United States Patent [191
`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
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,444,858 5/1969 Russell ................................ 128/260
`
`[76]
`
`Inventor: Wolfgang Schmidt, Reembroden 44,
`D-2000 Hamburg 63, Fed. Rep. of
`Germany
`
`[21] Appl. No.:
`
`60,689
`
`[22] PCT Filed:
`
`Oct. 7,1986
`
`[86) PCTNo.:
`§ 371 Date:
`§ 102(e) Date:
`
`PCf/EP86/00571
`Jun.9, 1987
`Jun. 9,1987
`
`[87) PCT Pub. No.: W087/02241
`PCT Pub. Date: Apr. 23, 1987
`
`[30]
`Foreign Application Priority Data
`Oct. 9, 1985 [DE] Fed. Rep. of Germany ....... 3536024
`
`Int. 0.4 ........................ A01W 1/02; A61K 9/00;
`[51]
`A61K 15/00; A61K 21/00
`[52] u.s. Cl •........................................ 427/2; 424/478;
`424/479;427/3
`[58] Field of Search ................ 427/2, 3; 424/478, 479
`
`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)
`ABSTRAcr
`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(cid:173)
`dients. After a corresponding prefragmentation, the
`administration form thus produced is particularly useful
`as an oral administration drug.
`
`15 Claims, No Drawings
`
`SUBJDG-0004744
`
`RBP_TEVA05024290
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`1
`
`4,849,246
`
`PROCESS FOR PRODUCING AN
`ADMINISTRATION OR DOSAGE FORM FOR
`DRUGS, REAGENTS OR OTHER ACTIVE
`INGREDffiNTS
`
`Drugs or pharmaceuticals can be orally administered
`in the form of powders, dropping solutions or juices. As
`precise dosing is difficult with such administration
`forms, preference is generally given to manufacturer- 10
`dosed administration forms such as tablets, dragees or
`capsules. Reagents and other active ingredients, e.g.
`sweeteners or flavouring agents are frequently also
`tableted for a precisely dosed administration. The pro(cid:173)
`duction procedure for tablets, dragees, capsules, etc. has 15
`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(cid:173)
`ble size of the individual dose. It is also substantially 20
`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(cid:173)
`tional operation and pack transfers in the form of fold(cid:173)
`ing boxes are required, which have a considerable
`empty volume and therefore take up additional storage
`space. Another serious disadvantage of dragees and 30
`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(cid:173)
`ing point can be split, but frequently fragments of un- 35
`equal size are obtained.
`Attempts have already been made to find a new ad(cid:173)
`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 fibres impregnated with
`an active ingredient solution or coated by application or
`sprinkling, dosing being achieved by perforating the
`support fllm in the manner of a sheet of postage stamps.
`The dosing 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 film forming agents, which are prefera(cid:173)
`bly in the form of water-soluble compounds, such as
`methyl and ethyl cellulose, but in particular hydroxy- 50
`propyl cellulose, hydroxyethyl cellulose or methylhy(cid:173)
`droxypropyl cellulose. The films can also contain fillers
`and parting agents. The thus obtained active ingredient(cid:173)
`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(cid:173)
`lehre" by P.H. 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 60
`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(cid:173)
`ally dosed drugs, which are graded according to the 65
`maximum permitted variations in per cent correspond(cid:173)
`ing to the particular average weight. This requirement
`is generally±5 to max. 10%. Corresponding values
`
`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(cid:173)
`ucts with an inadequate acceptance by the patient (e.g.
`5 it is difficult 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 film, difficulties are caused not only by the precise
`dosing, but also it is necessary to produce a separate film
`for each active ingredient, so that the production pro(cid:173)
`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(cid:173)
`vantages, which can be easily produced and can be very
`flexibly 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(cid:173)
`dients in the form of a tUm with an active ingredient-
`containing coating, which is characterized in that.
`(a) a water-soluble support film is produced from an
`aqueous composition based on starches, gelatins, glyc(cid:173)
`erol and/or sorbitol, as well as optionally natural and(cid:173)
`/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(cid:173)
`termined quantity (coating thickness) to at least one side
`of the support fllm.
`The inventively produced administration form has a
`large number of important advantages:
`One support film 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 efficaceous 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(cid:173)
`ances can be respected.
`If sterilization is necessary, this can be achieved with(cid:173)
`out difficulty 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(cid:173)
`logically acceptable printing inks.
`As a result of the relatively large surface area of e.g.
`55 4 to 10 cm2, detailed information for the user can be
`printed on the uncoated support material, or even subse(cid:173)
`quently.
`The dosage units can be rendered flexible by a corre(cid:173)
`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(cid:173)
`cists or hospital in accordance with details provided by
`the doctor.
`The inventive administration form shares the com(cid:173)
`mon advantage of the known film-form administration
`forms of extremely small space requirements. Thus, in
`place of folding boxes, it is e.g. possible to use pouches
`
`SUBJDG-0004745
`
`RBP_TEVA05024291
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,849,246
`
`3
`4
`e.g. preservatives, such as p-hydroxybenzoates, inert
`or bags made from plastic fllm or plastic-coated paper,
`into which the product is sealed, in much the same way
`soluble or insoluble fillers, sugar or other sweeteners,
`other polyols, waxes or dyes.
`as moist refreshing cloths.
`The possibility of printing the front and back of the
`The support film is manufactured in per se known
`manner using a continuously operating roll-based ftlm 5 support ftlm is a particular advantage of the inventive
`administration form. For example, it is possible to print
`machine. The coating process for producing the sup-
`port ftlm is based on the roller principle, i.e. the aqueous
`on the marking, details on the constituents, together
`composition for the support ftlm is applied by means of
`with dosage details. It is optionally even possible to
`rolls and doctor blades and spread out to form thin
`print on the back the entire content of a pack-in label,
`webs, predried on the rolls and then in the main drying 10 thereby rendering superfluous the need for such a sepa-
`process subsequently dried to the desired final moisture
`rate label, which is frequently lost. In the case of drugs
`content. The end product obtained is so strong and
`or pharmaceuticals which are regularly taken, e.g. in
`elastic that it can be wound onto reels and stored, if the
`the case of hormonal contraceptives, the complete ad-
`residual moisture content is not too high (risk of mould
`ministration program can be given in such a way that it
`formation).
`15 is possible to simply check the taking thereof. For print-
`ing purposes it is necessary to use physiologically ac-
`The width of the film can be of a random nature and
`is advantageously adapted to the coating machine
`ceptable inks (food colours), because the support ftlm
`width. It is obvious to adapt the two widths to one
`forms part of the orally administered administration
`another at the time of manufacture. It is technically also
`form.
`possible to carry out ftlm production and coating in 20
`The active ingredient-containing coating material is
`time succession on the same plant, which significantly
`an aqueous composition, which is physiologically inert
`improves the economics of the process.
`and whose individual constituents are suitable for phar-
`maceuticals or foods. Importance is attached to the
`The composition used is kept at the desired tempera-
`ture, viscosity and homogeneity, accompanied by
`reciprocal physical-chemical affinity and compatibility
`pumping round. The ftlm is subsequently dried in a 25 between the coating material and the support film and
`this is always particularly good if the components used
`heating tunnel. The thus obtained support film consti-
`tutes the inert support for the subsequent coating with
`are identical or have similar characteristics. Whilst tak-
`the different coating materials.
`ing account of the active ingredient added, the coating
`A physiologically unobjectionable composition is
`compound formulation consequently corresponds to
`used for producing the water-soluble support fllm. The 30 that given hereinbefore for the support film, the precise
`"water solubility" is to be defmed in such a way that the
`setting of the solids content and viscosity taking place
`by means of inert swelling and filling agents.
`film is produced from an aqueous composition and the
`fmished film subsequently dissolves or swells during use
`Thus, the material contains polymeric film forming
`in water or in gastric juice.
`agents, preferably gelatins and swelling or soluble
`The film formers are in particular gelatins, as well as 35 starches, as well as optionally celluloses or hemicellu-
`starches (potato starch, wheat starch, com starch), as
`loses. In addition, plasticizers are added, particularly
`well as polyvinyl-pyrrolidone (PVP), methyl and ethyl
`polyhydric alcohols, such as glycerol or sorbitol. In
`cellulose, as well as polyvinyl alcohol (PV A). It is also
`order to set the desired viscosity of the coating com-
`pound, which has the consistency of a slime, use is made
`possible to use water-soluble acrylic resin dispersions.
`Suitable plasticizers are in particular polyfunctional 40 of polymeric swelling agents, preferably alginates, pee-
`tins, chitins, lecithins or polyethylene glycols. These
`alcohols, such as glycerol and sorbitol (Karion).
`The components are appropriately cold mixed with
`latter substances can simultaneously serve as adhesives.
`water and accompanied by slight heating and constant
`It is also possible to add water-soluble synthetic or
`stirring are processed to a coatable slime. The stirring in
`natural resins or gums or gum Arabic, in order to im-
`of air must be avoided to the greatest possible extent, in 45 prove the adhesion of the coating to the support mate-
`rial. It is finally possible to add preservatives, such as
`order to obtain a clear, but slight opalescent material.
`The thickness of the support film is preferably be-
`e.g. p-hydroxybenzoates, dyes (food dyes), pigments,
`tween approximately SO and 2SO JLm. It can be con-
`such as titanium dioxide, or flavouring agents and
`trolled to a considerable extent. The characteristics of
`sweeteners.
`the support film can undergo significant quality influ- 50 Coating materials with a water content of approxi-
`ences by corresponding combination of film formers
`mately SO% and a viscosity of approximately 30 to
`10,000 cPs have proved particularly satisfactory. The
`and plasticizers. The support film must have a uniform
`thickness (preferably e.g. 100 JLm), must be slightly
`formulation and production is similar to that of a phar-
`elastic and bendable, but without breaking. The starch
`maceutical juice, in which the active ingredient or ac-
`proportion should be adequately high, so that moisture 55 tive ingredient combination is dissolved or uniformly
`is absorbed on applying the coating material, without
`dispersed. The coating material must have an adequate
`there being any sticking of the surface or softening of
`homogeneity and galenic stability, so that a uniform
`the complete film.
`active ingredient content of the fmished coating is en-
`The following basic formulation has proved satisfac-
`sured.
`tory for the support film:
`The following basic formulation has proved satisfac-
`Gelatin 8 to 10 g
`tory:
`Starch 4 to 8 g
`Gelatin 8 to 10 g
`Glycerol l to 2 g
`Starch 3 to 8 g
`Polyvinylpyrrolidone l to 2 g
`Glycerol 1 to 2 g
`Water 30 to SO g
`65 Water 30 to SO g
`The active ingredient is dissolved or dispersed in this
`Water-soluble natural and/or synthetic resins, e.g.
`acrylic resins and gums are also suitable. It is also possi-
`basic material. When a dispersion is used, for uniform
`ble to add to the material other conventional substances,
`distribution purposes, the active ingredient must be
`
`60
`
`SUBJDG-0004746
`
`RBP_TEVA05024292
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`20
`
`5
`extremely fmely divided and preferably the average
`particle size is in the range approximately 1 to 20 J.Lm.
`The desired active ingredient dose and the sought
`surface of the dosage units determine the coating thick(cid:173)
`ness, whilst account must be taken of the moisture con- 5
`tent of the coating material and the fmished coating.
`The inventive administration form is particularly
`suitable for drugs, which are administered with a low
`dose rate, i.e. in which the individual dose for oral ad(cid:173)
`ministration is between 0 mg (placebo) and approxi- 10
`mately 20 mg. Suitable drug active ingredients occur in
`all fields of oral therapy, particular reference being
`made inter alia to analeptic, antibiotic, antidiabetic,
`antiemetic, antiepileptic, antihypertonic, corticoid, geri(cid:173)
`atric, hypnotic, cardiac, hypostatic and bio-active ingre- 15
`dients.
`Approximately 4 to 20 g of active ingredient per m2
`( = 10,000 cm2) of support film can be applied in one
`coating process, so that 10 cm2 ( =2 standard postage
`stamps) can absorb up to 20 mg of active ingredient.
`The coating material is normally applied to one side
`of the support film, but it is also possible to coat both
`sides, particularly in the case of two different active
`ingredients.
`Each coating can contain one or more drug active 25
`ingredients. If, when using several active ingredients,
`they are not readily compatible with one another and
`cannot be contained in one coating material, it is possi(cid:173)
`ble in the case of the administration form according to
`the invention to apply the coating in the form of several 30
`individual coatings with different compositions and to
`separate the active ingredients from one another in this
`way; if necessary an active ingredient-free intermediate
`coating being provided. It is also possible to provide
`above the active ingredient-containing coating, a fur- 35
`ther protective coating, which protects the active ingre(cid:173)
`dient or ingredients against contact with the atmo(cid:173)
`sphere and/or light. In such cases, the protective coat(cid:173)
`ing must consequently be impermeable to air and mois(cid:173)
`ture and/or must be made impermeable to light by the 40
`addition of corresponding dyes or pigments.
`Through a corresponding build-up of the coating, it is
`possible to control the supply of active ingredient fol(cid:173)
`lowing the administration of the drug. For example, it is
`possible to place an active ingredient coating between at 45
`least two further coatings, which control the active
`ingredient resorption in the gastrointestinal tract in per
`se known manner. The active ingredient coating can
`e.g. be located between two acid-insoluble coatings, so
`that on administration it passes through the stomach and 50
`resorption only takes place in the gastric tract. In a
`similar way, different active ingredients can be superim(cid:173)
`posed in different coatings on the support film, so that
`resorption takes place successively and/or in delayed
`form.
`Similar pharmacokinetic effects can be obtained
`through the incorporation (e.g. suspension) of differ(cid:173)
`ently pre-prepared microencapsulated active ingredi(cid:173)
`ents.
`Coating of the support material with the active in- 60
`gredient-containing coating material takes place by
`means of a roll application or coating process. This
`process, which is particularly suitable for quantitative
`coating, operates according to a process similar to inta(cid:173)
`glio printing and which is called "Akkugravur". Suit- 65
`able machines are commercially available (Pagendarm,
`Hamburg) and permit application or coating weights of
`up to 80 gfm2 in the case of web speeds of severallOO
`
`55
`
`4,849,246
`
`6
`m/min. The reproducible constant weight is only
`±2.5% for 20 g!m2 and approximately ±10% for l
`gfm2 over entire surface. The coating material is ap(cid:173)
`plied continuously by means of rollers with a special
`fine engraving, the engraved grooves forming an angle
`of 30 to 60, particularly 45• to the direction of move(cid:173)
`ment of the support fllm. 27 to 80 grooves/em can be
`etched into the rollers. Corresponding to its shape and
`depth, the engraving can absorb a given quantity of
`coating material and subsequently supply it to the sup(cid:173)
`port fllm. By varying the advance rate, running direc(cid:173)
`tion and engraving, as well as indirect application by
`means of a further speed-variable roller, it is possible to
`very accurately adjust the coating quantities.
`A two-sided coating frequently gives advantages,
`because problems due to the warping of the support
`material and differing hygroscopicity are compensated.
`Multiple and even strip coatings and in fact even print(cid:173)
`ing style coatings are possible and offer a considerable
`variability when processing incompatible active ingre(cid:173)
`dients.
`Another suitable application process corresponds to
`the coating of paper or fllms. Raw papers are improved
`in that they are coated with coating materials on one or
`both sides. The aqueous coating materials initially pass
`onto a rolling mill, which receives same by means of a
`rotary roller, strips same to a clearly defined coating
`thickness with a doctor blade at a given spacing and
`then the roller supplies the coating material to the sup(cid:173)
`port. The support film, which has a width of0.30 to 7.50
`m, subsequently passes through a drying tunnel and is
`wound onto reels. This process can be repeated on one
`or both sides in one or more stages and an already
`coated surface can be coated again. The weight of the
`support material increases by that of the dry weight.
`The accuracy of the application process using this doc(cid:173)
`tor blade method is reproducibly ±5% and is depen(cid:173)
`dent on the coating thickness, which can vary between
`4 and 40 gfm2. Within the individual production runs, it
`is possible to achieve a weight tolerance per surface unit
`down to ±1%.
`When applying several coatings, as described herein(cid:173)
`before, they are successively applied and optionally
`each coating previously passes through a drying station.
`This can e.g. comprise a temperature-controlled pair of
`rollers and a drying tunnel which is controllable in
`sections. Following the fmal coating process, the coat(cid:173)
`ing material is wound onto reels.
`The active ingredient-coated support fllm is subse(cid:173)
`quently pre-divided into dosage units, which can be
`separated in much the same way as postage stamps. This
`pre-dividing is normally carried out by the drug manu(cid:173)
`facturer, but it is also conceivable to supply the coated
`material, e.g. to hospitals or pharmacists, where the
`pre-dividing can then be carried out in dose-dependent
`manner, or individually in accordance with information
`supplied by the doctor.
`Pre-dividing takes place in a very simple manner by
`perforation or punching, it being possible to combine
`this step with the printing of the support material. In
`many cases it is more advantageous to carry out the
`printing of the support material prior to coating.
`Before or preferably after pre-division of the active
`ingredient-coating into dosage units, the coated support
`material is cut into ready-for-use portions containing a
`given number of dosage units. It is also possible to cut
`the material on reels into narrow strips. It is then possi-
`
`SUBJDG-0004747
`
`RBP_TEVA05024293
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,849,246
`
`7
`ble to separate the individual dosage units from the reel
`in much the same way as individual postage stamps.
`As mainly natural substances, such as starches and
`gelatin are used as basic substances for producing the
`inventive administration form, products are obtained,
`which are similar to known wafers and whose oral
`ingestion presents no problems. It is important that the
`finished product is largely free from water, i.e. has a
`water content of less than 10 and preferably less than
`2%, because otherwise mould can form.
`The invention has been largely descn'bed hereinbe(cid:173)
`fore in connection with drugs, but is in no way limited
`thereto. For example, it is also possible to adopt the
`same procedure for dosage forms for chemical reagents,
`flavouring substances and the like.
`The following examples serve to further illustrate the
`invention.
`
`15
`
`8
`ingredient. The residual moisture content of the prod(cid:173)
`uct was 8.6% after drying.
`An administration form was obtained, which on oral
`administration rapidly swells and dissolves in the mouth
`and can therefore be easily swallowed.
`I claim:
`1. In a process for the production of an administration
`and dosage form for drugs, reagents or other active
`ingredients in the form of a ftlm with an active ingredi-
`10 ent-containing coating, in which process
`(a) a water-soluble support film is produced from an
`aqueous composition based on an effective amount
`of a compound selected from starches, gelatins, and
`their mixtures and an effective amount of a com(cid:173)
`pound selected from glycerol, sorbitol and their
`mixtures,
`(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(cid:173)
`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 fUm,
`the improvement that the basic composition of the sup(cid:173)
`port film corresponds to that of the coating material.
`2. Process according to claim 1, characterized in that
`the support fUm 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 fllm contains further
`additives selected from the group consisting of inert
`soluble and insoluble flllers, sugar and other sweeteners,
`plasticizers such as polyols, waxes and dyes, flavouring
`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 fill(cid:173)
`ers, sugar and other sweeteners, plasticizers such as
`polyols, waxes and dyes, flavouring substances and
`preservatives.
`5. Process according to claim 1, characterized in that
`the coating compound is applied to the support film in
`a continuous manner by means of grooved rollers,
`which absorb a clearly defined quantity of coating ma(cid:173)
`terial and then transfer it to the support fUm.
`6. Process according to claim 1, characterized in that
`the coating material is continuously applied to the sup(cid:173)
`port film by means of smooth roller pairs, which in
`speed-displaced synchronism absorb the material and
`transfer it to the support film in a clearly defined quan(cid:173)
`tity.
`7. Process according to claim 1, characterized in that
`the composition of the support film and of the coating
`material comprises 8 to 10 parts by weight of gelatin, 4
`60 to 8 parts by weight of starch, 1 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 film for producing a
`combination product.
`
`EXAMPLE
`Preparation of a drug administration form in the form 20
`of a coated f!lm.
`The following composition was used for producing a
`water-soluble support film:
`-------------------------------------25
`
`Gelatin
`Potato starch
`Glycerol
`Purified 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%
`
`The viscosity of the slime-like composition was ap- 30
`proximately 3000 cPs at so• C. With the aid of a coating
`process, the material was processed to a fUm which,
`after drying, had a 9.3% residual water content.
`Using the same basic substances as for the support
`f!lm, the coating material was prepared in accordance 35
`with the following formulation:
`
`Gelatin
`Potato starch
`Glyercol
`Active ingredient
`Purified 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%
`
`40
`
`The viscosity of the slime-like composition was be(cid:173)
`tween 4000 and 10000 cPs, as a function of the tempera- 45
`ture and active ingredient. To produce the coating ma(cid:173)
`terial, the gelatin was firstly dissolved in an adequate
`quantity of water, whereby firstly water at 90" to 95" C.
`was provided and into which the gelatin was intro(cid:173)
`duced, accompanied by stirring. The active ingredient 50
`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 so· to 6o· C. and
`accompanied by stirring. The gelatin solution and po(cid:173)
`tato starch suspension were added together and the 55
`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 film with a wet coating weight of
`55 g/m2. After drying, the coating weight was 23 gfm2,
`corresponding to an active ingredient content of 5
`gfm2. The active ingredient-coated film was then perfo- 65
`rated in box-like manner, so that the individual portions
`have a surface of 5 cm2, in the case of dimensions of
`2X2.5 em, such a portion containing 2.5 mg of active
`
`SUBJDG-0004748
`
`RBP_TEVA05024294
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`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(cid:173)
`plied in the form of separate coatings to the support film
`and an ingredient-free intermediate coating is provided
`between the two ingredient-containing coatings.
`U. Process according to claim 1, characterized in 10
`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 film.
`
`10
`13. Process according to claim 1, characterized in
`that a further coating is placed over the active ingredi(cid:173)
`ent coating and protects the active ingredient against
`contact with the atmosphere, against light or against
`5 both.
`14. Process according to claim 1, characterized in
`that the active ingredient-coated water-soluble film is
`subdivided into portions by perforation or punching
`and said portions contain defined 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.
`* * * • *
`
`4,849,246
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SUBJDG-0004749
`
`RBP_TEVA05024295
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC