`Intellectual Property
`Office
`
`Office de la Propriété
`lntellectuelle
`du Canada
`
`2
`(11)
`(43) 25_o5_1993
`
`(13)
`
`An Agency of
`Industry Canada
`
`Un organisme
`d'|ndustrie Canada
`
`(19)
`
`(12)
`
`(21)
`
`2 274 91°
`
`(22)
`
`14-11-1997
`
`196 52 188.2 DE 16.12.1996
`
`LTS LOHMANN THERAPIE-SYSTEME GMBH,
`lrlicher Strasse 55
`D-56567, NEUWIED, XX (DE).
`
`(30)
`
`(71)
`
`(54)
`
`(54)
`
`(51)
`
`Int. cw:
`
`A61K 031/485, A61 K 009/70
`
`(85)
`
`14.06.1999
`
`(86) PCT/EP97/06369
`
`(87) W098/26780
`(72)
`
`CREMER, Karsten (DE).
`LUESSEN, Henrik (DE).
`
`(74)
`
`Orange Chari Pillay
`
`PREPARATION MEDICAMENTEUSE PLATE POUR ADMINISTRER OU LIBERER, DANS LA CAVITE
`BUCCALE, DE LA BUPRENORPHINE OU UNE SUBSTANCE COMPARABLE SUR LE PLAN
`PHARMACOLOGIQUE ET PROCEDE PERMETTANT DE LA PREPARER
`FLAT MEDICAMENT PREPARATION FOR THE APPLICATION AND RELEASE OF BUPRENORPHINE OR A
`PHARMACOLOGICALLY COMPARABLE SUBSTANCE IN THE BUCCAL CAVITY, AND METHOD OF
`PRODUCING THE SAME
`
`(57)
`
`solid medicament
`a
`invention concerns
`The
`preparation which can decompose in aqueous media and
`has
`a
`flat-,
`foil-,
`paper- or wafer-type presentation
`for the application and release of active substances in
`the buccal
`cavity. The
`invention is characterized in
`that
`it contains buprenorphine,
`an active
`substance
`which is pharmacologically comparable thereto, or a
`therapeutically suitable
`salt
`of buprenorphine
`or
`of
`the
`pharmacologically
`comparable
`active
`substance.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`
`INTELLECTUELLE DC CANADA OPIC
`
`OFFICE DE LA FROI>RIE"rE'
`
`(12)(19)(CA) Demande-Application
`' CIPO
`CANADIAN INTELLECTUAL
`PROPERTY OFFICE
`
`(21) (A1) 2,274,910
`(86)
`1997/11/14
`(87)
`1998/06/25
`
`(72) CREMEK Karsten, DE
`(72) LUES SEN, Henrik, DE
`(71) LTS LOH1\/IANN THERAPIE-SYSTEME GMBH, DE
`
`(51) Int.Cl.6 A61K 31/485, A61K 9/70
`(30) 1996/12/16 (196 52 1882) DE
`(54) PREPARATION MEDICAMENTEUSE PLATE POUR
`ADMINISTRER OU LIBERER, DANS LA CAVITE BUCCALE,
`DE LA BUPRENORPHINE OU UNE SUBSTANCE
`
`COMPARABLE SUR LE PLAN PHARMACOLOGIQUE ET
`PROCEDE PERMETTANT DE LA PREPARER
`
`(54) FLAT MEDICANIENT PREPARATION FOR THE APPLICATION
`AND RELEASE OF BUPRENORPHINE OR A
`PHARMACOLOGICALLY COMPARABLE SUBSTANCE IN
`
`THE BUCCAL CAVITY, AND METHOD OF PRODUCING THE
`SAIVIE
`
`prep arati on
`une
`con c ern e
`I, ’ invention
`(57)
`medicamenteuse solide, pouvant se decomposer dans des
`substances aqueuses, a forme galénique plate, de type
`film: papier ou hostie: servant a administrer et a libérer
`des principes actif dans
`la cavite bI1ccale_ Cette
`preparation se caracterisc en ee qu’elle contient de la
`bup1‘e'noI'phine, un principe actifs comparable sur le plan
`pharmacologique a la buprenorphine ou un sel de
`buprénoiphine ou un sel de la substance comparable S111‘
`le plan pharmacologique et approprie sur
`le plan
`therapeutique.
`
`solid medicament
`a
`(57) The invention concerns
`preparation which can decompose in aqueous media and
`has a flat—, f0il—, paper— or wafer—type presentation for the
`application and release of active substances in the bucc al
`cavity. The invention is characterized in that it contains
`buprenorphine,
`an
`active
`substance which
`is
`pharmacologically
`comparable
`thereto,
`or
`a
`therapeutically suitable salt of buprenorphine or of the
`pharmacologically comparable active substance.
`
`IndustrIe Canada
`
`Industry Canada
`
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`CA 02274910 1999-06-14
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`13
`
`ABSTRACT
`
`A solid pharmaceutical preparation, disintegratable in
`
`aqueous media, with a flat, foil-shaped, paper-shaped or
`
`wafer-shaped administration form, for application and
`
`release of active substances in the oral cavity is charac-
`
`terized by a content of buprenorphine, of an active
`
`substance pharmacologically comparable to buprenorphine, or
`
`of a therapeutically suitable salt of bruprenorphine or the
`pharmacologically comparable active substance.
`
`TEVA EXHIBIT 1006
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`:—.———..._.»
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`Flat pharmaceutical preparation for application and release
`
`of buprenorphine or of a pharmacologically comparable
`
`substance in the oral cavity, and process for the
`
`production thereof
`
`The present invention relates to a pharmaceutical
`
`preparation for application of buprenorphine or
`
`pharmacologically comparable active substances in the
`
`region of the oral cavity, respectively the oral mucosa.
`
`More particularly, it relates to a preparation that is
`
`adapted to be flat and in the form of a foil-, paper— or
`
`wafer—shaped administration form.
`
`Flat active substance carriers have already been developed
`
`and produced for various purposes. DE-Os 27 46 414 can be
`
`regarded as fundamental to this administration form, said
`
`document describing a foil-type tape of active substance,
`
`binder and further active substances, with a direct
`
`relation existing, by reason of the homogeneous thickness,
`
`density and width, between a unit of length of the tape and
`
`the dose of active substance contained therein. The
`
`advantages of the continuous dosage property have been
`
`recognized also by other applicants and have been described
`
`in specific individual variants. Thus, DE—PS 36 30 603
`
`claims a flat-shaped carrier material, for example in the
`form of a separating layer, with an active substance-
`
`containing coating,
`
`the latter being peelable,
`
`in doses,
`
`off the carrier material after having been previously
`
`separated into dosage units.
`
`The practicability of the flat format in general and the
`advantages afforded in the manufacture of the adminis-
`
`tration form and in the dosing when employing such
`
`administration form have been recognized in the prior art.
`
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`Moreover, further advantages of such administration forms
`
`can be derived such as the fact that, relative to the
`
`weight of the administration form, a relatively large
`
`surface may be printed on the said administration form,
`
`thereby making it possible to increase intake safety, as
`
`well as affording the possibility of discrete intake
`
`without any liquid being available.
`
`Despite these obvious advantages, such flat administration
`
`forms have hitherto hardly been successful. Obviously,
`
`the
`
`advantage as compared to conventional administration forms
`
`does not suffice for many manufacturers of pharmaceutics to
`
`develop products of this type comprising the usual active
`
`ingredients and to pursue the legal drug approval thereof.
`
`Moreover, existing production machinery and existing know-
`
`how cannot be made use of for these novel products; this
`
`means that the necessity of large investments would arise.
`
`Despite the above—described advantages of flat,
`
`film— or
`
`paper-like administration forms,
`
`the therapeutic and/or
`
`economic advantage in administration of common active
`
`substances which are also perorally applicable is
`
`apparently not great enough as compared to conventional
`
`tablets to justify the costs of switching over to these
`administration forms.
`
`one of the substances that are little suitable for peroral
`
`administration is buprenorphine, an opiate which has been
`
`successfully used in the therapy of pain for years. After
`
`peroral application it is hardly bioavalable, i.e. it
`
`appears in the blood circulation only to the very small
`
`extent of a few percent of the dose taken (McQuay & Moore,
`
`in: Bupenorphine, ed. Cowan & Lewis, New York 1995).
`
`Presumably,
`
`the reason for the lack in bioavailability lies
`
`in the extensive decomposition of the substance during the
`
`first liver passage following gastrointestinal absorption
`
`("first—pass effect"). A possibility of avoiding the first-
`
`TEVA EXHIBIT 1006
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`pass effect in oral administration is to bring the active
`
`substance to absorption already on the oral mucosa. In
`
`order to enter the central systemic circulation, an active
`substance which enters into the blood via the oral mucosa
`
`does not have to first pass the portal system and thus,
`
`in
`
`concentrated form,
`
`the liver, which metabolizes the active
`
`substance. A prerequisite for buccal or sublingual
`
`application, however, is a sufficient permeability of the
`
`oral mucosa to the active substance,
`
`taking into
`
`consideration the required dose. Permeability in turn
`
`depends to a large extent on the physicochemical properties
`
`of the active substance. Since buprenorphine is effective
`
`in very small doses, and since it has the required
`
`physicochemical characteristics, buccal or sublingual
`
`application is very attractive.
`
`In fact, apart from injectable administration forms there
`
`are — at least in Germany — no commercially available
`
`peroral administration forms, but only so-called sublingual
`
`tablets, which comprise buprenorphine (Temgesic® sub-
`
`lingual). It is true that such tablets take into account
`
`the fact that sublingual application of the active
`
`substance is preferable to peroral administration - even
`
`though they do so above all by way of their intake
`
`directions as only these suggest the sublingual
`
`administration,
`
`not the tablet itself. However,
`
`they offer
`
`a vehicle which has considerable drawbacks for this purpose
`
`of application. Among these disadvantages is, firstly, the
`
`not inconsiderable disintegration time, which in the case
`of pressed tablets is at least several minutes even under
`
`favorable conditions, and in the case of the commercially
`
`available tablets is typically about 5 to 10 minutes. For
`
`patients suffering from severe, acute pain this
`
`disintegration time results in an unwanted delay of the
`
`onset of action; in a substitution or withdrawal therapy,
`
`however, this puts a strain on the medicinal personnel with
`
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`CA 02274910 1999-06-14
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`respect to the time required for administration, since the
`
`personnel must supervise that the tablets are used as
`
`directed and must prevent improper removal of the non-
`
`disintegrated tablet from the mouth. Further disadvantages
`
`of the tablet are the foreign body sensation occurring
`
`during the disintegration time, but also the great
`
`variability in the extent of sublingual absorption, which
`
`is caused by the active substance during or after
`
`disintegration of the tablet having for the most part no
`
`direct contact with the oral mucosa, but being released
`
`into the saliva;
`
`the saliva, however, can be retained in
`
`the oral cavity for a very variable time, which is more or
`
`less haphazard, before being swallowed.
`
`It is thus the object of the present invention to create
`
`pharmaceutical preparations based on, and having the
`
`general advantages of, flat, film-like or paper—like active
`
`substance carriers which by reason of the combination with
`
`a special active substance have additional economical
`
`and/or therapeutical advantages, apart from those mentioned
`
`above, over pharmaceutical preparations of the same active
`substance based on conventional administration forms such
`
`as tablets. In addition, it is likewise an object of the
`
`invention to provide an administration form for
`
`buprenorphine that releases the active substance in the
`
`oral cavity while not having the disadvantages described in
`
`the prior art.
`
`The object is achieved in accordance with the features of
`
`the claims by providing an administration form on the basis
`
`of a flat,
`
`foi1—, paper— or wafer-like active substance
`
`carrier, which administration form contains as active
`
`substance buprenorphine, respectively one of its
`
`therapeutically acceptable salts, or a therapeutically
`
`comparable active substance. As will be explained in the
`
`following, an administration form according to Claim 1 is
`
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`CA 02274910 1999-06-14
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`by far superior to a conventional administration form for
`
`administering buprenorphine - both from the economical as
`
`well as the therapeutical point of view - and it is
`
`especially suitable, on the one hand, for analgesia in
`
`cases of acute conditions of pain, and, on the other hand,
`
`for the therapy of opiate or cocaine addiction in the sense
`
`of a substitution therapy or a withdrawal program.
`
`The pharmaceutical preparation according to claim 1 can,
`
`upon application, be brought into direct contact with the
`
`oral mucosa. Due to the flat design,
`
`immediately after
`
`application about half of the surface of the administration
`
`form, which is large anyway, is located directly on the
`
`mucosa. The buprenorphine released thus encounters two
`
`factors particularly favorable for entry into the body,
`
`namely a short diffusion path and a large diffusion area.
`
`This reduces the portion of buprenorphine that is
`
`lswallowed, which in the case of many other active agents
`
`would not be a particular problem. However, with
`
`buprenorphine, swallowing of the active substance should be
`
`avoided if possible, or should be reduced since, for the
`
`above mentioned reasons, swallowed buprenorphine is
`
`ineffective. Even in the case of the most simple embodiment
`
`according to the invention, and given a disintegration time
`
`of a few minutes following application or following
`
`introduction into aqueous media,
`
`the superiority of a
`
`buprenorphine-containing film over a buprenorphine-
`
`containing tablet will thus become evident.
`
`An improved contact of the pharmaceutical preparation with
`
`the oral mucosa can be achieved through selecting auxiliary
`
`substances. It is known of certain orally applicable
`
`auxiliary agents which are commonly used in pharmaceutics
`
`that they have mucoadhesive properties. Examples for such
`
`mucoadhesive substances are polyacrylic acid, carboxy—
`
`methylcellulose,
`
`tragacanth, alginic acid, gelatin,
`
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`hydroxymethylcellulose, methylcellulose and gum arabic. In
`
`addition, it is known of various non-mucoadhesive
`
`substances that in certain mixing ratios they develop
`
`mucoadhesive properties too. An example for such a mixture
`
`is glycerol monooleate/water in a ratio of 84:16 (Engstrom
`et al., Pharm. Tech. Eur. 7 [1995], No. 2, pages 14-17).
`
`In the case that mucoadhesive auxiliary substances are
`
`. used, it is preferable for the administration form of the
`
`pharmaceutical preparation according to the invention to
`
`have a two—layer or mu1ti—layer structure. It can thereby
`
`be prevented that the preparation conglutinates various
`
`parts of the mucosa with each other, which would lead to
`sensations of considerable discomfort during application.
`
`In addition, it is in such a case preferable for the
`administration form to have a structure the non-
`
`mucoadhesive layer of which has a permeability to the
`
`active substance which is relatively smaller than that of
`
`the mucoadhesive layer, it thereby being possible to
`
`prevent that active substance losses occur due to active
`
`substance being released into the saliva instead of to the
`mucosa.
`
`Pharmaceutical preparations according to the present
`
`invention are also those containing, apart from the active
`
`substance buprenorphine or an active substance
`
`pharmacologically comparable thereto, one or more further
`
`active substances. Such a preparation can be advantageous
`
`in several respects. On the one hand it is a recognized
`
`method for treating several symptoms or conditions
`
`occurring simultaneously to administer a fixed active
`
`substance combination in a medicament. To this end, it is
`
`possible to incorporate any therapeutically appropriate
`
`active substances into the preparation according to the
`
`present invention. On the other hand,
`
`the combination, as
`
`according to the invention, of an opiate active substance
`
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`with another substance that is capable of reducing the
`
`specific risks of opiate administration is especially
`useful and advantageous.
`
`Thus — possibly partial — opiate antagonists, such as, for
`
`example, nalbuphine, naloxone or naltrexone, can be
`
`combined with the opiate active substance, which results in
`the risk of addiction or habituation involved in the
`
`repeated administration of the preparation being diminished
`
`by reason of the fact that the dose cannot be increased
`
`without at the same time accepting an increase of the
`
`antagonistic effect. The success of this strategy will
`
`depend on the selection of a suitable antagonist as well as
`the selection of the dose ratio.
`
`Though buprenorphine - optionally in the form of one of its
`
`therapeutically acceptable salts - is the most preferred
`
`active substance,
`
`the invention also relates to such active
`
`substances as are pharmacologically similar or comparable
`
`to buprenorphine since the advantages of the invention
`
`described herein also apply in these cases,
`
`though to
`
`different extent. Further suitable active substances, which
`
`are also described herein as being "pharmacologically
`
`similar or camparable“, are,
`
`in particular,
`
`those
`
`substances belonging to the opiates or opioids since many
`
`of these not only exhibit pharmacodynamic but also
`
`pharmacokinetic similarities to buprenorphine, that is a
`
`relatively low dose, good capacity for permeating
`
`membranes, and a high first—pass effect. Particularly
`
`preferred are morphine derivatives or dihydromorphine
`
`derivatives as well as substances from the methadone and
`
`fentanyl group.
`
`In order not to promote any improper application or one
`
`that does not conform to the intended use, pharmaceutical
`
`preparations according to the invention will typically be
`
`present predivided into doses and separated from each other
`
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`in a suitable package, so that when removing a dosage unit
`
`it will be possible to remove only one unit at a time, such
`
`as in the case of a blister pack, where each dosage unit is
`
`sealed individually in a deep-drawn cup. Within programs
`
`for treatment of opiate or cocaine addiction it may,
`
`however, also be useful to supply physicians who are
`
`providing the medical care, for example, with preparations
`
`in the form of packaging units wherein said preparations
`
`are present as undivided sheet—like or tape-like material,
`
`from which the dosage units can be separated for the
`
`purpose of application. This facilitates mass application
`
`and affords the physicians who are administering the
`
`preparations the possibility of separating from one and the
`
`same material various dosage units in accordance with the
`
`given dosage requirements.
`
`Since the pharmaceutical preparation according to the
`
`present invention is expected to exhibit increased bio-
`
`availability as compared to known preparations, it will
`
`possibly be necessary to adjust the dosage. In the case of
`
`buprenorphine the individual analgesic dose will be about
`
`0.1 to 1 mg;
`
`in addiction or substitution therapy, however,
`
`this value might be considerably higher.
`In accordance with the invention the manufacture of the
`
`pharmaceutical preparation is performed in several steps.
`
`For preparing the web-shaped starting material — from which
`
`ultimately either individual doses or entire packaging
`
`units will be separated by cutting or punching — two basic
`
`process variants are suitable. The first group of processes
`
`includes those where a tape, or a process sheet or foil, is
`
`evenly coated with aqueous or solvent-containing liquids
`
`being in part of higher viscosity, and where this is
`
`subsequently subjected to a drying process. To this end,
`
`first, a coating mass is prepared, for which purpose at
`
`least one water—soluble polymer capable of forming a film,
`
`the active substance(s) and a suitable, vaporizable liquid
`
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`must be intimately mixed. If required it is possible to
`
`incorporate further auxiliary substances such as
`
`disintegration-modifying polymers, softeners, fillers,
`
`texture-providing substances, pigments, dyes, taste
`
`corrigents, solubilizers, substances for adjusting the pH,
`
`*smoothing agents, dulling agents, disintegration
`
`promoters, etc. As an alternative,
`
`the web—like starting
`
`material may be made by thermoplastic forming, i.e. without
`
`the aid of liquids. Suitable processes are, inter alia, any
`
`hot—melt coating methods as well as any extrusion methods.
`
`As a prerequisite,
`
`the polymer or polymer mixture capable
`
`of film—formation must in this case be thermoplastically
`
`formable. The required ingredients are mixed and, under
`
`action of pressure and/or heat,
`
`formed by extruding,
`
`blowing or by coating of tapes, sheets or foils, and, after
`
`solidification,
`
`transferred for further processing.
`
`Suitable for the manufacture of preparations according to
`
`the present invention that have a multi—layer structure are
`
`correspondingly modified methods, it being irrelevant
`
`whether several web-shaped materials are simultaneously or
`
`subsequently produced and combined.
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`10
`
`CLAIMS
`
`1.
`
`Buccal pharmaceutical preparation for treating acute
`
`conditions of pain or for addiction therapy, comprising as
`
`active substance buprenorphine or a pharmacologically
`
`comparable substance as such or as a therapeutically
`
`suitable salt, characterized by a wafer-shaped adminis-
`
`tration form, disintegratable in the aqueous medium of the
`
`oral cavity, which has a mucoadhesive, active substance-
`
`containing layer based on water-soluble, film-forming
`
`polymers of small thickness, for rapid active substance
`
`transfer through short diffusion paths, while having a
`
`large surface appropriate to the effective dose.
`
`2.
`
`Pharmaceutical preparation according to claim 1,
`
`characterized by a mono— or multi—layered structure having‘
`
`a mucoadhesive active substance-containing layer based on
`
`water—so1ub1e, film-forming polymers of small thickness for
`
`rapid active substance uptake through short diffusion
`
`paths.
`
`3.
`
`Pharmaceutical preparation according to claim 1 or 2,
`
`characterized by a non-mucoadhesive outer layer, opposed to
`
`the mncoadhesive surface, which outer layer has a lower
`permeability to the active substance.
`
`4. Pharmaceutical preparation according to any one of the
`
`preceding claims, characterized by a single—dose
`
`buprenorphine content of 0.1 — 1 mg.
`
`5.
`
`Pharmaceutical preparation according to any one of the
`
`preceding claims, characterized in that it is equipped with
`
`bioadhesive or mucoadhesive properties by the addition of
`
`an adhesion—promoting auxiliary substance or auxiliary
`substance mixture.
`
`TEVA EXHIBIT 1006
`TEVAPHARMACEUWCALSUSAJNC.V.MONOSOLRXJlC
`
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`CA 02274910 1999-06-14
`
`ll
`
`6.
`
`Pharmaceutical preparation according to claim 5,
`
`characterized in that further active substance is present
`
`which is suitable for treating addiction to opiates.
`
`7.
`
`Pharmaceutical preparation according to claim 6,
`
`characterized in that further active substance is, at least
`
`partially, capable of opiate antagonist action.
`
`8.
`
`Pharmaceutical preparation according to claim 7,
`
`characterized in that it contains nalbuphine, naloxone or
`naltrexone.
`
`9.
`
`Pharmaceutical preparation according to one or more of
`
`the preceding claims, characterized in that it is present
`
`as an undivided, sheet—shaped or tape—shaped material,
`
`from
`
`which it is possible to separate dosage units for the
`
`purpose of application.
`
`10. Pharmaceutical preparation according to one or more of
`
`the preceding claims, characterized in that it is present
`
`predivided into doses.
`
`11. Pharmaceutical preparation according to one or more
`
`of the preceding claims, characterized in that, per dosage
`unit, it has a content of active substance which is
`
`suitable for analgesia.
`
`12. Pharmaceutical preparation according to one or more of
`
`the preceding claims, characterized in that, per dosage
`unit, it has a content of active substance which is
`
`suitable for opiate or cocaine substitution therapy.
`
`13. Method of producing a pharmaceutical preparation
`
`according to one or more of the preceding claims,
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`CA 02274910 1999-06-14
`
`12
`
`characterized in that in a first step the active sub-
`
`stance(s),
`
`together with a water-soluble polymer capable of
`
`film-formation, is (are) dissolved in a suitable,
`
`hydrophile solvent, optionally in presence of further
`
`dissolved or suspended auxiliary agents, that in a second
`
`step the solution or suspension is applied,
`
`in a continuous
`
`process and with even thickness,
`
`to a tape or a process
`
`sheet or foil, where,
`
`in a third step, it is largely freed
`
`u from the solvent,
`
`thereby forming a sheet-shaped or tape-
`
`shaped starting material, wherefrom,
`
`in a fourth step,
`
`the
`
`dosage or mnltidosage units are separated by cutting or
`
`punching.
`
`14. Method of producing a pharmaceutical preparation
`
`according to one or more of the preceding claims,
`
`characterized in that in a first step the active sub-
`
`stance(s),
`
`together with a water—soluble,
`
`thermoplastic
`
`polymer capable of film-formation, is (are) formed, under
`
`action of heat and/or pressure, and optionally in presence
`
`of further auxiliary substances,
`
`into a sheet-shaped or
`
`tape-shaped starting material,
`
`from which starting material
`
`the dosage or multidosage units are separated by cutting or
`punching.
`
`15. Method of producing a pharmaceutical preparation
`
`according to claim 13 or 14, characterized in that a
`
`plurality of simultaneously or subsequently prepared,
`
`sheet-shaped or tape-shaped starting materials are combined
`
`to form a multilayered material,
`
`from which the dosage or
`
`multidosage units are separated.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC