111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008603514B2
`
`c12) United States Patent
`Yang et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,603,514 B2
`Dec. 10, 2013
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61F 13100
`A61K9/00
`A61K9170
`(52) U.S. Cl.
`USPC ........................................... 424/435; 424/484
`(58) Field of Classification Search
`None
`See application file for complete search history.
`References Cited
`
`(51)
`
`(56)
`
`(75)
`
`(54) UNIFORM FILMS FOR RAPID DISSOLVE
`DOSAGE FORM INCORPORATING
`TASTE-MASKING COMPOSITIONS
`Inventors: Robert K. Yang, Pushing, NY (US);
`Richard C. Fuisz, McLean, VA (US);
`Garry L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, Washington, DC (US)
`(73) Assignee: MonoSol RX, LLC, Warren, NJ (US)
`( *) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 779 days.
`(21) Appl. No.: 11/775,484
`Jul. 10, 2007
`(22) Filed:
`Prior Publication Data
`(65)
`
`Feb. 21, 2008
`US 2008/0044454 AI
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 10/768,809,
`filed on Jan. 30, 2004, now Pat. No. 7,357,891, and a
`continuation-in-part
`of
`application
`No.
`PCT/US02/32575, filed on Oct. 11, 2002, and a
`continuation-in-part of application No. 10/074,272,
`filed on Feb. 14, 2002, now Pat. No. 7,425,292, said
`application No. 10/768,809 is a continuation-in-part of
`application No. PCT/US02/32594, filed on Oct. 11,
`2002, and a continuation-in-part of application No.
`10/074,272, said application No. 10/768,809 is a
`continuation-in-part
`of
`application
`No.
`PCT/US02/32542, filed on Oct. 11, 2002, and a
`continuation-in-part of application No. 10/074,272,
`application No.
`11/775,484, which
`is
`a
`continuation-in-part of application No. 10/856,176,
`filed on May 28, 2004, now Pat. No. 7,666,337, and a
`continuation-in-part of application No. 10/768,809.
`
`(60) Provisional application No. 60/443,741, filed on Jan.
`30, 2003, provisional application No. 60/386,937,
`filed on Jun. 7, 2002, provisional application No.
`60/328,868, filed on Oct. 12, 2001, provisional
`application No. 60/414,276, filed on Sep. 27, 2002,
`provisional application No. 60/473,902, filed on May
`28, 2003.
`
`U.S. PATENT DOCUMENTS
`
`307,537 A
`688,446 A
`
`1111884 Foulks
`12/1901 Stempel
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`
`111976
`2432925
`4/1976
`2449865
`(Continued)
`OTHER PUBLICATIONS
`
`Lazaridou et a!.; Thermophysical properties of chitosan, chi to san(cid:173)
`starch and chitosan-pullulan films near the glass transition; Carbo(cid:173)
`hydrate Polymers, Applied Science Publishers, Ltd; Barking, GB,
`vol. 48, No.2, May 1, 2002, pp. 170-190.
`
`(Continued)
`Primary Examiner- Anand Desai
`Assistant Examiner- Melissa Mercier
`(74) Attorney, Agent, or Firm- Hoffmann & Baron, LLP
`ABSTRACT
`(57)
`The present invention relates to rapid dissolve thin film drug
`delivery compositions for the oral administration of active
`components. The active components are provided as taste(cid:173)
`masked or controlled-release coated particles uniformly dis(cid:173)
`tributed throughout the film composition. The compositions
`may be formed by wet casting methods, where the film is cast
`and controllably dried, or alternatively by an extrusion
`method.
`
`76 Claims, 34 Drawing Sheets
`
`10
`,-/
`
`14
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`12
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`14
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`DRL - EXHIBIT 1001
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`US 8,603,514 B2
`Page 2
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`(56)
`
`References Cited
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`US 8,603,514 B2
`Page 3
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`(56)
`
`References Cited
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`FOREIGN PATENT DOCUMENTS
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`
`3/1988
`10/1987
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`10/1991
`10/1992
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`9/1993
`12/1993
`8/1994
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`5/2004
`5/1978
`5/1991
`9/1992
`
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`9505416
`9518046
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`W00042992
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`
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`cal films produced by hot-melt extrusion; Journal of Controlled
`Release; vol. 70; pp. 341-351; 2001.
`* cited by examiner
`
`DRL - EXHIBIT 1001
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`U.S. Patent
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`Dec. 10, 2013
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`Sheet 1 of 34
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`US 8,603,514 B2
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`10
`
`14
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`12
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`14
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`FIG. 1
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`10
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`FIG. 3
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`FIG. 4
`
`FIG. 5
`
`DRL - EXHIBIT 1001
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`U.S. Patent
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`Sheet 2 of 34
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`US 8,603,514 B2
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`20
`
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`
`22
`
`\ 6heaf
`
`46
`
`FIG. 6
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`DRL - EXHIBIT 1001
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`Dec. 10, 2013
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`Sheet 3 of 34
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`US 8,603,514 B2
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`DRL - EXHIBIT 1001
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`Dec. 10, 2013
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`Sheet 4 of 34
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`U.S. Patent
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`Sheet 5 of 34
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`110
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`100
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`FIG. 9
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`Sheet 6 of 34
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`100
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`FIG. 10
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`Sheet 7 of 34
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`FIG. 11
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`100
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`Sheet 8 of 34
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`FIG. 12
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`Sheet 9 of 34
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`100
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`FIG. 13
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`100
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`FIG. 14
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`Sheet 11 of 34
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`100
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`Sheet 12 of 34
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`FIG. 16
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`FIG. 18
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`FIG. 21
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`FIG. 23
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`FIG. 24
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`FIG. 25
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`U.S. Patent
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`FIG. 28
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`Sheet 25 of 34
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`FIG. 29
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`Sheet 26 of 34
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`FIG. 30
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`U.S. Patent
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`US 8,603,514 B2
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`FIG. 31
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`C)
`
`c-.i = = ~I
`
`u..
`~ 1000 ~
`
`(_)
`<(I
`:z
`0::
`ro
`:::r::
`::2
`~ -E
`E
`8 100 ~------~~~~--~~-------4--------------+--------------t-
`
`Q)
`0
`
`~I
`~ = ~
`
`100
`
`110102 _JoeCumminsMHaRNA _ Cy51FN _ 0002.gpr (control)
`1000
`10000
`100000
`
`Selected Gene List:
`X-axis:
`Y -axis:
`
`all genes (1235)
`joe cumm1ns (Default lnterpretationl: .. .
`JOe cummins (Default Interpretation : .. .
`
`Colored by:
`Gene List:
`
`joe cummins (Default Interpretation)
`all genes ( 1235)
`
`Normalized to GAPDH, most of the ISGs are induced.
`
`FIG. 32
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`c ('D
`~ ....
`
`~0
`N
`
`0 ....
`
`(.H
`
`('D
`('D
`
`rFJ =(cid:173)
`.....
`N
`QO
`
`0 .....
`
`(.H
`.j;o.
`
`d
`rJl
`00
`
`0.., = w u.
`""""' ~ = N
`
`DRL - EXHIBIT 1001
`DRL031
`
`

`
`U.S. Patent
`
`Dec. 10, 2013
`
`Sheet 29 of 34
`
`US 8,603,514 B2
`
`~
`
`~(J'
`'-..:...
`Q...
`
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`.
`(.9
`u.
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`
`-
`
`DRL - EXHIBIT 1001
`DRL032
`
`

`
`U.S. Patent
`
`Dec. 10, 2013
`
`Sheet 30 of 34
`
`US 8,603,514 B2
`
`"="""'
`~(S
`\...:....
`0....
`
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`......
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`
`DRL - EXHIBIT 1001
`DRL033
`
`

`
`U.S. Patent
`
`Dec. 10, 2013
`
`Sheet 31 of 34
`
`US 8,603,514 B2
`
`100
`
`~
`
`110
`
`120
`
`101
`
`102
`
`103
`
`FIG. 35
`
`DRL - EXHIBIT 1001
`DRL034
`
`

`
`U.S. Patent
`
`Dec. 10, 2013
`
`Sheet 32 of 34
`
`US 8,603,514 B2
`
`200
`
`~
`
`~-+--------+----+--------+----+--------+------....
`
`201
`
`202
`
`203
`
`FIG. 36
`
`DRL - EXHIBIT 1001
`DRL035
`
`

`
`U.S. Patent
`
`Dec. 10, 2013
`
`Sheet 33 of 34
`
`US 8,603,514 B2
`
`•
`C.9
`u.
`
`DRL - EXHIBIT 1001
`DRL036
`
`

`
`50.0
`
`6600
`
`3440
`
`37.5
`
`121,200
`
`30.0
`
`82,000
`
`2.21
`
`2.86
`
`2.27
`
`1.96
`
`4.21
`
`Tear
`Resistance
`
`Excellent
`
`Low to
`moderate
`Excellent
`
`Excellent
`
`4
`
`Weak
`
`4.5 Adequate
`to good
`4.1 Good
`
`3.45 Weak
`
`Good
`
`30.0
`
`185,000
`
`3.07
`
`3.5 Adequate
`
`Vety low
`
`37.5
`
`21,200
`
`1.65
`
`4
`
`Good
`
`Excellent
`
`17,000
`
`Tendency to go
`to roof of
`mouth
`Low
`
`180'
`Film
`bend molding
`test
`Passed
`
`No
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Failed
`
`Passed
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`High
`
`High
`
`High
`
`High
`
`High
`
`High
`
`High
`
`Rating of
`Dis-
`solution dissolution
`(sec)
`in mouth
`Fast to
`3
`Moderate
`Fast
`
`3
`
`Fast to
`Moderate
`Slow
`
`Slow to
`Moderate
`Slow
`
`Fast
`
`3
`
`5
`
`3
`
`4
`
`4
`
`4
`
`Time
`in oven
`(min)
`9
`
`8
`
`8
`
`9
`
`9
`
`9
`
`8
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`c ('D
`~ ....
`
`~0
`N
`
`0 ....
`
`(.H
`
`rFJ =(cid:173)
`.....
`
`('D
`('D
`
`[x. Polymer f%' Solids Viscosity %
`Film
`Film
`~omponent of
`(cp} at 5 moisture thickness strength
`Reference solution
`rpm
`(mils)
`[I IP[q/_PVP
`3.8 Adequate
`45.0
`14800
`1160/40)
`[J lfJ£qf,PVP
`1140/60)
`£K lfJ£ql,~tarch 40.0
`1180/20)
`£L IP£qi,~MC
`1180/20)
`EM IP£q(CMC
`1160/40)
`EN IP£q(~MC
`1140/60)
`FIG. 38 £0 IP£qf,HPC
`1180/20)
`[p lfJ£qf,HPC
`1160/40)
`£0 lfJ£qf,~PC
`1140/60)
`£R IP£q(_HPC
`1120/80)
`£S IP£q(~PMC
`1180/20)
`£T IP£q(HPMC 37.5
`1160/40)
`[lj lfJ£qf,HPMC 35.0
`1140/60)
`£V IP£qf,~PMC 35.0
`1120/80)
`£W IP£q(~VA
`1180/20)
`
`37.5
`
`42.5
`
`43,400
`
`42.5
`
`46,400
`
`37.5
`
`29,000
`
`47,000
`
`54,800
`
`96,600
`
`37.5
`
`41,600
`
`2.84
`
`2.83
`
`2.33
`
`2.14
`
`2.37
`
`3.55
`
`4.43
`
`2.92
`
`3.8 Adequate
`
`4.5 Poor to
`adequate
`4.4 Adequate
`to good
`4.4 Adequate
`
`3.9 Poor to
`adequate
`4.5 Adequate
`to good
`4.5 Good
`
`9
`
`Weak
`
`Excellent
`
`Poor to
`good
`Poor
`
`Good
`
`Slight
`
`Low
`
`Low
`
`Moderate
`
`High
`
`Low
`
`High
`
`High
`
`Low
`
`Low
`
`High
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`Passed
`
`No
`
`No
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`No
`
`Fast
`
`Fast to
`Moderate
`Slow
`
`Fast to
`Moderate
`Fast to
`Moderate
`Slow
`
`Slow
`
`Moderate
`
`7
`
`14-15
`
`4
`
`3
`
`8
`
`22
`
`3
`
`9
`
`7
`
`9
`
`8
`
`9
`
`8
`
`10
`
`10
`
`(.H
`.j;o.
`
`0 .....
`
`(.H
`.j;o.
`
`d
`rJl
`00
`
`0.., = w u.
`""""' ~ = N
`
`DRL - EXHIBIT 1001
`DRL037
`
`

`
`US 8,603,514 B2
`
`1
`UNIFORM FILMS FOR RAPID DISSOLVE
`DOSAGE FORM INCORPORATING
`TASTE-MASKING COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`2
`As an alternative to tablets and pills, films may be used to
`carry active ingredients such as drugs, pharmaceuticals, and
`the like. However, historically films and the process of mak(cid:173)
`ing drug delivery systems therefrom have suffered from a
`5 number of unfavorable characteristics that have not allowed
`them to be used in practice.
`Films that incorporate a pharmaceutically active ingredient
`are disclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et
`a!. ("Fuchs"). These films may be formed into a sheet, dried
`10 and then cut into individual doses. The Fuchs disclosure
`alleges the fabrication of a uniform film, which includes the
`combination of water-soluble polymers, surfactants, flavors,
`sweeteners, plasticizers and drugs. These allegedly flexible
`films are disclosed as being useful for oral, topical or enteral
`use. Examples of specific uses disclosed by Fuchs include
`application of the films to mucosal membrane areas of the
`body, including the mouth, rectal, vaginal, nasal and ear areas.
`Examination of films made in accordance with the process
`disclosed in Fuchs, however, reveals that such films suffer
`from the aggregation or conglomeration of particles, i.e.,
`self-aggregation, making them inherently non-uniform. This
`result can be attributed to Fuchs' process parameters, which
`although not disclosed likely include the use of relatively long
`drying times, thereby facilitating intermolecular attractive
`forces, convection forces, air flow and the like to form such
`agglomeration.
`The formation of agglomerates randomly distributes the
`film components and any active present as well. When large
`dosages are involved, a small change in the dimensions of the
`film would lead to a large difference in the amount 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
`devoid of any active. Since sheets of film are usually cut into
`unit doses, certain doses may therefore be devoid of or con(cid:173)
`tain an insufficient amount of active for the recommended
`treatment. Failure to achieve a high degree of accuracy with
`respect to the amount of active ingredient in the cut film can
`be harmful to the patient. For this reason, dosage forms
`formed by processes such as Fuchs, would not likely meet the
`40 stringent standards of governmental or regulatory agencies,
`such as the U.S. Federal Drug Administration ("FDA"), relat(cid:173)
`ing to the variation of active in dosage forms. Currently, as
`required by various world regulatory authorities, dosage
`forms may not vary more than 10% in the amount of active
`45 present. When applied to dosage units based on films, this
`virtually mandates that uniformity in the film be present.
`The problems of self-aggregation leading to non-unifor(cid:173)
`mity of a film were addressed in U.S. Pat. No. 4,849,246 to
`Schmidt ("Schmidt"). Schmidt specifically pointed out that
`50 the methods disclosed by Fuchs did not provide a uniform
`film and recognized that that the creation of a non-uniform
`film necessarily prevents accurate dosing, which as discussed
`above is especially important in the pharmaceutical area.
`Schmidt abandoned the idea that a mono-layer film, such as
`55 described by Fuchs, may provide an accurate dosage form
`and instead attempted to solve this problem by forming a
`multi-layered film. Moreover, his process is a multi-step pro(cid:173)
`cess that adds expense and complexity and is not practical for
`commercial use.
`Other U.S. patents directly addressed the problems of par-
`ticle self-aggregation and non-uniformity inherent in conven(cid:173)
`tional film forming techniques. In one attempt to overcome
`non-uniformity, U.S. Pat. No. 5,629,003 to Horstmann eta!.
`and U.S. Pat. No. 5,948,430 to Zerbe et a!. incorporated
`65 additional ingredients, i.e. gel formers and polyhydric alco(cid:173)
`hols respectively, to increase the viscosity of the film prior to
`drying in an effort to reduce aggregation of the components in
`
`This application is a continuation-in-part of U.S. applica(cid:173)
`tion Ser. No. 10/768,809, filed Jan. 30, 2004, which claims
`benefit to U.S. Provisional Application No. 60/443,741 filed
`Jan. 30, 2003; U.S. application Ser. No. 10/768,809 is also a
`continuation-in-part of PCTIUS02/32575, filed Oct. 11,
`2002, which claims priority to U.S. Provisional Application
`No. 60/386,937, filed Jun. 7, 2002, and is a continuation-in- 15
`part of U.S. application Ser. No. 10/074,272, filed Feb. 14,
`2002, which claims priority to U.S. Provisional Application
`No. 60/328,868, filed Oct. 12, 2001; U.S. application Ser. No.
`10/768,809 is also a continuation-in-part of PCT/US02/
`32594, filed Oct. 11, 2002, which claims priority to U.S. 20
`Provisional Application No. 60/414,276, filed Sep. 27,2002,
`and U.S. Provisional Application No. 60/386,937, filed Jun.
`7, 2002, and is a continuation-in-part ofU.S. application Ser.
`No. 10/074,272, filed Feb. 14,2002, which claims priority to
`U.S. Provisional Application No. 60/328,868, filed Oct. 12, 25
`2001; and U.S. application Ser. No. 10/768,809 is also a
`continuation-in-part of PCTIUS02/32542, filed Oct. 11,
`2002, which claims priority to U.S. Provisional Application
`No. 60/386,937, filed Jun. 7, 2002, and U.S. Provisional
`Application No. 60/371,940, filed Apr. 11, 2002, and is a 30
`continuation-in-part ofU.S. application Ser. No. 10/074,272,
`filed Feb. 14, 2002, which claims priority to U.S. Provisional
`Application No. 60/328,868, filed Oct. 12, 2001; this appli(cid:173)
`cation is also a continuation-in-part of U.S. application Ser.
`No. 10/856,176, filed May 28,2004, which claims priority to 35
`U.S. Provisional Application No. 60/473,902, filed May 28,
`2003; U.S. application Ser. No. 10/856,176 is also a continu(cid:173)
`ation-in-part of U.S. application Ser. No. 10/768,809; the
`contents all of which are incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to rapidly dissolving films
`and methods of their preparation. The films contain a polymer
`component and active ingredients as taste-masked or con(cid:173)
`trolled-release coated particles uniformly distributed
`throughout the film.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`Active ingredients, such as drugs or pharmaceuticals, may
`be prepared in a tablet form to allow for accurate and consis(cid:173)
`tent dosing. However, this form of preparing and dispensing
`medications has many disadvantages including that a large
`proportion of adjuvants that must be added to obtain a size
`able to be handled, that a larger medication form requires
`additional storage space, and that dispensing includes count(cid:173)
`ing the tablets which has a tendency for inaccuracy. In addi(cid:173)
`tion, many persons, estimated to be as much as 28% of the 60
`population, have difficulty swallowing tablets. While tablets
`may be broken into smaller pieces or even crushed as a means
`of overcoming swallowing difficulties, this is not a suitable
`solution for many tablet or pill forms. For example, crushing
`or destroying the tablet or pill form to facilitate ingestion,
`alone or in admixture with food, may also destroy the con(cid:173)
`trolled release properties.
`
`DRL - EXHIBIT 1001
`DRL038
`
`

`
`US 8,603,514 B2
`
`3
`the film. These methods have the disadvantage of requiring
`additional components, which translates to additional cost
`and manufacturing steps. Furthermore, both methods employ
`the use the conventional time-consuming drying methods
`such as a high-temperature air-bath using a drying oven,
`drying tunnel, vacuum drier, or other such drying equipment.
`The long length of drying time aids in promoting the aggre(cid:173)
`gation of the active and other adjuvant, notwithstanding the
`use of viscosity modifiers. Such processes also run the risk of
`exposing the active, i.e., a drug, or vitamin C, or other com- 10
`ponents to prolonged exposure to moisture and elevated tem(cid:173)
`peratures, which may render it ineffective or even harmful.
`In addition to the concerns associated with degradation of
`an active during extended exposure to moisture, the conven(cid:173)
`tional drying methods themselves are unable to provide uni- 15
`form films. The length of heat exposure during conventional
`processing, often referred to as the "heat history", and the
`manner in which such heat is applied, have a direct effect on
`the formation and morphology of the resultant film product.
`Uniformity is particularly difficult to achieve via conven- 20
`tiona! drying methods where a relatively thicker film, which is
`well-suited for the incorporation of a drug active, is desired.
`Thicker uniform films are more difficult to achieve because
`the surfaces of the film and the inner portions of the film do
`not experience the same external conditions simultaneously 25
`during drying. Thus, observation of relatively thick films
`made from such conventional processing shows a non-uni(cid:173)
`form structure caused by convection and intermolecular
`forces and requires greater than 10% moisture to remain
`flexible. The amount of free moisture can often interfere over 30
`time with the drug leading to potency issues and therefore
`inconsistency in the final product.
`Conventional drying methods generally include the use of
`forced hot air using a drying oven, drying tunnel, and the like.
`The difficulty in achieving a uniform film is directly related to
`the rheological properties and the process of water evapora(cid:173)
`tion in the film-forming composition. When the surface of an
`aqueous polymer solution is contacted with a high tempera(cid:173)
`ture air current, such as a film-forming composition passing
`through a hot air oven, the surface water is immediately
`evaporated forming a polymer film or skin on the surface.
`This seals the remainder of the aqueous film-forming com(cid:173)
`position beneath the surface, forming a barrier through which
`the remaining water must force itself as it is evaporated in
`order to achieve a dried film. As the temperature outside the
`film continues to increase, water vapor pressure builds up
`under the surface of the film, stretching the surface of the film,
`and ultimately ripping the film surface open allowing the
`water vapor to escape. As soon as the water vapor has
`escaped, the polymer film surface reforms, and this process is
`repeated, until the film is completely dried. The result of the
`repeated destruction and reformation of the film surface is
`observed as a "ripple effect" which produces an uneven, and
`therefore non-uniform film. Frequently, depending on the
`polymer, a surface will seal so tightly that the remaining water
`is difficult to remove, leading to very long drying times,
`higher temperatures, and higher energy costs.
`Other factors, such as mixing techniques, also play a role in
`the manufacture of a pharmaceutical film suitable for com(cid:173)
`mercialization and regulatory approval. Air can be trapped in
`the composition during the mixing process or later during the
`film making process, which can leave voids in the film prod(cid:173)
`uct as the moisture evaporates during the drying stage. The
`film frequently collapse around the voids resulting in an
`uneven film surface and therefore, non-uniformity of the final
`film product. Uniformity is still affected even if the voids in
`the film caused by air bubbles do not collapse. This situation
`
`4
`also provides a non-uniform film in that the spaces, which are
`not uniformly distributed, are occupying area that would oth(cid:173)
`erwise be occupied by the film composition. None of the
`above-mentioned patents either addresses or proposes a solu(cid:173)
`tion to the problems caused by air that has been introduced to
`the film.
`Therefore, there is a need for methods and compositions
`for film products, which use a minimal number of materials or
`components, and which provide a substantially non-self-ag(cid:173)
`gregating uniform heterogeneity throughout the area of the
`films. Desirably, such films are produced through a selection
`of a polymer or combination of polymers that will provide a
`desired viscosity, a film-forming process such as reverse roll
`coating, and a controlled, and desirably rapid, drying process
`which serves to maintain the uniform distribution of non-self(cid:173)
`aggregated components without the necessary addition of gel
`formers or poly hydric alcohols and the like which appear to
`be required in the products and for the processes of prior
`patents, such as the aforementioned Horstmarm and Zerbe
`patents. Desirably, the films will also incorporate composi(cid:173)
`tions and methods of manufacture that substantially reduce or
`eliminate air in the film, thereby promoting uniformity in the
`final film product.
`
`SUMMARY OF THE INVENTION
`
`In one aspect, this invention provides rapid-dissolve film
`products for drug delivery whereby the active agents are
`taste-masked or controlled-release coated particles uniformly
`distributed throughout the film. The uniform films of this
`invention can be divided into equally sized dosage units hav-
`ing substantially equal amounts of each compositional com(cid:173)
`ponent present. This advantage is particularly useful because
`it permits large area films to be initially formed, and subse-
`35 quently cut into individual dosage units without concern for
`whether each unit is compositionally equal. Pharmaceutical
`film dosage forms to date have not been marketed largely due
`to the inability to achieve this result. Thus, for example, the
`films of the present invention have particular applicability as
`40 pharmaceutical dosage delivery systems because each dosage
`unit, e.g., each individual dosage film unit, will contain the
`proper predetermined amount of drug.
`In a further aspect of the present invention, methods of
`forming the films of this invention are provided, by wet cast-
`45 ing methods and hot melt extrusion methods. In a wet casting
`method, the film product is formed by combining a polymer
`and a polar solvent, forming the combination into a film, and
`drying the film in a controlled manner. Preferably, the film is
`dried initially only applying heat to the bottom side of the
`50 film, in order to maintain a non-self-aggregating uniform
`heterogeneity. Desirably, during the initial bottom drying
`stage, substantially no convection currents, i.e., hot air cur(cid:173)
`rents, are permitted to travel across the top of the film until the
`visco-elastic properties of the film are such that the film
`55 components are "locked" in place and cannot move to cause
`non-uniformity. At that stage, other methods of heating to
`effect drying may be employed.
`The films may be formed with a polar solvent which may
`be water, a polar organic solvent, or a combination thereof. An
`60 active ingredient may be added to the polymer and water
`combination prior to the drying step. Alternatively, or in addi(cid:173)
`tion to controlling the drying the film, the polymer may be
`selected in order to provide a viscosity that maintains the
`non-self-aggregating unifo