Please type a plus sign(+) inside this box -
`
`GJ
`
`\~
`
`PTO/SB/16 (5-03)
`Approved for use through 4/30/2003. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of infonnation unless it displays a valid OMB control number.
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`~
`This is a requestfor filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`~
`P---------------------------------I•N•VE•N•T•O•R•t(-:5----------------------------------~-~~~~
`w _o
`:c 1> -......._
`Residence
`::>!;: 1- _co
`(City and either State or Foreign Country}_
`~C\J
`138-10 Franklin Avenue, Apt. #2C, Flushing, NY 113S5 ~~ ~- ......._
`o~ =~:
`1287 Ballantrae Farm Drive, McLean, VA 22101
`;:!,
`.
`908 Colfax Avenue, Kingsport, TN 37660
`5700 Cricket Place, McLean, VA 22101
`
`Given Name (first and middle [if any])
`Robert K.
`Richard C.
`Gary L.
`Joseph M.
`
`Family Name or Surname
`Yang
`Fuisz
`Myers
`Fuisz
`
`D Additional inventors are being named on th1 __ separately numbered sheets attached hereto
`
`TITLE OF THE INVENTION (280 characters max)
`POLYETHYLENE OXIDE-BASED FILMS AND DRUG DELIVERY SYSTEMS MADE THEREFROM
`
`Direct all correspondence to:
`
`I:8J Customer Number 1.-------2-3_8_6_9--------.~
`
`CORRESPONDENCE ADDRESS
`
`OR
`
`D Firm or
`
`Individual Name
`
`Address
`
`Type Customer Number here
`
`l l
`
`Address
`City
`
`Country
`
`•'
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`ZIP
`
`I
`I
`
`I
`I State
`I Telephone!
`Fax
`ENCLOSED APPLICATION PARTS (check all that apply)
`Specification Number of Pages
`90
`
`Drawing(s) Number of Sheets
`
`33
`
`Application Data Sheet. See 37 CFR 1. 76
`
`I
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`I
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`D CD(s), Number
`D Other (specify)
`
`METHOD OF PAYMENT OF FILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
`~
`FILING FEE
`Applicant claims small entity status. See 37 CFR 1.27.
`AMOUNT($)
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`A check or money order is enclosed to cover the filing fees
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`~ The Director is hereby authorized to charge filing
`2461
`08
`fees or credit any overpayment to Deposit Account NumbedL ________ _,
`D
`Payment by credit card. Form PT0-2038 is attached.
`The invention was made by an agency of the United States Government or under a contract with an agency of the
`United States Government.
`~No.
`D Yes, the name of the U.S. Government agency and the Government contract number are:
`
`$80.00
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`Respectfully submitted,
`
`SIGNATURE ~~
`TYPED or PRIN.;;g-N~ME Ja!nie M. Larmann
`
`Date
`
`I 05/28/2003 I
`
`48,623
`REGISTRATION No.I
`~=======~
`(if appropriate)
`1199-4A
`Docket Number:
`
`(973) 331-1700
`TELEPHONE
`USE ONLY FOR FILING A PROVISIONAL APPLICATION FOR PATENT
`
`This collection of information is required by 37 CFR 1.51. The information is used by the public to file (and by the PTO to process) a provisional application.
`Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 8 hours to complete, including gathering, preparing, and submitting
`the complete provisional application to the PTO. Time wilt vary depending upon the individual case. Any comments on the amount of time you require to complete this
`form and/or suggestions for reducing this burden, should be sent to the Chief lnfonnation Officer, U.S. Patent and Trademark Office, U.S. Department of Commerce,
`P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mail Stop Provisional Application,
`Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`If you need asssilance in completing the form, ca/11-800-PT0-9199 and select option 2.
`
`P1 MALL/REV05
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`RBP_TEVA05018582
`
`DRL - EXHIBIT 1011
`DRL001
`
`

`
`CERTIFICATE OF MAILING BY "EXPRESS MAIL" (37 CFR 1.10)
`Applicant(s): YANG ET AL.
`
`Serial No.
`Unassigned
`
`Filing Date
`Herewith
`
`Examiner
`Unassigned
`
`Docket No.
`
`1199-4A
`
`Group Art Unit
`Unassigned
`
`Invention: POLYETHYLENE OXIDE-BASED FILMS AND DRUG DELIVERY SYSTEMS MADE THEREFROM
`
`I hereby certify that the following correspondence:
`
`Provisional Application for Patent Cover Sheet, Patent Application flopages)
`
`is being deposited with the United States Postal Service "Express Mail Post Office to Addressee" service under 37
`
`CFR 1.10 in an envelope addressed to: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450 on
`
`(IdentifY type of correspondence)
`
`May 28,2003
`(Date)
`
`Barbara Kemmlein
`J.XJ!»ed.ru:..l!rinted Name of Person Mailing Correspondence)
`.c ~ =:::::::::--
`\ ~" ~
`--r. .
`of Person Mailing Correspondence)
`
`C ·~
`
`EV261770833US
`("Express Mail" Mailing Label Number)
`
`Note: Each paper must have its own certificate of mailing.
`
`P06NREV02
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`RBP_TEVA05018583
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`DRL - EXHIBIT 1011
`DRL002
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`

`
`I
`·~
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`1199-4A
`
`POLYETHYLENE OXIDE-BASED FILMS AND DRUG
`DELIVERY SYSTEMS MADE THEREFROM
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation-in-part ofPCT/US02/32575 filed October 11, 2002,
`
`which claims priority to U.S. Application No. 10/074,272, filed February 14, 2002 which claims
`
`priority to U.S. Provisional Application No. 60/328,868, filed October 12, 2001 and U.S.
`
`Provisional Application No. 60/386,937, filed June 7, 2002; PCTIUS02/32594, filed October 11,
`
`2002, which claims priority to U.S. Provisional Application No. 60/414,276, filed September 27,
`
`2002, U.S. Application No. 10/074,272, filed February 14, 2002, which claims priority to U.S.
`
`Provisional Application No. 60/328,868, filed October 12, 2001 and U.S. Provisional
`
`Application No. 60/386,937, filed June 7, 2002; and PCTIUS02/32542, filed October 11, 2002,
`
`which claims priority to U.S. Provisional Application No. 60/371,940, filed April 11, 2002, U.S.
`
`Application No. 10/074,272, filed February 14, 2002, which claims priority to U.S. Provisional
`
`Application No. 60/328,868, filed October 12, 2001 and U.S. Provisional Application No.
`
`60/386,937, filed June 7, 2002.
`
`FIELD OF THE INVENTION
`
`The invention relates to rapidly dissolving films and methods of their preparation. The
`
`films contain a polymer component, which includes polyethylene oxide optionally blended with
`
`cellulosic polymers. 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 elimination of air pockets prior to and during film formation and
`
`the use of a 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 consistent 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
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`RBP_TEVA05018584
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`DRL - EXHIBIT 1011
`DRL003
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`

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`I
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`'t
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`storage space, and that dispensing includes counting the tablets which has a tendency for
`
`inaccuracy. In addition, 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,
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`alone or in admixture with food, may also destroy the controlled 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 making 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 U.S.
`
`Patent 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,
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`topical or enteral use. Examples of specific uses disclosed by Fuchs include application of the
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`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(cid:173)
`
`aggregation, making them inherently non-uniform. This result can be attributed to Fuchs'
`
`process parameters, which although not disclosed likely include the use of relatively long drying
`
`times, thereby facilitating intermolecular attractive forces, convection forces, air flow and the
`
`like to form such agglomeration.
`
`The formation of agglomerates randomly distributes the film components and any active
`
`present as well. When large dosages are involved, a small change in the dimensions of the film
`
`would lead to a large difference in the amount of active per film. If such films were to include
`
`2
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`RBP_TEVA05018585
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`DRL - EXHIBIT 1011
`DRL004
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`

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`) ,.
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`low dosages of active, it is possible that portions of the film may be substantially devoid of any
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`active. Since sheets of film are usually cut into unit doses, certain doses may therefore be devoid
`
`of or contain an insufficient amount of active for the recommended treatment. Failure to achieve
`
`a high degree of accuracy with respect to the amount of active ingredient in the cut film can be
`
`harmful to the patient. For this reason, dosage forms formed by processes such as Fuchs, would
`
`not likely meet the stringent standards of governmental or regulatory agencies, such as the U.S.
`
`Federal Drug Administration ("FDA"), relating 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
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`virtually mandates that uniformity in the film be present.
`
`The problems of self-aggregation leading to non-uniformity of a film were addressed in
`
`U.S. Patent 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
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`film, such as described by Fuchs, may provide an accurate dosage form and instead attempted· to
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`solve this problem by forming a multi-layered film. Moreover, his process is a multi-step
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`process that adds expense and complexity and is not practical for commercial use.
`
`Other U.S. Patents directly addressed the problems of particle self-aggregation and non(cid:173)
`
`uniformity inherent in conventional film forming techniques. In one attempt to overcome non(cid:173)
`
`uniformity, U.S. Patent 5,629,003 to Horstmann et al. and U.S. Patent 5,948,430 to Zerbe et al.
`
`incorporated additional ingredients, i.e. gel formers and polyhydric alcohols respectively, to
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`increase the viscosity of the film prior to drying in an effort to reduce aggregation of the
`
`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(cid:173)
`
`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 aggregation of the active and
`
`other adjuvant, notwithstanding the use of viscosity modifiers. Such processes also run the risk
`
`3
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`RBP_TEVA05018586
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`DRL - EXHIBIT 1011
`DRL005
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`

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`I
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`i
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`of exposing the active, i.e., a drug, or vitamin C, or other components to prolonged exposure to
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`moisture and elevated temperatures, which may render it ineffective or even harmful.
`
`In addition to the concerns associated with degradation of an active during extended
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`exposure to moisture, the conventional drying methods themselves are unable to provide uniform
`
`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
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`morphology of the resultant film product. Uniformity is particularly difficult to achieve via
`
`conventional drying methods where a relatively thicker film, which is well-suited for the
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`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
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`external conditions simultaneously during drying. Thus, observation of relatively thick films
`
`made from such conventional processing shows a non-uniform structure caused by convection
`
`and intermolecular forces and requires greater than 10% moisture to remain flexible. The
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`amount of free moisture can often interfere over time with the drug leading to potency issues and
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`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 evaporation in the film-forming composition.
`
`When the surface of an aqueous polymer solution is contacted with a high temperature 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 composition beneath the surface, forming a barrier through which
`
`the remaining water must force itself as it is evaporated in order to achieve a dried film. As the
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`temperature outside the film continues to increase, water vapor pressure builds up under the
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`surface of the film, stretching the surface of the film, and ultimately ripping the film surface open
`
`allowing the water vapor to escape. As soon as the water vapor has escaped, the polymer film
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`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
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`4
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`RBP_TEVA05018587
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`DRL - EXHIBIT 1011
`DRL006
`
`

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`i
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`surface will seal so tightly that the remaining water is difficult to remove, leading to very long
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`drying times, higher temperatures, and higher energy costs.
`
`Other factors, such as mixing techniques, also play a role in the manufacture of a
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`pharmaceutical film suitable for commercialization 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 product as the moisture evaporates during the drying stage. The film
`
`frequently collapse around the voids resulting in an uneven film surface and therefore, non(cid:173)
`
`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 also provides a non-uniform film in that the
`
`spaces, which are not uniformly distributed, are occupying area that would otherwise be
`
`occupied by the film composition. None of the above-mentioned patents either addresses or
`
`proposes a solution to the problems caused by air that has been introduced to the film.
`
`Therefore, there is a need for methods and compositions for film products, which use a
`
`minimal number of materials or components, and which provide a substantially non-self(cid:173)
`
`aggregating uniform heterogeneity throughout the area of the films. Desirably, such films are
`
`produced through a selection of a polymer or combination of polymers that will provide a
`
`desired viscosity, a film- forming process such as reverse roll coating, and a controlled, and
`
`desirably rapid, drying process which serves to maintain the uniform distribution of non-self(cid:173)
`
`aggregated components without the necessary addition of gel formers or 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. Desirably, the films will also incorporate
`
`compositions 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
`
`The present invention is directed to rapid-dissolve film products containing at least one
`
`water-soluble polymer including polyethylene oxide alone or in combination with a hydrophilic
`
`cellulosic polymer, wherein the film product is free of added plasticizers.
`
`5
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`RBP_TEVA05018588
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`DRL - EXHIBIT 1011
`DRL007
`
`

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`Another embodiment of the rapid-dissolve film product includes at least one water(cid:173)
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`soluble polymer containing about 20% to 100% by weight polyethylene oxide, about 0% to 80%
`
`by weight hydroxypropylmethyl cellulose, and about 0% to 80% by weight hydroxypropyl
`
`cellulose; an active component; sucralose; precipitated calcium carbonate; at least one flavoring;
`
`simethicone; water; and at least one colorant, wherein the film product is free of added
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`plasticizers, surfactants, and polyalcohols.
`
`Yet another embodiment of the present invention is directed to an edible water-soluble
`
`delivery system in the form of a film composition, which contains at least one water-soluble
`
`polymer comprising polyethylene oxide alone or in combination with a polymer selected from
`
`the group consisting of hydroxypropylmethyl cellulose and hydroxypropyl cellulose, wherein the
`
`edible water-soluble delivery system is essentially free of organic solvents, plasticizers,
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`surfactants, and polyalcohols.
`
`The present invention is also directed to processes for making a film having a
`
`substantially uniform distribution of components, including the steps of: (a) combining at least
`
`one water-soluble polymer comprising polyethylene oxide alone or in combination with a
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`hydrophilic cellulosic polymer, a solvent, and an active component to form a matrix with a
`
`uniform distribution of the components; (b) forming a film from the matrix; and (c) drying the
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`film, wherein the film is free of added plasticizers.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows a side view of a-package containing a unit dosage film of the present
`
`invention.
`
`Figure 2 shows a top view of two adjacently coupled packages containing individual unit
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`dosage forms of the present invention, separated by a tearable perforation.
`
`Figure 3 shows a side view ofthe adjacently coupled packages of Figure 2 arranged in a
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`stacked configuration.
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`6
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`RBP_TEVA05018589
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`DRL - EXHIBIT 1011
`DRL008
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`

`
`f
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`Figure 4 shows a perspective view of a dispenser for dispensing the packaged unit dosage
`
`forms, dispenser containing the packaged unit dosage forms in a stacked configuration.
`
`Figure 5 is a schematic view of a roll of coupled unit dose packages of the present
`
`invention.
`
`Figure 6 is a schematic view of an apparatus suitable for preparation of a pre-mix,
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`addition of an active, and subsequent formation of the film.
`
`Figure 7 is a schematic view of an apparatus suitable for drying the films of the present
`
`invention.
`
`Figure 8 is a sequential representation of the drying process of the present invention.
`
`Figure 9 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 10 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 11 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 12 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 13 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 14 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`7
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`RBP_TEVA05018590
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`DRL - EXHIBIT 1011
`DRL009
`
`

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`Figure 15 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 16 is a photographic representation of a film dried by conventional drying
`
`processes.
`
`Figure 17 is a photographic representation of a film dried by the inventive drying process.
`
`Figure 18 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`Figure 19 is a photomicrographic representation of a film containing fat coated particles
`
`r
`
`dried by the inventive drying process.
`
`Figure 20 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`Figure 21 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`Figure 22 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`Figure 23 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`Figure 24 is a photomicrographic representation of a film containing fat coated particles
`
`dried by the inventive drying process.
`
`8
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`RBP_TEVA05018591
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`DRL - EXHIBIT 1011
`DRL010
`
`

`
`Figure 25 is a photomicrographic representation of a film containing fat coated particles
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`dried by the inventive drying process.
`
`Figure 26 is a photomicrographic representation of fat coated particles not in film, heated
`
`for 9 minutes at 80°C.
`
`Figure 27 is a photomicrographic representation of fat coated particles not in film, heated
`
`for 9 minutes at 80°C.
`
`Figure 28 is a photomicrographic representation of fat coated particles at room
`
`temperature prior to processing.
`
`Figure 29 is a photomicrographic representation of fat coated particles at room
`
`temperature prior to processing.
`
`Figure 30 is a photomicrographic representation of fat coated particles at room
`
`temperature prior to processing.
`
`Figure 31 is a photomicrographic representation of fat coated particles at room
`
`temperature prior to processing.
`
`Figure 32 is a graphical representation of a microarray on the blood of a human after
`
`ingestion by the human of a film of the present invention containing a bovine derived protein.
`
`Figure 33 is a graphical representation of the temperature differential between the inside
`
`and outside of a film of the present invention during drying.
`
`Figure 34 is a graphical representation of the temperature differential between the inside
`
`and outside of a film of the present invention during drying.
`
`9
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`RBP_TEVA05018592
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`DRL - EXHIBIT 1011
`DRL011
`
`

`
`Figure 35 is a schematic representation of a continuously-linked zone drying apparatus in
`
`accordance with the present invention.
`
`Figure 36 is a schematic representation of a separate zone drying apparatus in accordance
`
`with the present invention.
`
`Figure 37 is a schematic representation of a extrusion device for use in producing films of
`
`the present invention.
`
`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 films ofthe 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, aggregation or conglomeration of components within the film as is
`
`normally experienced when films are formed by conventional drying methods such as a high(cid:173)
`
`temperature air-bath using a drying oven, drying tunnel, vacuum drier, or other such drying
`
`equipment. The term heterogeneity, as used in the present invention, includes films that will
`
`incorporate a single component, such as a polymer, as well as combinations of components, such
`
`as a polymer and an active. Uniform heterogeneity includes the substantial absence of
`
`aggregates or conglomerates as is common in conventional mixing and heat drying methods used
`
`to form films.
`
`Furthermore, the films 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(cid:173)
`
`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 ofthe
`
`components within them by utilizing a selected casting or deposition method and a controlled
`
`10
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`RBP_TEVA05018593
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`DRL - EXHIBIT 1011
`DRL012
`
`

`
`drying process. Examples of controlled drying processes include, but are not limited to, the use
`
`ofthe apparatus disclosed in U.S. Patent No. 4,631,837 to Magoon ("Magoon"), 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 of the present invention is
`
`controlled radiation drying, in the absence of uncontrolled 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 drying 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 of the film
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`first or otherwise preventing the formation of polymer film formation (skin) on the top surface of
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`the film prior to drying the depth of the film. This may be achieved by applying heat to the
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`bottom surface of the film with substantially no top air flow, or alternatively by the introduction
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`of controlled microwaves to evaporate the water or other polar solvent within the film, again
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`with substantially no top air flow. Yet alternatively, drying may be achieved by using balanced
`
`fluid flow, such as balanced air flow, where the bottom and top air flows are controlled to
`
`provide a uniform film. In such a case, the air flow directed at the top of the film should not
`
`create a condition which would cause movement of particles present in the wet film, due to
`
`forces generated by the air currents. Additionally, air currents directed at the bottom of the film
`
`should desirably be controlled such that the film does not lift up due to forces from the air.
`
`Uncontrolled air currents, either above or below the film, can create non-uniformity in the final
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`film products. The humidity level of the area surrounding the top surface may also be
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`appropriately adjusted to prevent premature closure or skinning of the polymer surface.
`
`This manner of drying the films provides several advantages. Among these are the faster
`
`drying times and a more uniform surface of the film, as well as uniform distribution of
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`components for any given area in the film. In addition, the faster drying time allows viscosity to
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`quickly build within the film, further encouraging a uniform distribution of components and
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`11
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`DRL013
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`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
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`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
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`and eliminating excessive air in the mixing process, selecting polymers and solvents to provide a
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`controllable viscosity and by drying the film in a rapid manner from the bottom up, such films
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`result.
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`The products and processes of the 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(cid:173)
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`aggregation of the components within the films. Specifically, these steps include the particular
`
`method used to form the film, making the composition mixture to prevent air bubble inclusions,
`
`controlling the viscosity of the film forming composition and the method of drying the film.
`
`More particularly, a greater viscosity of components in the mixture is particularly useful when
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`the active is not soluble in the selected polar solvent in order to prevent the active from settling
`
`out. However, the viscosity must not be too great as to hinder or prevent the chosen method of
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`casting, which desirably includes reverse roll coating due to its ability to provide a film of
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`substantially consistent thickness.
`
`In addition to the viscosity ofthe film or film-forming components or matrix, there are
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`other considerations taken into account by the present invention for achieving desirable film
`
`uniformity. For example, stable suspensions are achieved which prevent solid (such as drug
`
`particles) sedimentation in non-colloidal applications. One approach provided by the present
`
`invention is to balance the density of the particulate (pp) and the liquid phase (Pt) and increase
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`the viscosity of the liquid phase (J.L). For an isolated particle, Stokes law relates the terminal
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`settling velocity (Vo) of a rigid spherical body of radius (r) in a viscous fluid, as follows:
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`Yo = (2gr}(pp - Pt)/9J.L
`
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`At high particle concentrations, however, the local particle concentration will affect the
`
`local viscosity and density. The viscosity of the suspension is a strong function of solids volume
`
`fraction, and particle-particle and particle-liquid interactions will further hinder settling velocity.
`
`Stokian analyses has shown that the incorporation of a third phase, dispersed air or
`
`nitrogen, for example, promotes suspension stability. Further, increasing the number of particles
`
`leads to a hindered settling effect based on the solids volume fraction. In dilute particle
`
`suspensions, the rate of sedimentation, v, can be expressed as:
`vN0 = 1/(1 + K<p)
`where K = a constant, and <p is the volume fraction of the dispersed phase. More particles
`
`suspended in the liquid phase results in decreased velocity. Particle geometry is also an
`
`important factor since the particle dimensions will affect particle-particle flow interactions.
`
`Similarly, the viscosity of the suspension is dependent on the volume fraction of
`
`dispersed solids. For dilute suspensions of non-interaction spherical particles, an expression for
`
`the suspension viscosity can be expressed as:
`
`~J.lo = 1 + 2.5$
`
`where J.lo is the viscosity of the continuous phase and cp is the solids volume fraction. At higher
`
`volume fractions, the viscosity of the dispersion can be expressed as
`~J.lo= 1 + 2.5<p + C1<p2 + Cz<p3 + .....
`
`where C is a constant.
`
`The viscosity of the liquid phase is critical and is desirably modified by customizing the
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`liquid composition to a viscoelastic non-Newtonian fluid with low yield stress values. This is the
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`equivalent of producing a high viscosity continuous phase at rest. Formation of a viscoelastic or
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`a highly structured fluid phase provides additional resistive forces to particle sedimentation.
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`Further, flocculation or aggregation can be controlled minimizing particle-particle interactions.
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`The net effect would be the preservation of a homogeneous dispersed phase.
`
`The addition ofhydrocolloid