US007425292B2
`
`(12) Unlted States Patent
`Yang et a].
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,425,292 B2
`Sep. 16, 2008
`
`(54) THIN FILM WITH
`NON-SELF-AGGREGATING UNIFORM
`
`IZISEBEEZIQJSIIDELWERY
`
`(75) Inventors: Robert K. Yang, Elushing,NY (US);
`Richard C. Fuisz, McLean, vA (US);
`Gary L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, McLean, VA (US)
`
`2,352,691 A
`2,501,544 A
`
`7/1944 Curtis
`3/1950 Shrontz
`
`2,980,554 A
`3,249,109 A
`
`4/1961 Gentile et 31.
`5/1966 Maeth et a1.
`
`5/1969 Russell _
`3’444’858 A
`3,536,809 A 10/1970 Applezwelg
`3,551,556 A 12/1970 Kliment et 31.
`3,598,122 A
`8/1971 Zaffaroni
`
`IN Us
`_ M 5 1R LLC P
`73 A _
`(
`)
`sslgnee'
`‘mo 0
`X’
`’ wage’
`(
`)
`
`3,632,740 A
`3,640,741 A
`
`1/1972 Robinson et a1.
`2/1972 Etes
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC 154 b b 621 d .
`( ) y
`ays
`
`(Continued)
`
`(21) APPl- N91 10/074,272
`
`FOREIGN PATENT DOCUMENTS
`
`(22) Filedi
`
`Feb-14, 2002
`
`DE
`
`2432925 B2
`
`1/1976
`
`(65)
`
`Prior Publication Data
`
`US 2003/0107149 A1
`
`Jun. 12, 2003
`
`t' D t
`R1 tdU.S.A l'
`e a 6
`PP ‘ca 1°“ a a
`(60) Provisional application No. 60/328,868, ?led on Oct.
`12’ 2001_
`
`(51) Int. Cl.
`(2006.01)
`B32B 43/00
`(200601)
`B29D 7/01
`264/172.19; 264/212; 264/217
`(52) US. Cl. ...... .... ......
`(58) Fleld of Classl?catlon Search .......... .. 264/ 172.19,
`264/173.1, 175, 212, 217, 211.12, 260, 234;
`424/484, 488; 484/434, 435; 34/509, 502,
`34/493, 443
`See application ?le for complete search history.
`References Cited
`
`(56)
`
`US. PATENT DOCUMENTS
`
`307,537 A 11/1884 Foulks
`688,446 A 12/1901 Stempel
`2,142,537 A
`1/1939 TisZa
`2,277,038 A
`3/1942 Curtis
`
`(Continued)
`OTHER PUBLICATIONS
`
`Dr. June V. Engel, The Bene?ts of Eating Fibre from http://WWW.
`diabetes .ca/ Secti oniAbout/ ?bre .asp . *
`_
`(Con?rmed)
`Primary ExamineriPhilip C Tucker
`Assistant Examinerising P Chan
`(74) Attorney Agent] or FirmiHOffmann & Baron’ LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to the ?lm products and methods of their
`preparation that demonstrate a non-self-aggregating uniform
`heterogeneity. Desirably the ?lms disintegrate in Water and
`may be formed by a controlled drying process, or other pro
`cess that maintains the required uniformity of the ?lm.
`
`22 Claims, 2 Drawing Sheets
`
`Page 1
`
`Mylan v. MonoSol
`IPR2017-00200
`MonoSol Ex. 2025
`
`

`

`US 7,425,292 B2
`Page 2
`
`US. PATENT DOCUMENTS
`
`2/1972 Gould eta1~
`3,641,237 A
`5/1973 Zaffaroni
`3,731,683 A
`8/1973 Boroshok
`3,753,732 A
`6/1974 Lubens
`3,814,095 A
`7/1975 Albert
`3,892,905 A
`3,911,099 A 10/1975 DeFoneyetal
`3972995 A
`8/1976 Tsuk eta1~
`3,996,934 A 12/1976 Zaffaroni
`3,998,215 A 12/1976 Anderson et a1.
`4,029,757 A
`6/1977 Mlodozeniec etal.
`4,029,758 A
`6/1977 Mlodozeniec eta1~
`4,031,200 A
`6/1977 Reif
`4,123,592 A 10/1978 R?ineretal
`4,128,445 A 12/1978 smrzeneggeretal
`4,136,145 A
`V1979 Fuchs er 91-
`4,136,162 A
`1/1979 Fuchsetal.
`4,139,627 A
`2/1979 Laneetal.
`4,226,848 A 10/1980 Nagai 9t 91
`4251400 A
`2/1981 Columbus
`4,292,299 A
`9/1981 Suzuki etal.
`4,294,820 A 10/1981 Keithetal.
`4,302,465 A 11/1981 Ekensmmetal
`4,307,075 A 12/1981 Martin
`4,325,855 A
`4/1982 Dickmann
`4,373,036 A
`2/1983 Chang etal-
`4406708 A
`9/1983 Hesselgren
`4,432,975 A
`2/1984 Libby
`4438158 A
`3/1984 Graham
`4,460,562 A
`7/1984 Keithet a1.
`4,466,973 A
`8/1984 Rennie
`4,478,658 A 10/1984 WittWer ..................... .. 156/69
`4,503,070 A
`3/1985 Eby
`4,515,162 A
`5/1985 Ymmoto eta1~
`4,517,173 A
`5/1985 KiZaWaetaL
`4529601 A
`7/1985 Broberg eta1~
`4,529,748 A
`7/1985 Wienecke
`4,562,020 A 12/1985 Hijiya eta1~
`4,569,837 A
`2/1986 Suzuki eta1~
`4,593,053 A
`6/1986 Jevne
`4,608,249 A
`8/1986 Otsuka eta1~
`4,615,697 A 10/1986 Robinson
`4623394 A 11/1986 Nakamura eta1~
`4,631,837 A 12/1986 Magoon .................... .. 34/353
`4,652,060 A
`3/1987 Miyake
`4,659,714 A
`4/1987 Watt-Smith
`4,675,009 A
`6/1987 Hymes er 91-
`4,695,465 A
`9/1987 Kigasawa eta1~
`4,704,119 A 11/1987 Shaw eta1~
`4713239 A 12/1987 Babaian er 91-
`
`5/1990 Sorrentino et a1.
`4,927,634 A
`5/1990 Hijiya et a1.
`4,927,636 A
`6/1990 Mezeietal.
`4,937,078 A
`7/1990 Jenkins et a1.
`4,940,587 A
`g/1990 Browning
`4,948,580 A
`9/1990 Asaba etal.
`4,958,580 A
`4,978,531 A 12/1990 Yamazaki et a1.
`4,981,693 A
`1/1991 Higashi et a1.
`4,981,875 A
`1/1991 Leusneretal.
`5,023,082 A
`6/1991 Friedman et a1.
`5,024,701 A
`6/199l Desmarais
`5,028,632 A
`7/1991 FuiSZ
`5,044,761 A *
`9/1991 Yuhki et a1. ............... .. 366/139
`5,047,244 A
`9/1991 Sanvordeker et a1.
`5,064,717 A 11/1991 Suzuki et a1.
`5,089,307 A
`2/1992 Ninomiya etal.
`5,137,729 A *
`8/1992 Kuroya etal. ............. .. 424/435
`5,158,825 A 10/1992 AitWiI-th
`5,166,233 A 11/1992 Kuroya
`5,186,938 A
`2/1993 Sablotsky et a1.
`5,229,164 A
`7/1993 Pins et a1.
`5,234,957 A
`g/1993 Mantelle
`5,271,940 A l2/1993 clearyetal‘
`5,272,191 A 12/1993 Ibrahim et a1.
`5,346,701 A
`9/1994 Heiberetal.
`5,393,528 A
`2/1995 Swab
`5,411,945 A
`5/1995 0Za1<i et al.
`5,413,792 A
`5/1995 Ninomiya etal.
`5,433,960 A
`7/1995 Meyers
`5,455,043 A 10/1995 Fischel-Ghodsian
`5,462,749 A 10/1995 Rencher
`5,472,704 A 12/1995 SaIllTuS et a1.
`5518902 A
`5/1996 ()Zaki et 31‘
`5,567,431 A 10/1996 Ven et a1.
`5,620,757 A
`4/1997 Ninomiya etal.
`5,629,003 A
`5/1997 Horstmann etal.
`5,700,478 A 12/1997 Biegajskietal.
`5,700,479 A 12/1997 Lundgren
`424/480
`5,733,575 A *
`3/1998 Mehraetal.
`5,759,599 A *
`6/1998 Wampleretal. ............ .. 426/89
`5,766,620 A
`6/1998 Herber et a1.
`5,881,476 A
`3/1999 Strobush et a1.
`5,948,430 A
`9/1999 Zerbe et al.
`6,047,484 A *
`4/2000 B611and et a1. .............. .. 34/197
`6,153,210 A 11/2000 Robens etal‘
`6,177,096 B1
`1/2001 Zerbe et a1.
`6,231,957 B1
`5/2001 Zerbe et a1.
`6,238,700 B1* 5/2001 Dohneretal. ..
`6,284,264 B1* 9/2001 Zerbe et a1.
`6,428,825 B2* 8/2002 sharma et a1.
`6,552,024 B1* 4/2003 Chenet a1.
`
`424/484
`424/435
`424/777
`. 514/252.16
`
`
`
`4,713,243 A 12/1987 Schiraldi er 91- 4,722,761 A 2/1988 Cartmell er 91-
`
`
`
`
`
`
`
`6,660,292 B2* 12/2003 Zerbe etal. 2001/0006677 A1 7/2001 McGinty etal.
`
`4/1988 Yukimatsu eta1~
`4,740,365 A
`5/1988 Busciglio
`4,748,022 A
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`4,765,983 A
`9/ 1988 Inoue et a1.
`4,772,470 A
`4,777,046 A 10/1988 IWakura et a1.
`4,789,667 A 12/1988 Makino et a1.
`4,849,246 A
`7/1989 Schmidt
`4,851,394 A
`7/1989 Kubodera .................. .. 514/54
`4,860,754 A
`8/1989 Shariketal.
`RE33,093 E
`10/1989 Schiraldi et a1.
`4,876,092 A 10/1989 Mizobuchiet a1.
`4,876,970 A 10/1989 Bolduc
`4,888,354 A 12/1989 Chang etal.
`4,894,232 A
`1/1990 Reuletal.
`4,900,552 A
`2/1990 Sanvordekeretal.
`4,900,554 A
`2/1990 Yanagibashietal.
`4,900,556 A
`2/1990 Wheatley etal.
`4,910,247 A
`3/1990 Haldar et a1.
`4,915,950 A
`4/1990 Miranda et a1.
`4,925,670 A
`5/1990 Schmidt
`
`9/2001 Leung etal.
`2001/0022964 A1
`2001/0046511 A1 11/2001 Zerbe etal.
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`W0
`W0
`
`4/1976
`2449865 B2
`3/1988
`3630603 C2
`0241178 A1 10/1987
`0219762 Bl
`12/1990
`0259749 Bl
`8/1991
`200508
`10/1991
`273069
`10/1992
`0 514 691
`ll/l992
`0250187 B1
`9/1993
`0452446 B1
`12/1993
`381194
`8/1994
`1110 546
`6/2001
`1110546 A1
`6/2001
`W0 91/05540 A1
`5/1991
`W0 92/15289 A1
`9/1992
`
`Page 2
`
`

`

`US 7,425,292 B2
`Page 3
`
`WO 95/05416 A2
`WO 95/18046 Al
`WO 00/18365
`WO 00/42992
`WO 01/70194
`WO 01/91721
`
`2/1995
`7/1995
`4/2000
`7/2000
`9/2001
`12/2001
`
`OTHER PUBLICATIONS
`
`Lazaridou et 211.; Thermophysical properties of chitosan, chitosan
`starch and chitosan-pullulan ?lms near the glass transition; Elsevier
`Science Ltd.; 2002; pp. 179-190.
`
`* cited by examiner
`
`Page 3
`
`

`

`US. Patent
`
`Sep. 16, 2008
`
`Sheet 1 of2
`
`US 7,425,292 B2
`
`14
`
`14
`
`72
`
`FIGT
`
`FIG. 5
`
`Page 4
`
`

`

`US. Patent
`
`Sep. 16, 2008
`
`Sheet 2 of2
`
`US 7,425,292 B2
`
`20
`
`24
`
`22
`
`32’
`
`28
`/\_/
`
`5 6
`40
`
`K
`
`48
`
`44 Aheaf
`
`46
`
`FIG. 6
`
`Page 5
`
`

`

`US 7,425,292 B2
`
`1
`THIN FILM WITH
`NON-SELF-AGGREGATING UNIFORM
`HETEROGENEITY AND DRUG DELIVERY
`SYSTEMS MADE THEREFROM
`
`This application claims the bene?t of US. Provisional
`Application No. 60/328,868, ?led on Oct 12, 2001.
`
`FIELD OF THE INVENTION
`
`The invention relates to rapidly dissolving ?lms and meth
`ods of their preparation. The ?lms may also contain an active
`ingredient that is evenly distributed throughout the ?lm. The
`even or uniform distribution is achieved by controlling one or
`more parameters, and particularly the drying process that
`reduces aggregation or conglomeration of the components in
`the ?lm as it forms into a solid structure.
`
`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 form 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 di?iculty sWalloWing tablets. While tablets
`may be broken into smaller pieces or even crushed as a means
`of overcoming sWalloWing di?iculties, 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.
`As an alternative to tablets and pills, ?lms may be used to
`carry active ingredients such as drugs, pharmaceuticals, and
`the like. HoWever, historically ?lms and the process of mak
`ing drug delivery systems therefrom have suffered from a
`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 US. Pat. No. 4,136,145 to Fuchs, et
`al. (“Fuchs”). These ?lms may be formed into a sheet, dried
`and then cut into individual doses. The Fuchs disclosure
`alleges the fabrication of a uniform ?lm, Which includes the
`combination of Water-soluble polymers, surfactants, ?avors,
`sWeeteners, plasticiZers and drugs. These allegedly ?exible
`?lms are disclosed as being useful for oral, topical or enteral
`use. Examples of speci?c uses disclosed by Fuchs includes
`application of the ?lms to mucosal membrane areas of the
`body, including the mouth, rectal, vaginal, nasal and ear areas.
`Examination of ?lms made in accordance With the process
`disclosed in Fuchs, hoWever, reveals that such ?lms 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 ?oW and the like to form such
`agglomeration.
`The formation of agglomerates randomly distributes the
`?lm components and any active present as Well. When large
`dosages are involved, a small change in the dimensions of the
`?lm Would lead to a large difference in the amount of active
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`per ?lm. If such ?lms Were to include loW dosages of active,
`it is possible that portions of the ?lm may be substantially
`devoid of any active. Since sheets of ?lm are usually cut into
`unit doses, certain doses may therefore be devoid of or con
`tain an insu?icient 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 ?lm can
`be harmful to the patient. For this reason, dosage forms
`formed by processes such as Fuchs, Would not likely meet the
`stringent FDA standards relating to the variation of active in
`dosage forms. Currently, by laW, dosage forms may not vary
`more than 10% in the amount of active present. When applied
`to dosage units based on ?lms, this virtually mandates that
`uniformity in the ?lm be present.
`The problems of self-aggregation leading to non-unifor
`mity ofa ?lm Were addressed in US. Pat. No. 4,849,246 to
`Schmidt (“Schmidt”). Schmidt speci?cally pointed out that
`the methods disclosed by Fuchs did not provide a uniform
`?lm and recogniZed that that the creation of a non-uniform
`?lm necessarily prevents accurate dosing, Which as discussed
`above is especially important in the pharmaceutical area.
`Schmidt abandoned the idea that a mono-layer ?lm, such as
`described by Fuchs, may provide an accurate dosage form
`and instead attempted to solve this problem by forming a
`multi-layered ?lm. Moreover, his process is a multi-step pro
`cess that adds expense and complexity and is not practical for
`commercial use.
`Other US. Patents directly addressed the problems of par
`ticle self-aggregation and non-uniformity inherent in conven
`tional ?lm forming techniques. In one attempt to overcome
`non-uniformity, US. Pat. No. 5,629,003 to Horstmann et al.
`and US. 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 of the ?lm prior to
`drying in an effort to reduce aggregation of the components in
`the ?lm. 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
`gation of the active and other adjuvant, notWithstanding the
`use of viscosity modi?ers. Such processes also run the risk of
`exposing the active, i.e., a drug, or vitamin C, or other com
`ponents to prolonged exposure to moisture and elevated tem
`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
`tional drying methods themselves are unable to provide uni
`form ?lms. 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 ?lm product.
`Uniformity is particularly di?icult to achieve via conven
`tional drying methods Where a relatively thicker ?lm, Which is
`Well-suited for the incorporation of a drug active, is desired.
`Thicker uniform ?lms are more di?icult to achieve because
`the surfaces of the ?lm and the inner portions of the ?lm do
`not experience the same external conditions simultaneously
`during drying. Thus, observation of relatively thick ?lms
`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
`?exible. The amount of free moisture can often interfere over
`time With the drug leading to potency issues and therefore
`inconsistency in the ?nal product.
`
`Page 6
`
`

`

`US 7,425,292 B2
`
`3
`Conventional drying methods generally include the use of
`forced hot air using a drying oven, drying tunnel, and the like.
`The dif?culty in achieving a uniform ?lm is directly related to
`the rheological properties and the process of Water evapora
`tion in the ?lm-forming composition. When the surface of an
`aqueous polymer solution is contacted With a high tempera
`ture air current, such as a ?lm-forming composition passing
`through a hot air oven, the surface Water is immediately
`evaporated forming a polymer ?lm or skin on the surface.
`This seals the remainder of the aqueous ?lm-forming com
`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 ?lm. As the temperature outside the
`?lm continues to increase, Water vapor pressure builds up
`under the surface of the ?lm, stretching the surface of the ?lm,
`and ultimately ripping the ?lm surface open alloWing the
`Water vapor to escape. As soon as the Water vapor has
`escaped, the polymer ?lm surface reforms, and this process is
`repeated, until the ?lm is completely dried. The result of the
`repeated destruction and reformation of the ?lm surface is
`observed as a “ripple effect” Which produces an uneven, and
`therefore non-uniform ?lm. Frequently, depending on the
`polymer, a surface Will seal so tightly that the remaining Water
`is dif?cult 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 ?lm suitable for com
`mercialiZation and Federal approval. Air is generally trapped
`in the composition during the mixing process, Which can
`leave voids as the moisture evaporates during the drying
`stage. The results is non-uniformity in the ?nal ?lm product.
`Therefore, there is a need for methods and compositions
`for ?lm products, Which use a minimal number of materials or
`components, and Which provide a substantially non-self-ag
`gregating uniform heterogeneity throughout the area of the
`?lms. Desirably, such ?lms are produced through a selection
`of a polymer or combination of polymers that Will provide a
`desired viscosity, a ?lm-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
`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 Horstmann and Zerbe
`patents.
`
`SUMMARY OF THE INVENTION
`
`In one aspect of the present invention, there is provided a
`?lm and a method of forming same Which can be divided into
`equally siZed dosage units having substantially equal
`amounts of each compositional component present. This
`advantage is particularly useful because it permits large area
`?lms to be initially formed, and subsequently cut into indi
`vidual dosage units Without concern for Whether each unit is
`compositionally equal. For example, the ?lms of the present
`invention have particular applicability as pharmaceutical dos
`age delivery systems because each dosage unit, e. g., each
`individual dosage ?lm unit, Will contain the proper amount of
`drug. Pharmaceutical ?lm dosage forms to date have not been
`marketed largely due to the inability to achieve this result.
`In a further aspect of the present invention, there is pro
`vided a ?lm product that is formed by combining a polymer
`and a polar solvent, forming the combination into a ?lm, and
`drying the ?lm in a controlled manner, desirably by initially
`only applying heat to the bottom side of the ?lm, in order to
`maintain a non-self-aggregating uniform heterogeneity.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`4
`Desirably, during the initial bottom drying stage, substan
`tially no convection currents, i.e. hot air currents, are permit
`ted to travel across the tops of the ?lms. Once the visco-elastic
`properties of the ?lm are such that the ?lm components are
`5 “locked” in place and cannot move to cause non-uniformity,
`other methods of heating may then be employed. The polar
`solvent may be Water, a polar organic solvent, or a combina
`tion thereof. An active ingredient may be added to the poly
`mer and Water combination prior to the drying step. Altema
`tively, or in addition to controlling the drying the ?lm, the
`polymer may be selected in order to provide a viscosity that
`maintains the non-self-aggregating uniform heterogeneity.
`Moreover, the composition desirably is mixed in a manner to
`minimiZe the incorporation of air into the mixture and is
`desirably deaerated, such as by conditioning at room tem
`perature, vacuum 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 ?nal ?lm product, thereby
`further improving uniformity. Reverse roll is one particularly
`useful coating technique may also be used to form the ?lm.
`In another aspect of the invention, there is a process for
`preparing a ?lm With a substantially uniform distribution of
`components. The process includes the steps of combining a
`polymer component and Water to form a uniformly distrib
`uted matrix. This matrix is then formed into a ?lm and fed
`onto the top side of a substrate surface having top and bottom
`sides. Heat is applied to the bottom side of the substrate
`surface in order to dry the ?lm. The matrix from Which the
`?lm is formed may also include an active ingredient. Also,
`either alternatively, or in addition to the particular method
`used to dry the ?lm, the polymer may be selected in order to
`provide a viscosity that maintains the non-self-aggregating
`uniform heterogeneity. Reverse roll coating technique may
`also be used to form the ?lm.
`A further aspect of the present invention is a method of
`orally administering an active including the steps of:
`(a) preparing a ?lm by the steps of:
`(i) combining a polymer, an active component, and
`Water to form a material With a non-self-aggregating
`uniform heterogeneity;
`(ii) forming the material into a ?lm; and
`(iii) drying the ?lm in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity; and
`(b) introducing the ?lm to the oral cavity of a mammal.
`An even further aspect of the present invention is method of
`introducing an active component to liquid including the steps
`of:
`(a) preparing a ?lm by the steps of:
`(i) combining a polymer, an active component, and
`Water to form a material With a non-self-aggregating
`uniform heterogeneity;
`(ii) forming the material into a ?lm; and
`(iii) drying the ?lm in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity; and
`(b) placing the ?lm into a liquid; and
`(c) alloWing the ?lm to dissolve.
`A still further aspect of the present invention provides a
`dosage form for the administration of an active including:
`(a) a ?rst layer including a ?lm formed by the steps of:
`(i) combining a polymer, an active component, and
`Water to form a material With a non-self-aggregating
`uniform heterogeneity;
`(ii) forming said material into a ?lm; and
`(iii) drying said ?lm in a controlled manner to maintain
`said non- self-aggregating uniform heterogeneity; and
`(b) a substantially non-Water soluble second layer.
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`US 7,425,292 B2
`
`5
`Another aspect of the present invention provides a method
`of preparing a dosage form for the administration of an active
`including the steps of:
`(a) combining a polymer, an active component, and Water
`to form a material With a non-self-aggregating uniform
`heterogeneity;
`(b) forming the material into a ?lm;
`(c) applying the ?lm to a substantially non-Water soluble
`support; and
`(d) drying the ?lm in a controlled manner to maintain the
`non- self-aggregating uniform heterogeneity.
`In still another aspect of the present invention there is
`provided another method of admini stering an active including
`the steps of:
`(a) preparing dosage form by the steps of:
`(i) combining a polymer, an active component, and
`Water to form a material With a non-self-aggregating
`uniform heterogeneity;
`(ii) forming the material into a ?lm;
`(iii) applying the ?lm to a substantially non-Water
`soluble support; and
`(iv) drying the ?lm in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity;
`(b) removing the ?lm from said support; and
`(c) applying the ?lm to the oral cavity of a mammal.
`Another aspect of the invention provides a ?lm product
`formed by the steps of:
`(a) combining a polymer and a liquid carrier to form a
`material With a non-self-aggregating uniform heteroge
`neity;
`(b) forming said material into a ?lm; and
`(c) removing said liquid carrier, for example, by evapora
`tive methods or by permitting volatiliZation to occur at
`selected temperatures, from said ?lm in a manner to
`maintain said non- self-aggregating uniform heterogene
`ity.
`Also provided is a process for making a ?lm having a
`substantially uniform distribution of components including:
`(a) combining a polymer component and liquid carrier to
`form a matrix With a uniform distribution of said com
`ponents;
`(b) forming a ?lm from said matrix; and
`(c) removing said liquid carrier, for example, by evapora
`tive methods or by permitting volatiliZation to occur at
`selected temperatures, from said ?lm in a manner to
`maintain said uniform distribution.
`A still further aspect of the present invention provides
`process for making a ?lm having a substantially uniform
`distribution of components including:
`(a) combining a polymer component and a polar solvent to
`form a matrix With a uniform distribution of said com
`ponents, said polymer selected to provide a viscosity
`suf?cient to maintain said uniform distribution; and
`(b) forming a ?lm from said matrix.
`The invention also includes ?lms and a process for prepar
`ing ?lms having a substantially uniform distribution of com
`ponents. The process includes the steps of combining a poly
`mer component and Water to form a uniformly distributed
`matrix. This matrix is then formed into a ?lm and fed onto a
`substrate surface having top and bottom sides Where the bot
`tom side is in substantially uniform contact With a bottom
`drying medium, such as a Water bath or heated air space
`controlled at a temperature suf?cient to dry the ?lm. Desir
`ably, no external air currents or heat is applied directly to the
`exposed top surface of the ?lm during the drying process until
`the ?lm structure has solidi?ed suf?ciently to prevent ?oW,
`migration and intermolecular attractive forces from creating
`
`6
`aggregates or conglomerates. Desirably the heat is controlla
`bly conducted by the substrate surface to the ?lm to effectuate
`drying. The matrix from Which the ?lm is formed may also
`include an active ingredient. Also, either alternatively, or in
`addition to rapidly drying the ?lm, the polymer may be
`selected in order to provide a viscosity that maintains the
`non- self-aggregating uniform heterogeneity.
`A pharmaceutical and/or cosmetic dosage form is also
`provided that includes a ?lm having a uniformly dispersed
`composition including a polymer, a pharmaceutical and/or
`cosmetic active and a solvent, said ?lm being formed by
`depositing a Wet ?lm of said composition onto a substrate
`surface and controllably drying the Wet ?lm from the side
`contacting the substrate to prevent self-aggregation and
`achieve compositional uniformity.
`A still further aspect of the present invention includes a
`pharmaceutical and/or cosmetic dosage form including a
`polymeric ?lm having no more than a 10% variance of a
`pharmaceutical and/or cosmetic active per unit area.
`The present invention also provides a pharmaceutical com
`position in the form of a ?lm for external or topical adminis
`tration, including a composition having a uniformly distrib
`uted combination of a polymer, a polar solvent, and a
`pharmaceutical active, said composition in its dried ?lm form
`maintaining the uniform distribution of components through
`the application of controlled bottom drying of the ?lm.
`A pharmaceutical dispenser is also provided that includes
`individual unit dosage forms of the pharmaceutical compo
`sitions and ?lms of the present invention. The dosage forms
`may be optionally stacked in a dispenser or in a roll.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shoWs a side vieW of a package containing a unit
`dosage ?lm of the present invention.
`FIG. 2 shoWs a top vieW of tWo adjacently coupled pack
`ages containing individual unit dosage forms of the present
`invention, separated by a tearable perforation.
`FIG. 3 shoWs a side vieW of the adjacently coupled pack
`ages of FIG. 2 arranged in a stacked con?guration.
`FIG. 4 shoWs a perspective vieW of a dispenser for dispens
`ing the packaged unit dosage forms, dispenser containing the
`packaged unit dosage forms in a stacked con?guration.
`FIG. 5 is a schematic vieW of a roll of coupled unit dose
`packages of the present invention.
`FIG. 6 is a schematic vieW of an apparatus suitable for
`preparation of a pre-mix, addition of an active, and subse
`quent formation of the ?lm.
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`For the purposes of the present invention the term non- self
`aggregating uniform heterogeneity refers to the ability of the
`?lms of the present invention, Which are formed from one or
`more components in addition to a polar solvent, to provide a
`substantially reduced occurrence of, i.e. little or no, aggrega
`tion or conglomeration of components Within the ?lm as is
`normally experienced When ?lms are formed by conventional
`drying methods such as a high-temperature air-bath using a
`drying oven, drying tunnel, vacuum drier, or other such dry
`ing equipment. The term heterogeneity, as used in the present
`invention, includes ?lms that Will incorporate a single com
`ponent, such as a polymer, as Well as combinations of com
`ponents, such as a polymer and an active. Uniform heteroge
`neity includes the substantial absence of aggregates or
`conglomerates as is common in conventional mixing and heat
`drying methods used to form ?lms.
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`US 7,425,292 B2
`
`7
`Furthermore, the ?lms of the present invention have a
`substantially uniform thickness, Which is also not provided by
`the use of conventional drying methods used for drying Water
`based polymer systems. The absence of a uniform thickness
`detrimentally affects uniformity of component distribution
`throughout the area of a given ?lm.
`The ?lm products of the present invention are produced by
`a combination of a properly selected polymer and a polar
`solvent, optionally including an active ingredient as Well as
`other ?llers knoWn in the art. These ?lms provide a non-self
`aggregating uniform heterogeneity of the components Within
`them by utiliZing a selected casting or deposition method and
`a controlled drying process. Examples of controlled drying
`processes include, but are not limited to, the use of the appa
`ratus disclosed in Us. Pat. No. 4,631,837 to Magoon (“Ma
`goon”), herein incorporated by reference, as Well as hot air
`impingement across the bottom substrate and bottom heating
`plates. Another drying technique for obtaining the ?lms of the
`present invention is controlled radiation drying in the absence
`of air currents, such as infrared and radio frequency radiation
`(i.e. microWaves).
`The objective of the drying process is to provide a method
`of drying the ?lms that avoids complications, such as the
`noted “rippling” effect, that are associated With conventional
`drying methods and Which initially dry the upper surface of
`the ?lm, trapping moisture inside. In conventional oven dry
`ing methods, as the moisture trapped inside subsequently
`evaporates, the top surface is altered by being ripped open and
`then reformed. These complications are avoided by the
`present invention, and a uniform ?lm is provided by drying
`the bottom surface of the ?lm ?rst or otherWise preventing the
`formation of polymer ?lm formation (skin) on the top surface
`of the ?lm prior to drying the depth of the ?lm. This may be
`achieved by applying heat to the bottom surface of the ?lm
`With substantially no top air ?oW, or alternatively by the
`introduction of controlled microWaves to evaporate the Water
`or other polar solvent Within the ?lm, again With substantially
`no top air How. The humidity level of the area surrounding the
`top surface may also be appropriately adjusted to prevent
`premature closure or skinning of the polymer surface.
`This manner of drying the ?lms provides several advan
`tages. Among these are the faster drying times and a more
`uniform surface of the ?lm, as Well as uniform distribution of
`components for any given area in the ?lm. In addition, the
`faster drying time alloWs viscosity to quickly build Within the
`?lm, further encouraging a uniform distribution of compo
`nents and decrease in aggregation of components in the ?nal
`?lm product. Desirably, the drying of the ?lm Will occur
`Within about ten minutes or feWer, or more desirably Within
`about ?ve minutes or feWer.
`The present