WO 2008/025791
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`PCT/EP2007/058978
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`EURO-CELTIQUES.A.
`OurReference: E 9665 / DB
`
`Munich, 29 August 2007
`
`EURO-CELTIQUES.A.
`
`122, Boulevard de la Pétrusse, 2330 Luxembourg, Luxembourg
`
`Thepresentinvention relates to oral pharmaceutical dosage forms comprising buprenorphine
`with the dosage form releasing buprenorphine instantly upon oral, preferably sublingual,
`application of the dosage form. The present inventionalso relates to the use of such dosage
`forms for treating pain in a human or animalor for drug substitution therapy in drug-
`
`dependent human subjects.
`
`Backgroundof the Invention
`
`Chronic pain, which may be dueto 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. Manyof these prejudices were
`
`due to someofthe 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
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`These usually undesired characteristics of opioids can however become importantin certain
`scenarios such as drug substitution therapies for drug addicts. One of the fundamental
`
`problemsofillicit drug abuse by drug addicts (‘‘junkies”) who are dependenton 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 majorfactor that counteracts efficient and long-lasting
`
`withdrawal and abstinence from drugs.
`
`Therefore, programmeshave been developed, particularly in the United States and western
`
`European countries, in which drug addicts are allowed to take prescription drugs under close
`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 becauseof their legal
`character and prescription by medical practitioners do not lead to the aforementioned
`described drug-related criminalactivities.
`In a second and / or alternate step in the treatment
`of drug 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 used in drug substitution therapy programmeshasfora 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 purposeis the
`
`opioid buprenorphine, which is a mixed opioid agonist/antagonist.
`
`Nowadays, buprenorphine preparations are administered in drug substitution programmesin
`the formof a tablet for sublingual administration. One of the reasons that the tablets are
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`formulated for sublingual administration is that this the preferred route of administration for
`buprenorphine. Furthermore, if a patient swallows such tablets 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 orthe 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 naloxoneis intended to prevent parenteral abuse of
`buprenorphineas parenteral co-administration of buprenorphine and naloxonein e.g. an
`opioid-dependentaddict 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 usedin drug substitution therapy as described above.
`Additionally, it would be desirable to have a buprenorphine preparation available whichis
`diversion and / or abuse-resistant in cases where the preparation is used for drug substitution
`therapy and which couldalso provide efficient analgesia in cases where the preparation is
`administered to alleviate pain in a patient.
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`Object and Summaryofthe Invention
`
`It is an object of the present invention to provide an oral pharmaceutical dosage form of the
`
`active agent buprenorphinethatis 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 ofthe
`active agent buprenorphinethat can be used for drug substitution therapy and/orpain
`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 buprenorphine or said pharmaceutically acceptable salt thereof instantly upon
`or oral, preferably sublingual, application of the dosage form.It is, however, understoodthat
`the invention and its various embodiments which are 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.
`
`Aninstant release of buprenorphine or a pharmaceutically acceptable salt thereof uponoral,
`preferably sublingual, application meansthat substantially all of the buprenorphineor said
`pharmaceutically acceptablesalt thereof will be released within less than three minutes,
`preferably within less than two minutes or less than one minute. Even more preferably,
`substantially all of the buprenorphineor 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.
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`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
`
`In the case of a dose of 8 mg
`mg buprenorphine hydrochloride being administered.
`buprenorphine HC1being administered, the Cmax 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.
`
`Yet another preferred embodiment of the invention relates to oral pharmaceutical dosage
`forms which may provide for the above-mentioned characteristics and/or an average Tmaxof
`
`from approximately 45 to approximately 90 minutes.
`
`In a particularly preferred embodimentthe dosage formswill additionally comprise an opioid
`antagonist, preferably naloxone or 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 embodimentrelates to a method of manufacturing the afore- mentioned described
`
`dosage forms.
`
`Embodimentsof the present invention also relate to the use of the afore-describedoral,
`preferably sublingual, pharmaceutical dosage forms in the manufacture of a medicament for
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`treating pain in a humanoranimal 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 formsare
`administered to a drug-dependent subject in need thereof.
`
`Detailed description of the invention
`
`From the 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.
`
`Thesuitability 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. As a
`consequence drug addicts who participate in drug substitution therapy haveto report less
`frequently to the medical agency orhealthcare 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 may beableto divert the tablet betore subsequently
`either selling the tablets on the street or isolating the active agents therefrom.
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`In order to reduce of eliminate these problems, the present invention providesoral
`pharmaceutical dosage forms which comprise the active agent buprenorphine and which
`release buprenorphineinstantly after oral, preferably sublingual, administration ofthe 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, maleate, hydrobromide, hydroiodide, 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 buprenorphineor a
`pharmaceutically acceptable salt thereof in e.g. film-like or wafer-like shapes which allows
`for instant release of the active agent upon oral, 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
`amountof 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 morepreferably within less than one minute.
`
`In a particularly preferred embodiment, instant release refers to the situation that substantially
`all of the buprenorphineor the respective pharmaceutically acceptable salt thereof will be
`released within less than thirty seconds, within less than twenty seconds, or within less than
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`In an even more preferred embodiment, the term “instant release” meansthat
`ten seconds.
`substantially all of the buprenorphine will be released from the dosage form withinless than
`
`five seconds or within less than three seconds.
`
`The term “substantially all” means that approximately 95% of the drug will have been
`
`released.
`
`The term “approximately” in the context of the present invention describes a deviation from
`the indicated value of 10% and preferably of 5%.
`
`Suchefficient release of the drug is hard to achieve with a sublingual tablet which generally
`
`requires a greater amountof time to meltor to disintegrate.
`
`Fast-dissolving or rapidly disintegrating dosage forms for other pharmaceutically active
`compoundsare known which disintegrate within seconds upon contact with the mucosal
`saliva of the mouth and particularly the sublingual mucosa.
`
`These pharmaceutical dosage forms and formulation principles are well knownto the person
`skilled in the art and will be described in moredetail below.
`
`As regards 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 amountswill 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.
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`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/ml in the case of a dose of 4
`mg buprenorphine hydrochloride being administered. A preferred Cmax 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 Cmax 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 Cmax may
`preferably be in the range of approximately 5 to 7 ng/ml.
`In a preferred embodiment the Cmax
`may be between 5.5 and 6.5 ng/ml if 16 mg of buprenorphine hydrochloride are administered.
`
`The AUCo-as (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.
`In a 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.43 may be approximately in the range of 15 to 25 hours x ng/ml.
`In a preferred
`embodiment the AUCo.4g 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.43 may bein
`the range of 25 to 40 hours x ng/ml.
`In a preferred embodiment the AUCo-ag 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.
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`It is understood that the aforementioned pharmacokinetic parame ters Cmax and AUCo-ag are
`average valuesthat are obtained by measuring the blood plasmalevels in a groupofeight 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 dosage per day is 32 mg of buprenorphine. Oncea patient 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 formsof the invention will additionally comprise
`an opioid antagonist. Such antagonists may be selected from the group comprising
`naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone,
`ketylcyclazocine, norbinaltorphimine,naltrindol, 6-8-naloxol and 6-8-naltrexol or the
`phannaceutically acceptable salts thereof.
`
`Especially preferred antagonists comprise naltrexone, nalmefene and naloxone. Specifically
`preferred as an antagonist is naloxone andits 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 beparticularly preferable in combination with buprenorphine
`
`hydrochloride.
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`The pharmaceutical dosage forms in accordance with the invention will comprise
`
`buprenorphine and the antagonist, which preferably is naloxone, in a weight ratio of from 1:1
`to 10:1. A weight ratio of from 2:1 to 8:1 may be preferred, with a weight ratio 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 approximately 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 hydrochloride it will
`
`comprise e.g. 2 mg naloxone hydrochloride.
`
`A particularly preferred embodimentthusrelates 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
`seconds after sublingual application of the dosage form.
`In addition, the dosage forms may
`provide the preferred values of the aforementioned pharmacokinetic parameters Cmax, and
`
`AUCo.a3.
`
`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 which at the same time disintegrates rapidly enoughto release
`
`the active agents instantly.
`
`In one embodiment one may use nor gelatin film materials, e.g. films of modified cellulose
`materials as dosage forms.
`In this case, buprenorphine and optionally opioid antagonists such
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`as naloxone are 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 normgelatin polymeric film, e.g. a
`dry cellulose etherfilm, resulting in the active ingredient(s) and/orliquid carrier phase being
`transported through the surface ofthe “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 neverthelessfinally forming a single discrete film,
`after curing. Films according to this aspect of the invention are typically made up of one or
`more soluble polymeror 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 basesincludee.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 antr
`blocking agents.
`
`Once onehasafilm 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,
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`brush painting or whipping. Further details of the preparation of such films can be taken e.g.
`from WO 2005/079750 A2 which is incorporated by reference herewith.
`
`Anotherpossible technology in order to provide the afore-described pharmaceutical dosage
`forms of buprenorphine and preferably naloxone is described in WO 03/030883.
`In this latter
`embodiment of 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 taste- masking agent may be coated or intimately associate with the
`active agent(s) to provide taste masking of the active agent(s). The flowable water-soluble
`film-forming matrix together with the active agent(s) is formable into a dry film of 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 mayusethe 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 anotherinteresting technology relates to immediate release drug delivery forms as
`
`described in WO 99/17744, which is also incorporated by reference herein asfar 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 theart.
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`A particularly interesting technology for fast-releasing dosage forms that may be usedfor 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 agentselegiline 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 encompassingall 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 forms as described in UKpatent
`
`number 1548022,that is, a solid fast-dispersing dosage form comprising a network of 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 placedin 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
`psyllium seed proteins, gums such as acacia, guar, agar, and xanthan, polysaccharides,
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`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 aluminiumsilicates; and
`
`amino acids having from 2 to 12 carbon atomssuchas 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 be present in 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 componentssuch as 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.
`
`Such fast-dispersing dosage forms containing buprenorphine andpreferably an opioid
`antagonist such as naloxone maybesimilarly obtained as described in GB 1548022B or
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`WO 96/26720, in particular Example 1 of the latter, which are incorporated herein in their
`
`entirety.
`
`A particularly preferred embodiment of the present invention relates to dosage forms, which
`
`are produced along the lines described in WO 03/070227 A1.
`
`This priorart 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 optional feature.
`
`Flat active agent carriers that have a film- type or wafer-type structure provide for various
`advantages. As a consequenceof 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 mucosa of the oral cavity and particularly
`sublingually if the active agent is absorbable at all via that route. Thus, in case of
`
`buprenorphine such very flat film-type or wafer-type dosage formsare highly desirable as
`they will allow for the provision of an instant release of active ingredient, thereby minimising
`
`the abuse problems encountered with the formulationsof the priorart,
`
`Flat active agent carriers have been developed fordifferent purposes. One ofthe basic prior
`
`art references in this context is DE 27 46 414 in which active agent, binding agent and
`
`additional excipients are processed to yield a dosage form in the form of film type strand.
`
`Oneof the advantages of wafer-type pharmaceutical dosage formsas described in WO
`
`03/070227 A1 is that there is a direct correlation between the amountof the active agent and
`
`the length of a certain part of the strand in view of the homogenous thickness, density and
`
`

`

`WO 2008/025791
`
`PCT/EP2007/058978
`
`-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 comprises as one ofits basic substances water-soluble polymers or mixtures of such
`
`polymers. Preferably synthetic or partially synthetic polymers or 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 mayalso 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 mayalso
`
`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 anhydride.
`
`The personskilled in the art will appreciate that the extent to which buprenorphine and
`optionally an opioid antagonist such as naloxoneare instantly released dependsinpart on the
`
`

`

`WO 2008/025791
`
`PCT/EP2007/058978
`
`-18-
`
`type of matrix- forming polymer chosen. For example, a dosage form using polyvinylalcohol
`as matrix- forming polymer may disintegrate faster than a dosage form using HPMCas
`
`matrix- forming polymer. The disintegration time may be adjusted by mixing a combination
`
`of different polymers in suitable amounts.
`
`The person skilled in the art also knowsdisintegrating agents, which can “‘pull” waterinto the
`matrix which then pushes the dosage forms apart, Thus, such disintegrating agents may also
`
`be used for adjustmentof the disintegration time.
`
`In order to allow absorption of buprenorphine over the mucosa of the mouth, andparticularly
`sublingually, in one embodiment the dosage forms mayadditionally use agents that enhance
`absorption of the active agent, i.e. so-called permeation enhancers.
`
`Such permeation enhancers maybe selected from the group comprising propandiol,
`dexpanthenol, and oleic acid. The permeation enhancers mayalso be selected from the group
`comprising saturated or unsaturated fatty acids, hydrocarbons,linear or branchedfatty
`alcohols, dimethylsulfoxide, propylene glycol, decanol, dodecanol, 2-octyldodecanol,
`
`glycerine, ethanol or other alcohols.
`
`According to a preferred embodiment the film-type or wafer-type oral dosage formsof the
`present invention in the presence of saliva can disintegrate within e.g. one second to three
`minutes or within five seconds to one minute or five secondsto thirty seconds,
`
`The disintegration times of the oral dosage forms in accordance with the invention are
`measured according to the European pharmacopoeia, 4'" editi

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