111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007666337B2
`US007666337B2
`
`(12) United States Patent
`(12) United States Patent
`Yang et al.
`Yang et al.
`
`(10) Patent No.:
`(10) Patent No.:
`(45) Date of Patent:
`(45) Date of Patent:
`
`US 7,666,337 B2
`US 7,666,337 B2
`Feb. 23,2010
`Feb. 23, 2010
`
`(54) POLYETHYLENE OXIDE-BASED FILMS AND
`(54) POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`THEREFROM
`
`(75)
`(75)
`
`Inventors: Robert K. Yang, Flushing, NY (US);
`Inventors: Robert K. Yang, Flushing, NY (US);
`Richard C. Fuisz, McLean, VA (US);
`Richard C. Fuisz, McLean, VA (US);
`Gary L. Myers, Kingsport, TN (US);
`Gary L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, McLean, VA (US)
`Joseph M. Fuisz, McLean, VA (US)
`Assignee: MonoSol Rx, LLC, Portage, IN (US)
`(73)
`(73) Assignee: MonoSol Rx, LLC, Portage, IN (US)
`Notice:
`(*)
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 619 days.
`U.S.c. 154(b) by 619 days.
`
`Appl. No.: 10/856,176
`(21)
`(21) Appl. No.: 10/856,176
`Filed:
`(22)
`(22) Filed:
`(65)
`(65)
`
`May 28, 2004
`May 28, 2004
`
`Prior Publication Data
`Prior Publication Data
`US 2005/0037055 A1
`Feb. 17, 2005
`US 2005/0037055 Al
`Feb. 17,2005
`
`Related U.S. Application Data
`Related U.S. Application Data
`Continuation-in-part of application No. 10/768,809,
`(63)
`(63) Continuation-in-part of application No. 101768,809,
`filed on Jan. 30, 2004, now Pat. No. 7,357,891, and a
`filed on Jan. 30, 2004, now Pat. No. 7,357,891, and a
`continuation-in-part of application No. PCT/US02/
`continuation-in-part of application No. PCT/US021
`32575, filed on Oct. 11, 2002, and a continuation-in
`32575, filed on Oct. 11, 2002, and a continuation-in(cid:173)
`part of pplication No. PCT/US02/32594, filed on Oct.
`part of application No. PCTIUS02/32594, filed on Oct.
`11, 2002, and a continuation-in-part of application No.
`11,2002, and a continuation-in-part of application No.
`PCT/US02/32542, filed on Oct. 11, 2002.
`PCT/US02/32542, filed on Oct. 11, 2002.
`Provisional application No. 60/473,902, filed on May
`(60)
`(60) Provisional application No. 60/473,902, filed on May
`28, 2003, provisional application No. 60/443,741,
`28, 2003, provisional application No. 60/443,741,
`filed on Jan. 30, 2003, provisional application No.
`filed on Jan. 30, 2003, provisional application No.
`60/371,940, filed on Apr. 11, 2002.
`60/371,940, filed on Apr. 11,2002.
`
`(51)
`(51)
`
`Int. Cl.
`Int. Cl.
`B29C 39/14
`B29C 39/14
`
`(2006.01)
`(2006.01)
`
`
`
`(52) U.S. CI. .................. 264/172.19; 264/212; 264/234;
`(52) U.S. Cl. .................. 2641172.19; 2641212; 264/234;
`264/319; 264/344
`264/319; 264/344
`(58) Field of Classification Search ....................... None
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`See application file for complete search history.
`References Cited
`References Cited
`
`(56)
`(56)
`
`U.S. PATENT DOCUMENTS
`|U.S. PATENT DOCUMENTS
`
`307,537 A
`307,537 A
`
`1 1/1884 Foulks
`1111884 Foulks
`(Continued)
`(Continued)
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`
`1/1976
`2432925 B2
`111976
`2432925 B2
`(Continued)
`(Continued)
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`XP-002298105; Polyethylenglykole; Internet: www.roempp.com;
`XP-002298105; Polyethylenglykole; Internet: www.roempp.com;
`Sep. 20, 2004.
`Sep. 20, 2004.
`
`(Continued)
`(Continued)
`Primary Examiner—Edmund H. Lee
`Primary Examiner-Edmund H. Lee
`(74) Attorney, Agent, or Firm—Hoffmann & Baron, LLP
`(74) Attorney, Agent, or Firm-Hoffmann & Baron, LLP
`(57)
`ABSTRACT
`(57)
`ABSTRACT
`The invention relates to the film products and methods of their
`The invention relates to the film products and methods of their
`preparation that demonstrate a non-self-aggregating uniform
`preparation that demonstrate a non-self-aggregating uniform
`heterogeneity. Desirably, the films disintegrate in water and
`heterogeneity. Desirably, the films disintegrate in water and
`may be formed by a controlled drying process, or other pro
`may be formed by a controlled drying process, or other pro(cid:173)
`cess that maintains the required uniformity of the film. The
`cess that maintains the required uniformity of the film. The
`films contain a polymer component, which includes polyeth
`films contain a polymer component, which includes polyeth(cid:173)
`ylene oxide optionally blended with hydrophilic cellulosic
`ylene oxide optionally blended with hydrophilic cellulosic
`polymers. Desirably, the films also contain a pharmaceutical
`polymers. Desirably, the films also contain a pharmaceutical
`and/or cosmetic active agent with no more than a 10% vari
`and/or cosmetic active agent with no more than a 10% vari(cid:173)
`ance of the active agent pharmaceutical and/or cosmetic
`ance of the active agent pharmaceutical and/or cosmetic
`active agent per unit area of the film.
`active agent per unit area of the film.
`
`30 Claims, 34 Drawing Sheets
`30 Claims, 34 Drawing Sheets
`
`20
`
`,-/
`
`22
`
`44 b.heaf
`
`46
`
`MonoSol2012-0001
`
`Dr. Reddys v. MonoSol
`IPR2016-01112
`
`

`
`US 7,666,337 B2
`US 7,666,337 B2
`Page 2
`Page 2
`
`|U.S. PATENT DOCUMENTS
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`
`FOREIGN PATENT DOCUMENTS
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`
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`
`MonoSol2012-0002
`
`

`
`US 7,666,337 B2
`US 7,666,337 B2
`Page 3
`Page 3
`
`EP
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`WO 00/42992
`WO 00/42992
`7/2000
`7/2000
`WO 01/70 194
`9/2001
`WO 01170194
`9/2001
`WO 01/70 194 A1
`9/2001
`WO 01170194 Al
`9/2001
`
`WO 01/91721 A2 12/2001
`WO
`WOO1l91nl A2
`WO
`1212001
`WO 03/030882
`4/2003
`WO
`WO
`WO 03/030882
`412003
`WO 03/030883
`4/2003
`WO
`WO
`WO 03/030883
`4/2003
`WO WO 2005/102287
`1 1/2005
`1112005
`WO
`WO 2005/102287
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`Repka et al.; Influence of Vitamin E. TPGS on the properties of
`Repka et al.; Influence of Vitamin E. TPGS on the properties of
`hydrophilic films produced by hot-melt extrusion; International Jour
`hydrophilic films produced by hot-melt extrusion; International Jour(cid:173)
`nal of Pharmaceutics; vol. 202, pp. 63-70; 2000.
`nal of Pharmaceutics; vol. 202, pp. 63-70; 2000.
`Repka et al.; Bioadhesive properties of hydroxypropylcellulose topi
`Repka et al.; Bioadhesive properties ofhydroxypropylcellulose topi(cid:173)
`cal films produced by hot-melt extrusion; Journal of Controlled
`cal films produced by hot-melt extrusion; Journal of Controlled
`Release; vol. 70; pp. 341-351; 2001.
`Release; vol. 70; pp. 341-351; 2001.
`* cited by examiner
`* cited by examiner
`
`MonoSol2012-0003
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23, 2010
`
`Sheet 1 of 34
`Sheet 1 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`10
`10
`_/ 4
`;-\----) )~
`
`14
`
`/
`
`12
`12
`
`14
`14
`
`FIG. 1
`FIG. 1
`
`1 O
`10
`C
`
`10'
`10’
`/
`
`* 1s
`1
`'- 16
`FIG.2
`FIG. 2
`10
`10
`
`/
`
`
`
`FIG.4
`
`10' 16 10
`
`1 B""'---':::-L--_lL
`
`FIG.5
`F|G. 5
`
`MonoSol2012-0004
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 2 of 34
`Sheet 2 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`20
`
`,-/
`
`32'
`30'~
`
`
`
`
`
`34'
`
`J2
`30
`^2-s /
`
`\ ~heaf
`
`46
`
`FIG.6
`
`MonoSol2012-0005
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23, 2010
`
`Sheet 3 of 34
`Sheet 3 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`44
`
`42
`
`~tp)tp)~
`64'~ ~ C ~64
`
`>>>>> S >> S >> S >> S >>
`YZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZX
`60'
`-::s ~ ~ '=0::
`
`-
`
`
`
`-=60
`
`62'
`
`58'
`
`62
`
`58
`
`56
`
`54
`
`________ 50
`
`52
`
`FIG.7
`FIG. 7
`
`MonoSol2012-0006
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 4 of 34
`Sheet 4 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
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`ii g
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`MonoSol2012-0007
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 5 of 34
`Sheet 5 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`110
`
`100
`1 OO
`
`FIG. 9
`FIG. 9
`
`MonoSol2012-0008
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 6 of 34
`Sheet 6 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`1 10
`110
`
`100
`1 OO
`
`FIG. 10
`FIG 10
`
`MonoSol2012-0009
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 7 of 34
`Sheet 7 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`1 10
`110
`
`FIG. 11
`FIG 11
`
`100
`1 OO
`
`MonoSol2012-0010
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 8 of 34
`Sheet 8 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`110
`1 1 O
`
`100
`1 OO
`
`FIG. 12
`F|G. 12
`
`MonoSol2012-0011
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 9 of 34
`Sheet 9 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`110
`1 10
`
`700
`100
`
`FIG. 13
`FIG. 13
`
`MonoSol2012-0012
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 10 of 34
`Sheet 10 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`1 1 O
`110
`
`100
`1 OO
`
`FIG. 14
`FIG. 14
`
`MonoSol2012-0013
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 11 of 34
`Sheet 11 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`1 1 O
`
`100
`1 OO
`
`FIG. 15
`FIG. 15
`
`MonoSol2012-0014
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 12 of 34
`Sheet 12 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`1 1 O
`110
`
`OO
`1
`
`F|G. 16
`FIG. 16
`
`MonoSol2012-0015
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23,2010
`Feb. 23, 2010
`
`Sheet 13 of 34
`Sheet 13 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`200
`200
`
`FIG. 17
`FIG. 17
`
`MonoSol2012-0016
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 14 of 34
`Sheet 14 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 18
`FIG. 18
`
`MonoSol2012-0017
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 15 of 34
`Sheet 15 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 19
`FIG. 19
`
`MonoSol2012-0018
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23,2010
`Feb. 23, 2010
`
`Sheet 16 of 34
`Sheet 16 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`: tiºn
`
`500
`OO
`5
`
`F|G. 20
`FIG. 20
`
`MonoSol2012-0019
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 17 of 34
`Sheet 17 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 21
`FIG. 21
`
`MonoSol2012-0020
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 18 of 34
`Sheet 18 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`F|G. 22
`FIG. 22
`
`MonoSol2012-0021
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 19 of 34
`Sheet 19 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 23
`FIG. 23
`
`MonoSol2012-0022
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 20 of 34
`Sheet 20 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`5
`OO
`
`FIG. 24
`FIG. 24
`
`MonoSol2012-0023
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 21 of 34
`Sheet 21 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 25
`FIG. 25
`
`MonoSol2012-0024
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 22 of 34
`Sheet 22 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`F~G. 26
`FIG. 26
`
`MonoSol2012-0025
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 23 of 34
`Sheet 23 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`FIG. 27
`FIG. 27
`
`MonoSol2012-0026
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 24 of 34
`Sheet 24 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 28
`FIG. 28
`
`MonoSol2012-0027
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 25 of 34
`Sheet 25 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 29
`FIG. 29
`
`MonoSol2012-0028
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 26 of 34
`Sheet 26 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 30
`F|G. 30
`
`MonoSol2012-0029
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 27 of 34
`Sheet 27 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`
`
`500
`500
`
`FIG. 31
`FIG. 31
`
`MonoSol2012-0030
`
`

`
`U.S. Patent
`
`~
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`Selected Gene Us!:
`X -axis:
`Y -axis:
`
`all genes (1235)
`joe cummins IDefaun Interpretationl: .. .
`Joe cummins Default Interpretation: .. .
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`Colored by:
`Gene Us!:
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`joe cummins /Defaun Interpretation)
`all genes (1235)
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`Normalized to GAPDH, most of the ISGs are induced.
`
`FIG. 32
`
`MonoSol2012-0031
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 29 of 34
`Sheet 29 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
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`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 30 of 34
`Sheet 30 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
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`MonoSol2012-0033
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 31 of 34
`Sheet 31 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
`100
`100
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`120
`120
`
`101
`101
`
`102
`102
`
`103
`103
`
`FIG. 35
`FIG. 35
`
`MonoSol2012-0034
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 32 of 34
`Sheet 32 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
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`
`201
`
`202
`
`203
`
`FIG. 36
`F|G. 36
`
`MonoSol2012-0035
`
`

`
`u.s. Patent
`U.S. Patent
`
`Feb. 23, 2010
`Feb. 23,2010
`
`Sheet 33 of 34
`Sheet 33 of 34
`
`US 7,666,337 B2
`US 7,666,337 B2
`
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`MonoSol2012-0036
`
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`Feb. 23, 2010
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`Tendency to go
`10 roof of
`mouth
`low
`
`film
`180'
`bend molding
`lesl
`Passed
`
`No
`
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`
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`
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`
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`
`High
`
`High
`
`Passed
`
`Passed
`
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`
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`
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`
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`
`No
`
`No
`
`No
`
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`
`No
`
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`
`Hating of
`Ois-
`solution dissolution
`{sec}
`in moulh
`fosllo
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`fosl
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`(min)
`9
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`8
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`8
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`9
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`9
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`8
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`Excellent
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`4
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`4.5 Adequate
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`4.1 Good
`
`145 Weak
`
`Good
`
`2.21
`
`2.86
`
`2.27
`
`1.96
`
`4.21
`
`50.0
`
`6600
`
`3440
`
`37.5
`
`121,200
`
`82,000
`
`30.0
`
`30.0
`
`185,000
`
`107
`
`15 Adequate
`
`37.5
`
`21,200
`
`1.65
`
`4
`
`Good
`
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`
`Sheet 34 of 34
`
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`
`US 7,666,337 B2
`
`-....l = N
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`Excellenl
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`
`Slighl
`
`Low
`
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`
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`
`High
`
`High
`
`Low
`
`High
`
`High
`
`Low
`
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`
`High
`
`Passed
`
`Passed
`
`PassfJd
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`No
`
`No
`
`No
`
`Yes
`
`Yes
`
`res
`
`No
`
`No
`
`4
`
`7
`
`14-15
`
`4
`
`3
`
`8
`
`22
`
`3
`
`fasl
`
`fosl to
`Moderate
`Slow
`
`fasllo
`Noderale
`fosllo
`Moderate
`Slow
`
`Slow
`
`Noderale
`
`~-
`
`9
`
`7
`
`9
`
`8
`
`9
`
`8
`
`10
`
`10
`
`!
`
`!
`
`Ex. Polymer ff Solids Viscosity %
`film
`film
`"'omponent of
`(cp) 015 moislure thickness strength
`Reference solulion
`rpm
`(mils)
`18 Adequate
`45.0
`14800
`EI PEql,PYP
`160/40)
`[J PEql,PVP
`140/60)
`E/( PEql,~torch 40.0
`'80/20}
`EL PEql,a,C
`/80/20)
`EN PEql,CMC
`/60140)
`EN PEql,CMC
`/40/60)
`FIG. 38 EO PEqJ;.HPC
`80;20)
`EP PEqljlPC
`1/60/40)
`EO ipEq;~PC
`1/40160)
`ER IPEql,~PC
`1/20/80)
`ES IfJEql!!PNC 37.5
`1/80;20)
`ET IPEql,HPNC 37.5
`1/60;40)
`EU IfJEql,HPMC 35.0
`1/40;60)
`EV PEql,~PNC 35.0
`1/20/80)
`FW IfJEql!VA
`!/80;20)
`
`37.5
`
`42.5
`
`43,400
`
`42.5
`
`46,400
`
`29,000
`
`17,000
`
`2.84
`
`3.8 Adequate
`
`2.83
`
`2.33
`
`4.5 Poor 10
`adequate
`4.4 Adequate
`10 good
`2.14 U Adequate
`
`47,000
`
`54,800
`
`2.37
`
`3.55
`
`96,600 U3
`
`J.9 Poor 10
`adequate
`4.5 Adequate
`10 good
`4.5 Good
`
`37.5
`
`41,600
`
`2.92
`
`9
`
`Weak
`
`MonoSol2012-0037
`
`

`
`US 7,666,337 B2
`US 7,666,337 B2
`
`1
`1
`POLYETHYLENE OXIDE-BASED FILMS AND
`POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`THEREFROM
`
`CROSS-REFERENCE TO RELATED
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`APPLICATIONS
`
`2
`2
`the like. However, historically films and the process of mak
`the like. However, historically films and the process ofmak(cid:173)
`ing drug delivery systems therefrom have suffered from a
`ing drug delivery systems therefrom have suffered from a
`number of unfavorable characteristics that have not allowed
`number of unfavorable characteristics that have not allowed
`them to be used in practice.
`them to be used in practice.
`Films that incorporate a pharmaceutically active ingredient
`Films that incorporate a pharmaceutically active ingredient
`are disclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et
`are disclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et
`al. (“Fuchs”). These films may be formed into a sheet, dried
`al. ("Fuchs"). These films may be formed into a sheet, dried
`and then cut into individual doses. The Fuchs disclosure
`and then cut into individual doses. The Fuchs disclosure
`alleges the fabrication of a uniform film, which includes the
`alleges the fabrication of a uniform film, which includes the
`combination of water-soluble polymers, surfactants, flavors,
`combination of water-soluble polymers, surfactants, flavors,
`sweeteners, plasticizers and drugs. These allegedly flexible
`sweeteners, plasticizers and drugs. These allegedly flexible
`films are disclosed as being useful for oral, topical or enteral
`films are disclosed as being useful for oral, topical or enteral
`use. Examples of specific uses disclosed by Fuchs include
`use. Examples of specific uses disclosed by Fuchs include
`application of the films to mucosal membrane areas of the
`application of the films to mucosal membrane areas of the
`body, including the mouth, rectal, vaginal, nasal and earareas.
`body, including the mouth, rectal, vaginal, nasal and ear areas.
`Examination offilms made in accordance with the process
`Examination of films made in accordance with the process
`disclosed in Fuchs, however, reveals that such films suffer
`disclosed in Fuchs, however, reveals that such films suffer
`from the aggregation or conglomeration of particles, i.e.,
`from the aggregation or conglomeration of particles, i.e.,
`self-aggregation, making them inherently non-uniform. This
`self-aggregation, making them inherently non-uniform. This
`result can be attributed to Fuchs’ process parameters, which
`result can be attributed to Fuchs' process parameters, which
`although not disclosed likely include the use of relatively long
`although not disclosed likely include the use of relatively long
`drying times, thereby facilitating intermolecular attractive
`drying times, thereby facilitating intermolecular attractive
`forces, convection forces, air flow and the like to form such
`forces, convection forces, air flow and the like to form such
`agglomeration.
`agglomeration.
`The formation of agglomerates randomly distributes the
`The formation of agglomerates randomly distributes the
`film components and any active present as well. When large
`film components and any active present as well. When large
`dosages are involved, a small change in the dimensions of the
`dosages are involved, a small change in the dimensions of the
`film would lead to a large difference in the amount of active
`film would lead to a large difference in the amount of active
`per film. If such films were to include low dosages of active,
`per film. If such films were to include low dosages of active,
`it is possible that portions of the film may be substantially
`it is possible that portions of the film may be substantially
`devoid of any active. Since sheets of film are usually cut into
`devoid of any active. Since sheets of film are usually cut into
`unit doses, certain doses may therefore be devoid of or con
`unit doses, certain doses may therefore be devoid of or con(cid:173)
`tain an insufficient amount of active for the recommended
`tain an insufficient amount of active for the recommended
`treatment. Failure to achieve a high degree of accuracy with
`treatment. Failure to achieve a high degree of accuracy with
`respect to the amount of active ingredient in the cut film can
`35 respect to the amount of active ingredient in the cut film can
`35
`be harmful to the patient. For this reason, dosage forms
`be harmful to the patient. For this reason, dosage forms
`formed by processes such as Fuchs, would not likely meet the
`formed by processes such as Fuchs, would not likely meet the
`stringent standards of governmental or regulatory agencies,
`stringent standards of governmental or regulatory agencies,
`such as the U.S. Federal Drug Administration (“FDA’’), relat
`such as the U. S. Federal Drug Administration ("FDA"), reI at -
`ing to the variation of active in dosage forms. Currently, as
`40 ing to the variation of active in dosage forms. Currently, as
`40
`required by various world regulatory authorities, dosage
`required by various world regulatory authorities, dosage
`forms may not vary more than 10% in the amount of active
`forms may not vary more than 10% in the amount of active
`present. When applied to dosage units based on films, this
`present. When applied to dosage units based on films, this
`virtually mandates that uniformity in the film be present.
`virtually mandates that uniformity in the film be p