`
`Exhibit 1003
`
`U.S. Patent No. 6,004,581 (“the ‘581
`Patent”)
`
`

`
`Ulllted States Patent [19]
`Ulllted States Patent
`[19]
`J epsen et al.
`Jepsen et al.
`
`US006004581A
`US006004581A
`[11] Patent Number:
`[11] Patent Number:
`[45] Date of Patent:
`[45] Date of Patent:
`
`6,004,581
`6,004,581
`*Dec. 21, 1999
`*Dec. 21, 1999
`
`[54] MODIFIED RELEASE ORAL
`4,960,765
`10/1990 Halskov ................................ .. 514/166
`[54] MODIFIED RELEASE ORAL
`4,960,765 10/1990 Halskov ................................ .. 514/166
`PHARMACEUTICAL COMPOSITION AND
`4,980,173
`12/1990 Halskov . . . . . .
`. . . .. 424/490
`PHARMACEUTICAL COMPOSITION AND
`4,980,173 12/1990 Halskov .... ..
`.. 424/490
`METHOD FOR THE TREATMENT OF
`5,294,448
`3/1994 Ring et al. ..
`424/497
`0F 2:31:23
`3/122: §::‘%°”i" ;
`32/22;
`,
`,
`0 es e a. ..
`5,401,512
`3/1995 Rhodes et al. ..
`424/458
`BOWEL DISEASES
`5,716,648
`2/1998 Halskov et al.
`........................ 424/682
`5,716,648
`2/1998 Halskov et al. ...................... .. 424/682
`BOWEL DISEASES
`[75]
`Inventors: Svenn Kliiver Jepsen, Holte; Saren
`FOREIGN PATENT DOCUMENTS
`[75] Inventors: Svenn Kliiver Jepsen, Holte; Sqziren
`FOREIGN PATENT DOCUMENTS
`Halskov, Virum, both of Denmark
`Halskov, Virum, both of Denmark
`WO91/07949
`6/1991 WIPO .
`WO91/07949 6/1991 WIPO .
`“109408911 12/1994 WIPO -
`W094/28911
`12/1994 WIPO ~
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`[73] Assignee: Farmaceutisk Laboratorium Ferring
`[73] Assignee: Farmaceutisk Laboratorium Ferring
`A/S» Vai110Se> Denmark
`A/S> Vanlose, Denmark
`
`
`
`[*] Notice:
`[*] Notice:
`
`This patent issued on a continued pros-
`This patent issued on a continued pros-
`ecution application filed under 37 CFR
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the twenty year
`1.53(d), and is subject to the tWenty year
`patent
`term provisions of 35 U.S.C.
`patent term provisions of 35 U.S.C.
`154(a)(2).
`154(a)(2).
`
`[21] Appl' NO‘: 08/772’273
`[21] Appl' No’: 08/772373
`[22]
`Filed;
`Dec_ 20, 1996
`[22]
`Filed;
`[)ee_ 20, 1996
`
`Related U.S. Application Data
`Related US. Application Data
`Provisional application No. 60/045,788, Dec. 21, 1995,
`Provisional a lication No. 60/045,788, Dec. 21, 1995,
`abandoned PP
`abandoned.
`
`[60]
`60
`[
`]
`
`Int. Cl.6 .............................. .. A61K 9/58; A61K 9/62
`[51]
`Int. Cl.6 .............................. .. A61K 9/58; A61K 9/62
`[51]
`[52] US. Cl. ........................ .. 424/461; 424/462; 424/495;
`[52] U.s. Cl.
`........................ .. 424/461; 424/462; 424/495,
`424/497
`424/497
`[58] Field of Search ................................... .. 424/490, 462,
`[58] Field of Search ................................... .. 424/490, 462,
`424/495, 497, 461
`424/495’ 497’ 461
`
`[56]
`[56]
`
`4,496,553
`4,496,553
`
`References Cited
`References Cited
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`1/1985 Halskov ................................ .. 514/166
`1/1985 Halskov ................................ .. 514/166
`
`Bechgaard, H., Acta Pharmaceutica Technologica 28(2),
`Bechgaard, H., Acta Pharmaceutica Technologica 28(2),
`1982, pp. 149-157.
`1982, pp. 149—157.
`Fallingborg, J. et al, Aliment. Pharmacol. Therap. (1989) 3,
`Fallingborg, J. et al, Aliment. Pharmacol. Therap. (1989) 3,
`pp. 605-613.
`pp. 605—613.
`Christensen, L.A. et al, Br. J. Clin. Pharmac. (1987), 23, pp.
`Christensen, L.A. et al, Br. J. Clin. Pharmac. (1987), 23, pp.
`365-369.
`365—369.
`Primary Examiner—Thurman K. Page
`Primary Examiner—Thurman K. Page
`Assistant Examiner—L. Channavajjala
`Assistant Examiner—L. Channavajjala
`Attorney, Agent, or Firm—Jacobson, Price, Holman &
`Attorney, Agent, or Firm—Jacobson, Price, Holman &
`Stern, PLLC
`Stern, PLLC
`
`[57]
`[57]
`
`ABSTRACT
`ABSTRACT
`
`Modified release pharmaceutical composition and method
`Modi?ed release pharmaceutical composition and method
`for the treatment ofin?arnrnatory bowel diseases (IBD) such
`for the treatment of inflammatory bowel diseases (IBD) such
`as Crohn’s disease and Colitis Ulccrosa, said compositions
`as Crohn’s disease and Colitis Ulccrosa, said compositions
`Comprising as active the ingredient 5-aminosalicylic acid
`eempiisiiig as aetiVe the ingredient 5-aiiiiiiesalieylie aeid
`(S-ASA), and being adapted for modi?ed and targeted
`(5-ASA), and being adapted for modified and targeted
`release so as to obtain a clinically important localized effect
`release so as to obtain a clinically important localiZed effect
`pro?le of S-ASA by means of releasing an appropriate
`profile of 5-ASA by means of releasing an appropriate
`amount of 5-ASA in both the small and large bowel.
`amount of S-ASA in both the small and large boWel.
`
`37 Claims, 12 Drawing Sheets
`37 Claims, 12 Drawing Sheets
`
`MycoNovo, Inc.
`Foxhill Opportunity
`Fund, L.P.
`Ex 1003
`
`

`
`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 1 0f 12
`Sheet 1 of 12
`
`6,004,581
`6,004,581
`
`Figure 1
`Figure 1
`
`Image Analysis of Spherical Granules (Batch
`Image Analysis of Spherical Granules (Batch
`322202)
`322202)
`
`

`
`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 2 0f 12
`Sheet 2 of 12
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`6,004,581
`6,004,581
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`000; 020.0 0000 F050 .52 .
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`

`
`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 3 0f 12
`Sheet 3 of 12
`
`6,004,581
`6,004,581
`
`Figure 3
`Figure 3
`
`Image Analysis of Spherical Granules (Batch
`Image Analysis of Spherical Granules (Batch
`437601)
`437601)
`
`

`
`U.S. Patent
`
`Dec. 21, 1999
`
`Sheet 4 of 12
`
`6,004,581
`
`
`
`
`
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`U.S. Patent
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`Dec. 21, 1999
`
`Sheet 5 of 12
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`6,004,581
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`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 6 0f 12
`Sheet 6 of 12
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`6,004,581
`6,004,581
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`U.S. Patent
`U.S. Patent
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`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 7 0f 12
`Sheet 7 of 12
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`6,004,581
`6,004,581
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`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 8 0f 12
`Sheet 8 of 12
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`6,004,581
`6,004,581
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`
`U.S. Patent
`
`Dec. 21, 1999
`
`Sheet 9 of 12
`
`6,004,581
`
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`U.S. Patent
`U.S. Patent
`
`Dec. 21, 1999
`Dec. 21, 1999
`
`Sheet 10 0f 12
`Sheet 10 of 12
`
`6,004,581
`6,004,581
`
`Disposition data of Spherical Granules (Batch 437601)
`Disposition data of Spherical Granules (Batch 437601)
`
`1
`1
`2
`2
`3
`3
`4-
`4-
`5
`5
`7
`7
`8
`8
`9
`9
`Mean
`Mean
`SD
`SD
`RSD %
`RSD 7o
`Median
`Median
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`Gostric Emptying
`Gastric Emptying
`Time (mins)
`Time (mins)
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`22
`60
`22
`50
`33
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`33
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`65
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`Colon Arrival
`Time (mins)
`Time (mins)
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`T100%
`Tsoz
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`100
`121
`100
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`308
`727
`308
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`260
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`277
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`253
`261
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`292
`469
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`4-59
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`172
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`82
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`82
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`205
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`86
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`85
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`42
`62
`42
`62
`227
`269
`227
`259
`
`FIG. 10
`FIG. 10
`
`

`
`U.S. Patent
`
`0
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`
`6,004,581
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`
`U.S. Patent
`
`Dec. 21, 1999
`
`Sheet 12 of 12
`
`6,004,581
`
`
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`

`
`6,004,581
`6,004,581
`
`1
`1
`MODIFIED RELEASE ORAL
`MODIFIED RELEASE ORAL
`PHARMACEUTICAL COMPOSITION AND
`PHARMACEUTICAL COMPOSITION AND
`METHOD FOR THE TREATMENT OF
`METHOD FOR THE TREATMENT OF
`BOWEL DISEASES
`BOWEL DISEASES
`CROSS-REFERENCE TO RELATED
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`APPLICATIONS
`
`This application is based on provisional application Ser.
`This application is based on provisional application Ser.
`No. 60/045,788, filed Dec. 21, 1995, now abandoned.
`No. 60/045,788, ?led Dec. 21, 1995, noW abandoned.
`FIELD OF THE INVENTION
`FIELD OF THE INVENTION
`The present invention provides improved oral pharma-
`The present invention provides improved oral pharma
`ceutical compositions for the treatment of inflammatory
`ceutical compositions for the treatment of in?ammatory
`bowel diseases (IBD) such as Crohn’s disease, Colitis Ulce-
`boWel diseases (IBD) such as Crohn’s disease, Colitis Ulce
`rosa and related diseases, e.g. an unclassifiable form of said
`rosa and related diseases, eg an unclassi?able form of said
`diseases or a diagnosed subtype of one of said diseases. The
`diseases or a diagnosed subtype of one of said diseases. The
`invention also provides a method for the treatment of IBD.
`invention also provides a method for the treatment of IBD.
`The composition of the present invention comprises as
`The composition of the present invention comprises as
`active ingredient 5-aminosalicylic acid (5-ASA) or pharma
`active ingredient 5-aminosalicylic acid (5-ASA) or pharma-
`ceutically acceptable salts or esters thereof and is adapted
`ceutically acceptable salts or esters thereof and is adapted
`for modified and targeted release of said 5-ASA in the
`for modi?ed and targeted release of said 5-ASA in the
`diseased parts of the intestine, so as to obtain an advanta-
`diseased parts of the intestine, so as to obtain an advanta
`geous and clinically important release and effect profile of
`geous and clinically important release and effect pro?le of
`5-ASA. Thus, said administration form and release are
`5-ASA. Thus, said administration form and release are
`improved compared to knoWn therapy regimens.
`improved compared to known therapy regimens.
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`10
`10
`
`15
`15
`
`20
`20
`
`25
`25
`
`2
`2
`Thus, in the examples of the above U.S. patents, prepa-
`Thus, in the examples of the above US. patents, prepa
`rations of granulates pressed to form tablets with a diameter
`rations of granulates pressed to form tablets With a diameter
`of 13.5 mm and a weight of 650 mg/tablet containing 250
`of 13.5 mm and a Weight of 650 mg/tablet containing 250
`mg of 5-AsA. The resulting tablets were used in clinical
`mg of 5-AsA. The resulting tablets Were used in clinical
`tests.
`tests.
`In the examples of the U.S. patents,
`two intermediary
`In the examples of the US. patents, tWo intermediary
`preparations of granulates were described, one of them
`preparations of granulates Were described, one of them
`comprising 5-ASA, and the other being a “helper” granulate
`comprising 5-ASA, and the other being a “helper” granulate
`Without 5-ASA, said “helper” granulate being prepared and
`without 5-ASA, said “helper” granulate being prepared and
`admixed in order to facilitate the tablet compression involv-
`admixed in order to facilitate the tablet compression involv
`ing the addition of talc and a lubricant mixture.
`ing the addition of talc and a lubricant mixture.
`The 173 patent more specifically claims a method for the
`The 173 patent more speci?cally claims a method for the
`preparation of sustained-release tablets, useful for the treat-
`preparation of sustained-release tablets, useful for the treat
`ment of colitis ulcerosa or Crohn’s disease, comprising the
`ment of colitis ulcerosa or Crohn’s disease, comprising the
`steps of
`steps of
`a) preparing a first granulate from 5-ASA or a pharma-
`a) preparing a ?rst granulate from 5-ASA or a pharma
`ceutically acceptable salt or ester thereof and bout 10%
`ceutically acceptable salt or ester thereof and bout 10%
`by weight (solids content based on the 5-ASA) of
`by Weight (solids content based on the 5-ASA) of
`polyvinylpyrrolidone in an organic solvent thereby to
`polyvinylpyrrolidone in an organic solvent thereby to
`provide granules of a particle size from about 0.7 to 1
`provide granules of a particle siZe from about 0.7 to 1
`mm, upon evaporation of the solvent.
`mm, upon evaporation of the solvent.
`b) applying onto said granules a coating composition,
`b) applying onto said granules a coating composition,
`comprising a solution in an organic solvent of a phar-
`comprising a solution in an organic solvent of a phar
`maceutically acceptable coating material Which Will
`maceutically acceptable coating material which will
`gradually release the active ingredient upon arrival at
`gradually release the active ingredient upon arrival at
`the small intestine, thereby to provide coated granules
`the small intestine, thereby to provide coated granules
`upon evaporation of the solvent,
`upon evaporation of the solvent,
`c) mixing the ?rst granulate With about 5% by Weight,
`c) mixing the first granulate with about 5% by weight,
`calculated on the total solids content, of a lubricant and
`calculated on the total solids content, of a lubricant and
`a conventional pharmaceutical
`tablet carrier in an
`a conventional pharmaceutical tablet carrier in an
`amount in accordance with the desired size and active
`amount in accordance With the desired siZe and active
`ingredient content of the tablet, and
`ingredient content of the tablet, and
`d) forming tablets from the resulting mixture
`d) forming tablets from the resulting mixture
`Preferably the coating material is a cellulose derivative.
`Preferably the coating material is a cellulose derivative.
`The specific requirements to the 5 -ASA release properties
`The speci?c requirements to the 5 -ASA release properties
`of the granule composition as identified by the present
`of the granule composition as identi?ed by the present
`inventors and defined by the present
`invention, were
`inventors and de?ned by the present invention, Were
`nowhere described or suggested in said U.S. patents, let
`noWhere described or suggested in said US. patents, let
`alone any hint or guidance as to how to arrive at the specific
`alone any hint or guidance as to hoW to arrive at the speci?c
`embodiments of the invention, said embodiments solving
`embodiments of the invention, said embodiments solving
`the problems identified and thus providing advantages in a
`the problems identi?ed and thus providing advantages in a
`non-predictable way.
`non-predictable Way.
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`Surprisingly, according to the present invention, particu-
`Surprisingly, according to the present invention, particu
`lar geometrical shapes of each of the granules in combina-
`lar geometrical shapes of each of the granules in combina
`tion with the choice of and mixing of particular types of
`tion With the choice of and mixing of particular types of
`helper ingredients, provide granules with an especially
`helper ingredients, provide granules With an especially
`advantageous and clinically important 5-ASA gastro-
`advantageous and clinically important 5-ASA gastro
`intestinal release.
`intestinal release.
`Surprisingly,
`the granule composition of the present
`Surprisingly, the granule composition of the present
`invention provides an advantageous release profile securing
`invention provides an advantageous release pro?le securing
`a clinically important bio-availability. Such a useful bio-
`a clinically important bio-availability. Such a useful bio
`availability is obtained due to the following characteristics:
`availability is obtained due to the folloWing characteristics:
`only a minor release of 5-ASA in the stomach is obtained,
`only a minor release of 5-ASA in the stomach is obtained,
`whereas a considerable amount of 5-ASA is available for an
`Whereas a considerable amount of 5-ASA is available for an
`appropriate period of time in the small intestine, and also a
`appropriate period of time in the small intestine, and also a
`considerably amount of 5-ASA is available in the large
`considerably amount of 5-ASA is available in the large
`intestine.
`intestine.
`Thus, in one of its main aspects, the invention provides a
`Thus, in one of its main aspects, the invention provides a
`composition for oral administration, said composition being:
`composition for oral administration, said composition being:
`an oral modified release composition ensuring bioavail-
`an oral modi?ed release composition ensuring bioavail
`ability of said 5-ASA in both the small and large
`ability of said 5-ASA in both the small and large
`intestine, and comprising:
`intestine, and comprising:
`individually coated granules, each granule comprising:
`individually coated granules, each granule comprising:
`
`The composition of the invention is individually coated
`The composition of the invention is individually coated
`granules adapted for oral administration as such,
`i.e.
`the
`granules adapted for oral administration as such, ie the
`composition is a “granulate” composition ready for use. The
`composition is a “granulate” composition ready for use. The
`granule composition of the invention is an advantageous
`granule composition of the invention is an advantageous
`administration form in many clinical situations, e.g. with
`administration form in many clinical situations, eg with
`respect to patient having difficulties in swallowing and with
`respect to patient having dif?culties in sWalloWing and With
`respect to children not wanting to swallow tablets.
`respect to children not Wanting to sWalloW tablets.
`A further advantage is that the granules or the invention
`A further advantage is that the granules or the invention
`may be packaged in unit dosage forms comprising larger
`may be packaged in unit dosage forms comprising larger
`amounts of active 5-ASA, e.g. in sachets or sticks.
`amounts of active 5-ASA, eg in sachets or sticks.
`In principle, there is, in contrast to the maximal content of
`In principle, there is, in contrast to the maximal content of
`tablets and capsules, no upper limit to the amount of active
`tablets and capsules, no upper limit to the amount of active
`ingredients in a unit dosage form of the composition accord-
`ingredients in a unit dosage form of the composition accord
`ing to the invention.
`ing to the invention.
`Thus, an advantage of the granule composition of the
`Thus, an advantage of the granule composition of the
`present invention is that it enables improved compliance
`present invention is that it enables improved compliance
`values with respect to the therapy regimen, a clinically
`values With respect to the therapy regimen, a clinically
`important parameter for the treatment of chronic diseases.
`important parameter for the treatment of chronic diseases.
`Overall, it should be noted that the question of a satis-
`Overall, it should be noted that the question of a satis
`factory compliance is especially important in the case of
`factory compliance is especially important in the case of
`IBD, since failure to respond to medical treatment in many
`IBD, since failure to respond to medical treatment in many
`cases necessitates surgery, with the standard surgical opera-
`cases necessitates surgery, With the standard surgical opera
`tion in the treatment of ulcerative colitis in many cases being
`tion in the treatment of ulcerative colitis in many cases being
`total proctocolectomy (removal of the colon and the
`total proctocolectomy (removal of the colon and the
`rectum).
`rectum).
`U.S. Pat. Nos. 4,496,553 and 4,980,173 (llalskov) provide
`US. Pat. Nos. 4,496,553 and 4,980,173 (lIalskov) provide
`a method for the treatment of IBD by oral administration of
`a method for the treatment of IBD by oral administration of
`5-ASA compositions consisting essentially of free 5-ASA
`5-ASA compositions consisting essentially of free 5-ASA
`and carriers which will control the release of an effective
`and carriers Which Will control the release of an effective
`amount of 5-ASA.
`amount of 5-ASA.
`However, as opposed to the present invention, no mention
`HoWever, as opposed to the present invention, no mention
`of the administration of 5-ASA granules as such was
`of the administration of 5-ASA granules as such Was
`disclosed, and the compositions described for clinical use
`disclosed, and the compositions described for clinical use
`were all in the form of tablets. The disclosure of said U.S.
`Were all in the form of tablets. The disclosure of said US.
`patents, including the examples, is totally silent about the
`patents, including the examples, is totally silent about the
`provision of a specific type of granule composition for direct
`provision of a speci?c type of granule composition for direct
`oral intake. Nowhere in said patent specification is it sug-
`oral intake. NoWhere in said patent speci?cation is it sug
`gested to develop or administer a granule composition.
`gested to develop or administer a granule composition.
`
`30
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`55
`
`60
`60
`
`65
`
`

`
`3
`3
`a core comprising 5 -aminosalicylic acid (5 -ASA) (or
`a core comprising 5 -aminosalicylic acid (5 -ASA) (or
`a salt or an ester thereof) and a physiologically
`a salt or an ester thereof) and a physiologically
`acceptable first helper ingredient, preferably a
`acceptable ?rst helper ingredient, preferably a
`cellulose derivative, in particular microcrystalline
`cellulose derivative, in particular microcrystalline
`cellulose, and
`cellulose, and
`a coating confining said core, said coating compris-
`a coating con?ning said core, said coating compris
`ing a second helper ingredient, preferably a semi-
`ing a second helper ingredient, preferably a semi
`permeable polymer, in particular, ethylcellulose;
`permeable polymer, in particular, ethylcellulose;
`and
`and
`the majority of the granules, preferably more than 80%,
`the majority of the granules, preferably more than 80%,
`more preferably more than 90%, of the granules being
`more preferably more than 90%, of the granules being
`essentially spherical as defined by an aspect
`ratio
`essentially spherical as de?ned by an aspect ratio
`within 1.00-1.25, preferably within 1.00-1.20, more
`Within 1.00—1.25, preferably Within 1.00—1.20, more
`preferably within 1.00-1.15; and
`preferably Within 1.00—1.15; and
`the majority of the granules, preferably more than 70%,
`the majority of the granules, preferably more than 70%,
`more preferably more than 90%, of the granules of the
`more preferably more than 90%, of the granules of the
`composition exerting sieve values in the range of 0.5
`composition exerting sieve values in the range of 0.5
`mm-2.0 mm, preferably in the range of 0.7 mm-1.1
`mm—2.0 mm, preferably in the range of 0.7 mm—1.1
`mm; and
`mm; and
`the composition exerting the following in vitro dissolu-
`the composition exerting the folloWing in vitro dissolu
`tion rates [when measured in a model system using
`tion rates [When measured in a model system using
`simulated intestinal fluid in USP Paddle System 2
`simulated intestinal ?uid in USP Paddle System 2
`operated at 37° C. with stirring speed 100 rpm]:
`operated at 37° C. With stirring speed 100 rpm]:
`a) within 2—20%, preferably within 5—15%, of the total
`a) Within 2—20%, preferably Within 5—15%, of the total
`5-ASA is released after 15 minutes in the model
`5-ASA is released after 15 minutes in the model
`system;
`system;
`b) within 20-50%, preferably within 25-45%, of the
`b) Within 20—50%, preferably Within 25—45%, of the
`total 5 -ASA is released after 60 minutes in the model
`total 5 -ASA is released after 60 minutes in the model
`system;
`system;
`c) within 30-70%, preferably within 40-60% of the
`c) Within 30—70%, preferably Within 40—60% of the
`