC wherein the high and low viscosity HPMC are in a ratio yielding a zero order
`release profile for the medicament.
`
`55
`
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`DRL - EXHIBIT 1002
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`EP 0 440 462 81
`
`5
`
`15
`
`In the present invention it has unexpectedly been found that a zero-order release profile can be
`obtained by controlling the ratio of high to low viscosity HPMC in a carrier base formulation.
`A high viscosity HPMC is defined as one having a molecular weight of 60,000 or greater. A low
`viscosity HPMC is defined as one having a molecular weight of 50,000 or less.
`The preferred low viscosity HPMCs available as Dow Methocel cellulose ethers, are: E5, 28-30%
`methoxy, 7-12% hydroxypropyl, viscosity = 4-6 cP; E15LV, 28-30% methoxy, 7-12% hydroxypropyl
`viscosity = 12-18 cP; E50LV, 28-30% methoxy, 7-12% hydroxylpropyl, viscosity = 40-60; and K100LV, 19-
`24% methoxy 7-12% hydroxypropyl, viscosity = 100 cP. The preferred high viscosity HPMCs, available as
`Dow Methocel cellulose ethers are: E4M-CR, 28-30% methoxy, 7-12% hydroxypropyl, viscosity = 4000 cP;
`10 E10M-CR, 28-30% methoxy, 7-12% hydroxypropyl viscosity = 10,000 cP; K4M, 19-24% methoxy, 7-12%
`hydroxypropyl, viscosity = 4000 cP; K15M, 19-24% methoxy, 7-12% hydroxypropyl, viscosity = 15,000
`cP; and K100M, 19-24% methoxy, 7-12% hydroxypropyl, viscosity = 100,000 cP.
`The medicament in the present invention may be selected from ibuprofen, or salts of ibuprofen. Most
`preferably the medicament is ibuprofen lysine which should be taken to mean all stereoisomeric configura-
`tions including racemic ibuprofen lysine and (S)-ibuprofen-(S)-Iysine;i.e. the salt formed from (S)-ibuprofen
`and (S)-Iysine.
`It should be appreciated that a zero order release profile is obtained only with a certain relative range of
`high to low viscosity HPMC. This may be illustrated by the combination of 1 part high viscosity E1 OM CR
`and a varying amount of any of the preferred low viscosity HPMC wherein a zero order release was found,
`for example:
`(i) 1 part E1 OM CR: 3 parts E5;
`(ii) 1 part E1 OM CR: 2 to 4 parts E15L V;
`(iii) 1 part E1 OM CR: 3 to 9 parts E50L V;
`(iv) 1 part E10M CR: 3 to 9 parts K100LV.
`These ranges are not limited to combinations where the high viscosity HPMC is E1 OM CR but are to be
`expected with any of the other preferred high viscosity HPMC.
`The medicament, preferably ibuprofen lysine is mixed with Povidone USP (PVP) which functions as a
`binding agent. Typically the ratio of drug to PVP is 20:1.
`The percent of drug/PVP granules in the pharmaceutical composition is 33.3 to 83%.
`The range of ibuprofen in this invention is preferably 1 00 to 600 mg per tablet.
`Where the medicament is ibuprofen lysine the weight range is 100 to 600 mg measured in mg
`ibuprofen.
`The percent range of HPMC carrier base is 17-66%.
`An example of the composition and processing of the controlled release dosage form is provided below:
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`Composition:
`
`Ibuprofen Lysine
`PVP
`Carrier Base
`Magnesium Stearate
`
`61.8%
`3.0%
`34.1%
`1.0%
`Total 99.9%
`
`Fillers such as Avice!, lactose, manito!, dicalcium phosphate, starch or pregelatin starch 1500 may be
`added to the composition. Binders such as corn starch, pregelatin starch 1500, Klucel LF, methocel E3, E5,
`gelatin or acacia may be added as necessary by those skilled in the art. Besides magnesium stearate, other
`lubricants such as stearic acid, sodium stearate fumerate or calcium stearate may be employed.
`
`Processing
`
`A batch of ibuprofen lysine granules containing PVP was prepared. An appropriate amount of granules,
`typically 3.21 grams was removed and mixed in a V-blender for 1 0 minutes with a carrier base, usually 1. 71
`55 grams, chosen from the preferred high viscosity and low viscosity HPMC. The resultant mixture was then
`mixed in a V-blender for three minutes with magnesium stearate, which had previously been sieved through
`a #60 mesh screen. Tablets of about 980 mg were compressed on an F-press.
`
`3
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`DRL - EXHIBIT 1002
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`EP 0 440 462 81
`
`Tables 1-V provide release profiles for controlled release tablets prepared following the processing
`described above and containing 600 mg Ibuprofen Lysine and 330 mg carrier base. Dissolution determina(cid:173)
`tions were conducted using an automated dissolution testing unit such as a Beckman Spectrophotometer,
`model DU65, connected with a Vanderkamp 600 six-spindle dissolution tester. Samples were taken every
`hour for at least 12 to 24 hours and absorbance was read spectrophotometrically at 260 nm.
`All the HPMC polymers described are available from the Dow Chemical Company. Racemic ibuprofen
`lysine may be prepared following the description in U.S. Patent 4,279,926. (S)-ibuprofen-(S)-Iysine is
`prepared as described in copending application S.N. 422,466 filed October 18, 1989.
`
`TABLE I
`
`Release Profiles of Ibuprofen Lysine Using 25% E4MCR and 75% of a Low Viscosity HPMC
`
`Time [hr]
`
`75% E15LV MEAN
`ABSORBANCE
`
`75% E50 MEAN ABSORBANCE
`
`75% K1 DOL V MEAN
`ABSORBANCE
`
`0.0000
`0.1125
`0.1885
`0.2570
`0.3180
`0.3735
`0.4265
`0.4945
`0.5975
`0.6855
`0.7280
`0.7520
`0.7540
`0.7500
`0.7445
`0.7405
`
`0.0000
`0.1160
`0.1935
`0.2615
`0.3230
`0.4080
`0.5290
`0.6265
`0.6820
`0.7190
`0.7405
`0.7555
`0.7620
`0.7675
`0.7680
`0.7670
`
`0.0000
`0.0820
`0.1400
`0.1940
`0.2440
`0.2920
`0.3375
`0.3860
`0.4445
`0.5045
`0.5750
`0.6350
`0.6845
`0.7225
`0.7515
`0.7695
`0.7785
`0.7825
`0.7835
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`4
`
`DRL - EXHIBIT 1002
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`
`

`
`EP 0 440 462 81
`
`TABLE II
`
`Release Profiles of Ibuprofen Lysine Using Various Ratios of E1 OMCR
`and a Low Viscosity HPMC
`
`Time
`[hr]
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`20% E10MCR:
`33.3% E10MCR:
`25% E10MCR:
`80% E15LV
`66.7% E15LV
`75% E5
`MEAN
`MEAN
`MEAN
`ABSORBANCE ABSORBANCE ABSORBANCE
`0.0010
`0.0010
`0.0000
`0.1140
`0.1615
`0.0985
`0.2420
`0.1670
`0.1720
`0.2335
`0.2210
`0.3130
`0.3055
`0.2630
`0.3760
`0.4345
`0.3050
`0.3960
`0.3450
`0.5265
`0.4800
`0.3840
`0.5630
`0.5975
`0.4220
`0.6525
`0.6505
`0.6875
`0.4600
`0.7095
`0.7165
`0.7475
`0.4970
`0.7235
`0.5345
`0.7565
`0.7255
`0.5835
`0.7590
`0.6410
`0.7260
`0.7600
`0.7245
`0.6915
`0.7575
`0.7240
`0.7230
`0.7530
`0.7240
`0.7525
`0.7395
`0.7240
`0.7425
`0.7520
`0.7245
`0.7435
`0.7520
`0.7255
`0.7455
`0.7440
`0.7265
`0.7275
`0.7420
`0.7420
`0.7290
`0.7410
`0.7290
`0.7310
`0.7395
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`5
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`DRL467
`
`

`
`EP 0 440 462 81
`
`TABLE II Cont'd
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`25% E10MCR· 10% E10MCR
`5 Time 25% E10MCR
`10% E10MCR
`75% K100LV
`90% K100LV
`[hr] 75% E50
`90% E50LV
`MEAN
`MEAN
`MEAN
`MEAN
`ABSORBANCE ABSORBANCE ABSORBANCE ABSORBANCE
`0.0000
`0.0005
`0.0000
`0.0005
`0.1095
`0.1250
`0.1120
`0.0790
`0.1855
`0.1960
`0.1360
`0.1775
`0.2540
`0.1845
`0.2325
`0.2570
`0.2845
`0.3220
`0.3065
`0.2300
`0.2715
`0.3325
`0.3870
`0.3580
`0.4110
`0.3125
`0.3825
`0.4505
`0.4810
`0.3525
`0.4360
`0.5140
`0.4900
`0.5780
`0.5475
`0.3905
`0.5595
`0.6220
`0.5990
`0.4305
`0.6235
`0.6645
`0.6525
`0.4730
`0.5210
`0.6785
`0.6885
`0.7020
`0.7170
`0.5685
`0.7255
`0.7080
`0.7365
`0.7200
`0.6045
`0.7395
`0.7275
`0.6415
`0.7390
`0.7510
`0.6715
`0.7370
`0.7560
`0.7310
`0.7360
`0.7600
`0.7290
`0.6905
`0.7340
`0.7630
`0.7260
`0.7080
`0.7225
`0.7360
`0.7650
`0.7260
`0.7670
`0.7345
`0.7395
`0.7680
`0.7440
`0.7700
`0.7725
`0.7450
`0.7740
`0.7755
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`6
`
`DRL - EXHIBIT 1002
`DRL468
`
`

`
`EP 0 440 462 81
`
`TABLE Ill
`
`Release Profiles of Ibuprofen Lysine Using Various Ratios of K4M and a Low Viscosity HPMC
`
`5
`
`Time [hr]
`
`25% K4M 75%
`25% K4M 75% E5
`25% K4M 75% E15L V
`50% K4M 50% E5
`MEAN ABSORBANCE MEAN ABSORBANCE MEAN ABSORBANCE K100LV MEAN
`ABSORBANCE
`
`0.0000
`0.0815
`0.1390
`0.1895
`0.2365
`0.2815
`0.3260
`0.3705
`0.4225
`0.4850
`0.5435
`0.6000
`0.6500
`0.6740
`0.6920
`0.7040
`0.7220
`0.7315
`0.7380
`
`0.0000
`0.0995
`0.1565
`0.2110
`0.2630
`0.3130
`0.4395
`0.5270
`0.5815
`0.6305
`0.6580
`0.6775
`0.6950
`0.7060
`0.7175
`0.7245
`0.7260
`0.7275
`0.7270
`0.7305
`0.7305
`0.7320
`0.7310
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`0.0000
`0.1155
`0.1795
`0.2315
`0.2815
`0.3655
`0.4095
`0.4465
`0.4925
`0.5695
`0.6550
`0.7045
`0.7235
`0.7360
`0.7400
`0.7460
`0.7535
`0.7525
`0.7555
`0.7605
`0.7605
`0.7650
`0.7635
`0.7660
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`0.0000
`0.1010
`0.1700
`0.2335
`0.2905
`0.3490
`0.4360
`0.5510
`0.6430
`0.6990
`0.7405
`0.7560
`0.7565
`0.7515
`0.7445
`0.7415
`0.7450
`0.7435
`0.7415
`0.7405
`0.7400
`0.7425
`
`7
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`

`
`EP 0 440 462 81
`
`TABLE IV
`
`Release Profiles of Ibuprofen Lysine Using Various Ratios of K15M and a Low Viscosity HPMC
`
`5
`
`Time [hr]
`
`25% K15M 75% E15L V 25% K15M 75% E50 25% K15M 75%
`25% K15M 75% E5
`MEAN ABSORBANCE MEAN ABSORBANCE MEAN ABSORBANCE K100LV MEAN
`ABSORBANCE
`
`0.0000
`0.0855
`0.1425
`0.1915
`0.2390
`0.2810
`0.3265
`0.3970
`0.4890
`0.5535
`0.5945
`0.6125
`0.6400
`0.6590
`0.6910
`0.7085
`0.7295
`0.7395
`0.7400
`0.7330
`0.7355
`0.7255
`
`0.0000
`0.0950
`0.1640
`0.2225
`0.2740
`0.3215
`0.3665
`0.4120
`0.4575
`0.5040
`0.5485
`0.5910
`0.6245
`0.6490
`0.6650
`0.6845
`0.7035
`0.7160
`0.7235
`0.7305
`0.7345
`0.7385
`0.7415
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`0.0000
`0.1280
`0.2110
`0.2830
`0.3640
`0.4350
`0.5060
`0.6475
`0.7215
`0.7360
`0.7415
`0.7410
`0.7395
`0.7435
`0.7475
`0.7490
`0.7520
`0.7505
`0.7515
`0.7485
`0.7525
`0.7500
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`0.0000
`0.0935
`0.1540
`0.2085
`0.2590
`0.3070
`0.3530
`0.3980
`0.4470
`0.5505
`0.6200
`0.6655
`0.6815
`0.6850
`0.7040
`0.7250
`0.7365
`0.7395
`0.7390
`0.7405
`0.7405
`0.7360
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`EP 0 440 462 81
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`TABLE V
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`Release Profiles of Ibuprofen Lysine Using 25% K1 OOM and 75% of a Low Viscosity HPMC
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`Time [hr]
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`75% E15L V MEAN ABSORBANCE
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`75% E50 MEAN ABSORBANCE
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`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`0.0000
`0.0820
`0.1330
`0.1800
`0.2225
`0.2630
`0.3025
`0.3405
`0.3805
`0.4240
`0.4880
`0.5510
`0.5945
`0.6335
`0.6650
`0.6950
`0.7195
`0.7395
`0.7530
`0.7680
`0.7740
`0.7795
`0.7825
`
`0.0000
`0.1005
`0.1615
`0.2180
`0.2680
`0.3150
`0.3630
`0.4230
`0.4950
`0.5465
`0.5940
`0.6350
`0.6715
`0.7000
`0.7215
`0.7370
`0.7485
`0.7575
`0.7655
`0.7710
`0.7755
`0.7770
`0.7785
`0.7800
`0.7820
`
`Claims
`
`1. A carrier base material combined with ibuprofen or a salt thereof and shaped and compressed to a
`solid sustained release pharmaceutical dosage form having a zero order release profile upon admin(cid:173)
`istration in which the carrier base material consists essentially of (a) HPMC having a molecular weight
`of 60,000 or greater, and (b) HPMC having a molecular weight of 50,000 or less; and wherein the ratio
`of (a) to (b) is from 1:2 to 1 :9.
`
`2. A zero order release pharmaceutical formulation according to Claim 1 in which the high viscosity HPMC
`is selected from a methocel cellulose ether wherein:
`a)% methoxy = 19-24.% hydroxypropyl = 7-12, viscosity = 4000 cps;
`b)% methoxy = 28-30,% hydroxypropyl = 7-12, viscosity = 10,000;
`c)% methoxy = 28-30,% hydroxypropyl = 7-12, viscosity = 4,000;
`d)% methoxy = 19-24,% hydroxypropyl = 7-12, viscosity = 15,000;
`e)% methoxy = 19-24,% hydroxypropyl = 7-12, viscosity = 100,000;
`and the low viscosity HPMC is selected from a methocel cellulose ether wherein:
`a)% methoxy = 28-30,% hydroxypropyl = 7-12, viscosity = 4-6;
`b)% methoxy = 28-30,% hydroxypropyl = 7-12, viscosity = 12-18;
`c)% methoxy = 28-30,% hydroxypropyl = 7-12, viscosity = 40-60;
`d)% methoxy = 19-24,% hydroxypropyl = 7-12, viscosity = 100.
`
`3. A zero order release pharmaceutical formulation according to Claim 2 wherein the high viscosity HPMC
`is 1 part methocel cellulose ether wherein% methoxy = 28-30,% hydroxypropyl = 7-12 and viscosity
`= 10,000 and wherein the low viscosity HPMC is selected from:
`a) 3 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity = 4-6;
`
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`EP 0 440 462 81
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`b) 2 to 4 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity = 12-18;
`c) 3 to 9 parts wherein % methoxy = 28-30, % hydroxypropyl = 7-12, and viscosity = 40-60; or
`d) 3 to 9 parts wherein% methoxy = 19-24,% hydroxypropyl = 7-12, and viscosity = 100.
`
`4. A zero order release pharmaceutical formulation according to Claim 2 wherein the high viscosity HPMC
`is 1 part wherein % methoxy = 19-24, % hydroxypropyl = 7-12, and viscosity = 4,000 and wherein
`the low viscosity HPMC is selected from:
`a) 2 to 4 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity
`28-30,% hydroxypropyl = 7-12, and viscosity
`b) 3 to 9 parts wherein% methoxy
`c) 3 to 9 parts wherein% methoxy = 19-24,% hydroxypropyl = 7-12, and viscosity
`
`12-18;
`40-60;
`100.
`
`5. A zero order release pharmaceutical formulation according to Claim 2 wherein the high viscosity HPMC
`is 1 part wherein % methoxy = 28-30, % hydroxypropyl = 7-12, and viscosity = 4,000 and wherein
`the low viscosity HPMC is selected from:
`a) 1 part wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity = 4-6;
`b) 2 to 4 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity
`12-18;
`c) 3 to 9 parts wherein % methoxy = 28-30, % hydroxypropyl = 7-12, and viscosity = 40-60;
`d) 3 to 9 parts wherein% methoxy = 19-24,% hydroxypropyl = 7-12, and viscosity = 100.
`
`6. A zero order release pharmaceutical formulation according to Claim 2 wherein the high viscosity HPMC
`is one part wherein % methoxy = 19-24, % hydroxypropyl = 7-12, and viscosity = 15,000 and
`wherein the low viscosity HPMC is selected from:
`a) 1 to 3 parts wherein % methoxy = 28-30, % hydroxypropyl = 7-12, and viscosity = 4-6;
`b) 1 to 3 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity = 12-18;
`c) 1 to 3 parts wherein % methoxy = 28-30, % hydroxypropyl = 7-12, and viscosity = 40-60;
`d) 3 to 9 parts wherein% methoxy = 19-24,% hydroxypropyl = 7-12, and viscosity = 100.
`
`7. A zero order release pharmaceutical formulation according to Claim 2 wherein the high viscosity HPMC
`is 1 part wherein % methoxy = 19-24,% hydroxypropyl = 7-12, and viscosity = 100,000 and wherein
`the low viscosity HPMC is selected from:
`a) 1 to 3 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity
`b) 1 to 3 parts wherein% methoxy = 28-30,% hydroxypropyl = 7-12, and viscosity
`
`12-18;
`40-60.
`
`8. A zero order release pharmaceutical formulation according to Claim 2 wherein the medicament is
`selected from:
`a) ibuprofen; or
`b) salts of ibuprofen.
`
`9. A formulation according to Claim 8 wherein the medicament is ibuprofen lysine.
`
`10. A formulation according to Claim 9 wherein the medicament is (S)-ibuprofen-(S)-Iysine.
`
`11. A formulation according to Claim 10 wherein the amount of medicament as ibuprofen is 100 to 600 mg.
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`1. Tragergrundmaterial, kombiniert mit Ibuprofen oder einem Salz davon und geformt und komprimiert zu
`einer festen pharmazeutischen Dosierungsform mit langanhaltender Freisetzung mit einem Freiset(cid:173)
`zungsprofil nullter Ordnung bei der Verabreichung, worin das Tragergrundmaterial im wesentlichen
`besteht aus (a) HPMC eines Molekulargewichts von 60 000 oder mehr und (b) HPMC eines Molekular(cid:173)
`gewichts von 50 000 oder weniger und worin das Verhaltnis von (a) zu (b) 1:2 bis 1:9 betragt.
`
`2. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 1, worin die
`hochviskose HPMC ausgewahlt ist aus einem Methocei-Celluloseether, worin:
`a)% Methoxy = 19-24,% Hydroxypropyl = 7-12, Viskositat = 4 000 cps,
`b)% Methoxy = 28-30,% Hydroxypropyl = 7-12, Viskositat = 10 000,
`c)% Methoxy = 28-30,% Hydroxypropyl = 7-12, Viskositat = 4 000,
`d)% Methoxy = 19-24,% Hydroxypropyl = 7-12, Viskositat = 15 000,
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`e)% Methoxy = 19-24,% Hydroxypropyl = 7-12, Viskositat = 100 000,
`und worin das niederviskose HPMC ausgewahlt ist aus einem Methocei-Celluloseether, worin:
`a)% Methoxy = 28-30,% Hydroxypropyl = 7-12, Viskositat = 4-6,
`b)% Methoxy = 28-30,% Hydroxypropyl = 7-12, Viskositat = 12-18,
`c)% Methoxy = 28-30,% Hydroxypropyl = 7-12, Viskositat = 40-60,
`d)% Methoxy = 19-24,% Hydroxypropyl = 7-12, Viskositat = 100.
`
`3. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin die
`hochviskose HPMC zu einem Teil Methocei-Celluloseether ist, worin % Methoxy = 28-30, % Hydrox-
`ypropyl = 7-12 und Viskositat = 10 000 und worin das niederviskose HPMC ausgewahlt ist aus:
`a) 3 Teilen, worin % Methoxy = 28-30, % Hydroxypropyl = 7-12 und Viskositat = 4-6,
`b) 2 bis 4 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 12-18,
`c) 3 bis 9 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 40-60 oder
`d) 3 bis 9 Teilen, worin% Methoxy = 19-24,% Hydroxypropyl = 7-12 und Viskositat = 100.
`
`4. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin die
`hochviskose HPMC 1 Teil ist, worin% Methoxy = 19-24,% Hydroxypropyl = 7-12 und Viskositat = 4
`000 und worin die niederviskose HPMC ausgewahlt ist aus:
`a) 2 bis 4 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 12-18,
`b) 3 bis 9 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 40-60,
`c) 3 bis 9 Teilen, worin% Methoxy = 19-24,% Hydroxypropyl = 7-12 und Viskositat = 100.
`
`5. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin die
`hochviskose HPMC 1 Teil ist, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 4
`000 und worin die niederviskose HPMC ausgewahlt ist aus:
`a) 1 Teil, worin % Methoxy = 28-30, % Hydroxypropyl = 7-12 und Viskositat = 4-6,
`b) 2 bis 4 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 12-18,
`c) 3 bis 9 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 40-60,
`d) 3 bis 9 Teilen, worin% Methoxy = 19-24,% Hydroxypropyl = 7-12 und Viskositat = 100.
`
`6. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin die
`hochviskose HPMC 1 Teil ist, worin % Methoxy = 19-24, % Hydroxypropyl = 7-12 und Viskositat
`15 000 und worin die niederviskose HPMC ausgewahlt ist aus:
`a) 1 bis 3 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 4-6,
`b) 1 bis 3 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 12-18,
`c) 1 bis 3 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 40-60,
`d) 3 bis 9 Teilen, worin% Methoxy = 19-24,% Hydroxypropyl = 7-12 und Viskositat = 100.
`
`7. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin die
`hochviskose HPMC 1 Teil ist, worin % Methoxy = 19-24, % Hydroxypropyl = 7-12 und Viskositat
`100 000 und worin die niederviskose HPMC ausgewahlt ist aus:
`a) 1 bis 3 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 12-18,
`b) 1 bis 3 Teilen, worin% Methoxy = 28-30,% Hydroxypropyl = 7-12 und Viskositat = 40-60.
`
`8. Pharmazeutische Formulierung mit einer Freisetzung nullter Ordnung nach Anspruch 2, worin das
`Medikament ausgewahlt ist aus:
`a) Ibuprofen oder
`b) Salzen von Ibuprofen.
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`9. Formulierung nach Anspruch 8, worin das Medikament Ibuprofen-Lysin ist.
`
`10. Formulierung nach Anspruch 9, worin das Medikament (S)-Ibuprofen-(S)-Lysin ist
`
`11. Formulierung nach Anspruch 9, worin die Menge des Medikaments als Ibuprofen 100 bis 600 mg
`betragt.
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`EP 0 440 462 81
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`28-30, le pourcentage de groupes hydroxypropyle
`
`28-30, le pourcentage de groupes hydroxypropyle
`
`19-24, le pourcentage de groupes hydroxypropyle
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`28-30, le pourcentage de groupes hydroxypropyle
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`28-30, le pourcentage de groupes hydroxypropyle
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`19-24, le pourcentage de groupes hydroxypropyle
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`7-
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`7-
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`7-
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`7-
`
`7-
`
`7-
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`7-
`
`7-
`
`7-
`
`Revendications
`1. Materiau de base de vehicule associe a de l'ibuprofeme ou un sel de celui-ci et fagonne et comprime
`en une forme pharmaceutique solide a liberation prolongee, ayant un profil de courbe de liberation
`d'ordre zero apres administration, caracterise en ce que le materiau de base de vehicule consiste
`essentiellement en (a) une HPMC ayant une masse moleculaire de 60 000 ou plus et (b) une HPMC
`ayant une masse moleculaire de 50 000 ou moins; et en ce que le rapport de (a) a (b) va de 1:2 a 1 :9.
`2. Composition pharmaceutique a vitesse de liberation d'ordre zero selon Ia revendication 1, dans laquelle
`Ia HPMC a haute viscosite est choisie parmi un ether de cellulose de type Methocel dans lequel:
`a) le pourcentage de groupes methoxy
`19-24, le pourcentage de groupes hydroxypropyle
`12, viscosite = 4 000 centipoises (cP);
`b) le pourcentage de groupes methoxy
`12, viscosite = 10 000 cP;
`c) le pourcentage de groupes methoxy
`12, viscosite = 4 000 cP;
`d) le pourcentage de groupes methoxy
`12, viscosite = 15 000 cP;
`19-24, le pourcentage de groupes hydroxypropyle
`e) le pourcentage de groupes methoxy
`12, viscosite = 100 000 cP;
`et Ia HPMC a faible viscosite est choisie parmi un ether de cellulose de type Methocel dans lequel:
`a) le pourcentage de groupes methoxy
`28-30, le pourcentage de groupes hydroxypropyle
`12, viscosite = 4-6 cP;
`b) le pourcentage de groupes methoxy
`12, viscosite = 12-18 cP;
`c) le pourcentage de groupes methoxy
`12, viscosite = 40-60 cP;
`d) le pourcentage de groupes methoxy
`12, viscosite = 1 00 cP.
`3. Composition pharmaceutique a vitesse de liberation d'ordre zero selon Ia revendication 2, dans laquelle
`Ia HPMC a haute viscosite consiste en 1 partie d'ether de cellulose de type Methocel dans lequel le
`pourcentage de groupes methoxy = 28-30, le pourcentage de groupes hydroxypropyle = 7-12 et Ia
`viscosite = 10 000 cP, et dans lequel Ia HPMC a faible viscosite est choisie parmi:
`a) 3 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy = 28-30, le pourcenta(cid:173)
`ge de groupes hydroxypropyle = 7-12 et Ia viscosite = 4-6 cP;
`b) 2 a 4 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 12-18 cP;
`c) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 40-60 cP; et
`d) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 100 cP.
`4. Composition pharmaceutique a vitesse de liberation d'ordre zero selon Ia revendication 2, dans laquelle
`Ia HPMC a haute viscosite consiste en 1 partie d'une HPMC dans laquelle le pourcentage de groupes
`methoxy = 19-24, le pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 4 000 cP, et
`dans laquelle Ia HPMC a faible viscosite est choisie parmi:
`a) 2 a 4 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 12-18 cP;
`b) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 40-60 cP;
`c) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 100 cP.
`5. Composition pharmaceutique a vitesse de liberation d'ordre zero selon Ia revendication 2, dans laquelle
`Ia HPMC a haute viscosite consiste en 1 partie d'une HPMC dans laquelle le pourcentage de groupes
`methoxy = 28-30, le pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 4 000 cP, et
`dans laquelle Ia HPMC a faible viscosite est choisie parmi:
`
`28-30, le
`
`28-30, le
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`19-24, le
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`28-30, le
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`28-30, le
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`19-24, le
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`EP 0 440 462 81
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`28-30, le
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`28-30, le
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`19-24, le
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`28-30, le
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`28-30, le
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`28-30, le
`
`19-24, le
`
`a) 1 partie d'une HPMC dans laquelle le pourcentage de groupes methoxy = 28-30, le pourcentage
`de groupes hydroxypropyle = 7-12 et Ia viscosite = 4-6 cP;
`b) 2 a 4 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 12-18 cP;
`c) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 40-60 cP; et
`d) 3 a 9 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 100 cP.
`6. Composition pharmaceutique a vitesse de liberation d'ordre zero selon Ia revendication 2, dans laquelle
`Ia HPMC a haute viscosite consiste en 1 partie d'une HPMC dans laquelle le pourcentage de groupes
`methoxy = 19-24, le pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 15 000 cP, et
`dans laquelle Ia HPMC a faible viscosite est choisie parmi:
`a) 1 a 3 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosite = 4-6 cP;
`b) 1 a 3 parties d'une HPMC dans laquelle le pourcentage de groupes methoxy
`pourcentage de groupes hydroxypropyle = 7-12 et Ia viscosi