United States Patent [19]
`Horstmann et al.
`
`USOO5629003A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,629,003
`May 13, 1997
`
`[54] RAPIDLY DISINTEGRATING SHEET-LIKE
`PRESENTATIONS OF MULTIPLE DOSAGE
`UNITS
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`[7 5] Inventors: Michael Horstmann, Neuwied;
`Wolfgang Laux, Dietz; Stefan
`Hungerbach, Nortershausen. all of
`Germany
`
`[73] Assignee: LTS Lohmann Therapie-Systeme
`GmbH & Co. KG, Neuwied, Germany
`
`[21] Appl. No.: 300,115
`
`[22] Filed:
`
`Sep. 2, 1994
`
`Related US. Application Data
`
`[63] Continuation of Ser. No. 988,372, Dec. 4, 1992, abandoned,
`which is a continuation of Ser. No. 709,941, Jun. 4, 1991,
`abandoned.
`
`[30]
`
`Foreign Application Priority Data
`
`Jun. 7, 1990 [DE]
`
`Germany ........................ .. 4O 18 247.9
`
`[51] Int. Cl.6 ............................. .. A61K 7/00; A61K 9/42;
`A61K 9/70
`[52] US. Cl. ........................ .. 424/401; 424/439; 424/447;
`424/476; 424/478; 424/479; 424/480; 424/488;
`
`.
`
`424/49
`
`[58] Field of Search ................................... .. 424/401, 441,
`424/443, 465, 485, 488, 48; 206/363, 368-370,
`531, 534.1, 823, 828
`
`352,466 11/1886 Huttemeyer ........................... .. 424/440
`2,852,433
`9/1958 Hiatt ........... ..
`167/82
`4,128,445 12/1978 Sturzenegger et a1.
`156/64
`4,136,145
`1/1979 Fuchs ....................... .. 264/164
`
`. . . . .. 424/439
`4,683,256
`7/1987 Porter et a1. . . . . .
`.... .. 424/435
`4,777,046 10/1988 IWakura et a1. ..
`4,906,488
`3/1990 Pera .......................... .. 426/573
`5,077,053 12/1991 Kuncewitch et a1. ................ .. 424/441
`
`FOREIGN PATENT DOCUMENTS
`
`2028224 12/1970 Germany ............................. .. 424/472
`2009597 6/1978 United Kingdom.
`Primary Examiner—Neil S. Levy
`Attorney, Agent, or F irm—Sprung Horn Kramer & Woods
`[57]
`ABSTRACT
`
`A presentation which, in the form of a ?lm, permits the
`individual dosage of drugs, confectionary, other food, cos
`metics and the like for oral application or intake. The
`presentation is characterized by the fact that it comprises a
`mass of 20 to 60%-wt. of at least a ?lm former, 2 to 40%-wt.
`of at least a gel former, 0.1 to 35%-wt of at least an active
`substance, and up to 40%-Wt. of an inert ?lling agent. being
`applied on a canier, or by consisting of a mass having the
`aforementioned composition but is unsupported. In the
`production thereof, an intimate mixture of said components
`is prepared. optionally with the addition of up to 30%-wt. of
`a polar solvent, and processed to form a homogeneous,
`spreadable or extrudable mass.
`
`7 Claims, No Drawings
`
`DRL - EXHIBIT 1028
`DRL001
`
`

`
`1
`RAPIDLY DISINTEGRATING SHEET-LIKE
`PRESENTATIONS OF MULTIPLE DOSAGE
`UNITS
`
`5,629,003
`
`2
`Although a number of ?at-shaped forms of administration
`and processes for the production thereof are lmown in the
`art, there still is a considerable lack as to the galenic
`composition, i.e., the selection of adjuvants, and as to the
`conception of the physico-chemical ?ne structure of such
`sheet-like carriers. Many purposes and aims have to be,
`taken into consideration: Rapid disintegration is required for
`many drugs to allow rapid swallowing of the dosage unit;
`other circumstances, in turn, require that the drug tempo
`rarily sticks on the mucous membrane of the mouth, and in
`other occasions-e.g., in case of a medicinal agent with
`short-time action—a considerably retarded disintegration is
`desired. In case of sweets, a medium retention time in the
`mouth, e.g., of ?avoring substances, will in general be
`desirable. Cosmetic, ?lm-like toothpastes should be ?exible
`and disintegrate as soon as possible. In general, sheet-like
`presentations may not be too fragile so as to ensure safe
`transfer of the portions to the place of destination. If a carrier
`is used, both materials must have an adhesion behavior
`exactly adapted to each other; this is for two reasons: on the
`one hand, the separation of the doses, e.g., by means of
`partial punching and peeling otf the partitioning inserts, is
`ensured during production, and, on the other hand. the bond
`to the carrier is effected even during storage. If drying is
`required during the production, it should be possible to
`render the formulation spreadable with the least possible
`solvent proportion (preferably water) so that the energy
`involved during drying may be maintained as low as pos
`sible.
`The galenic compositions known until today, do not
`satisfy these requirements. Basic principles of the tablet
`technology are described in connection with ?lm-like tapes
`by DE 27 46 414; that is the use of optionally thermoplastic
`binders and other auxiliary agents, the chemical cross
`linking, or the addition of hydrophobic substances to delay
`the disintegration, the combination of several layers and the
`use of micro-encapsulated active substances. Conventional
`tablet-disintegrants are used therein as disintegration auxil
`iaries for ?lms. According to our own ?ndings, the proposals
`cannot cope with the new pharmaceutic products. The
`classic disintegrants require a porous, mechanically stable
`surrounding created by bonding forces between the
`particles, if they are to cause disintegration through swelling
`by water addition, or by stored Hooke’s deformation energy.
`However, these preconditions do not exist in case of sheet
`like presentations which always remain slightly ?exible and
`are of low porosity. Swelling particles may even delay the
`disintegration of the ?lms due to withdrawal of water.
`According to DE 24 32 925 a formulation contains
`water-soluble cellulose ethers and separating agents and,
`optionally, ?llers. Since, however, a predominating portion
`of water-soluble polymers always requires the addition of a
`large amount of water to achieve a su?iciently low viscosity
`of the mass being ready to spread or cast, this structure
`involves high drying cost during fabrication.
`In addition, the adhesive bond to the base is affected due
`to such an extreme material shrinkage. When sheet-like
`forms of applications are produced by spreading water-base
`masses to a paper or ?lm which were rendered dehesive, the
`liquid readily drops-o? the support or at least forms zones of
`di?erent ?lm thicknesses due to the surface tension.
`Although the viscosity may be increased by adding cellulose
`derivatives, etc., spreading through the small gap will
`become more di?icult. According to other sources (e.g., DE
`35 34 981, DE 36 30 603) viscosity formers are therefore
`preferred; they result in low-viscosity solutions in the heat
`(in the coating machine), irmnediately afterwards, however,
`
`This application is a continuation of application Ser. No.
`07/988,372, ?led Dec. 4, 1992, now abandoned, which is a
`continuation of application Ser. No. 07/709,941 ?led Jun. 4,
`1991 now abandoned.
`DESCRIPTION
`The present invention relates to sheet-like forms of
`administration of drugs, confectionary, other food, cosmet
`ics and the like for oral application or intake.
`Presentations of drugs, sweets and other foodstuffs,as well
`as cosmetics which are to be applied in the oral region or
`have to be taken by deglutition, in principle, can either be
`freely dosed by the applicant or are already pre-divided into
`dosage units by the manufacturer. Such prepared forms are
`particularly common in pharmaceutics in the form of tablets,
`capsules, coated tablets, pills, vials and the like. Compared
`to dropping-solutions, ointments, or creams which have to
`be dosed by the user, unintentional wrong dosage by appli
`cant is avoided in these cases.
`From the application technological point of view, tablets
`must have a certain minimum size (5 to 6 mm diameter) and
`a certain minimum weight (approximately 100 to 200 mg),
`in order to case handling of these presentations. Thus, highly
`e?icacious drugs may contain about 99% of inactive
`ingredients, relative to the tablet weight
`Even foodstuff, in particular confectionary, is frequently
`found on the market in individually dosed form (candies,
`sweetener tablets, peppermint lozenges, etc.). In this case
`too—-for instance as regards candies—there is the wish to
`achieve the desired sensation of taste using less “adjuvants”
`(here usually sugar).
`For this reason many technical proposals have been made
`recently; they are aiming at a reduction of the amount of
`inactive ingredients in presentations and, at the same time,
`ensuring safe handling of these substances.
`A proposal of particular interest in this connection is the
`production of sheet-like active substance carriers, e.g., as
`disclosed by DE 35 34 983, DE 27 46 414, BE 637 363, DE
`24 32 925, or DE 36 30 603.
`According to the known production processes such paper
`like carriers are manufactured without any active substance
`?rst, and they are then sprayed (e.g. GB 1 061 557) with an
`active substance-containing solution or coated/printed with
`an active substance-containing layer of higher concentration
`(e.g. EP 0 219 762).
`However, common complete or partial dissolution of
`active and inactive substances in water or other solvents (DE
`24 49 865) followed by spreading—or casting (e.g. JP
`69026674)--and drying may be expected to be the process
`of choice for the skilled artisan. Extrusion under the action
`of heat was also proposed (Research Disclosure, 1986, No.
`263, March, 145 to 146 (No. 26341).
`Film-like presentations offer a great variety of possibili
`ties to separate the individual doses. They can be imag'ned
`to have the form of sheets of stamps in which the portion is
`taken out of the complete composite only a short time prior
`to use (e.g. BE 637 363, EP 0 219 762). Individual doses of
`different size can be offered on a tape-like presentation as
`well, e.g., separated by perforation (e.g. DE 27 46 414). In
`particular when an inedible carrier is used (e.g. DE 36 30
`603), complete separation into individual portions is indica
`tive; this permits a more hygienic, comfortable, and safe
`removal.
`
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`DRL - EXHIBIT 1028
`DRL002
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`

`
`3
`provide gel-like, stabilized ?lms on cooling, which then
`perfectly dry in the air, e.g., agar-agar or gelatin. However,
`this method cannot satisfy because drying does not permit
`the application of high temperatures since the mass drops-off
`again. The drying of such wet masses at low temperatures is
`uneconomic due to the long dwell times in the apparatus.
`It was accordingly the object of the present invention to
`provide a sheet-like, individually dosed presentation which
`rapidly disintegrates in water. It was a further object of the
`present invention to provide a process for the production of
`such presentations. This process requires only a very small
`amount of water for processing to achieve su?icient ?uidity
`for dosage by means of knife or roll coating procedures but
`nevertheless provides a ?lm of uniform thickness on a
`dehesive carrier; in dry condition good adherence to the
`carrier is achieved, at the same time, however, easy removal
`from the carrier, both during subsequent treatment, e.g.,
`during separating by punching, and prior to application is
`possible.
`This object is achieved according to the present invention
`by a presentation which in the form of a sheet permits single
`dosage of drugs, confectionary and other food, cosmetics,
`and the like intended for oral application or intake, and
`which is characterized by the fact that it comprises a mass
`consisting of 20 to 60%-wt. of at least one ?lm-forming
`agent, 2 to 40%-wt of at least one gel-forming agent, 0.1 to
`35%-wt of at least one active substance, and up to 40%-wt.
`of at least one inert ?lling agent being applied on a carrier,
`or which is unsupported and consists of a mass having the
`aforementioned composition. The object to provide a pro
`cess for the production of such a form of administration was
`achieved by preparing an intimate mixture of the above
`mentioned components, optionally with adding up to 30%
`Wt of a polar solvent, and processing it to a homogeneous,
`spreadable or extrudable mass. In this connection, the indi
`cations of the percentage by weight relate to the solvent-?'ee
`mass of the four basic components.
`Surprisingly, the formulations according to the present
`invention may be rendered spFeadable by adding only a
`small amount of a polar solvent. In contrast to the formu
`lations known in the art, they result in uniform films on
`adehesive carriers already in cold condition. In dried
`condition, the products may be separated by punching them
`in such a way that the individual doses may remain on a
`common can'ier already used for spreading and drying. The
`presentation according to the present invention completely
`disintegrates in the mouth within 10 minutes, and may
`exclusively be manufactured of components admissible
`under the present German Law on Food Products.
`Suitable ?llers include carbonates, phosphates, silicates,
`sulfates, and oxides of the alkaline earth metals, zinc oxide,
`silicas, cellulose and the derivatives thereof, talc or titanium
`dioxide; however, slightly soluble sugars or derivatives
`thereof, such as lactose, or starch derivatives, such as
`cyclodextrins may be used as well, provided that they are
`present in the products in a substantially undissolved form
`so that they meet the mechanical properties of a ?ller.
`The term ?lm formers is to embrace ingredients, such as
`sugars, sugar alcohols and the derivatives thereof, e.g., cane
`sugar, sorbitol, mannitol, xylitol, glucose, fructose, lactose,
`galactose, low-molecular organic acids, such as succinic
`acid, malic acid, or adipic acid, polyethylene glycol, or
`mixtures of these substances, for example, honey.
`The third essential component according to the present
`invention is a gel former being swellable in water and which,
`in general, is composed on the basis of polymeric
`carbohydrates, e.g., starch and the derivatives thereof, agar
`agar, alginic acid, arabinogalactans, galactomannan, cellu
`lose and the derivatives thereof, carrageen, dextran,
`
`35
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`5,629,003
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`4
`tragacanth, and many gums of vegetable origin. However,
`synthetic polymers soluble or swellabe in water may also be
`used according to the present invention, examples thereof
`include polyvinyl-pyrrolidone, polyvinyl alcohol, poly
`acrylic acid, or polyacrylamide. Even polypeptides, such as
`gelatin, albumin, collagen, or eggwhite may be used.
`A component acting as ?ller, the ?lm former and the gel
`former are essential components giving the product the
`desired properties but only on the condition that when the
`quantity of formulation is determined they are processed
`commonly and in accordance with the individual substance
`properties. In this connection, a ?ller or an active agent
`acting as ?ller may be used. The above mentiond advanta
`geous properties result, if certain intervals of mixture ratios
`are maintained: Of ?lm former 20 to 60%-wt., of gel former
`2 to 40%-wt, of active substance 0.1 to 35%-wt., and of ?ller
`up to 40%-wt.
`The layer thickness of the mass amounts to 0.003 to 4
`mm, preferably 20 to 400 um, and in particular 70 to 150 pm.
`Processing may be conducted according to processes
`known to the skilled artisan. In general, the starting com
`ponents will be premixed in dry condition, and then they will
`be transformed to a spreadable consistency under stirring by
`adding a polar solvent in an amount not exceeding 30%-Wt
`The use of homogenizers to render the mixture more
`intimate, or the application of a vacuum to remove air
`bubbles may be useful.
`Dispersing and grinding devices having ?oating grinding
`elements (ball mills) are preferred in this connection. The
`application of heat may accelerate the dispersion process
`and provide the desired physicochemical property of the
`initial products, however, this depends on the special prop
`erties of the gel and ?lm formers.
`The addition of water may possibly be unnecessary, if the
`?lm-forming agent melts. A super?cially homogeneous
`spreadable or extrudable mass results. Shaping in general is
`carried out by means of spreading/knife coating or extrusion
`processes in which the mass passes a gap of de?ned
`diameter, e.g., a slot die of an extruder, thus giving it the
`outer shape. If a solvent is still present, this is at least
`partially withdrawn in suitable drying devices known to the
`skilled artisan.
`The product is advantageously dried on a carrier to which
`it sticks due to adhesion even after drying. If, due to process
`technology, it is not possible to achieve a su?icient thiclmess
`of the initial product, two or more layers may be laminated
`on top of each other by pressure and, if necessary, heat.
`Division into the individual doses is effected by cutiing,
`punching, embossing or similar processes providing areas of
`de?ned size which are separated or separable. If drying is
`effected on a carrier, the presentation may remain on this
`carrier after said separation procedure until it is applied; this
`considerably eases taking it off.
`The present invention will be illustrated in more detail by
`the following examples:
`EXAMPLE 1
`75 g acetylated starch
`62 g honey
`55 g calcium sulfate dihydrate
`5 g citric acid
`50 g water
`are mixed in a closed stirring apparatus and heated to 50° C.
`The mixture is homogenized under stining for two hours
`and subsequently cooled to room temperature. Stirring is
`continued for half an hour under vacuum and the evaporated
`water is added again.
`2 ml of peppermint oil are added and incorporated by
`stining over a 5-minute period.
`
`DRL - EXHIBIT 1028
`DRL003
`
`

`
`5
`The homogeneous mass is spread on siliconized paper
`with a coating device at a gap width of 500 pm and dried at
`80° C. for 15 minutes.
`Cuts outlining the later shape are inserted into the dried
`mass without damaging the paper carrier by means of
`suitable cutting devices. The material remaining between the
`obtained individually dosed presentations is removed in one
`process step by mechanical withdrawal. To protect the
`presentations from drying-up, groups of each 12 of them
`being placed on a common piece of paper canier are sealed
`into a composite packaging material of paper/aluminum!
`ethylenevinyl-acetate which is substantially impermeable to
`water vapor.
`Use: ?avor carrier (sweets)
`
`EXAMPLE 2
`100 g polyethylene glycol (molecular weight approximately
`1,500 gmol)
`8 g carboxyvinyl copolymer
`are kneaded until homogeneous in a heatable double-Z
`lmeader at 80° C. (duration: 2 hours)
`70 g lactose
`are added and kneaded into the basic mass within 30
`minutes. The temperature is reduced to 50° C.
`8 g glibenclamide
`are added; the preparation is kneaded for another 30-minute
`period. The hot mixture is ?lled into a plunger-type extruder
`(available volume: approximately 150 ml) which has been
`pre-heated to 50° C. Extrusion is started immediately and at
`a conveyance speed of approximately 10 g/min through a
`10><1 mm sheet die; cooling until solidi?ed on a cold, clean
`working surface. The resulting extrudate is divided into
`sections of 10 mm by means of a knife. An orally admin
`istrable form of a drug with approximately 3 mg of active
`substance and a weight of approximately 80 mg results
`which disintegrates in the mouth.
`
`EXAMPLE 3
`25 g acetylated starch
`20 g sorbitol
`30 g calcium carbonate
`1 g titanium dioxide
`22 g water
`8 g glycerol
`are mixed in a closed stirring apparatus and heated to 50° C.
`The mixture is homogenized under stirring within two hours
`and subsequently cooled to room temperature.
`Stirring is continued for half an hour under vacuum, the
`evaporated Water is compensated. 0.5 ml of peppermint oil
`is added and homogeneously incorporated by stirring over a
`5-minute period. The mass is spread on siliconized paper
`with a coating device at a gap width of 500 pm and dried at
`80° C. for 10 minutes.
`Cuts outlining the later shape are inserted into the dried
`mass without damaging the paper carrier by means of a
`suitable cutting device. The material remaining between the
`obtained individually dosed presentations is removed by
`mechanical peeling. On the paper carrier each presentation
`is individually sealed into a paper/aluminum/
`ethylenevinylacetate-composite packaging material which is
`substantially impermeable to water vapor.
`Use: instant toothpaste
`
`EXAIVIPLE4
`600 g acetylated starch
`440 g calcium sulfate dihydrate
`40 g citric acid
`
`5,629,003
`
`6
`are weighed into a porcelain ball mill provided with 10
`grinding elements (diameter appr. 4 cm) and premixed in dry
`condition in the closed mill at 10 rpm for 1 hour. A
`suspension of
`'
`20 g titanium dioxide in
`550 g water
`is added and the mixture agitated under the same conditions
`for one hour.
`500 g of honey are added. Homogenization is continued
`at 10 1pm for 2 hours. Finally, 16 ml of peppermint oil are
`added and rotation continued for 18 hours. The further
`treatment of the mass thus obtained is e?iected as described
`for Example 1.
`It is understood that the speci?cation and examples are
`illustrative but not limitative of the present invention and
`that other embodiments within the spirit and scope of the
`invention will suggest themselves to those skilled in the art.
`We claim:
`’
`1. A sheet comprising multiple dosage units which disin
`tegrate in water and which contain as active substance, a
`cosmetic, perfnning or ?avoring application, and compris
`ing a mass of
`(a) 20-60%-wt of atv least one ?lm-forming agent,
`(b) 2-40%-wt. of at least one gel-forming agent,
`(c) 0.1—35%-wt. of at least one active substance and
`(d) up to 40%-wt. of at least one inert ?lling agent,
`the percentage relating to the solvent-free mass of these four
`components and the dosage units being supported on a
`carrier,
`wherein the ?lm former comprises a compound selected
`from the group consisting of monomeric and oligo
`meric sugars, sugar alcohols, organic acids having up to
`6 carbon atoms and polyethylene glycol,
`wherein the gel former is water swellable and consists of
`at least one component selected from the group con
`sisting of polymeric carbohydrates, esters thereof,
`gelatin, albumin, collagen, egg white, carboxyvinyl
`copolymers, polyacryl amide, polyvinyl pyrrolidone
`and polyvinyl alcohol,
`wherein the ?ller comprises at least one physiologically
`acceptable compound selected from the group consist
`ing of carbonates, phosphates, silicates, sulfates and
`oxides of an alkaline earth metal, silicas, slightly
`soluble sugars, cellulose, cyclodextrin as a starch
`derivative, talc, titanium dioxide, zinc oxide and mag
`nesium stearate, undissolved or crystalline partial
`amounts of active substances simultaneously acting as
`?lling agents, and
`wherein the layer thiclmess of the dosage units is from
`0.003 to 4 mm
`2. A sheet presentation according to claim 1, comprising
`at least two active substance-containing layers.
`3. A sheet according to claim 1, wherein the layer thick
`ness of the dosage units is from 20 to 400 pm.
`4. A sheet according to claim 3, wherein the layer thick
`ness is from 70 to 150 pm.
`5. A sheet according to claim 1, wherein the active
`substance is of organic nature.
`6. A sheet according to claim 1, which is provided with a
`release paper or a release ?lm and is divisible into individual
`doses of areas of de?ned size.
`7. A sheet according to claim 1, wherein the multiple
`dosage units comprise an instant toothpaste composition.
`
`*****
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`DRL - EXHIBIT 1028
`DRL004