USOO7425292B2
`
`(12) Unlted States Patent
`(10) Patent No.:
`US 7,425,292 B2
`
`Yang et a].
`(45) Date of Patent:
`Sep. 16, 2008
`
`(54) THIN FILM WITH
`NON-SELF-AGGREGATING UNIFORM
`ggfi‘fifflifigfifififigfimLIVERY
`
`(75)
`
`Inventors: Robert K. Yang, Flushing, NY (US);
`Richard C. Fuisz, McLean, VA (US);
`Gary L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, McLean, VA (US)
`
`.
`(73) A551gnee. MonoSol RX, LLC, Portage, IN (US)
`( * ) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154 b b 621 d
`.
`( ) y
`ays
`
`(21) APPI- N04 10/074,272
`
`(22)
`
`Filed:
`
`Feb- 14, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0107149 A1
`
`Jun. 12, 2003
`
`Related US. Application Data
`(60) Provisional application No. 60/328,868, filed on Oct.
`12, 2001.
`
`(51)
`
`Int. Cl.
`(2006.01)
`B323 43/00
`(200601)
`329D ”01
`264/172.19; 264/212; 264/217
`(52) US. Cl.
`........
`(58) Fleld 0f C216aj/slli7igzlltlil75segfgh217211 12626107223491,
`424/484, 488; 484/434, 435; 34/509, 502,
`34/493, 443
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U-S- PATENT DOCUMENTS
`307,537 A
`11/1884 Foulks
`688,446 A
`12/1901 St6mpe1
`2,142,537 A
`1/1939 Tisza
`2,277,038 A
`3/ 1942 Curtis
`
`2,352,691 A
`2,501,544 A
`2,980,554 A
`3,249,109 A
`
`3’444’858 A
`3,536,809 A
`3,551,556 A
`3,598,122 A
`3,632,740 A
`3,640,741 A
`
`7/1944 Curtis
`3/1950 Shrontz
`4/1961 Gentile et 31.
`5/1966 Maeth et al.
`
`_
`5/1969 Russell
`10/1970 Applezwelg
`12/1970 Kliment et 31.
`8/1971 Zaffaroni
`1/1972 Robinson et al.
`2/1972 Etes
`
`(Continued)
`FOREIGN PATENT DOCUMENTS
`
`DE
`
`2432925 B2
`
`1/1976
`
`(Continued)
`OTHER PUBLICATIONS
`
`Dr. June V. Engel, The Benefits of Eating Fibre from http://WWW.
`diabetes .ca/SectioniAbout/fibre .asp . *
`.
`(Confirmed)
`Primary ExamineriPhilip C Tucker
`Assistant ExamineriSing P Chan
`(74) Attorney, Agent, or FirmiHoffmann & Baron, LLP
`(57)
`ABSTRACT
`
`The invention relates to the film products and methods oftheir
`preparation that demonstrate a non-self—aggregating uniform
`heterogeneity. Desirably the films disintegrate in water and
`may be formed by a controlled drying process, or other pro-
`cess that ma1nta1ns the requ1red un1form1ty of the film.
`
`22 Claims, 2 Drawing Sheets
`
`
`
`P3991
`
`BDSI EXHIBIT 1023
`
`Page 1
`
`

`

`US 7,425,292 B2
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`2/1972 Gouldet al.
`3,641,237 A
`5/1973 Zaffaroni
`3,731,683 A
`8/1973 Boroshok
`3,753,732 A
`6/1974 Lubeus
`3,814,095 A
`7/1975 Albert
`3,892,905 A
`10/1975 DeFoneyetal.
`3911099 A
`8/1976 Tsuk 6131
`3972995 A
`12/1976 Zaffaroni
`3,996,934 A
`12/1976 Anderson et 31.
`3,998,215 A
`6/1977 Mlodozeniec etal.
`4,029,757 A
`6/1977 Mlodozeniec 6131
`4,029,758 A
`6/1977 Reif
`4,031,200 A
`10/1978 Raineretal~
`4,123,592 A
`12/1978 Sturzenegger 9181
`4,128,445 A
`1/1979 Fuchs 6131
`4,136,145 A
`1/1979 Fuchsetal.
`4,136,162 A
`2/1979 Laneetal.
`4,139,627 A
`10/1980 Nagaieta1~
`4,226,848 A
`2/1981 Columbus
`4,251,400 A
`9/1981 Suzuki etal.
`4,292,299 A
`10/1981 Keithetal.
`4,294,820 A
`11/1981 Ekenstameta1
`4,302,465 A
`12/1981 Martin
`4307075 A
`4/1982 Dickmann
`4,325,855 A
`2/1983 Chang 9181
`4,373,036 A
`9/1983 Hesselgren
`4,406,708 A
`2/1984 Libby
`4,432,975 A
`3/1984 Graham
`4,438,258 A
`7/1984 Keithet a1.
`4,460,562 A
`8/1984 Rennie
`4,466,973 A
`4,478,658 A * 10/1984 Wittwer ....................... 156/69
`4503070 A
`3/1985 Eby
`4,515,162 A
`5/1985 Yamamoto 6131
`4,517,173 A
`5/1985 Kizawaetal~
`4,529,601 A
`7/1985 Broberg etal.
`4,529,748 A
`7/1985 Wienecke
`4,562,020 A
`12/1985 Hijiya 6131
`4,569,837 A
`2/1986 Suzuki 6131
`4,593,053 A
`6/1986 Jevne
`4,608,249 A
`8/1986 Otsuka 6131
`4,615,697 A
`10/1986 Robinson
`4,623,394 A
`11/1986 Nakamura 6131
`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 6131
`4,695,465 A
`9/1987 Kigasawaeta1~
`4,704,119 A
`11/1987 Shaw 6131
`4,713,239 A
`12/1987 Babaian 6181
`4,713,243 A
`12/1987 Sohiraldi 6131
`4,722,761 A
`2/1988 Cartmell 6131
`47401365 A
`4/1988 Yukimatsu 6131
`4748022 A
`5/1988 Busoiglio
`4,765,983 A
`8/1988 Takayanagiet al.
`4,772,470 A
`9/ 1988 Inoue et a1.
`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 al.
`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 Ha1dar et a1.
`4,915,950 A
`4/1990 Miranda et a1.
`4,925,670 A
`5/1990 Schmidt
`
`4,927,634 A
`5/1990 Sorrentino et al.
`4,927,636 A
`5/1990 Hijiya et a1.
`4,937,078 A
`6/1990 Mezeiet 31.
`4,940,587 A
`7/1990 Jenkins et a1.
`4,948,580 A
`8/1990 Browning
`4,958,580 A
`9/1990 Asaba etal.
`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
`6/1991 Desmarais
`5,028,632 A
`7/1991 Fuisz
`5,044,761 A *
`................. 366/139
`9/1991 Yuhki et a1.
`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
`8/1993 Mantelle
`5,271,940 A
`12/1993 Clearyetal.
`5,272,191 A
`12/1993 Ibrahim et al.
`5,346,701 A
`9/1994 Heiberetal.
`5,393,528 A
`2/1995 Staab
`5,411,945 A
`5/1995 Ozaki et a1.
`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 Santus et a1.
`5,518,902 A
`5/1996 Ozaki et a1.
`5,567,431 A
`10/1996 Vert 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
`5,733,575 A
`................ 424/480
`3/1998 Mehraetal.
`
`5,759,599 A
`6/1998 Wamp1er etal.
`.............. 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 a1.
`6,047,484 A *
`4/2000 Bolland et a1.
`6,153,210 A
`“/2000 Roberts etal.
`6,177,096 B1
`1/2001 Zerbe et a1.
`6,231,957 B1
`5/2001 Zerbe et a1.
`6,238,700 B1*
`424/484
`5/2001 Dohneretal.
`..
`
`
`6,284,264 B1*
`424/435
`9/2001 Zerbe et a1.
`.....
`6,428,825 B2*
`424/777
`8/2002 Sharma et a1.
`
`6,552,024 B1*
`. 514/252.16
`4/2003 Chenet a1.
`
`6,660,292 B2* 12/2003 Zerbe etal. .............. 424/439
`7/2001 McGinty etal.
`2001/0006677 A1
`2001/0022964 A1
`9/2001 Leung etal.
`2001/0046511 A1
`11/2001 Zerbe etal.
`
`................ 34/197
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`W0
`W0
`
`2449865 B2
`3630603 C2
`0241178 A1
`0219762 B1
`0259749 B1
`200508
`273069
`0 514 691
`0250187 B1
`0452446 B1
`381194
`1110 546
`1110546 A1
`W0 91/05540 A1
`W0 92/15289 A1
`
`4/1976
`3/1988
`10/1987
`12/1990
`8/1991
`10/1991
`10/1992
`11/1992
`9/1993
`12/1993
`8/1994
`6/2001
`6/2001
`5/1991
`9/1992
`
`Page 2
`
`Page 2
`
`

`

`US 7,425,292 B2
` Page 3
`
`W0
`W0
`W0
`W0
`W0
`
`W0
`
`W0 95/05416 A2
`WO 95/18046 A1
`W0 00/18365
`WO 00/42992
`WO 01/70194
`
`2/1995
`7/1995
`4/2000
`7/2000
`9/2001
`
`WO 01/91721
`
`12/2001
`
`OTHER PUBLICATIONS
`_
`_
`_
`_
`_
`Lazalrlldog elt1Ial.; Therrllllolphygical propflrltles1 0f chltoseim, ehlltosgn-
`sta-rc
`an 0 1t0san-pu u an ms near
`e g ass trans1t10n, E seV1er
`Selence Ltd.; 2002; pp. 179-190.
`
`* cited by examiner
`
`Page 3
`
`Page 3
`
`

`

`US. Patent
`
`Sep. 16, 2008
`
`Sheet 1 of2
`
`US 7,425,292 B2
`
`
`
`Page 4
`
`Page 4
`
`

`

`US. Patent
`
`Sep. 16, 2008
`
`Sheet 2 of2
`
`US 7,425,292 B2
`
`
`
`Page 5
`
`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 benefit of US. Provisional
`Application No. 60/328,868, filed on Oct 12, 2001.
`
`FIELD OF THE INVENTION
`
`The invention relates to rapidly dissolving films and meth-
`ods of their preparation. The films may also contain an active
`ingredient that is evenly distributed throughout the film. 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 film 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 difliculty swallowing tablets. While tablets
`may be broken into smaller pieces or even crushed as a means
`of overcoming swallowing difliculties, 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, 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 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 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 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 includes
`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 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 of the
`film would lead to a large difference in the amount of active
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`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-
`tain an insuflicient 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
`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 films, this virtually mandates that
`uniformity in the film be present.
`The problems of self-aggregation leading to non-unifor-
`mity ofa film were addressed in US. 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 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 film 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 film prior to
`drying in an effort to reduce aggregation ofthe components in
`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-
`gation of the active and other adjuvant, notwithstanding the
`use 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 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 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 diflicult 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 diflicult 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.
`
`Page 6
`
`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 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-
`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-
`position beneath the surface, forrning 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 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 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 final film product.
`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 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 ofnon- 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
`film 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
`films to be initially formed, and subsequently cut into indi-
`vidual dosage units without concern for whether each unit is
`compositionally equal. For example, the films of the present
`invention have particular applicability as pharmaceutical dos-
`age delivery systems because each dosage unit, e. g., each
`individual dosage film unit, will contain the proper amount of
`drug. Pharmaceutical film 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 film product that is formed by combining a polymer
`and a polar solvent, forming the combination into a film, and
`drying the film in a controlled manner, desirably by initially
`only applying heat to the bottom side of the film, in order to
`maintain a non-self—aggregating uniform heterogeneity.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 ofthe films. Once the visco-elastic
`properties of the film are such that the film components are
`“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 film, 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 final film product, thereby
`further improving uniformity. Reverse roll is one particularly
`useful coating technique may also be used to form the film.
`In another aspect of the invention, there is a process for
`preparing a film 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 film 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 film. The matrix from which the
`film is formed may also include an active ingredient. Also,
`either alternatively, or in addition to the particular method
`used to dry the film, 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 film.
`
`A further aspect of the present invention is a method of
`orally administering an active including the steps of:
`(a) preparing a film 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 film; and
`(iii) drying the film in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity; and
`(b) introducing the film to the oral cavity of a mammal.
`An even further aspect ofthe present invention is method of
`introducing an active component to liquid including the steps
`of:
`
`(a) preparing a film 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 film; and
`(iii) drying the film in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity; and
`(b) placing the film into a liquid; and
`(c) allowing the film to dissolve.
`A still further aspect of the present invention provides a
`dosage form for the administration of an active including:
`(a) a first layer including a film 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 film; and
`(iii) drying said film in a controlled manner to maintain
`said non- self-aggregating uniform heterogeneity; and
`(b) a substantially non-water soluble second layer.
`
`Page 7
`
`Page 7
`
`

`

`US 7,425,292 B2
`
`5
`Another aspect of the present invention provides a method
`ofpreparing 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 film;
`(c) applying the film to a substantially non-water soluble
`support; and
`(d) drying the film 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 ofadmini 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 film;
`(iii) applying the film to a substantially non-water
`soluble support; and
`(iv) drying the film in a controlled manner to maintain
`the non-self-aggregating uniform heterogeneity;
`(b) removing the film from said support; and
`(c) applying the film to the oral cavity of a mammal.
`Another aspect of the invention provides a film 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 film; and
`(c) removing said liquid carrier, for example, by evapora-
`tive methods or by permitting volatilization to occur at
`selected temperatures, from said film in a manner to
`maintain said non— self-aggregating uniform heterogene-
`ity.
`Also provided is a process for making a film 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 film 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 film in a manner to
`maintain said uniform distribution.
`
`A still further aspect of the present invention provides
`process for making a film 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
`sufficient to maintain said uniform distribution; and
`(b) forming a film from said matrix.
`The invention also includes films and a process for prepar-
`ing films 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 film 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 sufficient to dry the film. Desir-
`ably, no external air currents or heat is applied directly to the
`exposed top surface ofthe film during the drying process until
`the film structure has solidified sufficiently to prevent flow,
`migration and intermolecular attractive forces from creating
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`aggregates or conglomerates. Desirably the heat is controlla-
`bly conducted by the substrate surface to the film to effectuate
`drying. The matrix from which the film is formed may also
`include an active ingredient. Also, either alternatively, or in
`addition to rapidly drying the film, 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 film having a uniformly dispersed
`composition including a polymer, a pharmaceutical and/or
`cosmetic active and a solvent, said film being formed by
`depositing a wet film of said composition onto a substrate
`surface and controllably drying the wet film 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 film 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 film 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 film form
`maintaining the uniform distribution of components through
`the application of controlled bottom drying of the film.
`A pharmaceutical dispenser is also provided that includes
`individual unit dosage forms of the pharmaceutical compo-
`sitions and films 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 film 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 configuration.
`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 configuration.
`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 film.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`For the purposes ofthe present invention the term non- self-
`aggregating uniform heterogeneity refers to the ability of the
`films 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 film as is
`normally experienced when films 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 films 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 films.
`
`Page 8
`
`Page 8
`
`

`

`US 7,425,292 B2
`
`7
`Furthermore, the films of the present invention have a
`substantially uniform thickness, which is also not provided by
`the use ofconventional 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 film.
`The film 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 fillers known in the art. These films 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 U.S. 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 films ofthe
`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 films 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 film, 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 film is provided by drying
`the bottom surface ofthe film first or otherwise preventing the
`formation ofpolymer film formation (skin) on the top surface
`of the film prior to drying the depth of the film. This may be
`achieved by applying heat to the bottom surface of the film
`with substantially no top air flow, or alternatively by the
`introduction of controlled microwaves to evaporate the water
`or other polar solvent within the film, again with substantially
`no top air flow. The humidity level ofthe 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 films provides several advan-
`tages. Among these are the faster drying times and a more
`uniform surface ofthe film, as well as uniform distribution of
`components for any given area in the film. In addition, the
`faster drying time allows viscosity to quickly build within the
`film, further encouraging a uniform distribution of compo-
`nents and decrease in aggregation of components in the final
`film product. Desirably, the drying of the film will occur
`within about ten minutes or fewer, or more desirably within
`about five minutes or fewer.
`
`The present invention yields exceptionally uniform film
`products when attention is paid to reducing the aggregation of
`the compositional components. By avoiding the introduction
`of and eliminating excessive air in the mixing process, select-
`ing polymers and solvents to provide a controllable viscosity
`and by drying the film in a rapid manner from the bottom up,
`such films result.
`
`The products and processes ofthe present invention rely on
`the interaction among various steps of the production of the
`films in order to provide films that substantially reduce the
`self-aggregation of the components within the films. Specifi-
`cally, these steps inc