`
`Exhibit 1011
`
`U.S. Patent No. 6,551,620 (“the ‘620
`Patent”)
`
`

`
`United States Patent
`(12) United States Patent
`(12)
`Otterbeck
`Otterbeck
`
`(10) Patent N0.:
`(10) Patent N0.:
`(45) Date of Patent:
`(45) Date of Patent:
`
`US 6,551,620 B2
`US 6,551,620 B2
`*Apr. 22, 2003
`*Apr. 22, 2003
`
`US006551620B2
`US006551620B2
`
`(54) PELLET FORMULATION FOR THE
`(54) PELLET FORMULATION FOR THE
`TREATMENT OF THE INTESTINAL TRACT
`TREATMENT OF THE INTESTINAL TRACT
`
`6,277,412 B1 *
`8/2001 Otterbeck
`6,277,412 B1 * 8/2001 Otterbeck
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`4236025
`4236025
`006200
`006200
`0148811
`0148811
`0248447
`0248447
`0308665
`0308665
`
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`
`(75)
`Inventor: Norbert Otterbeck, Uberlingen (DE)
`(75) Inventor: Norbert Otterbeck, Uberlingen (DE)
`
`(73) Assignee: Dr. Falk Pharma GmbH, Freiburg
`(73) Assignee: Dr. Falk Pharma GmbH, Freiburg
`(DE)
`(DE)
`
`( * ) Notice:
`( * ) Notice:
`
`Subject. to any disclaimer, the term of this
`
`Subject to any disclaimer, the term of this gusenct liszxéenge‘i) (21f adjusted under 35
`patent is extended or adjusted under 35
`U30 154(9) by 0 days"
`"
`"
`"
`( ) y
`ays"
`.
`.
`.
`.
`.
`_
`_
`_
`_
`_
`This Patent 15 S11bJ€Ct
`10 a tefmlnal 0115-
`Thls Pawnt 1S sublect to a termlnal (115-
`claimer.
`claimer.
`
`.
`
`0.:
`
`,
`
`(21) Appl. No.: 09/906,494
`21 Appl N 09/906 494
`(22) Filed:
`Jul. 16, 2001
`(22)
`Filed;
`Jul, 16, 2001
`_
`_
`_
`_
`_
`_
`Pnor Pubhcatlon Data
`Pnor Pubhcatlon Data
`Us 2001/0055616 A1 Dec 27’ 2001
`Us 2001/0055616 A1 Dec. 27, 2001
`
`(65)
`(65)
`
`Related US, Application Data
`Related US, A lication Data
`PP
`
`(63) Continuation of application No. 09/194,213, filed as appli—
`(63) Continuation of application No. 09/194,213, ?led as appli-
`0311011 N0- PCT/E1398/02319 011 APR 20; 1993
`Cation N°~ PCT/EP98/02319 on APL 20, 1998-
`Int. Cl.7 .................... .. A6iK 31/60; A61K 31/615;
`(51)
`(51) Int. c1.7 .................... .. A61K 31/60; A61K 31/615;
`A61K 9/14; A61K 9/20; A61K 9/22
`A61K 9/14; A61K 9/20; A61K 9/22
`(52) US. Cl. ..................... .. 424/489- 424/464- 424/490-
`..................... .. 424/489; 424/464; 424/490;
`(52) U.s. Cl.
`424/468; 424/469; 424/486; 424/487; 514/159,
`424/468; 424/469; 424/486; 424/487; 514/159;
`5 14/166
`5 14/ 166
`(58) Field Of Search ............................... .. 424/464, 465,
`(58) Field of Search ............................... .. 424/464, 465,
`.
`_
`424/468’ 469’ 486’ 487’ 489’ 490’ 514/115696’
`424/468, 469, 486, 487, 489, 490, 514/115696,
`
`(56)
`(56)
`
`References Cited
`References Cited
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`9/1985 Bauer ....................... .. 514/162
`4,540,685 A
`52:: """"""""
`2
`514/163
`12/1986 Bauer
`4,632,921 A
`514/163
`4,699,902 A
`10/1987 Bauer ................ ..
`514/163
`4:699:902 A 10/1987 Bauer ................ ..
`5,316,772 A
`5/1994 Jurgensj Jr. et at
`...... N 424/472
`5,316,772 A
`5/1994 lurgensj Jr_ et a1_ ______ __ 424/472
`5,541,170 A
`7/1996 Rhodes et a1,
`,, 514/166
`5,541,170 A
`7/1996 Rhodes 61 a1, ,,,,,,,,,,,, __ 514/166
`5,541,171 A
`7/1996 Rhodes et al.
`..... ..
`514/166
`5,541,171 A
`7/1996 Rhodes et al. ..... ..
`514/166
`5,879,705 A *
`3/1999 Heafield et al.
`.......... .. 424/464
`5,879,705 A * 3/1999 Hea?eld et al. .......... .. 424/464
`r,‘
`A
`.
`the plasma ccncentra 16:;
`Mezm value DI
`5—ASA (n4”m1)
`of
`
`An orally adminsterable pharmaceutical pellet formulation
`fA“ Ohrauy admlnstefmlflle .pha”.na‘i9““°a1. p‘:’11.19t1f°r:1n“1aItl1.°:l‘
`for the treatment of the intestinal tract is disclosed, Which
`or t e. treatment o t e intestina tract is
`isc ose , W.lC
`C0mPr1SeS *1 C0“? and all emerlc Coatmga Fhe COFC lllcludlnga
`Comprises a Core and an enteric Coating the Core including
`as a pharmaceutical active compound, aminosalicylic acid or
`as a pharmaceutical active compound, aminosalicylic acid or
`a pharmaceutically tolerable salt or a derivative thereof.
`a pharmaceutically tolerable salt or a derivative thereof.
`
`17 Claims, 2 Drawing Sheets
`17 Claims, 2 Drawing Sheets
`
`
`
`Mezm value of the plasma concentration
`
`of 545A (no/m1)
`
`—-— Fe}1e[5
`
`—-<9" Comparison font
`
`—‘— Pellets
`
`——e-- Comparison forlr
`
`1.200
`
`1500
`
`1400
`
`1200
`
`(Harm) 100D
`
`b sue
`
`
`
`MycoNovo, Inc.
`Foxhill Opportunity Fund, L.P.
`
`EX 1001
`
`.......... .. A61K/9/36
`.......... .. A61K/9/36
`A61K/9/02
`A61K/9/02
`A61K/9/00
`A61K/9/00
`A61K/9/22
`A61K/9/22
`A61K/9/00
`A61K/9/00
`
`I... A61K/9/50
`A61K/9/50
`A61K/9/28
`A61K/9/28
`A61K/9/50
`A61K/9/50
`.......... .. A61K/9/24
`.......... .. A61K/9/24
`
`
`
`4/1994
`4/1994
`10/1982
`10/1982
`7/1985
`7/1985
`12/1987
`12/1987
`3/1989
`3/1989
`2: 12;
`
`2; 1g; 12/1993
`0572486
`12/1993
`0572486
`5/1994
`0595110
`5/1994
`0595110
`12/1994
`0629398 A1
`0629398 A1 12/1994
`0671168
`9/1995
`0671168
`9/1995
`.
`.
`(List continued on next page.)
`(List continued on neXt page.)
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`“Dictionary Entries: ‘Mesalamine,’ ‘Proctosigmoiditis’ and
`“Dictionary Entries: ‘Mesalamine,’ ‘Proctosigmoiditis’ and
`‘Inflammation’”, Stedman’s Medical Dictionary, Obtained
`‘In?ammation”’, Stedman’s Medical Dictionary, Obtained
`from the Physician’s Desk Reference Electronic Library on
`from the Physician’s Desk Reference Electronic Library on
`the World Wide Web at http://WWW.pdrel.com/>, on Dec. 17,
`the World Wide Web at http://WWW.pdrel.com/>, on Dec. 17,
`1999, 5 p., (1999).
`1999, 5 p., (1999).
`“Dictionary Entry: ‘Pentasa Capsules’ (Mesalamine/5—ami-
`“Dictionar Entr : ‘Pentasa Ca sules’ Mesalamine/5—ami
`y
`y
`P
`nosalicylic Acid)”, Physician’s Desk Reference, Obtained
`nosalicylic Acid)”, Physician’s Desk Reference, Obtained
`from the Physician’s Desk Reference Electronic Library on
`from the Physician’s Desk Reference Electronic Library on
`the World Wide Web at http://WWW.pdrel.com/>, on Dec. 17,
`the World Wide Web at http://WWW.pdrel.com/>, on Dec. 17,
`1999» 3 P» (1999)
`“
`.
`1999> 3 P» (1999)
`_
`BadaW1, A.A., et al., “Drug Release From Matrices Made of
`Badawi, A.A:, et al., Drug Release From l\./Iatrices Made of
`Polymers With Reacting Sites”, International Journal Of
`gzlymers W,“h geggtlgg S1“9‘°*8S0> 1”’"”“"0”“’ ~’0”’”“’ of
`Pharmaceutics) 6’ 5542’ (1980)
`‘””“’Ce“"CS»
`>
`‘
`> (
`)~
`(List continued on next page.)
`(List continued on neXt page.)
`.
`Primar
`.
`.
`y Examiner—Thurman K. Page
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Amy E Pulliam
`Assistant Examiner
`y E Pumam
`(74) Attorney, Agent, or Firm—SchWegman, Lundberg,
`(74) Attorney, Agent, or Firm—SchWegman, Lundberg,
`Woessner & Kluth’ PA‘
`Woessner & Kluth, P.A.
`(57)
`ABSTRACT
`(57)
`ABSTRACT
`
`

`
`US 6,551,620 B2
`US 6,551,620 B2
`Page 2
`Page 2
`
`EP
`EP
`FR
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`0673645
`A61K/9/28
`9/1995
`9/1995
`0673645
`A61K/9/28
`0759303
`2/1997
`A61K/47/26
`
`0759303
`2/1997
`A61K/47/26
`2692484
`12/1993
`.......... .. A61K/9/32
`12/1993
`2692484
`2/1983
`.......... .. A61K/9/32
`83/00435
`83/00435
`2/1983
`9/1992
`92/14452
`.......... .. A61K/9/50
`92/14452
`9/1992
`4/1993
`*
`W0 93/07859
`WO 93/07859
`* 4/1993
`4/1993
`93/07859
`93/07859
`4/1993
`95/1645 1
`6/1995
`95/16451
`6/1995
`95/18622
`7/1995
`95/18622
`7/1995
`95/35 100
`12/1995
`95/35100
`12/1995
`96/049 18
`2/1996
`96/04918
`2/1996
`9/1996
`96/29058
`96/29058
`9/1996
`96/31202
`10/1996
`96/31202
`10/1996
`97/23 199
`7/1997
`97/23199
`7/1997
`
`.......... .. A61K/9/16
`A61K/31/60
`A61K/31/60
`
`....... .. A61K/31/615
`.......... .. A61K/9/48
`A61K/31/57
`A61K/31/57
`
`.......... .. A61K/9/16
`........ .. A61K/38/13
`.......... .. A61K/9/16
`
`.......... .. A61K/9/48
`
`.......... .. A61K/9/16
`
`........ .. A61K/38/13
`
`.......... .. A61K/9/16
`
`.......... .. A61K/9/32
`
`.......... .. A61K/9/32
`
`.......... .. A61K/9/50
`
`.......... .. A61K/9/16
`
`....... .. A61K/31/615
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`Barry, M., “Selected side-effects: 9. Mesalazine and renal
`Barry, M., “Selected side—effects: 9. MesalaZine and renal
`impairment”, Prescriber’s Journal, Vol. 32, No. 5, pp.
`impairment”, Prescriber’s Journal, vol. 32, No. 5, pp.
`205—209, (1992).
`205-209, (1992).
`Lin, S.Y., et al., “Calcium Alginate Beads as Core Carriers
`Lin, S.Y., et al., “Calcium Alginate Beads as Core Carriers
`of 5—Aminosalicylic Acid”, Pharmaceutical Research, 9 (9),
`of 5-Aminosalicylic Acid”, Pharmaceutical Research, 9 (9),
`1128-1131, (1992).
`1128—1131, (1992).
`Watts, P.J., et al., “Encapsulation of 5-aminosalicylic Acid
`Watts, P.J., et al., “Encapsulation of 5—aminosalicylic Acid
`into Eudragit RS Microspheres and Modulation of their
`into Eudragit RS Microspheres and Modulation of their
`Release Characteristics by Use of Surfactants”, Journal of
`Release Characteristics by Use of Surfactants”, Journal of
`Controlled Release, 16, 311-318, (1991).
`Controlled Release, 16, 311—318, (1991).
`Stedman’s Medical Dictionary—0 search terms include
`Stedman’s Medical Dictionary—0 search terms include
`mesalamine, proctosigmoiditis, inflammation.*
`mesalamine, proctosigmoiditis, in?ammation.*
`Physician’s Desk Reference—5-aminosalycylic acid.*
`Physician’s Desk Reference—5—aminosalycylic acid.*
`* cited by examiner
`* cited by examiner
`
`

`
`U.S. Patent
`U.S. Patent
`
`Apr. 22, 2003
`Apr. 22, 2003
`
`Sheet 1 0f 2
`Sheet 1 of 2
`
`US 6,551,620 B2
`US 6,551,620 B2
`
`Mean value of the plasma concentration
`Mean value of the plasma concentration
`
`of S-ASA (ng/ml)
`of 5-ASA (ng/ml)
`
`"‘+"' Pellets
`Pellets
`
`--e"’ Comparison form
`"<9” Comparison form
`
`1800
`1800
`
`1600
`1600
`
`1400
`1400
`
`HN o o
`1200
`
`1000
`
`3259: 1000
`(ng/ml)
`
`Plasmaconc.
`
`
`. UCOU @Em@H&
`
`800
`
`600
`
`400
`
`Fig.
`Fig.
`
`1
`l
`
`Time (h)
`Time (h)
`
`

`
`U.S. Patent
`U.S. Patent
`
`Apr. 22, 2003
`Apr. 22, 2003
`
`Sheet 2 0f 2
`Sheet 2 of 2
`
`US 6,551,620 B2
`US 6,551,620 B2
`
`Mean value of the plasma concentration
`Mean value of the plasma concentration
`
`of Ac—5-ASA (ng/ml)
`of Ac—5—ASA (ng/ml)
`
`Pellets
`Pellets
`
`"-e"" Comparison form
`“49“ Comparison form
`
`SEES
`
`Plasmaconc.(ng/ml)
`
`
`. UGOU MEWGHQ
`
`2600
`2500
`
`2400
`2400
`
`2200
`2200
`
`2000
`
`1800
`
`.
`
`n
`
`I
`
`p
`
`1600
`
`1400
`
`1200
`
`1000
`
`800
`
`600
`
`Fig.
`
`2
`
`Time (h)
`Time (h)
`
`

`
`US 6,551,620 B2
`US 6,551,620 B2
`
`1
`1
`PELLET FORMULATION FOR THE
`PELLET FORMULATION FOR THE
`TREATMENT OF THE INTESTINAL TRACT
`TREATMENT OF THE INTESTINAL TRACT
`RELATED APPLICATIONS
`RELATED APPLICATIONS
`This application is a continuation of U.S. Application Ser.
`This application is a continuation of US. Application Ser.
`No. 09/194,213, filed Aug. 30, 1999, which was a filing
`No. 09/194,213, ?led Aug. 30, 1999, Which Was a ?ling
`under 35 U.S.C. 371 from PCT/EP98/02319, filed Apr. 20,
`under 35 U.S.C. 371 from PCT/EP98/02319, ?led Apr. 20,
`1998, which claimed priority from German Application No.
`1998, Which claimed priority from German Application No.
`197 32 903.9, filed Jul. 30, 1997, which applications are
`197 32 903.9, ?led Jul. 30, 1997, Which applications are
`incorporated by reference and made a part hereof.
`incorporated by reference and made a part hereof.
`The present invention relates to a pellet formulation for
`The present invention relates to a pellet formulation for
`the treatment of the intestinal tract, which comprises, as a
`the treatment of the intestinal tract, Which comprises, as a
`pharmaceutical active compound, aminosalicylic acid or a
`pharmaceutical active compound, aminosalicylic acid or a
`pharmaceutically tolerable salt or derivatives thereof.
`pharmaceutically tolerable salt or derivatives thereof.
`The active compound aminosalicylic acid (in particular
`The active compound aminosalicylic acid (in particular
`5-ASA) or its derivatives have been used successfully for a
`5-ASA) or its derivatives have been used successfully for a
`relatively long time for the treatment of intestinal disorders,
`relatively long time for the treatment of intestinal disorders,
`such as, for example, ulcerative colitis and Crohn’s disease
`such as, for example, ulcerative colitis and Crohn’s disease
`(DE 31 51 196 A1).
`(DE 31 51 196 A1).
`The use of 5-ASA and its derivatives as a chemothera-
`The use of 5-ASA and its derivatives as a chemothera
`peutic agent in colonic cancer is likewise known, polyps in
`peutic agent in colonic cancer is likeWise knoWn, polyps in
`the colon and rectum being associated with an increased risk
`the colon and rectum being associated With an increased risk
`of carcinoma (WO 95/18622).
`of carcinoma (WO 95/18622).
`A coloscopic polypectomy in patients with polyps in the
`A coloscopic polypectomy in patients With polyps in the
`colon and/or rectum results in a considerable reduction in
`colon and/or rectum results in a considerable reduction in
`risk of the formation of colonic carcinomas and is recom-
`risk of the formation of colonic carcinomas and is recom
`mended as a therapy, in particular in the case of colorectal
`mended as a therapy, in particular in the case of colorectal
`polyps. The reccurrence rate after polypectomy, however, is
`polyps. The reccurrence rate after polypectomy, hoWever, is
`high and amounts to about 6—30% per year. Aminosalicylic
`high and amounts to about 6—30% per year. Aminosalicylic
`acid is suitable for the longer-term treatment of such patients
`acid is suitable for the longer-term treatment of such patients
`and lowers the reccurrence rate of colorectal polyps.
`and loWers the reccurrence rate of colorectal polyps.
`The action of aminosalicylic acid in the treatment of
`The action of aminosalicylic acid in the treatment of
`intestinal disorders, or in the prevention of their recurrence
`intestinal disorders, or in the prevention of their recurrence
`or in the prevention of secondary disorders arising therefrom
`or in the prevention of secondary disorders arising therefrom
`and possible accompanying disorders takes place by means
`and possible accompanying disorders takes place by means
`of the contact of the active compound directly at the site of
`of the contact of the active compound directly at the site of
`the disorder in the intestine, the action of the aminosalicylic
`the disorder in the intestine, the action of the aminosalicylic
`acid, or a derivative thereof, being directly related to its local
`acid, or a derivative thereof, being directly related to its local
`concentration in the intestinal area to be treated.
`concentration in the intestinal area to be treated.
`Since inflammatory processes often affect relatively large
`Since in?ammatory processes often affect relatively large
`sections of the intestinal
`tract,
`the pharmaceutical form
`sections of the intestinal tract, the pharmaceutical form
`should spread reproducibly over wide areas of the intestine
`should spread reproducibly over Wide areas of the intestine
`and release the active compound only at the site of inflam-
`and release the active compound only at the site of in?am
`mation.
`mation.
`A problem in the treatment with aminosalicylic acid is
`A problem in the treatment With aminosalicylic acid is
`that the active compound is very easily absorbed and can be
`that the active compound is very easily absorbed and can be
`excreted via the kidney before its action can occur.
`excreted via the kidney before its action can occur.
`In the prior art, tablets and pellets are known which are
`In the prior art, tablets and pellets are knoWn Which are
`coated with an enteric coating in order to thus prevent a
`coated With an enteric coating in order to thus prevent a
`premature release of the active compounds.
`premature release of the active compounds.
`FR-A2 692 484 discloses a tablet for the controlled
`FR-A2 692 484 discloses a tablet for the controlled
`release of 4-ASA in a hydrophilic matrix which consists of
`release of 4-ASA in a hydrophilic matrix Which consists of
`swellable polymers forming a gel barrier, and having an
`sWellable polymers forming a gel barrier, and having an
`enteric coating. After dissolution of the coating, the matrix
`enteric coating. After dissolution of the coating, the matrix
`swells and forms a gel barrier through which the active
`sWells and forms a gel barrier through Which the active
`compound diffuses out. After an approximately two-hour lag
`compound diffuses out. After an approximately tWo-hour lag
`phase, the composition disclosed in FR-A2 692 484 releases
`phase, the composition disclosed in FR-A2 692 484 releases
`the active compound approximately linearly in the intestine
`the active compound approximately linearly in the intestine
`over a period of time of a further 14 h.
`over a period of time of a further 14 h.
`EP 0 453 001 A1 discloses a pharmaceutical composition
`EP 0 453 001 A1 discloses a pharmaceutical composition
`in which the active compound is covered with at least two
`in Which the active compound is covered With at least tWo
`membranes, of which one is soluble at a pH of 25.5 and the
`membranes, of Which one is soluble at a pH of 25.5 and the
`other is insoluble at this pH but is permeable to the intestinal
`other is insoluble at this pH but is permeable to the intestinal
`fluids.
`?uids.
`EP 0 148 811 A1 discloses a pharmaceutical composition
`EP 0 148 811 A1 discloses a pharmaceutical composition
`which consists of a core which contains the active com-
`Which consists of a core Which contains the active com
`
`5
`
`10
`10
`
`15
`15
`
`20
`
`25
`25
`
`30
`
`35
`35
`
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`
`65
`65
`
`2
`2
`pound. The core is surrounded by two layers, of which the
`pound. The core is surrounded by tWo layers, of Which the
`inner layer is a diffusion membrane and the second layer is
`inner layer is a diffusion membrane and the second layer is
`an anionic polymer and/or a fatty acid having a pKa of 4.5
`an anionic polymer and/or a fatty acid having a pKa of 4.5
`to 7.
`to 7.
`EP 0 629 398 A1 discloses pharmaceutical compositions
`EP 0 629 398 A1 discloses pharmaceutical compositions
`in which the active compound-containing core is surrounded
`in Which the active compound-containing core is surrounded
`by an enteric phase. According to Example 2, the core can
`by an enteric phase. According to Example 2, the core can
`contain small amounts of hydroxypropyl-cellulose. The
`contain small amounts of hydroxypropyl-cellulose. The
`active compound should be released rapidly after dissolution
`active compound should be released rapidly after dissolution
`of the enteric phase.
`of the enteric phase.
`EP 0 485 840 A2 discloses an oral pharmaceutical form
`EP 0 485 840 A2 discloses an oral pharmaceutical form
`which contains a shell material surrounding the active
`Which contains a shell material surrounding the active
`compound consisting of a polysaccharide and a film-forming
`compound consisting of a polysaccharide and a ?lm-forming
`polymer material.
`polymer material.
`A disadvantage in the case of the pharmaceutical formu-
`A disadvantage in the case of the pharmaceutical formu
`lations known in the prior art is that the active compound is
`lations knoWn in the prior art is that the active compound is
`also absorbed into the blood circulation. This amount of
`also absorbed into the blood circulation. This amount of
`active compound is thus lacking in the intestine, so that the
`active compound is thus lacking in the intestine, so that the
`effective dose of the medicament is reduced by the part of
`effective dose of the medicament is reduced by the part of
`the active compound which is found in the blood.
`the active compound Which is found in the blood.
`Moreover, patients who suffer from intestinal disorders
`Moreover, patients Who suffer from intestinal disorders
`frequently have to be further treated over relatively long
`frequently have to be further treated over relatively long
`periods with the active compound, or derivatives thereof,
`periods With the active compound, or derivatives thereof,
`after the acute disorder has died down in order to prevent the
`after the acute disorder has died doWn in order to prevent the
`disorder flaring up again or secondary disorders resulting
`disorder ?aring up again or secondary disorders resulting
`from the original disorder. In the case of such a long-term
`from the original disorder. In the case of such a long-term
`treatment, however, it has proven to be a problem that a
`treatment, hoWever, it has proven to be a problem that a
`certain nephrotoxicity of systemically available 5-ASA, i.e.
`certain nephrotoxicity of systemically available 5-ASA, i.e.
`5-ASA found in the bloodstream, or derivatives thereof
`5-ASA found in the bloodstream, or derivatives thereof
`cannot be excluded (M. Barry, Prescribers Journal, 1992, 32,
`cannot be excluded (M. Barry, Prescribers Journal, 1992, 32,
`205).
`205).
`It is thus an object of the present invention to make
`It is thus an object of the present invention to make
`available an orally administrable pharmaceutical formula-
`available an orally administrable pharmaceutical formula
`tion which does not have these disadvantages. According to
`tion Which does not have these disadvantages. According to
`the invention, formulations are therefore made available
`the invention, formulations are therefore made available
`which have a controlled release profile which results in a
`Which have a controlled release pro?le Which results in a
`high local active compound concentration at
`the site of
`high local active compound concentration at the site of
`action and simultaneously guarantees a blood level of the
`action and simultaneously guarantees a blood level of the
`active compound which is as low as possible.
`active compound Which is as loW as possible.
`In the context of the present invention, it has now been
`In the context of the present invention, it has noW been
`found that pellet formulations are particularly suitable for
`found that pellet formulations are particularly suitable for
`this purpose, since unlike a tablet they spread the pharma-
`this purpose, since unlike a tablet they spread the pharma
`ceutical form reproducibly over wide areas of the intestine
`ceutical form reproducibly over Wide areas of the intestine
`and are thus particularly suitable for treatment of inflam-
`and are thus particularly suitable for treatment of in?am
`matory processes, which often affect relatively large sections
`matory processes, Which often affect relatively large sections
`of the intestinal tract. In order to achieve the necessary local
`of the intestinal tract. In order to achieve the necessary local
`active compound concentration, the active compound must
`active compound concentration, the active compound must
`in this case be released at the site of inflammation within a
`in this case be released at the site of in?ammation Within a
`relatively short time (up to a few hours) without, however,
`relatively short time (up to a feW hours) Without, hoWever,
`it being released virtually immediately,
`in order that its
`it being released virtually immediately, in order that its
`action does not wear off too rapidly.
`action does not Wear off too rapidly.
`The use of a swellable, gel-forming matrix such as
`The use of a sWellable, gel-forming matrix such as
`described in FR-A 2 692 484 is not suitable for pellets
`described in FR-A 2 692 484 is not suitable for pellets
`having a diameter of 23 mm, since on account of the small
`having a diameter of 23 mm, since on account of the small
`diameter the polymer is very rapidly penetrated by the water,
`diameter the polymer is very rapidly penetrated by the Water,
`eroded as a result, and the active compound would thus be
`eroded as a result, and the active compound Would thus be
`released virtually immediately (about 30 min).
`released virtually immediately (about 30 min).
`In the context of the present invention, however, it has
`In the context of the present invention, hoWever, it has
`surprisingly been found that,
`if the active compound is
`surprisingly been found that, if the active compound is
`present in the pellet core in a non gel-forming polymer
`present in the pellet core in a non gel-forming polymer
`matrix which is essentially insoluble and permeable to
`matrix Which is essentially insoluble and permeable to
`intestinal
`fluids and the active compound, a markedly
`intestinal ?uids and the active compound, a markedly
`reduced release of the active compound into the blood, with
`reduced release of the active compound into the blood, With
`simultaneously increased local concentration of the active
`simultaneously increased local concentration of the active
`compound at the site of the disorder in the intestine, is
`compound at the site of the disorder in the intestine, is
`guaranteed in comparison with aminosalicylic acid formu-
`guaranteed in comparison With aminosalicylic acid formu
`lations already known in the prior art.
`lations already knoWn in the prior art.
`
`

`
`US 6,551,620 B2
`US 6,551,620 B2
`
`3
`3
`The present invention thus relates to an orally adminis-
`The present invention thus relates to an orally adminis
`trable pharmaceutical pellet formulation having a controlled
`trable pharmaceutical pellet formulation having a controlled
`release profile for the treatment of the intestinal tract, which
`release pro?le for the treatment of the intestinal tract, Which
`comprises a core and an enteric coating, and, if appropriate,
`comprises a core and an enteric coating, and, if appropriate,
`further pharmaceutically tolerable additives, the core includ-
`further pharmaceutically tolerable additives, the core includ
`ing as a pharmaceutically active compound aminosalicylic
`ing as a pharmaceutically active compound aminosalicylic
`acid or a pharmaceutically tolerable salt or derivative
`acid or a pharmaceutically tolerable salt or derivative
`thereof, wherein the active compound is present in the core
`thereof, Wherein the active compound is present in the core
`in a non gel-forming polymer matrix which is essentially
`in a non gel-forming polymer matrix Which is essentially
`insoluble in the intestinal tract and permeable to intestinal
`insoluble in the intestinal tract and permeable to intestinal
`fluids and the active compound, the matrix-forming polymer
`?uids and the active compound, the matrix-forming polymer
`making up at least 1% by weight of the total weight of the
`making up at least 1% by Weight of the total Weight of the
`core.
`core.
`The invention furthermore relates to a process for the
`The invention furthermore relates to a process for the
`production of the pellets described above and their use for
`production of the pellets described above and their use for
`the production of a medicament for the treatment of intes-
`the production of a medicament for the treatment of intes
`tinal disorders, such as inflammatory intestinal disorders,
`tinal disorders, such as in?ammatory intestinal disorders,
`preferably in the active phase and/or in the remission phase,
`preferably in the active phase and/or in the remission phase,
`for the prevention of these disorders, for the prevention of
`for the prevention of these disorders, for the prevention of
`the recurrrence of these disorders or secondary disorders
`the recurrrence of these disorders or secondary disorders
`resulting therefrom, and of possible accompanying disorders
`resulting therefrom, and of possible accompanying disorders
`and also for the treatment of intestinal cancer. The medica-
`and also for the treatment of intestinal cancer. The medica
`ment is particularly suitable for the treatment of inflamma-
`ment is particularly suitable for the treatment of in?amma
`tory intestinal disorders such as Crohn’s disease and ulcer-
`tory intestinal disorders such as Crohn’s disease and ulcer
`ative colitis, and for
`the prevention,
`treatment and/or
`ative colitis, and for the prevention, treatment and/or
`prevention of the reformation of polyps in the gastrointes-
`prevention of the reformation of polyps in the gastrointes
`tinal tract. Moreover,
`the medicament is suitable for the
`tinal tract. Moreover, the medicament is suitable for the
`prevention of colorectal carcinomas in patients with
`prevention of colorectal carcinomas in patients With
`adenomas and/or polypous groWth, in particular With poly
`adenomas and/or polypous growth, in particular with poly-
`pous growth in the intestine. The medicament is moreover
`pous groWth in the intestine. The medicament is moreover
`used for lowering the recurrence rate of colorectal polyps.
`used for loWering the recurrence rate of colorectal polyps.
`Preferred active compounds are 5-aminosalicylic acid
`Preferred active compounds are 5-aminosalicylic acid
`(also called mesalaZine), 4-aminosalicylic acid and, serving
`(also called mesalazine), 4-aminosalicylic acid and, serving
`as a prodrug for 5-ASA, 2-hydroxy-5-phenylazobenzoic
`as a prodrug for 5-ASA, 2-hydroxy-5-phenylaZobenZoic
`acid derivatives such as sulfasalazine (5-[4-(2-
`acid derivatives such as sulfasalaZine (5-[4-(2
`pyridylsulfamoyl)phenylaZo]salicylic acid) and balsalaZide
`pyridylsulfamoyl)phenylazo]salicylic acid) and balsalazide
`(the sodium salt of the azo derivative of 4-aminobenzoyl-
`(the sodium salt of the am derivative of 4-aminobenZoyl
`[3-alanine and 5-aminosalicylic acid). 5-ASA is particularly
`[3-alanine and 5-aminosalicylic acid). 5-ASA is particularly
`preferred.
`preferred.
`In addition to the active compound, the pellet core com-
`In addition to the active compound, the pellet core com
`prises 1% by weight, based on the total weight of the core,
`prises 1% by Weight, based on the total Weight of the core,
`of a matrix-forming, non gel-forming polymer which is
`of a matrix-forming, non gel-forming polymer Which is
`essentially insoluble in the intestinal tract and permeable to
`essentially insoluble in the intestinal tract and permeable to
`intestinal fluids and the active compound. Suitable matrix-
`intestinal ?uids and the active compound. Suitable matrix
`forming polymers are, for example, those polymers which
`forming polymers are, for example, those polymers Which
`are known in the prior art as coating lacquers for delayed-
`are knoWn in the prior art as coating lacquers for delayed
`release pharmaceuticals, such as, for example, (meth)acrylic
`release pharmaceuticals, such as, for example, (meth)acrylic
`ester copolymers.
`ester copolymers.
`Among the polymers which are essentially insoluble in
`Among the polymers Which are essentially insoluble in
`the intestinal tract and permeable to intestinal fluids and the
`the intestinal tract and permeable to intestinal ?uids and the
`active compound, those are preferred which are insoluble or
`active compound, those are preferred Which are insoluble or
`particularly preferably water-insoluble in the intestinal tract.
`particularly preferably Water-insoluble in the intestinal tract.
`Methyl acrylate copolymers and ammoniometh-acrylate
`Methyl acrylate copolymers and ammoniometh-acrylate
`copolymers of the type such as can be obtained under the
`copolymers of the type such as can be obtained under the
`tradename Eudragit® RS/RL/NE are particularly preferred.
`tradename Eudragit® RS/RL/NE are particularly preferred.
`As functional groups,
`these polymers have ester groups
`As functional groups, these polymers have ester groups
`(Eudragit® NE) or ammonium groups (Eudragit® RL/RS).
`(Eudragit® NE) or ammonium groups (Eudragit® RL/RS).
`Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl
`Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl
`acrylate, methyl methacrylate, trimethylammonioethyl
`acrylate, methyl methacrylate,
`trimethylammonioethyl
`methacrylate chloride) are preferred. These polymers are
`methacrylate chloride) are preferred. These polymers are
`obtainable, for example, as poly(ethyl acrylate, methyl
`obtainable,
`for example, as poly(ethyl acrylate, methyl
`methacrylate) 2:1 in 40% strength aqueous dispersion as
`methacrylate) 2:1 in 40% strength aqueous dispersion as
`Eudragit® NE 40 D and as poly(ethyl acrylate, methyl
`Eudragit® NE 40 D and as poly(ethyl acrylate, methyl
`methacrylate, trimethylammonioethyl methacrylate
`methacrylate,
`trimethylammonioethyl methacrylate
`chloride) 1:2:0.1 in 12.5% strength isopropanolic solution as
`chloride) 1:2:0.1 in 12.5% strength isopropanolic solution as
`Eudragit® RS 12.5 and in the composition 1:2:0.2 as
`Eudragit® RS 12.5 and in the composition 1:2:0.2 as
`Eudragit® RL 12.5. The most preferred is Eudragit® NE 40
`Eudragit® RL 12.5. The most preferred is Eudragit® NE 40
`D.
`D.
`
`10
`10
`
`15
`15
`
`20
`
`25
`25
`
`30
`
`35
`35
`
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`
`65
`65
`
`4
`4
`The polymer must be present in an amount which is
`The polymer must be present in an amount Which is
`sufficient to form a matrix for the active compound and
`suf?cient to form a matrix for the active compound and
`which guarantees a delayed release of the active compound.
`Which guarantees a delayed release of the active compound.
`For this purpose, an amount of at
`least 1% by weight,
`For this purpose, an amount of at least 1% by Weight,
`preferably at least 4% by weight, based on the total weight
`prefera