`
`(11) Application No. AU 199856532 BZ
`(12) PATENT
`
`(19) AUSTRALIAN PATENT OFFICE (10) Patent No. 741362
`
`(54)
`
`Title
`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
`
`(51)7
`
`International Patent Classification(s)
`A61 K 031/485
`A61 K 009/70
`
`(21)
`
`Application No: 199856532
`
`(22)
`
`Application Date: 1997.11.14
`
`(87) WIPO No: W098/26780
`
`(30)
`
`Priority Data
`
`(31)
`
`(43)
`(43)
`(44)
`
`(71)
`
`(72)
`
`(74)
`
`Number
`19652188
`
`(32) Date
`1996.12.16
`
`(33) Country
`DE
`
`1998.07.15
`Publication Date :
`Publication Journal Date : 1998.08.27
`Accepted Journal Date :
`2001.11.29
`
`Applicant(s)
`LTS Lohmann Therapie-Systeme GmbH
`
`Inventor(s)
`Karsten Cremer; Henrik Luessen
`
`Agent/Attorney
`DAVIES COLLISON CAVE,GPO Box 3876,SYDNEY NSW 2001
`
`
`
`
`
`(56)
`
`Related Art
`US 4673679
`US 4849246
`
`
`

`

`OPI
`
`AO‘JP DATE 27/08/98
`
`DATE 15/07/98 APPLN.
`
`PCT NUMBER PCT/EP97/06369
`
`ID
`
`56532/98
`
`iiiiliiiiiiiiiiliiililiili
`
`
`
`| || 1111111 111 Illlllll
`
`
`AU9856532
`
`u. .un.-..--‘v.u -uu UV." gunnu.” .--.4.4. . ..v- “kl-A 0““-.4; ”.4... A ALLA—(A‘A IIHVUA‘V \rc‘a/
`
`(51) Internationale Patentklassifikation 6 2
`A61K 31/485’ 9’70
`
`(11) Internationale Verfiffentlichungsnummer: WO 98/26780
`(43) Internationales
`Verfiffentlichungsdatum:
`
`25. Juni 1998 (25.06.98)
`
`.44
`
`(21) Internationales Aktenzeichen:
`
`PCT/EP97/06369
`
`(22) lnternationales Anmeldedatum:
`
`14. November 1997
`(14.11.97)
`
`(81) Bestimmungsstaaten: AU, CA, JP, KR, MX, NO, Sl, US,
`europiiischcs Patent (AT, BE, CH, DE, DK, ES, FI, FR.
`GB, GR, IE, IT, LU, MC, NL, PT, SE).
`
`(30) Prioritiitsdaten:
`196 52 188.2
`
`16. Dezember I996 (16.12.96)
`
`DE
`
`Veriiffentlicht
`Ohne internationalen Recherchenbericht und erneut zu
`verbflenllichen nach Erhalt des Berichls.
`
`
`
`LTS
`(71) Amneldcr (fu‘r alle Bestimmungsstaaten ausser US):
`LOHMANN THERAPIE—SYSTEME GMBH [DE/DE]; Ir-
`licher Strasse 55. D—56567 Neuwied (DE).
`
`(72) Erfinder; und
`(75) Erfinder/Anmelder (nurfu'r US): CREMER, Karstcn [DEDE];
`Vorgebirgsstrassc 47, D—531 19 Bonn (DE). LUESSEN,
`Henrik [DE/DE]; Tanncnweg 31, D—56S79 Rengsdmf (DE).
`
`(74) Anwalt: FLACCUS, Rolf—Dieter; Spcrlingsweg 32, D—50389
`Wesseling (DE).
`
`(54) Title: 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
`
`(54) Bezeichnung: FLACHE ARZNEIZUBEREITUNG'ZUR APPLIKATION UND FREISE’I‘ZUNG VON_ BUPRENORPHIN ODER
`EINER PHARMAKOLOGISCH VERGLEICHBAREN SUBSTANZ IN DER MUNDHOHLE UND VERFAHREN
`ZU IHRER HERSTELLUNG
`
`(57) Abstract
`
`foil—, paper—
`The invention concerns a solid medicament preparation which can decompose in aqueous media and has a flat—,
`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.
`
`(57) Zusammenfassung
`
`Eine festc, in wassrigen Medien zerfallsfllhige Arzneizubereitung mit flacher, folien—, papier— oder oblatenfbrmiger Darreichungsform
`zur Applikation und Freisetzung von Wirkstoffen in der Mundhohle ist gekennzeichnet durch einen Gehalt an Buprenorphin, eincm
`dem Buprenorphin pharmakologisch vergleichbaren Wirkstoff. oder einem therapeutisch gecigneten Salz des Buprenorphins oder des
`pharmakologisch vergleichbaren Wirkstoffes.
`
`
`
`.a.
`
`
`
`

`

`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.
`
`

`

`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.
`
`
`
`
`
`

`

`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-
`
`
`
`

`

`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
`
`the
`of application. Among these disadvantages is, firstly,
`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
`
`
`
`

`

`'0ooooOo. OOO.I...
`
`
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`
`o
`
`respect to the time required for administration, since the
`
`personnel must supervise that the tablets are used as
`
`Vdirected 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.
`
`in one aspect thereof,V
`The present invention provides,
`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,
`the present invention preferably
`provides an administration form for buprenorphine that
`
`releases the active substance in the oral cavity while not
`
`having the disadvantages described in the prior art.
`
`More specifically,
`
`the present invention provides,
`
`in one
`
`aspect, buccal pharmaceutical preparation for treating acute—
`conditions of pain or for addiction therapy, comprising as
`active substance buprenorphine or a therapeutically
`acceptable salt thereof, or an Opiate active substance or a
`
`therapeutically suitable salt thereof, characterised by a
`flat,
`film—like administration form, disintegratable in the
`
`aqueous medium of the oral cavity, which has a mucoadhesive,
`
`
`
`
`
`

`

`P:\WPDOCS\CRN\SheIlcy\7334ldispcfioc-ZOIOWOI
`
`4a
`
`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.
`
`Additionally,
`
`the invention provides method of producing a
`
`pharmaceutical preparation as herein before described,
`
`characterized in that in a first step the active
`
`substance(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 from the
`
`solvent,
`
`thereby forming a sheet—shaped or tape—shaped
`
`starting material, wherefrom,
`
`in a fourth step,
`
`the dosage
`
`or
`
`multidosage units are separated by cutting or punching.
`
`10
`
`15
`
`
`
`IIII0'.0000...I.
`
`oO00-000no.no,IIO.0-o..-no
`
`no
`
`.9
`
`I.
`
`20
`
`Further,
`
`the invention provides method of producing a
`
`pharmaceutical preparation as herein before described,
`
`characterized in that in a first step the active
`
`to...
`
`substance(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
`
`25
`
`30
`
`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.
`
`The invention may be achieved in accordance with the features
`
`of the claims providing an administration form on the basis of
`
`flat,
`
`foil—, paper- or wafer-like active substance carrier,
`
`which administration form contains an active substance
`
`buprenorphine, respectively one of its therapeutically
`
`35
`
`acceptable salts, or a therapeutically comparable active
`05TR42:\\substance. As will be explained in the following, an
`v
`.
`Z\
`
`
`
`
`
`

`

`administration form according to Claim 1 may be considered 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
`swallowed,
`.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.
`
`,
`
`."
`
` :
`
`.
`
`E
`2
`‘
`
`
`
`An improved contagt 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¥
`7’hylcellulose,
`tragacanth, alginic acid, gelatin,
`
`
`
`
`
`\
`O.
`o
`
`IO.0a...
`
`o o
`
`o,-
`
`too.IIocean...I.aoIt)on.canu00,.ooaonononI.Q..-
`
`

`

`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 (Engstrém
`
`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 multi-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
`
`

`

`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 comparable", 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
`
`
`
`

`

`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
`
`
`
`

`

`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, solubilisers, 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 o£~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.
`
`this specification and the claims which follow,.
`Throughout
`unless the context requires otherwise,
`the word "comprise",
`or variations such as "comprises” or "comprising", will be
`understood to imply the inclusimi of
`a stated integer or
`group of
`integers or steps but not
`the exclusion of any
`other integer or group of integers or steps.
`
`The reference to any prior art in this specification is not,
`and should not be taken as,
`
`
`
`I0IO.'0‘0...II-CO00ontoo.IononI.a..00.
`
`O
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`
`The claims defining the invention are as follows:
`
`Buccal pharmaceutical preparation for treating acute
`1.
`conditiOns of pain or for addiction therapy, comprising as
`active substance buprenorphine or a therapeutically
`‘
`acceptable salt thereof, or an opiate active substance or a
`therapeutically suitable salt thereof, characterised by a
`flat,
`film—like administration 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.
`
`Pharmaceutical preparation according to claim 1,
`2.
`characterized by a mono— or multi—layered structure having
`a mncoadhesive active subStance-containing layer based on
`water-soluble, film-forming polymers of small thickness for
`
`rapid active substance uptake through short diffusion
`paths.
`’
`
`Pharmaceutical preparation according to claim 1 or 2,
`3.
`characterized by'a non-mucoadhesive outer layer, opposed to
`the'mucoadhesive 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.
`
`o o
`
`o
`
`'0
`
`n
`
`0...f.COO-O...I. 0
`
`Pharmaceutical preparation according to any one of the
`5.
`preceding claims, characterized in that it is equipped with
`bioadhesive or mucoadhesive properties by the addition of
`an adhesion-promoting auxiliary substance or auxiliary
`‘
`stance mixture.
`
`
`
`
`
`

`

`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 apfi‘ication.
`
`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,
`
`
`
`

`

`I.
`
`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
`
`from the solvent,
`
`thereby forming a sheet-shaped or tape-
`
`shaped starting material, wherefrom, in a fourth step,
`
`the
`
`dosage or multidosage 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.
`
`
`
`

`

`F:\WPDOCS\CRN\Shcllcy\7334l¢.spe,dnc-ZD/09lol
`
`13
`
`16. Buccal pharmaceutical preparations or methods for
`
`producing same substantially as herein described with
`
`reference to the Examples.
`
`5
`
`DATED this 20th day of September, 2001
`
`LTS LOHMANN THERAPIE—SYSTEME GMBH
`
`By its Patent Attorneys
`DAVIES COLLISON CAVE
`
`10
`
`25
`
`3O
`
`
`
`