Europaisches Patentamt
`GD1
`
`European Patent Office
`DG1
`
`Office européen des brevets
`DG1
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten Unterlagen
`stimmen mit der urspriinglich
`eingereichten Fassung der
`auf dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung Uberein.
`
`The attached documents are
`exact copies of the
`Europeanpatent application
`described on the following
`page, asoriginallyfiled.
`
`Les documents fixés a cette
`attestation sont conformes a
`la version initialement
`déposée de la demande de
`brevet européen spécificée a
`la page suivante.
`
`PatentanmeldungNr.
`
`Patent application No.
`
`Demande de brevet n°
`
`06119839.6 / EP06119839
`
`The organization code and number of your priority application, to be usedfor filing abroad under the Paris
`Convention, is EP06119839
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`Le President de l'Office européen des brevets
`p.o.
`
`A ;
`
`*
`
`ry
`
`R.C. van Dijk
`
`EPA/EPO/OEB Form 1014
`
`02.00
`
`MS50949
`
`

`

`Europaisches Patentamt
`GD1
`
`European Patent Office
`DG1
`
`Office européen des brevets
`DG1
`
`Anmeldetag:
`Date offiling:
`Date de dépét:
`
`30.08.06
`
`Anmeldung Nr:
`Application no.:
`Demande no:
`
`06119839.6
`
`Anmelder/Applicant(s)/Demandeur(s):
`
`EURO-CELTIQUE S.A.
`122 Boulevard de la Petrusse
`2330 Luxembourg/LU
`
`Bezeichnung der Erfindung/Title of the invention/Titre de I'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, siehe Beschreibung.
`If no title is shown please refer to the description.
`Si aucun titre n'est indiqué se referer a la description.)
`
`Buprenorphine-wafer for drug substitution therapy
`
`In anspruch genommenePrioritat(en) / Priority(ies) claimed / Priorité(s) revendiquée(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. / Pays/Date/Numéro de dépét:
`
`Internationale Patentklassifikation / International Patent Classification / Classification internationale de brevets:
`
`A61K9/00
`
`Am Anmeldetag benannte Vertragstaaten / Contracting states designated at dateoffiling / Etats contractants désignées lors du dépdt:
`
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HUIE IS IT LLLT LU LV MC NL PL PT ROSE SI SK TR
`
`EPA/EPO/OEB Form 1014
`
`02.00
`
`2
`
`

`

`EURO-CELTIQUES.A.
`Our Reference: E 9047 / DB
`
`Munich, 30 August 2006
`
`EURO-CELTIQUE S.A.
`
`122, Boulevard de la Pétrusse, 2330 Luxembourg, Luxembourg
`
`The present invention relates to oral pharmaceutical dosage forms comprising buprenorphine
`
`with the dosage form releasing buprenorphineinstantly upon oral, preferably sublingual,
`
`application of the dosage form. The present invention also relates to the use of such dosage
`
`forms for treating pain in a human or animalor for drug substitution therapy in drug-
`
`dependent humansubjects.
`
`Backgroundof the Invention
`
`Chronic pain, which may be due to idiopathic reasons, cancer or other diseases such as
`
`rheumatism andarthritis, is typically treated with strong opioids.
`
`Overthe last decades prejudices in the medical community as to the use of strong opioids for
`
`treating chronic pain in patients has significantly decreased. Many ofthese prejudices were
`
`due to some of the characteristics being inherent to opioids.
`
`While opioids have always been knownto be useful in pain treatment, they also display an
`
`addictive potential in view of their euphorigenic activity. Thus, if opioids are taken by
`
`healthy human subjects with a drug seeking behaviour they may lead to psychological as well
`
`as physical dependence.
`
`E 9047 / DB:sch
`
`

`

`These usually undesired characteristics of opioids can however become important in certain
`
`scenarios such as drug substitution therapies for drug addicts. One of the fundamental
`
`problems of illicit drug abuse by drug addicts (“junkies”) who are dependent on the constant
`
`intake of illegal drugs such as heroin is the drug-related criminal activities resorted to by such
`
`addicts in order to raise enough moneyto fund their addiction. The constant pressures upon
`
`addicts to procure money for buying drugs and the concomitant criminal activities have been
`
`increasingly recognised as a major factor that counteracts efficient and long-lasting
`
`withdrawal and abstinence from drugs.
`
`Therefore, programmes have been developed, particularly in the United States and western
`
`European countries, in which drug addicts are allowed to take prescription drugs underclose
`
`supervision of medical practitioners instead of illegal drugs such as street heroin.
`
`The aim of drug substitution theory is thus to first enable addicts to lead a regular life by
`
`administering legal drugs to prevent withdrawal symptoms, but becauseoftheir legal
`
`character and prescription by medicalpractitioners do not lead to the aforementioned
`
`described drug-related criminal activities. In a second and/or alternate step in the treatment
`
`ofdrug addiction may be to slowly make the drug addict less dependent on the drug by
`
`gradually reducing the dose of the substitution drug or to bridge the time until a therapy place
`
`in a withdrawal programmeis available.
`
`The standard drug usedin drug substitution therapy programmeshasfor a long time been
`
`methadone. However, in recent years the potential of other opioids as substitution drugs in
`
`substitution therapy has been recognised. A particularly suitable drug for that purpose is the
`
`opioid buprenorphine, whichis a mixed opioid agonist/antagonist.
`
`Nowadays, buprenorphine preparations are administered in drug substitution programmesin
`
`the formof a tablet for sublingual administration. One of the reasonsthat the tablets are
`
`

`

`formulated for sublingual administration is that this the preferred route of administration for
`
`buprenorphine. Furthermore, if a patient swallows suchtablets they will not provide
`
`euphorigenic activity.
`
`One example of sublingual tablets for drug substitution therapy is the preparation Subutex®
`
`(being marketed in Germany by Essex Pharma).
`
`Nevertheless, drug addicts sometimesstill try to divert these sublingual buprenorphinetablets
`
`by removing them from the mouth when the supervising healthcare professional’s attention is
`
`directed to other activities. Later the tablets may be sold or the active agent buprenorphine
`
`isolated/extracted to apply it parenterally.
`
`Another buprenorphine preparation aimed at preventing this potential possibility of abuse has
`
`recently gained administrative approval in the United States (Suboxone®). The Suboxone®
`
`preparation comprises buprenorphine hydrochloride and the opioid antagonist naloxone
`
`hydrochloride dihydrate. The presence of naloxone is intended to prevent parenteral abuse of
`
`buprenorphine as parenteral co-administration of buprenorphine and naloxonein e.g. an
`
`opioid-dependent addict will lead to serious withdrawal symptoms.
`
`However, there remains a need for other diversion and / or abuse-resistant dosage forms of
`
`buprenorphine, which can be used in drug substitution therapy as described above.
`
`Additionally, it would be desirable to have a buprenorphinepreparation available whichis
`
`diversion and / or abuse-resistant in cases where the preparation is used for drug substitution
`
`therapy and which could also provide efficient analgesia in cases where the preparation is
`
`administered to alleviate pain in a patient.
`
`

`

`Object and Summaryof the Invention
`
`It is an object of the present invention to provide an oral pharmaceutical dosage form of the
`
`active agent buprenorphinethat is less prone to diversion and / or abuse in drug substitution
`
`therapy. It is another object of the present invention to provide an oral dosage form of the
`
`active agent buprenorphinethat can be used for drug substitution therapy and/or pain
`
`treatment.
`
`In one embodimentthe present invention relates to an oral pharmaceutical dosage form
`
`comprising at least buprenorphine or a pharmaceutically acceptable salt thereof with a dosage
`
`form releasing buprenorphineor said pharmaceutically acceptable salt thereof instantly upon
`
`or oral, preferably sublingual, application of the dosage form. It is, however, understood that
`
`the invention and its various embodiments whichare set out below, can be extended to any
`
`opioid or analgesic whose preferred route of administration is oral, prefereably sublingual, as
`
`is the case for buprenorphine.
`
`An instant release of buprenorphine or a pharmaceutically acceptable salt thereof upon oral,
`
`preferably sublingual, application meansthat substantially all of the buprenorphineor said
`
`pharmaceutically acceptable salt thereof will be released within less than three minutes,
`
`preferably within less than two minutesor less than one minute. Even more preferably,
`
`substantially all of the buprenorphine or said pharmaceutically acceptable salt thereof will be
`
`released within less than thirty seconds, twenty seconds, ten seconds or even within less than
`
`five secondsafter oral, preferably sublingual, application of the dosage form. In one of the
`
`preferred embodiments these oral dosage forms will comprise between approximately 0.1 mg
`
`and approximately 16 mg buprenorphineor the equivalent amounts of a pharmaceutically
`
`acceptable salt thereof.
`
`

`

`In a further preferred embodimentthese oral pharmaceutical dosage forms will achieve an
`
`average Cmax of between 1.5 ng/ml and approximately 2.25 ng/ml in the case of a dose of 0.4
`
`mg buprenorphine hydrochloride being administered. In the case of a dose of 8 mg
`
`buprenorphine HC1 being administered, the Cinax will typically be between approximately 2.5
`
`and 3.5 ng/ml and if a dose of 16 mg buprenorphine hydrochloride is administered the Cmax
`
`will preferably be between 5.5 to 6.5 ng/ml.
`
`Yct another preferred cmbodimentof the invention relates to oral pharmaccutical dosage
`
`forms which may provide for the above-mentioned characteristics and/or an average Tmax of
`
`from approximately 45 to approximately 90 minutes.
`
`In a particularly preferred embodiment the dosage forms will additionally comprise an opioid
`
`antagonist, preferably naloxoneor a pharmaceutically acceptable salt thereof.
`
`In yet a further preferred embodiment, the pharmaceutical dosage form will comprise
`
`buprenorphine and the opioid antagonist, which preferably is naloxone, in a weight ratio of
`
`from approximately 1:1 to approximately 10:1.
`
`One embodiment of the present invention also relates to oral pharmaceutical dosage forms,
`
`which may have someorall of the aforementioned characteristics and wherein the dosage
`
`form has a film-like or wafer-like shape.
`
`Another embedimentrelates to a method of manufacturing the afore-mentioned described
`
`dosage forms.
`
`Embodiments of the present invention also relate to the use of the afore-describedoral,
`
`preferably sublingual, pharmaceutical dosage forms in the manufacture of a medicament for
`
`

`

`treating pain in a humanor animal and/or for drug substitution therapy in drug-dependent
`
`humansubjects.
`
`Oneaspectof the invention also relates to a method of drug substitution therapy in drug-
`
`dependent human subjects wherein the aforementioned oral pharmaceutical dosage forms are
`
`administered to a drug-dependent subject in need thereof.
`
`Detailed description of the invention
`
`Fromthe prior art, sublingual tablets are known underthe trade names Subutex® or
`
`Suboxone® both of which comprise the active agent buprenorphine hydrochloride for drug
`
`substitution therapy.
`
`The suitability of particularly buprenorphine for drug substitution therapy had been
`
`recognised early on in view of buprenorphine’s very long elimination half-life (reported as
`
`approximately 20 to 37 hours), which allows a reduced frequency of administration. Asa
`
`consequence drug addicts who participate in drug substitution therapy have to report less
`
`frequently to the medical agency or healthcare professional supervising the substitution
`
`programme.
`
`Furthermore, the sublingual absorption of buprenorphine has the advantage that an abuse by
`
`swallowing tablets of buprenorphineis less likely to occur. The tablets that are currently on
`
`the market in the form of Subutex® and Suboxone® preparations are both for sublingual
`
`administration and typically disintegrate over a time period of five to ten minutes. However,
`
`within that time period the drug addict maybe able to divert the tablet before subsequently
`
`either selling the tablets on the street or isolating the active agents therefrom.
`
`

`

`In order to reduce of eliminate these problems, the present invention provides oral
`
`pharmaceutical dosage forms which comprise the active agent buprenorphine and which
`
`release buprenorphine instantly after oral, preferably sublingual, administration of the drug.
`
`It is understood that if reference is made in the context of this invention to the term
`
`“buprenorphine”this refers to the free base as well as to any pharmaceutically acceptable salt
`
`thereof such as the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate,
`
`phosphate, malate, malcate, hydrobromide, hydroiodidec, fumarate, succinate salts and the
`
`like.
`
`A particularly preferred pharmaceutically acceptable salt of buprenorphine is buprenorphine
`
`hydrochloride.
`
`The provision of a pharmaceutical dosage form comprising buprenorphine or a
`
`pharmaceutically acceptable salt thereof in e.g. film-like or wafer-like shapes which allows
`
`for instant release of the active agent uponoral, preferably sublingual, administration of the
`
`dosage form should prevent the type of abuse resulting from illicit diversion of the tablets by
`
`drug addicts participating in drug substitution therapy programmes.
`
`In the context of the present invention instant release meansthat substantially the whole
`
`amount of the buprenorphine or the respective pharmaceutically acceptable salt thereof will
`
`be released in less than five minutes. Preferably, substantially all of the buprenorphineorits
`
`pharmaceutically acceptable salt thereof will be released within less than four, within less
`
`than three, within less than two and more preferably within less than one minute.
`
`In a particularly preferred embodiment, instant release refers to the situation that substantially
`
`all of the buprenorphine or the respective pharmaceutically acceptable salt thereof will be
`
`released within less than thirty seconds, within less than twenty seconds, or within less than
`
`

`

`ten seconds. In an even more preferred embodiment, the term“instant release”? meansthat
`
`substantially all of the buprenorphine will be released from the dosage form within less than
`
`five seconds or within less than three seconds.
`
`The term “substantially all” meansthat approximately 95% of the drug will have been
`
`released.
`
`The term “approximatcly” in the context of the present invention describes a deviation from
`
`the indicated value of 10% and preferably of 5%.
`
`Such efficient release of the drug is hard to achieve with a sublingual tablet which generally
`
`requires a greater amount of time to melt or to disintegrate.
`
`Fast-dissolving or rapidly disintegrating dosage forms for other pharmaceutically active
`
`compounds are known which disintegrate within seconds upon contact with the mucosal
`
`saliva of the mouth andparticularly the sublingual mucosa.
`
`These pharmaceutical dosage forms and formulation principles are well knownto the person
`
`skilled in the art and will be described in more detail below.
`
`Asregards the dosage amount, the pharmaceutical compositions in accordance with the
`
`present invention will typically comprise between approximately 0.1 mg and approximately
`
`16 mg of buprenorphine or a pharmaceutically acceptable salt thereof such as buprenorphine
`
`hydrochloride. Preferred dosage amounts will be in the range of between approximately 0.4
`
`mg and approximately 12 mg or between approximately 2 mg and approximately 8 mg
`
`buprenorphine or a pharmaceutically acceptable salt thereof.
`
`

`

`The oral pharmaceutical dosage forms in accordance with the invention may havethe further
`
`characteristic of providing a Cmax of approximately 1.5 to 2.5 ng/mlin the case of a dose of 4
`
`mg buprenorphine hydrochloride being administered. A preferred Cina, in the case of a dose
`
`of 4 mg of buprenorphine hydrochloride being administered may be approximately between
`
`1.7 ng/ml to 2 ng/ml.
`
`In the case of a dose of 8 mg buprenorphine hydrochloride being administered, the Cmax may
`
`be approximately between 2.5 and 3.5 ng/ml. In a preferred embodiment the Cyax may be
`
`approximately between 2.75 ng/ml and 3.25 ng/ml in the case of a dose of 8 mg
`
`buprenorphine hydrochloride being administered.
`
`In case of a dose of 16 mg buprenorphine hydrochloride being administered, the Cynax may
`
`preferably be in the range of approximately 5 to 7 ng/ml. In a preferred embodimentthe Cmax
`
`may be between 5.5 and 6.5 ng/ml if 16 mg of buprenorphine hydrochloride are administered.
`
`The AUC.4s(i.e. the Area under the Curve for 48 hours after administration) may in the case
`
`of administration of 4 mg of buprenorphine hydrochloride be in the range of approximately 10
`
`to 15 hours x ng/ml. Ina preferred embodiment the AUCo_4g may be approximately 12 to 13
`
`hours x ng/ml. In the case of 8 mg buprenorphine hydrochloride being administered the
`
`AUCo.4g may be approximately in the range of 15 to 25 hours x ng/ml. In a preferred
`
`embodiment the AUCp-4 in this case may be between approximately 20 to 22 hours x ng/ml.
`
`In the case of 16 mg buprenorphine hydrochloride being administered, the AUCo-4g may bein
`
`the range of 25 to 40 hours x ng/ml. In a preferred embodiment the AUCo.4s in this case may
`
`be in the range of approximately 30 to 35 hours x ng/ml.
`
`The average Tmax values for such preparations will preferably be from approximately 45 to
`
`approximately 90 minutes.
`
`

`

`-10-
`
`It is understood that the aforementioned pharmacokinetic parameters Cmax and AUCo.43 are
`
`average values that are obtained by measuring the blood plasma levels in a group ofeight to
`
`approximately twenty-four patients. These patients will be selected according to inclusion
`
`and exclusion criteria, as they are commonfor drug substitution programmes. It is understood
`
`that such patients typically will be of average weight and Caucasian origin.
`
`The pharmaceutical dosage form in accordance with the invention will be administered such
`
`that the maximal dosageper day is 32 mg of buprenorphine. Oncca paticnt is enrolled in
`
`substitution therapy, the initial dosage will be typically between 2 mg to 4 mg of
`
`buprenorphine. The formulations may be administered once a day, every two days, preferably
`
`every three days or even less fequently.
`
`In a preferred embodiment, the oral dosage forms of the invention will additionally comprise
`
`an opioid antagonist. Such antagonists may beselected from the group comprising
`
`naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone,
`
`ketyleyclazocine, norbinaltorphimine, naltrindol, 6-8-naloxol and 6--naltrexol or the
`
`pharmaceutically acceptable salts thereof.
`
`Especially preferred antagonists comprise naltrexone, nalmefene and naloxone. Specifically
`
`preferred as an antagonist is naloxone and its hydrochloridesalt.
`
`It is understood, that if in the context of the present invention reference is made to an opioid
`
`antagonist, this also not only refers to the free base but also to pharmaceutically acceptable
`
`salts thereof such as those mentioned for buprenorphine.
`
`A particularly preferred antagonist is naloxone. Of the naloxonesalts, naloxone
`
`hydrochloride dihydrate may be particularly preferable in combination with buprenorphine
`
`hydrochloride.
`
`

`

`-ll-
`
`The pharmaceutical dosage forms in accordance with the invention will comprise
`
`buprenorphineand the antagonist, which preferably is naloxone, in a weightratio of from 1:1
`
`to 10:1. A weight ratio of from 2:1 to 8:1 may be preferred, with a weightratio of 4:1 being
`
`particularly preferred.
`
`Thus, if an oral dosage form in accordance with the present invention for example comprises
`
`2 mg buprenorphine hydrochloride it will comprise approximatcly 0.5 mg naloxone. If the
`
`dosage form comprises 0.4 mg buprenorphine hydrochloride, it will comprise 0.1 mg
`
`naloxone and if the dosage form comprises 8 mg buprenorphine hydrochlorideit will
`
`comprise e.g. 2 mg naloxone hydrochloride.
`
`A particularly preferred embodimentthus relates to an oral dosage form comprising
`
`buprenorphine, preferably buprenorphine hydrochloride, and naloxone, preferably naloxone
`
`hydrochloride, wherein the dosage form releases said active agents within less than one
`
`minute, preferably within less than thirty seconds and more preferably within less than ten
`
`secondsafter sublingual application of the dosage form. In addition, the dosage forms may
`
`providethe preferred values of the aforementioned pharmacokinetic parameters Cmax, and
`
`AUC o.4s.
`
`Thus, the person skilled in the art will have to ensure that indeed an oral dosage form is used
`
`whichis able to allow for incorporation of sufficient amounts of buprenorphine and
`
`preferably also of naloxone and whichat the sametime disintegrates rapidly enoughto release
`
`the active agents instantly.
`
`In one embodiment one may use non-gelatin film materials, e.g. films of modified cellulose
`
`materials as dosage forms. In this case, buprenorphine and optionally opioid antagonists such
`
`

`

`-12-
`
`as naloxoneare incorporated into the film matrix and films thus prepared may be
`
`administered orally.
`
`In accordance with this aspect of the invention, the active ingredients may be dissolved in a
`
`hydrophilic, organic system to form a homogenoussolution or dispersion. The solution or
`
`dispersion can then be applied to one or more surfaces of a non-gelatin polymeric film, e.g. a
`
`dry cellulose ether film, resulting in the active ingredient(s) and/or liquid carrier phase being
`
`transported through the surface of the “dry”film resulting in a new film composition.
`
`The film substrate may remain completely intact or relatively physically unchanged.
`
`immediately following the incorporation process. It can, however, be converted to any size or
`
`shape of unit dosage form. Alternatively, the film substrate may liquefy or dissolve partly or
`
`fully during the incorporation process, but nevertheless finally forming a single discrete film,
`
`after curing. Films accordingto this aspect of the invention are typically made up of one or
`
`more soluble polymer or polymers which will otherwise degrade at the intended site of release
`
`after administration in the mouth, e.g. sublingual administration, in order to provide the
`
`instant release of the active agents. Suitable cellulose ether film bases include e.g.
`
`hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
`
`hydroxyethylmethylcellulose (HEMC), hydroxyethylcellulose (HEC), methylcellulose (MC),
`
`carboxymethylcellulose (CMC) and salts and derivates ofall of the aforesaid materials. A
`
`particularly suitable cellulose ether for forming the film is HPMC.
`
`Optional ingredients may be added including colorants, emulsifiers, humectants, and anti-
`
`blocking agents.
`
`Once one has a film being based on a cellulose ether available, in a next step the active
`
`ingredient(s) will be applied in the form of a liquid to the film. Appropriate means of liquid
`
`application onto the film substrate include extrusion,roller application, pouring, spraying,
`
`

`

`-13-
`
`brush painting or whipping. Further details of the preparation of such films can be taken e.g.
`
`from WO 2005/079750 A2 whichis incorporated by reference herewith.
`
`Anotherpossible technology in order to provide the afore-described pharmaceutical dosage
`
`forms of buprenorphine and preferably naloxoneis described in WO 03/030883. In this latter
`
`embodimentof the present invention, a thin film drug delivery composition includes (i) a
`
`flowable water-soluble film-forming matrix and (ii) the active agent(s) uniformly stationed
`
`therein. Optionally a tastc-masking agent may be coated or intimatcly associate with the
`
`active agent(s) to provide taste masking ofthe active agent(s). The flowable water-soluble
`
`film-forming matrix together with the active agent(s) is formable into a dry filmof less than
`
`about 380 micronsin thickness, for example less than about 250 microns in thickness.
`
`The matrix may be a cellulosic material, a gum, a protein, a starch, a glucan and combinations
`
`thereof. For example one may usethe already aforementioned methylcellulose, HMC, HEC,
`
`HC, HPC, HPMC, HMPC, gum Arabic, xanthan gum etc. The films are prepared according
`
`to standard technology andthe active agents are displaced thereon and therein as described in
`
`WO 03/030883.
`
`Yet another interesting technology relates to immediate release drug delivery forms as
`
`described in WO 99/17744, which is also incorporated by reference herein as far asit
`
`describes fast releasing oral dosage forms. The person skilled in the art will understand that
`
`the processes and dosage forms in WO 99/17744 may be used to obtain the aforementioned
`
`described pharmaceutical dosage forms of buprenorphine and preferably also naloxone.
`
`One mayof course also use fast disintegrating tablets that disintegrate upon contacting the
`
`saliva, e.g. under the tongue, following oral administration. Such fast-disintegrating tablets
`
`are described e.g. in WO 99/44580 and are well knownto the person skilled in the art.
`
`

`

`-14-
`
`A particularly interesting technology for fast-releasing dosage forms that may be used for the
`
`purpose of the present invention to provide an oral dosage form of buprenorphine and
`
`preferably an opioid antagonist such as naloxone can be taken from WO 96/26720.
`
`Therein it is described how the active agent selegiline is formulated into a rapidly releasing
`
`dosage form that can be used e.g. for sublingual administration. WO 96/26720 describes in
`
`detail a “fast-dispersing dosage form” with the term encompassing all types of dosage forms
`
`being described in US patent 5,120,549, US 5,079,018, WO 93/12769, US 5,298,261 and WO
`
`91/04757.
`
`As for WO 96/26720 in the case of the active agent selegiline, the present invention
`
`contemplates particularly using fast-dispersing dosage formsas described in UK patent
`
`number 1548022, that is, a solid fast-dispersing dosage form comprising a networkof the
`
`active ingredient(s) and a water-soluble or water-dispersible carrier which is inert towards the
`
`active ingredient, the network having been obtained by subliming solvent from a composition
`
`in the solid state, that composition comprising the active ingredient and a solution of the
`
`carrier in a solvent.
`
`It is preferred that such a composition in accordance with the invention disintegrates within
`
`one to ten seconds, and particularly within two to eight seconds of being placed in the oral
`
`cavity and particularly sublingually.
`
`The composition will preferably contain in addition to the active ingredient, matrix forming
`
`agents and secondary components.
`
`Matrix forming agents suitable for use in this aspect of the present invention include materials
`
`derived from animal or vegetable proteins, such as gelatins, dextrins and soy, wheat and
`
`psylliumseed proteins, gums such as acacia, guar, agar, and xanthan, polysaccharides,
`
`

`

`alginates, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such
`
`as polyvinylpyrrolidone, and polypeptide/protein or polysaccharide complexes such as
`
`gelatin-acacia complexes.
`
`Other matrix forming agents suitable for use in the present invention include sugars such as
`
`mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin;
`
`inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and
`
`amino acids having from 2 to 12 carbon atomssuch as a glycine, L-alanine, L-aspartic acid,
`
`L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
`
`One or more matrix forming agents may be incorporated into the solution or suspension prior
`
`to solidification. The matrix forming agent may bepresentin addition to a surfactant or to the
`
`exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid
`
`in maintaining the dispersion of any active ingredient within the solution or suspension.
`
`Secondary components suchas preservatives, antioxidants, surfactants, viscosity enhancers,
`
`colouring agents, flavouring agents, pH modifiers, sweeteners or taste-masking agents may
`
`also be incorporated into the composition. Suitable colouring agents include red, black and
`
`yellow iron oxides. Suitable flavouring agents include mint, raspberry, liquorice, orange,
`
`lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these.
`
`Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and
`
`maleic acid. Suitable sweeteners include aspartame and thaumatin. Suitable taste-masking
`
`agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds,
`
`adsorbates or microencapsulated actives.
`
`Suchfast-dispersing dosage forms containing buprenorphine and preferably an opioid
`
`antagonist such as naloxone may be similarly obtained as described in GB 1548022B or
`
`

`

`-16-
`
`WO 96/26720, in particular Example 1 of the latter, which are incorporated herein in their
`
`entirety.
`
`A particularly preferred embodimentof the present invention relates to dosage forms, which
`
`are produced along the lines described in WO 03/070227 Al.
`
`This prior art reference describes taste-masked, film-type or wafer-type medicinal
`
`preparations. It is to be understood that the dosage forms in accordance with the present
`
`invention may preferably be such film-type or wafer-type medicinal preparations with the
`
`taste-masking being only an optionalfeature.
`
`Flat aclive agent carriers that have a film-type or wafer-lype structure provide for various
`
`advantages. As a consequence of the low thickness in comparison to the surface area, there is
`
`only a short diffusion pathway if such a dosage form is applied e.g. to the mucosa ofthe oral
`
`cavity. This typically leads to a very rapid release of the active agents which can then be
`
`quickly, efficiently and directly absorbed by the mucosaofthe oral cavity and particularly
`
`sublingually if the active agent is absorbableat all via that route. Thus, in case of
`
`buprenorphine such very flat film-type or wafer-type dosage forms are highly desirable as
`
`they will allow for the provision of an instant release of active ingredient, thereby minimising
`
`the abuse problems encountered with the formulations ofthe priorart.
`
`Flat active agent carriers have been developedfor different purposes. One of the basic prior
`
`art references in this context is DE 27 46 414 in whichactive agent, binding agent and
`
`additional excipients are processed to yield a dosage form in the form offilm-type strand.
`
`Oneof the advantages of wafer-type pharmaceutical dosage forms as described in WO
`
`03/070227 A1 is that there is a direct correlation between the amount of the active agent and
`
`the length of a certain part of the strand in view of the homogenousthickness, density and
`
`

`

`-17-
`
`width. Thus, one can easily obtain a certain unit dosage by simply cutting the wafer-like
`
`dosage form in to appropriately sized pieces.
`
`Such film-type or wafer-type dosage forms in accordance with the present invention are
`
`characterised in that they comprise a matrix which is formed from at least one matrix-forming
`
`polymerand in which buprenorphine and preferably an opioid antagonist such as naloxone
`
`are dissolved or homogenously dispersed.
`
`The rapidly disintegrating matrix of the pharmaceutical dosage forms in accordance with the
`
`invention comprisesas oneofits basic substances water-soluble polymers or mixtures of such
`
`polymers. Preferably synthetic or partially synthetic polymersor naturally occurring
`
`biopolymers are used which can form films and are water-soluble. Particularly suitable for
`
`this purpose are polymers which maybe selected from the group comprising cellulose
`
`derivatives, polyvinylalcohol, polyacrylates and polyvinylpyrrlidone.
`
`Within the cellulose derivatives, hydroxypropylmethylcellulose, carboxymethylcellulose,
`
`sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
`
`methylcellulose, and hydroxypropylmethylcellulose may be used. One may also use water-
`
`soluble polysaccharides being derived from plants or microbes. Preferred polysaccharides
`
`include pullulan, trantan, alginate, dextrin and pectins.
`
`One mayalso use proteins and preferably gelatin or other gel-forming proteins. One may also
`
`use starch and starch derivatives, gelatin, polyvinylpyrrilidone, gum Arabic, pullulan,
`
`acrylates, polyethylene oxide with a particular focus on polyox 10, polyox 80, polyox 205,
`
`polyox 301, polyox 750 or copolymers of methylvinylether and maleic acid anhydri

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