(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0087470 A1
`Oksche et al.
`(43) Pub. Date:
`Apr. 8, 2010
`
`US 20100087470A1
`
`(54) BUPRENORPHINE-WAFER FOR DRUG
`SUBSTITUTION THERAPY
`
`(75) Inventors:
`
`Alexander Oksche, Limburg (DE);
`William Heath, Cambridge (GB);
`Timothy Holden, Cambridge (GB);
`Derek A. Prater, Cambridge (GB);
`Richard s‘ sadder’ Greenwich’
`
`CT (US); Malcolm Walden,
`Cambridge (GB)
`
`Correspondence Address:
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.
`LC
`1100 NEW YORK AVENUE, N.W.
`WASHINGTON, DC 20005 (US)
`
`(73) Assignee:
`
`EURO-CELTIQUE S.A.,
`Luxembourg (LU)
`
`(21) Appl. No.:
`
`12/439,410
`
`(22) PCT Filed:
`
`Aug. 29, 2007
`
`(86) PCT No.:
`
`PCT/EP2007/058978
`
`§ 371 (0X1),
`(2), (4) Date?
`NOV- 9: 2009
`_
`_
`_
`_
`_
`Foreign Application Priority Data
`
`(30)
`
`Aug. 30, 2006 (EP) ................................ .. 061198396
`
`.
`.
`.
`.
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006-01)
`A61K 31/485
`(2006-01)
`A61P 25/04
`(52) US. Cl. ...................................................... .. 514/279
`
`ABSTRACT
`(57)
`The present invention relates to oral pharmaceutical dosage
`forms comprising buprenorphine With the dosage form
`releasing buprenorphine instantly upon oral, preferably sub
`lingual, application of the dosage form. The present invention
`also relates to the use of such dosage forms for treating pain
`in a human or animal or for drug substitution therapy in
`drug-dependent human subjects.
`
`TEVA EXHIBIT 1018
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 2010/0087470 A1
`
`Apr. 8, 2010
`
`BUPRENORPHINE-WAFER FOR DRUG
`SUBSTITUTION THERAPY
`
`[0001] The present invention 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
`invention also relates to the use of such dosage forms for
`treating pain in a human or animal or for drug substitution
`therapy in drug-dependent human subjects.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Chronic pain, Which may be due to idiopathic rea
`sons, cancer or other diseases such as rheumatism and arthri
`tis, is typically treated With strong opioids.
`[0003] Over the last decades prejudices in the medical com
`munity as to the use of strong opioids for treating chronic pain
`in patients has signi?cantly decreased. Many of the se preju
`dices Were due to some of the characteristics being inherent to
`opioids.
`[0004] While opioids have alWays been knoWn to 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 depen
`dence.
`[0005] These usually undesired characteristics of opioids
`can hoWever become important in certain scenarios such as
`drug substitution therapies for drug addicts. One of the fun
`damental problems of illicit drug abuse by drug addicts
`(“junkies”) Who are dependent on the constant intake of ille
`gal drugs such as heroin is the drug-related criminal activities
`resorted to by such addicts in order to raise enough money to
`fund their addiction. The constant pressures upon addicts to
`procure money for buying drugs and the concomitant crimi
`nal activities have been increasingly recognised as a major
`factor that counteracts e?icient and long-lasting WithdraWal
`and abstinence from drugs.
`[0006] Therefore, programmes have been developed, par
`ticularly 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.
`[0007] The aim of drug substitution theory is thus to ?rst
`enable addicts to lead a regular life by administering legal
`drugs to prevent WithdraWal symptoms, but because of their
`legal character and prescription by medical practitioners do
`not lead to the aforementioned described drug-related crimi
`nal activities. 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 programme is available.
`[0008] The standard drug used in drug substitution therapy
`programmes has for a long time been methadone. HoWever, in
`recent years the potential of other opioids as substitution
`drugs in substitution therapy has been recognised. A particu
`larly suitable drug for that purpose is the opioid buprenor
`phine, Which is a mixed opioid agonist/ antagonist.
`[0009] NoWadays, buprenorphine preparations are admin
`istered in drug substitution programmes in the form of a tablet
`for sublingual administration. One of the reasons that the
`tablets are 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.
`[0010] One example of sublingual tablets for drug substi
`tution therapy is the preparation Subutex® (being marketed
`in Germany by Essex Pharma).
`[0011] Nevertheless, drug addicts sometimes still try to
`divert these sublingual buprenorphine tablets by removing
`them from the mouth When the supervising healthcare pro
`fessional’s attention is directed to other activities. Later the
`tablets may be sold or the active agent buprenorphine iso
`lated/extracted to apply it parenterally.
`[0012] Another buprenorphine preparation aimed at pre
`venting 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 hydrochlo
`ride dihydrate. The presence of naloxone is intended to pre
`vent parenteral abuse of buprenorphine as parenteral co-ad
`ministration of buprenorphine and naloxone in e. g. an opioid
`dependent addict Will lead to serious WithdraWal symptoms.
`[0013] 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 buprenorphine
`preparation available Which is diversion and/or abuse-resis
`tant in cases Where the preparation is used for drug substitu
`tion therapy and Which could also provide e?icient analgesia
`in cases Where the preparation is administered to alleviate
`pain in a patient.
`
`OBJECT AND SUMMARY OF THE INVENTION
`
`[0014] It is an object of the present invention to provide an
`oral pharmaceutical dosage form of the active agent
`buprenorphine that 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
`buprenorphine that can be used for drug substitution therapy
`and/ or pain treatment.
`[0015] In one embodiment the 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 pharma
`ceutically acceptable salt thereof instantly upon or oral, pref
`erably sublingual, application of the dosage form. It is, hoW
`ever, understood that the invention and its various
`embodiments Which are set out beloW, can be extended to any
`opioid or analgesic Whose preferred route of admini stration is
`oral, preferably sublingual, as is the case for buprenorphine.
`[0016] An instant release of buprenorphine or a pharma
`ceutically acceptable salt thereof upon oral, preferably sub
`lingual, application means that substantially all of the
`buprenorphine or said pharmaceutically acceptable salt
`thereof Will be released Within less than three minutes, pref
`erably Within less than tWo minutes or 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 ?ve seconds after oral, pref
`erably sublingual, application of the dosage form. In one of
`the preferred embodiments these oral dosage forms Will com
`prise betWeen approximately 0.1 mg and approximately 16
`mg buprenorphine or the equivalent amounts of a pharmaceu
`tically acceptable salt thereof.
`
`TEVA EXHIBIT 1018
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 2010/0087470 A1
`
`Apr. 8, 2010
`
`[0017] In a further preferred embodiment these oral phar
`maceutical 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
`HCl being 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.
`[0018] Yet another preferred embodiment of the invention
`relates to oral pharmaceutical dosage forms Which may pro
`vide for the above-mentioned characteristics and/or an aver
`age Tmax of from approximately 45 to approximately 90
`minutes.
`[0019] In a particularly preferred embodiment the dosage
`forms Will additionally comprise an opioid antagonist, pref
`erably naloxone or a pharmaceutically acceptable salt
`thereof.
`[0020] In yet a further preferred embodiment, the pharma
`ceutical 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.
`[0021] One embodiment of the present invention also
`relates to oral pharmaceutical dosage forms, Which may have
`some or all of the aforementioned characteristics and Wherein
`the dosage form has a ?lm-like or Wafer-like shape.
`[0022] Another embodiment relates to a method of manu
`facturing the afore-mentioned described dosage forms.
`[0023] Embodiments of the present invention also relate to
`the use of the afore-described oral, preferably sublingual,
`pharmaceutical dosage forms in the manufacture of a medi
`cament for treating pain in a human or animal and/ or for drug
`substitution therapy in drug-dependent human subjects.
`[0024] One aspect of the invention also relates to a method
`of drug substitution therapy in drug-dependent human sub
`jects Wherein the aforementioned oral pharmaceutical dosage
`forms are administered to a drug-dependent subject in need
`thereof.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0025] From the prior art, sublingual tablets are knoWn
`under the trade names Subutex® or Suboxone® both of
`Which comprise the active agent buprenorphine hydrochlo
`ride for drug substitution therapy.
`[0026] The suitability of particularly buprenorphine for
`drug substitution therapy had been recognised early on in
`vieW of buprenorphine’s very long elimination half-life (re
`ported as approximately 20 to 37 hours), Which alloWs a
`reduced frequency of administration. As a 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.
`[0027] Furthermore, the
`sublingual absorption of
`buprenorphine has the advantage that an abuse by sWalloWing
`tablets of buprenorphine is less likely to occur. The tablets
`that are currently on the market in the form of Subutex® and
`Suboxone® preparations are both for sublingual administra
`tion and typically disintegrate over a time period of ?ve to ten
`minutes. HoWever, Within that time period the drug addict
`may be able to divert the tablet before subsequently either
`selling the tablets on the street or isolating the active agents
`therefrom.
`[0028] 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 sublin
`gual, administration of the drug.
`[0029] 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, bitar‘trate, phosphate,
`malate, maleate, hydrobromide, hydroiodide, fumarate, suc
`cinate salts and the like.
`[0030] A particularly preferred pharmaceutically accept
`able salt of buprenorphine is buprenorphine hydrochloride.
`[0031] The provision of a pharmaceutical dosage form
`comprising buprenorphine or a pharmaceutically acceptable
`salt thereof in eg ?lm-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.
`[0032] In the context of the present invention instant release
`means that substantially the Whole amount of the buprenor
`phine or the respective pharmaceutically acceptable salt
`thereof Will be released in less than ?ve minutes. Preferably,
`substantially all of the buprenorphine or its pharmaceutically
`acceptable salt thereof Will be released Within less than four,
`Within less than three, Within less than tWo and more prefer
`ably Within less than one minute.
`[0033] 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 sec
`onds. In an even more preferred embodiment, the term
`“instant release” means that substantially all of the buprenor
`phine Will be released from the dosage form Within less than
`?ve seconds or Within less than three seconds.
`[0034] The term “substantially all” means that approxi
`mately 95% of the drug Will have been released.
`[0035] The term “approximately” in the context of the
`present invention describes a deviation from the indicated
`value of 10% and preferably of 5%.
`[0036] Such e?icient 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.
`[0037] 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 and particularly the sublin
`gual mucosa.
`[0038] These pharmaceutical dosage forms and formula
`tion principles are Well knoWn to the person skilled in the art
`and Will be described in more detail beloW.
`[0039] 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 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.
`[0040] The oral pharmaceutical dosage forms in accor
`dance With the invention may have the further characteristic
`
`TEVA EXHIBIT 1018
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 2010/0087470 A1
`
`Apr. 8, 2010
`
`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.
`[0041] In the case of a dose of 8 mg buprenorphine hydro
`chloride 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 hydrochlo
`ride being administered.
`[0042] In case of a dose of 16 mg buprenorphine hydro
`chloride 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.
`[0043] The AUCO_48 (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><ng/ml. In a preferred embodi
`ment the AUCO_48 may be approximately 12 to 13 hours><ng/
`ml. In the case of 8 mg buprenorphine hydrochloride being
`administered the AUCO_48 may be approximately in the range
`of 15 to 25 hours><ng/ml. In a preferred embodiment the
`AUCO_48 in this case may be betWeen approximately 20 to 22
`hours><ng/ml. In the case of 16 mg buprenorphine hydrochlo
`ride being administered, the AUCO_48 may be in the range of
`25 to 40 hours ><ng/ml. In a preferred embodiment the AUCO_
`48 in this case may be in the range of approximately 30 to 35
`hours><ng/ml.
`[0044] The average Tmax values for such preparations Will
`preferably be from approximately 45 to approximately 90
`minutes.
`[0045] It is understood that the aforementioned pharmaco
`kinetic parameters Cmax and AUCO_48 are average values that
`are obtained by measuring the blood plasma levels in a group
`of eight to approximately tWenty-four patients. These patients
`Will be selected according to inclusion and exclusion criteria,
`as they are common for drug substitution programmes. It is
`understood that such patients typically Will be of average
`Weight and Caucasian origin.
`[0046] The pharmaceutical do sage form in accordance With
`the invention Will be administered such that the maximal
`dosage per day is 32 mg of buprenorphine. Once a patient is
`enrolled in substitution therapy, the initial dosage Will be
`typically betWeen 2 mg to 4 mg of buprenorphine. The for
`mulations may be administered once a day, every tWo days,
`preferably every three days or even less frequently.
`[0047] In a preferred embodiment, the oral dosage forms of
`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, norb
`inaltorphimine, naltrindol, 6-[3-naloxol and 6-[3-naltrexol or
`the pharmaceutically acceptable salts thereof.
`[0048] Especially preferred antagonists comprise naltrex
`one, nalmefene and naloxone. Speci?cally preferred as an
`antagonist is naloxone and its hydrochloride salt.
`[0049] 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.
`
`[0050] A particularly preferred antagonist is naloxone. Of
`the naloxone salts, naloxone hydrochloride dihydrate may be
`particularly preferable in combination With buprenorphine
`hydrochloride.
`[0051] 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 pre
`ferred.
`[0052] 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 nalox
`one. 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 eg 2 mg naloxone hydrochloride.
`[0053] A particularly preferred embodiment thus 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 seconds after sublingual application of the dos
`age form. In addition, the dosage forms may provide the
`preferred values of the aforementioned pharmacokinetic
`parameters Cm“, and AUCO_48.
`[0054] Thus, the person skilled in the art Will have to ensure
`that indeed an oral dosage form is used Which is able to alloW
`for incorporation of su?icient amounts of buprenorphine and
`preferably also of naloxone and Which at the same time dis
`integrates rapidly enough to release the active agents
`instantly.
`[0055] In one embodiment one may use non-gelatin ?lm
`materials, eg ?lms of modi?ed cellulose materials as dosage
`forms. In this case, buprenorphine and optionally opioid
`antagonists such as naloxone are incorporated into the ?lm
`matrix and ?lms thus prepared may be administered orally.
`[0056] In accordance With this aspect of the invention, the
`active ingredients may be dissolved in a hydrophilic, organic
`system to form a homogenous solution or dispersion. The
`solution or dispersion can then be applied to one or more
`surfaces of a non-gelatin polymeric ?lm, eg a dry cellulose
`ether ?lm, resulting in the active ingredient(s) and/or liquid
`carrier phase being transported through the surface of the
`“dry” ?lm resulting in a neW ?lm composition.
`[0057] The ?lm 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 ?lm
`substrate may liquefy or dissolve partly or fully during the
`incorporation process, but nevertheless ?nally forming a
`single discrete ?lm, after curing. Films according to 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 ?lm bases
`include
`e.g.
`hydroxypropylmethylcellulose (HPMC),
`hydroxypropylcellulose (HPC), hydroxyethylmethylcellu
`lose (HEMC), hydroxyethylcellulose (HEC), methylcellu
`lose (MC), carboxymethylcellulose (CMC) and salts and
`derivates of all of the aforesaid materials. A particularly suit
`able cellulose ether for forming the ?lm is HPMC.
`
`TEVA EXHIBIT 1018
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`

`
`US 2010/0087470 A1
`
`Apr. 8, 2010
`
`[0058] Optional ingredients may be added including colo
`rants, emulsi?ers, humectants, and anti-blocking agents.
`[0059] Once one has a ?lm 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 ?lm. Appropriate means of liquid
`application onto the ?lm substrate include extrusion, roller
`application, pouring, spraying, brush painting or Whipping.
`Further details of the preparation of such ?lms can be taken
`eg from WO 2005/079750 A2 Which is incorporated by
`reference hereWith.
`[0060] Another possible technology in order to provide the
`afore-described pharmaceutical dosage forms of buprenor
`phine and preferably naloxone is described in WO
`03/ 030883. In this latter embodiment of the present invention,
`a thin ?lm drug delivery composition includes (i) a ?oWable
`Water-soluble ?lm-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 ?oWable
`Water-soluble ?lm-forming matrix together With the active
`agent(s) is formable into a dry ?lm of less than about 380
`microns in thickness, for example less than about 250
`microns in thickness.
`[0061] The matrix may be a cellulosic material, a gum, a
`protein, a starch, a glucan and combinations thereof. For
`example one may use the already aforementioned methylcel
`lulose, HMC, HEC, HC, HPC, HPMC, HMPC, gum Arabic,
`xanthan gum etc. The ?lms are prepared according to stan
`dard technology and the active agents are displaced thereon
`and therein as described in WO 03/030883.
`[0062] Yet another interesting technology relates to imme
`diate release drug delivery forms as described in WO
`99/17744, Which is also incorporated by reference herein as
`far as it describes fast releasing oral dosage forms. The person
`skilled in the art Will understand that the processes and do sage
`forms in WO 99/ 17744 may be used to obtain the aforemen
`tioned described pharmaceutical dosage forms of buprenor
`phine and preferably also naloxone.
`[0063] One may of course also use fast disintegrating tab
`lets that disintegrate upon contacting the saliva, e.g. under the
`tongue, folloWing oral administration. Such fast-disintegrat
`ing tablets are described eg in WO 99/44580 and are Well
`knoWn to the person skilled in the art.
`[0064] A particularly interesting technology for fast-re
`leasing dosage forms that may be used for the purpose of the
`present invention to provide an oral do sage form of buprenor
`phine and preferably an opioid antagonist such as naloxone
`can be taken from WO 96/26720.
`[0065] Therein it is described hoW the active agent sel
`egiline 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. Pat. No. 5,120,549, US. Pat. No. 5,079,018, WO
`93/12769, US. Pat. No. 5,298,261 and WO 91/04757.
`[0066] 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 UK patent
`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 sub
`
`liming solvent from a composition in the solid state, that
`composition comprising the active ingredient and a solution
`of the carrier in a solvent.
`[0067] 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.
`[0068] The composition Will preferably contain in addition
`to the active ingredient, matrix forming agents and secondary
`components.
`[0069] Matrix forming agents suitable for use in this aspect
`of the present invention include materials derived from ani
`mal or vegetable proteins, such as gelatins, dextrins and soy,
`Wheat and psyllium seed proteins, gums such as acacia, guar,
`agar, and xanthan, polysaccharides, alginates, carboxymeth
`ylcelluloses, carrageenans, dextrans, pectins, synthetic poly
`mers such as polyvinylpyrrolidone, and polypeptide/protein
`or polysaccharide complexes such as gelatin-acacia com
`plexes.
`[0070] 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 cyclo
`dextrin; inorganic salts such as sodium phosphate, sodium
`chloride and aluminium silicates; and amino acids having
`from 2 to 12 carbon atoms such as a glycine, L-alanine,
`L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-iso
`leucine, L-leucine and L-phenylalanine.
`[0071] One or more matrix forming agents may be incor
`porated into the solution or suspension prior to solidi?cation.
`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.
`[0072] Secondary components such as preservatives, anti
`oxidants, surfactants, viscosity enhancers, colouring agents,
`?avouring agents, pH modi?ers, sWeeteners or taste-masking
`agents may also be incorporated into the composition. Suit
`able colouring agents include red, black and yelloW iron
`oxides. Suitable ?avouring agents include mint, raspberry,
`liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry
`and grape ?avours and combinations of these. Suitable pH
`modi?ers 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 microen
`capsulated actives.
`[0073] Such fast-dispersing dosage forms containing
`buprenorphine and preferably an opioid antagonist such as
`naloxone may be similarly obtained as described in GB
`1548022B or WO 96/26720, in particular Example 1 of the
`latter, Which are incorporated herein in their entirety.
`[0074] A particularly preferred embodiment of the present
`invention relates to dosage forms, Which are produced along
`the lines described in WO 03/070227 A1.
`[0075] This prior art reference describes taste-masked,
`?lm-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 ?lm-type or Wafer
`type medicinal preparations With the taste-masking being
`only an optional feature.
`[0076] Flat active agent carriers that have a ?lm-type or
`Wafer-type structure provide for various advantages. As a
`
`TEVA EXHIBIT 1018
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 2010/0087470 A1
`
`Apr. 8, 2010
`
`consequence of the loW thickness in comparison to the sur
`face area, there is only a short diffusion pathWay if such a
`dosage form is applied eg to the mucosa of the oral cavity.
`This typically leads to a very rapid release of the active agents
`Which can then be quickly, ef?ciently 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 ?at ?lm-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 formu
`lations of the prior art.
`[0077] Flat active agent carriers have been developed for
`different purposes. One of the 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 ?lm-type strand.
`[0078] One of 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
`homogenous thickness, density and Width. Thus, one can
`easily obtain a certain unit dosage by simply cutting the
`Wafer-like dosage form in to appropriately siZed pieces.
`[0079] Such ?lm-type or Wafer-type dosage forms in accor
`dance With the present invention are characterised in that they
`comprise a matrix Which is formed from at least one matrix
`forming polymer and in Which buprenorphine and preferably
`an opioid antagonist such as naloxone are dissolved or
`homogenously dispersed.
`[0080] The rapidly disintegrating matrix of the pharmaceu
`tical dosage forms in accordance With the invention com
`prises as one of its basic substances Water-soluble polymers
`or mixtures of such polymers. Preferably synthetic or par
`tially synthetic polymers or naturally occurring biopolymers
`are used Which can form ?lms and are Water-soluble. Particu
`larly suitable for this purpose are polymers Which may be
`selected from the group comprising cellulose derivatives,
`polyvinylalcohol, polyacrylates and polyvinylpyrrolidone.
`[0081] Within the cellulose derivatives, hydroxypropylm
`ethylcellulose, carboxymethylcellulose, sodium carboxym
`ethylcellulose, hydroxyethylcellulose, hydr