United States Patent [19]
`Schmidt
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,849,246
`Jul. 18, 1989
`
`[54] PROCESS FOR PRODUCING AN
`ADMINISTRATION OR DOSAGE FORM
`FOR DRUGS, REAGENTS OR OTHER
`ACTIVE INGREDIENTS
`
`[76] Inventor: Wolfgang Schmidt, Reembroden 44,
`D-2000 Hamburg 63, Fed. Rep. of
`Germany
`60,689
`Oct. 7, 1986
`
`[21] Appl. No.:
`[22] PCT Filed:
`
`[86] PCT No.:
`§ 371 Date:
`§ 102(e) Date:
`
`PCI/EP86/ 00571
`Jun. 9, 1987
`Jun. 9, 1987
`
`[87] PCT Pub. No.: WO87/02241
`PCT Pub. Date: Apr. 23, 1987
`Foreign Application Priority Data
`[30]
`Oct. 9, 1985 [DE] Fed. Rep. of Germany ..... .. 3536024
`
`[51] Int. 01.4 ...... .Q .............. .. A01W 1/02; A61K 9/00;
`A61K 15/00; A61K 21/00
`[52] US. Cl. ...................................... .. 427/2; 424/478;
`424/479; 427/3
`[58] Field of Search .............. .. 427/2, 3; 424/478, 479
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,444,858 5/1969 Russell .............................. .. 128/260
`
`FOREIGN PATENT DOCUMENTS
`2746414 4/ 1979 Fed. Rep. of Germany .
`51-54917 6/1976 Japan .
`139077 2/1920 United Kingdom .
`1061557 3/1967 United Kingdom .
`
`OTHER PUBLICATIONS
`Chemical Abstracts, vol. 85, 1976, p. 364.
`Primary Examiner——Michael Lusignan
`Attorney, Agent, or Firm-Cushman, Darby & Cushman
`[57]
`ABSTRACI‘
`A process for producing an administration or dosage
`form of drugs, reagents or other active ingredients. A
`watersoluble foil composed of starch, gelatin, glycerin
`and/or sorbit and if necessary other additives is coated
`by a roll coating process with a layer containing the
`active ingredients and composed of the samebasic ingre
`dients. After a corresponding prefragmentation, the
`administration form thus produced is particularly useful
`as an oral administration drug.
`
`15 Claims, No Drawings
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`1
`
`PROCESS FOR PRODUCING AN
`ADMINISTRATION OR DOSAGE FORM FOR
`DRUGS, REAGENTS OR OTHER ACTIVE
`INGREDIENTS
`
`15
`
`4,849,246
`2
`exist for solid drugs with respect to other parameters,
`such as the disintegration time and dissolving rate.
`The aforementioned prior art proposals lead to prod
`ucts with an inadequate acceptance by the patient (e.g.
`it is dif?cult to ingest paper portions) and do not permit
`an accurate dosing per surface unit, as is an absolute
`requirement. When incorporating the active ingredient
`into a ?lm, dif?culties are caused not only by the precise
`dosing, but also it is necessary to produce a separate ?lm
`for each active ingredient, so that the production pro
`cess is not economic.
`The problem of the present invention is to provide a
`“two-dimensional” administration and dosage form,
`which does not suffer from the aforementioned disad
`vantages, which can be easily produced and can be very
`?exibly adapted to the requirements of the market and
`different active ingredients.
`The invention therefore relates to a process for the
`production of an administration and dosage form for
`drug active ingredients, reagents or other active ingre
`dients in the form of a ?lm with an active ingredient
`containing coating, which is characterized in that.
`(a) a water—soluble support ?lm is produced from an
`aqueous composition based on starches, gelatins, glyc
`erol and/or sorbitol, as well as optionally natural and
`/ or synthetic resins and/ or gums,
`(b) an aqueous coating material is prepared from the
`active ingredient, as well as starches, gelatins, glycerol
`and/or sorbitol, as well as optionally natural and/or
`synthetic resins and/ or gums, and
`(c) the coating material is continuously applied by
`means of a roll coating process and in a precisely prede
`termined quantity (coating thickness) to at least one side
`of the support ?lm.
`The inventively produced administration form has a
`large number of important advantages:
`One support ?lm can be used for the most varied
`active ingredients and can therefore be economically
`produced in larger numbers.
`The active ingredient-containing coating can be very
`thin in the case of very ef?caceous drugs, because the
`support material ensures an adequate mechanical
`strength.
`With the aid of modern roll application processes the
`active ingredient-containing coating can be applied
`with a constant thickness, so that the necessary toler
`ances can be respected.
`If sterilization is necessary, this can be achieved with
`out dif?culty by radiation treatment due to the limited
`coating thickness.
`The support can be printed with different information
`on the front and in particular rear surface using physio
`logically acceptable printing inks.
`As a result of the relatively large surface area of e.g.
`4 to 10 cm2, detailed information for the user can be
`printed on the uncoated support material, or even subse
`quently.
`The dosage units can be rendered ?exible by a corre
`sponding pre-separation, e.g. by perforation, so that it is
`only necessary to produce one product for different
`dosages (e.g. for adults and children); whereby the pre
`separation can optionally be carried out in the pharma
`cists or hospital in accordance with details provided by
`the doctor.
`The inventive administration form shares the com
`mon advantage of the known ?lm-form administration
`forms of extremely small space requirements. Thus, in
`place of folding boxes, it is e.g. possible to use pouches
`
`Drugs or pharmaceuticals can be orally administered
`in the form of powders, dropping solutions or juices. As
`precise dosing is dif?cult with such administration
`forms, preference is generally given to manufacturer
`dosed administration forms such as tablets, dragees or
`capsules. Reagents and other active ingredients, e.g.
`sweeteners or ?avouring agents are frequently also
`tableted for a precisely dosed administration. The pro
`duction procedure for tablets, dragees, capsules, etc. has
`largely been completely developed, but it is not possible
`to overlook a number of system-related disadvantages.
`For low-dosed active ingredients, a large proportion
`of adjuvants must be added in order to obtain a handla
`ble size of the individual dose. It is also substantially
`impossible to precisely mark individual tablets or
`dragees. Therefore blister packs have been adopted,
`which contain a large number of tablets, dragees and
`also capsules and which are printed with the necessary
`information and in particular the product name. The
`25
`manufacture of such packs naturally involves an addi
`tional operation and pack transfers in the form of fold
`ing boxes are required, which have a considerable
`empty volume and therefore take up additional storage
`space. Another serious disadvantage of dragees and
`capsules is that splitting up is not possible, so that the
`minimum dose is predetermined. An accurate breaking
`up is also difficult in the case of tablets and only larger
`tablets provided with a notch as a predetermined break
`ing point can be split, but frequently fragments of un
`equal size are obtained.
`Attempts have already been made to ?nd a new ad
`ministration form for the oral administration of drugs in
`the form of active ingredient-containing films or foils.
`Belgian Pat. No. 637,363 discloses a paper-like support
`40
`material of insoluble cellulose ?bres impregnated with
`an active ingredient solution or coated by application or
`sprinkling, dosing being achieved by perforating the
`support ?lm in the manner of a sheet of postage stamps.
`The closing of the active ingredient is necessarily ex
`45
`tremely imprecise. DE-OS No. 24 32 925 and DE-OS
`No. 24 49 865 disclose the incorporation of drug active
`ingredients into ?lm forming agents, which are prefera
`bly in the form of water-soluble compounds, such as
`methyl and ethyl cellulose, but in particular hydroxy
`propyl cellulose, hydroxyethyl cellulose or methylhy
`droxypropyl cellulose. The ?lms can also contain ?llers
`and parting agents. The thus obtained active ingredient
`containing films can also be subdivided into individual
`portions by perforation for dosing purposes.
`However, these proposals have not led to practical
`adoption and in the latest text book “Arzneiformen
`lehre” by RH. List, fourth edition, Stuttgart 1985, no
`mention is made thereof. This is clearly based on the
`fact that the hitherto known proposals do not make it
`possible to obtain the requisite constant weight and
`uniform active ingredient distribution, such as are
`nowadays required. The Pharmakopoea Europae e.g.
`sets criteria for the uniformity of the weight of individu
`ally dosed drugs, which are graded according to the
`maximum permitted variations in per cent correspond
`ing to the particular average weight. This requirement
`is generally-i5 to max. 10%. Corresponding values
`
`35
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`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`3
`or bags made from plastic ?lm or plastic-coated paper,
`into which the product is sealed, in much the same way
`as moist refreshing cloths.
`The support ?lm is manufactured in per se known
`manner using a continuously operating roll-based ?lm
`machine. The coating process for producing the sup
`port ?lm is based on the roller principle, i.e. the aqueous
`composition for the support ?lm is applied by means of
`rolls and doctor blades and spread out to form thin
`webs, predried on the rolls and then in the main drying
`process subsequently dried to the desired ?nal moisture
`content. The end product obtained is so strong and
`elastic that it can be wound onto reels and stored, if the
`residual moisture content is not too high (risk of mould
`formation).
`The width of the ?lm can be of a random nature and
`is advantageously adapted to the coating machine
`width. It is obvious to adapt the two widths to one
`another at the time of manufacture. It is technically also
`possible to carry out ?lm production and coating in
`time succession on the same plant, which signi?cantly
`improves the economics of the process.
`The composition used is kept at the desired tempera
`ture, viscosity and homogeneity, accompanied by
`pumping round. The ?lm is subsequently dried in a
`heating tunnel. The thus obtained support ?lm consti
`tutes the inert support for the subsequent coating with
`the different coating materials.
`A physiologically unobjectionable composition is
`used for ‘producing the water-soluble support ?lm. The
`30
`“water solubility” is to be de?ned in such a way that the
`?lm is produced from an aqueous composition and the
`fmished ?lm subsequently dissolves or swells during use
`in water or in gastric juice.
`The film formers are in particular gelatins, as well as
`starches (potato starch, wheat starch, corn starch), as
`well as polyvinyl-pyrrolidone (PVP), methyl and ethyl
`cellulose, as well as polyvinyl alcohol (PVA). It is also
`possible to use water-soluble acrylic resin dispersions.
`Suitable plasticizers are in particular polyfunctional
`alcohols, such as glycerol and sorbitol (Karion).
`The components are appropriately cold mixed with
`water and accompanied by slight heating and constant
`stirring are processed to a coatable slime. The stirring in
`of air must be avoided to the greatest possible extent, in
`order to obtain a clear, but slight opalescent material.
`The thickness of the support ?lm is preferably be
`tween approximately 50 and 250 pm. It can be con
`trolled to a considerable extent. The characteristics of
`the support ?lm can undergo signi?cant quality in?u
`50
`ences by corresponding combination of ?lm formers
`and plasticizers. The support ?lm must have a uniform
`thickness (preferably e. g. 100 um), must be slightly
`elastic and bendable, but without breaking. The starch
`proportion should be adequately high, so that moisture
`is absorbed on applying the coating material, without
`there being any sticking of the surface or softening of
`the complete ?lm.
`The following basic formulation has proved satisfac
`tory for the support ?lm:
`Gelatin 8 to 10 g
`Starch 4 to 8 g
`Glycerol l to 2 g
`Polyvinylpyrrolidone l to 2 g
`Water 30 to 50 g
`Water-soluble natural and/or synthetic resins, e.g.
`acrylic resins and gums are also suitable. It is also possi
`ble to add to the material other conventional substances,
`
`4,849,246
`4
`e.g. preservatives, such as p-hydroxybenzoates, inert
`soluble or insoluble ?llers, sugar or other sweeteners,
`other polyols, waxes or dyes.
`The possibility of printing the front and back of the
`support ?lm is a particular advantage of the inventive
`administration form. For example, it is possible to print
`on the marking, details on the constituents, together
`with dosage details. It is optionally even possible to
`print on the back the entire content of a pack-in label,
`thereby rendering super?uous the need for such a sepa
`rate label, which is frequently lost. In the case of drugs
`or pharmaceuticals which are regularly taken, eg in
`the case of hormonal contraceptives, the complete ad
`ministration program can be given in such a way that it
`is possible to simply check the taking thereof. For print
`ing purposes it is necessary to use physiologically ac
`ceptable inks (food colours), because the support ?lm
`forms part of the orally administered administration
`form.
`The active ingredient-containing coating material is
`an aqueous composition, which is physiologically inert
`and whose individual constituents are suitable for phar
`maceuticals or foods. Importance is attached to the
`reciprocal physical-chemical af?nity and compatibility
`between the coating material and the support ?lm and
`this is always particularly good if the components used
`are identical or have similar characteristics. Whilst tak
`ing account of the active ingredient added, the coating
`compound formulation consequently corresponds to
`that given hereinbefore for the support ?lm, the precise
`setting of the solids content and viscosity taking place
`by means of inert swelling and ?lling agents.
`Thus, the material contains polymeric ?lm forming
`agents, preferably gelatins and swelling or soluble
`starches, as well as optionally celluloses or hemicellu
`loses. In addition, plasticizers are added, particularly
`polyhydric alcohols, such as glycerol or sorbitol. In
`order to set the desired viscosity of the coating com
`pound, which has the consistency of a slime, use is made
`of polymeric swelling agents, preferably alginates, pec
`tins, chitins, lecithins or polyethylene glycols. These
`latter substances can simultaneously serve as adhesives.
`It is also possible to add water-soluble synthetic or
`natural resins or gums or gum Arabic, in order to im
`prove the adhesion of the coating to the support mate
`rial. It is ?nally possible to add preservatives, such as
`e.g. p-hydroxybenzoates, dyes (food dyes), pigments,
`such as titanium dioxide, or ?avouring agents and
`sweeteners.
`Coating materials with a water content of approxi
`mately 50% and a viscosity of approximately 30 to
`10,000 cPs have proved particularly satisfactory. The
`formulation and production is similar to that of a phar
`maceutical juice, in which the active ingredient or ac
`tive ingredient combination is dissolved or uniformly
`dispersed. The coating material must have an adequate
`homogeneity and galenic stability, so that a uniform
`active ingredient content of the ?nished coating is en
`sured.
`The following basic formulation has proved satisfac
`tory:
`Gelatin 8 to 10 g
`Starch 3 to 8 g
`Glycerol l to 2 g
`Water 30 to 50 g
`The active ingredient is dissolved or dispersed in this
`basic material. When a dispersion is used, for uniform
`distribution purposes, the active ingredient must be
`
`60
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`15
`
`40
`
`45
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`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`20
`
`4,849,246
`5
`6
`extremely ?nely divided and preferably the average
`m/min. The reproducible constant weight is only
`particle size is in the range approximately 1 to 20 pm.
`1-2.5% for 20 g/m2 and approximately 1-10% for l
`The desired active ingredient dose and the sought
`g/m2 over entire surface. The coating material is ap
`surface of the dosage units determine the coating thick
`plied continuously by means of rollers with a special
`ness, whilst account must be taken of the moisture con
`?ne engraving, the engraved grooves forming an angle
`tent of the coating material and the ?nished coating.
`of 30 to 60, particularly 45° to the direction of move
`The inventive administration form is particularly
`ment of the support film. 27 to 80 grooves/cm can be
`suitable for drugs, which are administered with a low
`etched into the rollers. Corresponding to its shape and
`dose rate, i.e. in which the individual dose for oral ad
`depth, the engraving can absorb a given quantity of
`ministration is between 0 mg (placebo) and approxi
`coating material and subsequently supply it to the sup
`mately 20 mg. Suitable drug active ingredients occur in
`port ?lm. By varying the advance rate, running direc
`all ?elds of oral therapy, particular reference being
`tion and engraving, as well as indirect application by
`made inter alia to analeptic, antibiotic, antidiabetic,
`means of a further speed-variable roller, it is possible to
`antiemetic, antiepileptic, antihypertonic, corticoid, geri
`very accurately adjust the coating quantities.
`atric, hypnotic, cardiac, hypostatic and bio-active ingre
`A two-sided coating frequently gives advantages,
`dients.
`because problems due to the warping of the support
`Approximately 4 to 20 g of active ingredient per 1112
`material and differing hygroscopicity are compensated.
`(=l0,000 cm2) of support ?lm can be applied in one
`Multiple and even strip coatings and in fact even print
`coating process, so that 10 cm2 (=2 standard postage
`ing style coatings are possible and offer a considerable
`stamps) can absorb up to 20 mg of active ingredient.
`variability when processing incompatible active ingre
`The coating material is normally applied to one side
`dients.
`of the support ?lm, but it is also possible to coat both
`Another suitable application process corresponds to
`sides, particularly in the case of two different active
`ingredients.
`the coating of paper or ?lms. Raw papers are improved
`in that they are coated with coating materials on one or
`Each coating can contain one or more drug active
`both sides. The aqueous coating materials initially pass
`ingredients. If, when using several active ingredients,
`onto a rolling mill, which receives same by means of a
`they are not readily compatible with one another and
`rotary roller, strips same to a clearly de?ned coating
`cannot be contained in one coating material, it is possi
`thickness with a doctor blade at a given spacing and
`ble in the case of the administration form according to
`then the roller supplies the coating material to the sup
`the invention to apply the coating in the form of several
`port. The support film, which has a width of 0.30 to 7.50
`individual coatings with different compositions and to
`m, subsequently passes through a drying tunnel and is
`separate the active ingredients from one another in this
`wound onto reels. This process can be repeated on one
`way; if necessary an active ingredient-free intermediate
`coating being provided. It is also possible to provide
`or both sides in one or more stages and an already
`coated surface can be coated again. The weight of the
`above the active ingredient-containing coating, a fur
`support material increases by that of the dry weight.
`ther protective coating, which protects the active ingre
`The accuracy of the application process using this doc
`dient or ingredients against contact with the atmo
`tor blade method is reproducibly i5% and is depen
`sphere and/or light. In such cases, the protective coat
`ing must consequently be impermeable to air and mois
`dent on the coating thickness, which can vary between
`4 and 40 g/m2. Within the individual production runs, it
`ture and/ or must be made impermeable to light by the
`addition of corresponding dyes or pigments.
`is possible to achieve a weight tolerance per surface unit
`Through a corresponding build-up of the coating, it is
`down to i 1%.
`When applying several coatings, as described herein
`possible to control the supply of active ingredient fol
`before, they are successively applied and optionally
`lowing the administration of the drug. For example, it is
`each coating previously passes through a drying station.
`possible to place an active ingredient coating between at
`least two further coatings, which control the active
`This can e. g. comprise a temperature-controlled pair of
`ingredient resorption in the gastrointestinal tract in per
`rollers and a drying tunnel which is controllable in
`sections. Following the ?nal coating process, the coat
`se known manner. The active ingredient coating can
`ing material is wound onto reels.
`e.g. be located between two acid-insoluble coatings, so
`The active ingredient-coated support ?lm is subse
`that on administration it passes through the stomach and
`resorption only takes place in the gastric tract. In a
`quently pre-divided into dosage units, which can be
`similar way, different active ingredients can be superim
`separated in much the same way as postage stamps. This
`posed in different coatings on the support ?lm, so that
`pre-dividing is normally carried out by the drug manu
`resorption takes place successively and/or in delayed
`facturer, but it is also conceivable to supply the coated
`form.
`material, e.g. to hospitals or pharmacists, where the
`Similar pharmacokinetic effects can be obtained
`pre-dividing can then be carried out in dose-dependent
`through the incorporation (e.g. suspension) of differ
`manner, or individually in accordance with information
`ently pre-prepared microencapsulated active ingredi
`supplied by the doctor.
`ents.
`Pre-dividing takes place in a very simple manner by
`Coating of the support material with the active in
`perforation or punching, it being possible to combine
`gredient-containing coating material takes place by
`this step with the printing of the support material. In
`means of a roll application or coating process. This
`many cases it is more advantageous to carry out the
`process, which is particularly suitable for quantitative
`printing of the support material prior to coating.
`coating, operates according to a process similar to inta
`Before or preferably after pre-division of the active
`glio printing and which is called “Akkugravur”. Suit
`ingredient-coating into dosage units, the coated support
`able machines are commercially available (Pagendarrn,
`material is cut into ready-for-use portions containing a
`Hamburg) and permit application or coating weights of
`given number of dosage units. It is also possible to cut
`up to 80 g/m2 in the case of web speeds of several 100
`the material on reels into narrow strips. It is then possi
`
`55
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`
`40
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`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`EXAMPLE
`Preparation of a drug administration form in the form
`of a coated ?lm.
`The following composition was used for producing a
`water-soluble support ?lm:
`
`Gelatin
`Potato starch
`Glycerol
`Puri?ed water
`
`10.0 parts by weight = 25%
`8.0 parts by weight = 20%
`1.5 parts by weight = 3.75%
`20.5 parts by weight = 51.25%
`
`15
`
`20
`
`25
`
`4,849,246
`8
`7
`ingredient. The residual moisture content of the prod
`ble to separate the individual dosage units from the reel
`uct was 8.6% after drying.
`in much the same way as individual postage stamps.
`As mainly natural substances, such as starches and
`An administration form was obtained, which on oral
`administration rapidly swells and dissolves in the mouth
`gelatin are used as basic substances for producing the
`inventive administration form, products are obtained,
`and can therefore be easily swallowed.
`which are similar to known wafers and whose oral
`I claim:
`ingestion presents no problems. It is important that the
`1. In a process for the production of an administration
`fmished product is largely free from water, i.e. has a
`and dosage form for drugs, reagents or other active
`water content of less than 10 and preferably less than
`ingredients in the form of a ?lm with an active ingredi
`2%, because otherwise mould can form.
`ent-containing coating, in which process
`The invention has been largely described hereinbe
`(a) a water-soluble support ?lm is produced from an
`fore in connection with drugs, but is in no way limited
`aqueous composition based on an effective amount
`thereto. For example, it is also possible to adopt the
`of a compound selected from starches, gelatins, and
`same procedure for dosage forms for chemical reagents,
`their mixtures and an effective amount of a com
`?avouring substances and the like.
`pound selected from glycerol, sorbitol and their
`The following examples serve to further illustrate the
`mixtures,
`invention.
`(b) an aqueous coating material is prepared from an
`effective amount of the active ingredient, as well as
`an effective amount of a compound selected from
`starches, gelatins, and their mixtures and an effec
`tive amount of a compound selected from glycerol,
`sorbitol and their mixtures, and
`(c) the coating material is continuously applied by
`means of a roll coating process and in a precisely
`predetermined quantity to at least one side of the
`support ?lm,
`the improvement that the basic composition of the sup
`port ?lm corresponds to that of the coating material.
`2. Process according to claim 1, characterized in that
`the support ?lm and the coating material also comprises
`a substance selected from the group comprising natural
`and synthetic resins and gums and their mixtures.
`3. Process according to claim 1, characterized in that
`the composition of the support ?lm contains further
`additives selected from the group consisting of inert
`soluble and insoluble ?llers, sugar and other sweeteners,
`plasticizers such as polyols, waxes and dyes, ?avouring
`substances and preservatives.
`4. Process according to claim 1, characterized in that
`the coating material contains further additives selected
`from the group consisting of soluble and insoluble ?ll
`ers, sugar and other sweeteners, plasticizers such as
`polyols, waxes and dyes, ?avouring substances and
`preservatives.
`5. Process according to claim 1, characterized in that
`the coating compound is applied to the support ?lm in
`a continuous manner by means of grooved rollers,
`which absorb a clearly de?ned quantity of coating ma
`terial and then transfer it to the support ?lm.
`6. Process according to claim 1, characterized in that
`the coating material is continuously applied to the sup
`port ?lm by means of smooth roller pairs, which in
`speed-displaced synchronism absorb the material and
`transfer it to the support ?lm in a clearly de?ned quan
`tity.
`7. Process according to claim 1, characterized in that
`the composition of the support ?lm and of the coating
`material comprises 8 to 10 parts by weight of gelatin, 4
`to 8 parts by weight of starch, l to 2 parts by weight of
`glycerol and 20 to 50 parts by weight of water.
`8. Process according to claim 7, characterized in that
`the coating material comprises up to 10 parts by weight
`of the active ingredient.
`9. Process according to claim 1, characterized in that
`different active ingredients are applied to the top and
`bottom surfaces of the support ?lm for producing a
`combination product.
`
`The viscosity of the slime-like composition was be
`tween 4000 and 10000 cPs, as a function of the tempera
`ture and active ingredient. To produce the coating ma
`terial, the gelatin was ?rstly dissolved in an adequate
`quantity of water, whereby ?rstly water at 90° to 95° C.
`was provided and into which the gelatin was intro
`duced, accompanied by stirring. The active ingredient
`was dissolved together with the glycerol in water in a
`separate mixture. Finally, the potato starch was mixed
`in an adequate quantity of water at 50° to 60° C. and
`accompanied by stirring. The gelatin solution and po
`tato starch suspension were added together and the
`active ingredient suspension was slowly stirred into the
`mixture, whilst avoiding air inclusions.
`The temperature was kept at 55° to 60° C. Finally, the
`desired water content was adjusted by adding further
`water.
`By means of Akkugravur, the coating material was
`applied to the support ?lm with a wet coating weight of
`55 g/m2. After drying, the coating weight was 23 g/m2,
`corresponding to an active ingredient content of 5
`g/mz. The active ingredient-coated ?lm was then perfo
`rated in box-like manner, so that the individual portions
`have a surface of 5 cm2, in the case of dimensions of
`2X2.5 cm, such a portion containing 2.5 mg of active
`
`The viscosity of the slime-like composition was ap
`proximately 3000 cPs at 50° C. With the aid of a coating
`process, the material was processed to a ?lm which,
`after drying, had a 9.3% residual water content.
`Using the same basic substances as for the support
`?lm, the coating material was prepared in accordance
`with the following formulation:
`
`Gelatin
`Potato starch
`Glyercol
`Active ingredient
`Puri?ed water
`
`10.0 parts by weight = 18.2%
`5.0 parts by weight = 9.1%
`1.0 parts by weight = 1.8%
`5.0 parts by weight = 9.1%
`34.0 parts by weight = 61.8%
`
`60
`
`65
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,849,246
`9
`10. Process according to claim 1, characterized in
`that a coating material is used which comprises more
`than one active ingredient.
`11. Process according to claim 1, characterized in
`that mutually incompatible active ingredients are ap
`plied in the form of separate coatings to the support ?lm
`and an ingredient-free intermediate coating is provided
`between the two ingredient-containing coatings.
`12. Process according to claim 1, characterized in
`that an active ingredient coating is placed between at
`least two further coatings, which control the active
`ingredient resorption in the gastrointestinal tract and
`one of the coatings can be the support ?lm.
`
`10
`13. Process according to claim 1, characterized in
`that a further coating is placed over the active ingredi
`ent coating and protects the active ingredient against
`contact with the atmosphere, against light or against
`both.
`14. Process according to claim 1, characterized in
`that the active ingredient-coated water-soluble ?lm is
`subdivided into portions by perforation or punching
`and said portions contain de?ned dosage units of the
`active ingredient.
`15. Process according to claim 1, characterized in
`that the back of the support material is printed with the
`active ingredient composition or information relating to
`its medical application.
`It
`It
`
`* Ill
`
`*
`
`5
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC