WWMWWWWI MWWWWWWW
`
`U8008603514BZ
`
`(12) United States Patent
`Yang et a].
`
`[10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,603,514 32
`Dec. 10, 2013
`
`[54) UNIFORM FILMS FOR RAPID DISSOLVE
`DOSAGE FORM INCORPORATING
`TASTE-MASKING COMPOSITIONS
`
`(75)
`
`Inventors: Robert K. Yang. Pushing. NY (US):
`Richard (T. li‘uisz. McLean. VA (US):
`Garry L. Myers. Kingsport. TN (US):
`Joseph M. Fuisz. Washington, DC (US)
`
`(73) Assignee: MonoSol RX, LLC. Warren. NJ (US)
`
`( ’9‘ J Notice:
`
`Subject to any disclaimer. the term of this
`patent is extended or adjusted under 35
`U.S.(.‘.. 154(b) by 729 days.
`
`(21) Appl.No.: llfl75,484
`
`Filed:
`
`[22)
`(65)
`
`Jul. 10, 2007
`Prior Publication Data
`
`Feb. 21 , 2008
`US 2(l08t0044454 Al
`Related U.S. Application Data
`
`(63) Continuation-impart of application No. 101’768809.
`filed on Jan. 30. 2004. now Pat. No. 7.357.891. and a
`continuation-impart
`of
`application
`No.
`PC'I‘J’USDZHZSTS.
`filed on Oct.
`I]. 2002. and a
`continuation—in—part of application No. 102074.272.
`filed on Feb. 14. 2002. now Pat. No. 7.425.292. said
`application No. 101768.809 is a continuation-in-part of
`application No. PCITUSOZBZS‘J-il, filed on Oct. ll.
`2002. and a continuation-in-part of application No.
`l0f074.272. said application No.
`[037655.809 is a
`continuatimi-in-parl
`of
`application
`No.
`PC’I‘J’USDZBZS-‘rl
`filed on Oct.
`II. 2002. and a
`continuation—in—part of application No. 102074.272.
`application
`No.
`11r’775.484.
`which
`is
`a
`continuation-in-part of application No. 10i’856.l?6_.
`filed on May 28. 2004. now Pat. No. 7.666.337. and a
`continuation-in-part ol'application No. [0t768.809.
`
`(60) Provisional application No. 60t44334]. filed on Jan.
`30. 2003. provisional application No. 60.886337.
`filed on Jun. 7. 2002. provisional application No.
`601828.868.
`filed on Oct.
`12. 2001. provisional
`application No. 601414.276. filed on Sep. 27. 2002.
`provisional application No. 6(8473302. filed on May
`28. 2003.
`
`(51)
`
`Int. Cl.
`A6IF 13/00
`A61K 9/00
`AMK 9270
`(52) U.S. (:1.
`USPC
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`4241435: 4241484
`
`(58} Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`307.53? A
`688.446 A
`
`llt’l884 Foulks
`12:” l90| Stempel
`
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`Dli
`DE
`
`2432925
`2449865
`
`| I976
`4-1976
`
`(Continued)
`O'l‘l-Il'iR PUBLICA'I‘10NS
`
`Lazaridou et al.:_ '[hcrmophysical properties ot‘chitosan. chitesan-
`starch and chitosan—pullnlrm films near the glass Lransition: Carbo—
`hydrate Polymers. Applied Science Publishers. Ltd; Barking. GB.
`vol. 48. No. 2. May I. 2002. pp. ITO-I90.
`
`(Continued)
`
`Primij Examiner — Aliand Desai
`Assistant Exmniner — Melissa Mercier
`
`(74) Attorney. Agent. or Firm — Hoffmann & Baron. LL-P
`
`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~
`masked or controlled—release coated particles uniformly dis—
`tributed throughout the film composition. The compositions
`may be lbrmed by wet casting methods. where the film is cast
`and controllany dried. or alternatively by an extrusion
`method.
`
`76 Claims. 34 Drawing Sheets
`
`10
`
`/ I4
`
`12
`
`74
`
`Dr. Reddy's - EX1001
`Dr. Reddy’s — EX1001
`Page 1
`Page 1
`
`

`

`US 8,603,514 B2
`
`Page 2
`
`(56}
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`Page 2
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`
`

`

`US 8,603,514 B2
` Page 3
`
`(56)
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`Page 3
`Page 3
`
`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 1 of 34
`
`US 8,603,514 32
`
`70
`
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`14
`
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`
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`
`FIG. 1
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`
`Page 4
`Page 4
`
`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 2 of 34
`
`US 8,603,514 B2
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`
`
`Page 5
`Page 5
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`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 3 of 34
`
`US 8,603,514 B2
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`4
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`Page 6
`Page 6
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`US. Patent
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`Dec. 10, 2013
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`Sheet 4 of 34
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`US 8,603,514 B2
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`US. Patent
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`Dec. 10, 2013
`
`Sheet 5 of 34
`
`US 8,603,514 B2
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`
`Page 8
`Page 8
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`US. Patent
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`Dec. 10, 2013
`
`Sheet 6 of 34
`
`Us 8,603,514 B2
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`Page 9
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`

`

`
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`US. Patent
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`Dec. 10, 2013
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`Sheet 8 of 34
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`US 8,603,514 B2
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`US. Patent
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`Dec. 10, 2013
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`Sheet 9 of 34
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`Us 8,603,514 B2
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`US. Patent
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`Dec. 10, 2013
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`Sheet 10 of 34
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`Us 8,603,514 B2
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`US. Patent
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`Dec. 10, 2013
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`Sheet 11 of 34
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`Us 8,603,514 B2
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`US. Patent
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`Sheet 12 of 34
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`Us 8,603,514 B2
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`US. Patent
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`Sheet 13 of 34
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`FIG. 17
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`Sheet 14 0134
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`US 8,603,514 B2
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`FIG. 18
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`Sheet 15 0134
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`(23) 1t:
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`500
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`Sheet 16 0134
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`US 8,603,514 B2
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`500
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`Sheet 17 0134
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`US 8,603,514 B2
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`(2231K) 100um
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`500
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`US. Patent
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`Sheet 18 of 34
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`500
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`FIG. 22
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`Sheet 19 of 34
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`500
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`FIG. 23
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`500
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`FIG. 24
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`US 8,603,514 132
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`500
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`FIG. 25
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`FIG. 26
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`Sheet 23 MM
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`US 8,603,514 132
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`FIG. 27
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`Sheet 24 0134
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`500
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`FIG. 28
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`US. Patent
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`Sheet 26 of 34
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`Us 8,603,514 B2
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`
`
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`Page 29
`Page 29
`
`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 27 of 34
`
`US 8,603,514 B2
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`
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`500
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`Page 30
`Page 30
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`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 29 0f 34
`
`US 8,603,514 B2
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`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 30 of 34
`
`US 8,603,514 B2
`
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`Page 33
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`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 31 0f 34
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`US 8,603,514 32
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`Page 34
`Page 34
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`

`

`US. Patent
`
`Dec. 10, 2013
`
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`US 8,603,514 32
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`Page 35
`Page 35
`
`

`

`US. Patent
`
`Dec. 10, 2013
`
`Sheet 33 of 34
`
`US 8,603,514 B2
`
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`Page 37
`Page 37
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`

`

`US 8,603,514 BZ
`
`1
`UNIFORM FILMS FOR RAPID DISSOLVE
`DOSAGE FORM INCORPORA'I'ING
`'I‘ASTE-MASKING COMPOSITIONS
`
`('ROSS-RIil-‘liRliNCIi TO RlIiI .A'I'ED
`APPLICATIONS
`
`This application is a continuation-in-part ofU.S. applica‘
`tion Ser. No. 10f768,809. filed .1 an. 30. 2004. which claims
`benefit to U .S. Provisional Application No. GUM-43.741 filed
`Jan. 30. 2003; U.S. application Ser. No. 10i’ir'68.809 is also a
`continuation—in—part of PCTJUSO2I325?5.
`filed Oct. 11.
`2002. which claims priority to U.S. Provisional Application
`No. 60l386.937. filed Jun. 7. 2002. and is a continuation-irr-
`part of U.S. application Ser. No. 10f0?4.272. filed Feb. 14.
`2002. which claims priority to 11 .S. Provisional Application
`No. 60828868. filed Oct. 12. 2001: U.S. application Ser. No.
`101768.809 is also a continuation-in-part of PCTJ'USO2!
`32594. filed Oct. ll. 2002. which claims priority to U.S.
`Provisional Application No. 60!4l4.276. filed Sep. 27. 2002.
`and U.S. Provisional Application No. 60886931 filed Jun.
`7. 2002. and is a continuation-in-part ofU.S. application Ser.
`No. 10l074.272. filed Feb. 14. 2002. which claims priority to
`U.S. Provisional Application No. 602828.868. filed Oct. 12.
`200]: and US. application Ser. No. 10f768.809 is also a
`continuation-in-part of “(1050282542.
`filed Oct.
`1 l.
`2002. which claims priority to U .S. Provisional Application
`No. 601886.937. filed Jun. 7. 2002. and U.S. Provisional
`Application No. 60871940. filed Apr. 1]. 2002. and is a
`contimlation-in-part of U .3. application Ser. No. 10f0?4.272.
`liled Feb. 14. 2002. which claims priority to U.S. Provisional
`Application No. 601328.868. filed Oct. 12. 2001: this appli-
`cation is also a continuation-in-part of U .5. application Ser.
`No. 101856.176. filed May 28. 2004. which claims priority to
`U.S. Provisional Application No. 60F473.902. filed May 28.
`2003: U.S. application Ser. No. 10l856.176 is also a continu-
`ation-in-part of U.S. application Ser. No. 10l768.809: the
`contents all of which are incorporated herein by reference.
`
`FIELD OF TI-Il'i INVIiN'l‘ION
`
`The present invention relates to rapidly dissolving films
`and methods oftheir preparation. The films contain a polymer
`component and active ingredients as taste-masked or con-
`trolled-release
`coated
`particles
`unifonnly
`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-
`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 fonu requires
`additional storage space, and that dispensing includes count-
`ing the tablets which has a tendency for inaccuracy. In addi-
`tion. many persons. estimated to be as much as 28% of the
`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-
`trolled release properties.
`
`10
`
`'
`
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`
`35
`
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`
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`
`50
`
`55
`
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`
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`
`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-
`ing drug delivery systems therefrom have sulTered from a
`number of unfavorable characteristics that have not allowed
`lhem 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
`a1. (“Fuchs”). These films may be formed into a sheet. dried
`and then cut into individual doses. The Fuchs disclosure
`
`alleges the fabrication of a uniform film. which includes the
`combination ofwater—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 tirade in accordance with the process
`disclosed in Fuchs. however. reveals that such films suffer
`from the aggregation or conglomeratiou 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 ofrelatively 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 ofthe
`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 ofany active. Since sheets of film are usually cut into
`unit doses. certain doses may therefore be devoid of or con-
`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 fomrs
`formed by processes such as Fuchs. would not likely meet the
`stringent standards of governmental or regulatory agencies.
`such as the U.S. Federal Drug Administration (“FDA”). relat-
`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
`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-
`mity ol'a film were addressed in U.S. Pat. No. 4.849.246 to
`Schmidt (“Schmidt”). Schmidt specifically pointed out that
`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
`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 rnulti—step pro—
`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-
`tional film forming techniques. in one attempt to overcome
`nonwuniformity. U.S. Pat. No. 5.629.003 to Horstrnann et al.
`and U.S. Pat. No. 5.948.430 to Zerbe et al. incorporated
`additional ingredients. i.e. gel formers and polyhydric alco-
`hols respectively. to increase the viscosity ofthe frlm prior to
`drying in an effort to reduce aggregation ofthe components in
`
`
`Page 38
`Page 38
`
`

`

`3
`
`4
`
`US 8,603,514 BZ
`
`the filth. These methods have the disadvantage of requiring
`additional components. which translates to additional cost
`and manufacturing steps. Furthermore. botli 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 ofdrying time aids in promoting. the aggre—
`gation of the active and other adjuvant. notwithstanding the
`ttse ofviscosity modifiers. Such processes also run the risk of
`exposing the active. i.e.. a drug. or vitamin C. or other com-
`ponents to prolonged exposttre to moisture and elevated tem-
`peraturcs. which tuay render it ineffective or even harmful.
`In addition to the concerns associated with degradation of
`an active during extended exposure to moisture. the conven—
`tional drying methods themselves are unable to provide titli-
`form films. The length of heat exposure during conventional
`processing. often referred to as the “heat history”. and the
`mamier in which such heat is applied. have a direct effect on
`the limitation and morphology of the resultant Iiltn product.
`Uniformity is particularly difficult to achieve via conven-
`tional 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
`during drying. Thus, observation of relatively thick films
`made from such conventional processing shows a non-uni-
`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
`
`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—
`tion in the film-forming composition. When the surface of an
`aqueous polymer solution is contacted with a high tempera-
`tttre 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—
`position beneath the surface. forming a barrier through which
`the remaining water must force itselfas 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 ofthe film. stretching the surface ofthe 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-
`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-
`ttct 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
`
`It]
`
`3U
`
`35
`
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`
`45
`
`50
`
`55
`
`6t;
`
`also provides a non-uniform film in that the spaces. which are
`not uniformly distributed. are occupying area that would oth-
`erwise be occupied by the film composition. None of the
`above-mentioned patents either addresses or proposes a solu-
`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 ofmaterials or
`components. and which provide a substantially non-self-ag-
`gregating unifomi heterogeneity throughout the area of the
`films. Desirably. such films are produced through a selection
`ol‘a polymer or combination ofpolymers that will provide a
`desired viscosity. :1 film-limiting process such as reverse roll
`coating. and a controlled. and desirably rapid. drying process
`which serves to maintain the uniform distribution ofnonfiselfu
`
`aggregated components without the necessary addition of gel
`formers or polyhydric alcohols and the like which appear to
`be required in the products and for the processes of prior
`patents. such as the aforementioned l-lorstmann and Zerbe
`patents. Desirably. the films will also incorporate composi-
`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
`ta ste-ina sked or controlled-release coated particles uniformly
`distributed throughout the film. The uniform films of this
`invention can be divided into equally sired dosage tutits hav-
`ing substantially equal amounts of each compositional com-
`ponent present. This advantage is particularly useful because
`it permits large area films to be initially formed. and subSe-
`quently cut into individual dosage units without concem for
`whether each unit is compositional ly equal. Phamiaceutical
`film dosage forms to date have not been marketed largely dtte
`to the inability to achieve this result. Thus, for example. the
`films of the present invention have particular applicability as
`pha nnac eutical 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 filtns of this invention are provided. by wet cast-
`ing methods and hot melt extrusion methods. in a wet casting
`method. the film product is fomied 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
`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-
`rents. are pemiittcd to travel across the top ofthe film until the
`visco-elastic properties of the film are such that the film
`components are “locked” in place and cannot move to cause
`nonwuniformity. 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. ora combination thereof. An
`active ingredient may be added to the polymer and water
`combination prior to the drying step. Alternatively. or in addi-
`tion to controlling the drying the film. the polymer may be
`selected in order to provide a viscosity that maintains the
`no1i—self~'tggregating uniform heterogeneity. Moreover. the
`composition desirably is mixed in a manner to minimize the
`incorporation of air into the mixture and is desirably deaer-
`ated, such as by conditioning at room temperature. vacuum
`
`
`Page 39
`Page 39
`
`

`

`5
`
`6
`
`US 8,603,514 BZ
`
`treatment or the like. to allow trapped air to escape prior to the
`drying process. This serves to eliminate bubble and void
`formation in the final film product. thereby further improving
`uniformity. Reverse roll coating is one particularly useful
`coating technique may also be used to form the film.
`Another embodiment of the present invention may include
`a rapid—dissolve film product containing at least one water—
`soluble polymer including polyethylene oxide alone or in
`combination with a hydrophilic cellulosic polymer. wherein
`the film product may be free ofadded plasticizers. Preferably.
`the rapid-dissolve film product includes at least one water-
`soiuble polymer containing about 20% to 100% by weight
`polyethylene oxide. about 0% to 80% by weight hydroxypro-
`pylmethyl cellulose. and about 0% to 80% by weight hydrox—
`ypropyl cellulose: an active component: sweetener: at least
`one flavoring: and at least one colorant. wherein the film
`product optionally is free of added plasticizers. surfactants.
`and polyalcohols.
`the films
`invention.
`in another aspect of the present
`employing polyethylene oxide as the film-fonning polymer
`may be formed by a hot melt extrusion process. whereby an
`edible film—forming polymer is provided. and active compo»
`nents are added during manufacture; and the mixture is
`blended at elevated temperature in the absence of additional
`solvent to form a uniform matrix. and extruded to form a film.
`Desirably, the film will be further shaped by rollers to a
`specified thickness. and allowed to cool and harden to form a
`self supporting film. A particularly desirable film forming
`polymer for extrusion manufacture is polyethylene oxide,
`which is heated to about 65” (T. to about 80° C. during blend-
`ing to provide a pliable uniform matrix. The extrusion may be
`accomplished with a single screw extrusion apparatus or
`other suitable extrusion apparatus.
`A particular advantage of the aforementioned extrusion
`processes when employed with particulate coated active
`ingredients is that the absence ofadditional solvent during the
`manufacturing process lessens the likelihood of dissolution
`or release of the taste-masked or controlled-release coated
`active agent during manufacture due to dissolution or solvent
`efi‘ects.
`
`Another aspect of the present invention provides films
`containing coated particles that include an active agent and a
`taste—masking andJor controlled—release coating. Accord—
`ingly. there is provided a drug delivery composition that
`includes (i) a flowable water-soluble film fomiing matrix; (ii)
`a particulate bioeITecting agent uniformly stationed therein:
`and (iii) a taste-masking agent or controlled-release agent
`coated or inti inater associated with the particulate to provide
`taste~1nasking of the bioeffecting agent. In some embodiw
`ments. the combined particulate and taste—masking agent
`have a particle size of 200 microns or less and the fiowable
`water-soluble film fonning matrix is capable of being dried
`without loss of uniformin in the stationing of the particulate
`biocfl'ecting agent therein.
`the taste-masking or con-
`In sortie other embodiments.
`trolledwrelease coated particles may have a particle size of 50
`to 250 microns, and the fiowable water—soluble film forming
`matrix is capable of being dried without loss of uniformity in
`the stationing of the particulate bio-effecting agent therein.
`The importance of particle size is heightened in orally ingest-
`ible thin films. where uniformin is also of particular impor-
`tance. and the prior art has failed to recognize such critically
`important features.
`Desirably. the size of the combined particulate and taste—
`masking agent have a particle size of 150 microns or less. or
`100 microns or less. The [iowable water-soluble film forming
`matrix is formable into a dry film of less than about 380
`
`for example less than about 250
`microns in thickness.
`