`
`(19) World Intellectual Pmperty Organization
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`Intemationai Bureau
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`(43) International Publication Date P (10) International Publication Number
`6 March 2008 (06.03.2008)
`W0 2003/025791 A1
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`(51) International Patent Classification:
`A61K 31/485 (2006.01)
`A6IK 9/20 (2006.01)
`A61P 25/04 (2006.01)
`A6IK 9/70 (2006.01)
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`(21) International Application Number:
`PCT/EP2007/058978
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`(22) International Filing Date: 29 August 2007 (29.08.2007)
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`(25) Filing Language:
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`(26) Publication Language:
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`English
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`English
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`(30) Priority Data:
`06l19839.6
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`30 August 2006 (30.08.2006)
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`EP
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`[US/US]; 25 Windrose Way, Greenwich, CT 06830 (US).
`WALDEN, Malcolm [GB/GB]; c/o Mundipharma Re-
`search Limited, Cambridge Science Park, Milton Road,
`Cambridge CB4 OGW (GB).
`
`(74) Agent: BUEHLER, Dirk; Elisenhof, Elisenstrasse 3,
`80335 Miinchen (DE).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS. JP. KE, KG, KM, KN, KP. KR, KZ, LA, LC, LK.
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`
`(71) Applicant (for all designated States except US): EURO-
`CELTIQUE S.A. [LU/LU]; 122, Boulevard de la Pétrusse,
`L-2330 Luxembourg (LU).
`
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TJ. TM. TN. TR. TT. TZ. UA. UG. US. UZ. VC. VN. ZA.
`H5/l, ZW.
`
`(72) Inventors; and
`(75) Inventor-sIAppllcants (for US only): OKSCHE, A]exan-
`der [DE/DE]; Birkenstr.
`22, 65550 Limburg (DE).
`HEATH, William [GB/GB]; c/o Napp Pharmaceuticals
`Limited, Cambridge Science Park, Milton Road, Cam-
`bridge, CB4 OGW (GB). HOLDEN, Timothy [GB/GB];
`c/0 Napp Pharmaceuticals Limited, Cambridge Sci-
`ence Park, Milton Road, Cambridge, CB4 OGW (GB).
`PRATER, Derek A. [GB/GB]; c/o Mundipharma Re-
`Published:
`search Limited. Cambridge Science Park, Milton Road,
`Cambridge, CB4 OGW (GB). SACKLER, Richard S. — with international search report
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM. KE. LS. MW. MZ. NA. SD. SL SZ. TZ. UG. ZM.
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(54) Title: BUPRENOPHINE-WAFER FOR DRUG SUBS'['I'I'UTION THERAPY
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`008/025791A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`(‘S (57) Abstract: 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
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`EURO—CELTIQUE S.A.
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`Our Reference: E 9665 / DB
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`Munich, 29 August 2007
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`122, Boulevard de la Pétrusse, 2330 Luxembourg, Luxembourg
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`The present invention relates to oral pharmaceutical dosage forms comprising buprenorphine
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`with the dosage form releasing buprenorphine instantly upon oral, preferably sublingual,
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`application of the dosage form. The present invention also relates to the use of such dosage
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`forms for treating pain in a human or animal or for drug substitution therapy in drug-
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`dependent human subjects.
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`Background of the Invention
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`Chronic pain, which may be due to idiopathic reasons, cancer or other diseases such as
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`rheumatism and arthritis, is typically treated with strong opioids.
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`Over the last decades prejudices in the medical community as to the use of strong opioids for
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`treating chronic pain in patients has significantly decreased. Many of the se prejudices were
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`due to some of the characteristics being inherent to opioids.
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`While opioids have always been known to be useful in pain treatment, they also display an
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`addictive potential in view of their euphorigenic activity. Thus, if opioids are taken by
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`healthy human subjects with a drug seeking behaviour they may lead to psychological as well
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`as physical dependence.
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`These usually undesired characteristics of opioids can however become important in certain
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`scenarios such as drug substitution therapies for drug addicts. One of the fundamental
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`problems of illicit drug abuse by drug addicts (“junkies”) who are dependent on the constant
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`intake of illegal drugs such as heroin is the drug—related criminal activities resorted to by such
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`addicts in order to raise enough money to fund their addiction. The constant pressures upon
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`addicts to procure money for buying drugs and the concomitant criminal activities have been
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`increasingly recognised as a major factor that counteracts efficient and long— lasting
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`withdrawal and abstinence from drugs.
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`Therefore, programmes have been developed, particularly in the United States and western
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`European countries, in which drug addicts are allowed to take prescription drugs under close
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`supervision of medical practitioners instead of illegal drugs such as street heroin.
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`The aim of drug substitution theory is thus to first enable addicts to lead a regular life by
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`administering legal drugs to prevent withdrawal symptoms, but because of their legal
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`character and prescription by medical practitioners do not lead to the aforementioned
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`described drug—related criminal activities. In a second and / or alternate step in the treatment
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`of drug addiction may be to slowly make the drug addict less dependent on the drug by
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`gradually reducing the dose of the substitution drug or to bridge the time until a therapy place
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`in a withdrawal programme is available.
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`The standard drug used in drug substitution therapy programmes has for a long time been
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`methadone. However, in recent years the potential of other opioids as substitution drugs in
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`substitution therapy has been recognised. A particularly suitable drug for that purpose is the
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`opioid buprenorphine, which is a mixed opioid agonist/antagonist.
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`Nowadays, buprenorphine preparations are administered in drug substitution programmes in
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`the form of 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
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`buprenorphine. Furthermore, if a patient swallows such tablets they will not provide
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`euphorigenic activity.
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`One example of sublingual tablets for drug substitution therapy is the preparation SubuteX®
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`(being marketed in Germany by Essex Pharrna).
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`Nevertheless, drug addicts sometimes still try to divert these sublingual buprenorphine tablets
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`by removing them from the mouth when the supervising healthcare professional’s attention is
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`directed to other activities. Later the tablets may be sold or the active agent buprenorphine
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`isolated/extracted to apply it parenterally.
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`Another buprenorphine preparation aimed at preventing this potential possibility of abuse has
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`recently gained administrative approval in the United States (SuboXone®). The SuboXone®
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`preparation comprises buprenorphine hydrochloride and the opioid antagonist naloxone
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`hydrochloride dihydrate. The presence of naloxone is intended to prevent parenteral abuse of
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`buprenorphine as parenteral co—administration of buprenorphine and naloxone in e. g. an
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`opioid—dependent addict will lead to serious withdrawal symptoms.
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`However, there remains a need for other diversion and / or abuse—resistant dosage forms of
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`buprenorphine, which can be used in drug substitution therapy as described above.
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`Additionally, it would be desirable to have a buprenorphine preparation available which is
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`diversion and / or abuse—resistant in cases where the preparation is used for drug substitution
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`therapy and which could also provide efficient analgesia in cases where the preparation is
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`administered to alleviate pain in a patient.
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`Object and Summary of the Invention
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`It is an object of the present invention to provide an oral pharmaceutical dosage form of the
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`active agent buprenorphine that is less prone to diversion and / or abuse in drug substitution
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`therapy. It is another object of the present invention to provide an oral dosage form of the
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`active agent buprenorphine that can be used for drug substitution therapy and/or pain
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`treatment.
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`In one embodiment the present invention relates to an oral pharmaceutical dosage form
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`comprising at least buprenorphine or a pharmaceutically acceptable salt thereof with a dosage
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`form releasing buprenorphine or said pharmaceutically acceptable salt thereof instantly upon
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`or oral, preferably sublingual, application of the dosage form. It is, however, understood that
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`the invention and its various embodiments which are set out below, can be extended to any
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`opioid or analgesic whose preferred route of administration is oral, prefereably sublingual, as
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`is the case for buprenorphine.
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`An instant release of buprenorphine or a pharmaceutically acceptable salt thereof upon oral,
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`preferably sublingual, application means that substantially all of the buprenorphine or said
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`pharmaceutically acceptable salt thereof will be released within less than three minutes,
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`preferably within less than two minutes or less than one minute. Even more preferably,
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`substantially all of the buprenorphine or said pharmaceutically acceptable salt thereof will be
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`released within less than thirty seconds, twenty seconds, ten seconds or even within less than
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`five seconds after oral, preferably sublingual, application of the dosage form. In one of the
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`preferred embodiments these oral dosage forms will comprise between approximately 0.1 mg
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`and approximately 16 mg buprenorphine or the equivalent amounts of a pharmaceutically
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`acceptable salt thereof.
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`In a further preferred embodiment these oral pharmaceutical dosage forms will achieve an
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`average Cmax of between 1.5 ng/ml and approximately 2.25 ng/ml in the case of a dose of 0.4
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`mg buprenorphine hydrochloride being administered. In the case of a dose of 8 mg
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`buprenorphine HC1 being administered, the Cmax will typically be between approximately 2.5
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`and 3.5 ng/ml and if a dose of 16 mg buprenorphine hydrochloride is administered the Cmax
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`will preferably be between 5.5 to 6.5 ng/ml.
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`Yet another preferred embodiment of the invention relates to oral pharmaceutical dosage
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`forms which may provide for the above—mentioned characteristics and/or an average Tmax of
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`from approximately 45 to approximately 90 minutes.
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`In a particularly preferred embodiment the dosage forms will additionally comprise an opioid
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`antagonist, preferably naloxone or a pharrnaceutically acceptable salt thereof.
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`In yet a further preferred embodiment, the pharmaceutical dosage form will comprise
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`buprenorphine and the opioid antagonist, which preferably is naloxone, in a weight ratio of
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`from approximately 1:1 to approximately 10:1.
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`One embodiment of the present invention also relates to oral pharmaceutical dosage forms,
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`which may have some or all of the aforementioned characteristics and wherein the dosage
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`form has a film— like or wafer— like shape.
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`Another embodiment relates to a method of manufacturing the afore— mentioned described
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`dosage forms.
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`Embodiments of the present invention also relate to the use of the afore—described oral,
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`preferably sublingual, pharmaceutical dosage forms in the manufacture of a medicament for
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`DRL - EXHIBIT 1005
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`DRL006
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`DRL - EXHIBIT 1005
`DRL006
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`WO 2008/025791
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`PCT/EP2007/058978
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`treating pain in a human or animal and/or for drug substitution therapy in drug—dependent
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`human subjects.
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`One aspect of the invention also relates to a method of drug substitution therapy in drug-
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`dependent human subjects wherein the aforementioned oral pharmaceutical dosage forms are
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`administered to a drug— dependent subject in need thereof.
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`Detailed description of the invention
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`From the prior art, sublingual tablets are known under the trade names SubuteX® or
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`SuboXone® both of which comprise the active agent buprenorphine hydrochloride for drug
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`substitution therapy.
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`The suitability of particularly buprenorphine for drug substitution therapy had been
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`recognised early on in view of buprenorphine’s very long elimination half— life (reported as
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`approximately 20 to 37 hours), which allows a reduced frequency of administration. As a
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`consequence drug addicts who participate in drug substitution therapy have to report less
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`frequently to the medical agency or healthcare professional supervising the substitution
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`programme.
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`Furthermore, the sublingual absorption of bup renorphine has the advantage that an abuse by
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`swallowing tablets of buprenorphine is less likely to occur. The tablets that are currently on
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`the market in the form of SubuteX® and SuboXone® preparations are both for sublingual
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`administration and typically disintegrate over a time period of five to ten minutes. However,
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`within that time period the drug addict may be able to divert the tablet before subsequently
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`either selling the tablets on the street or isolating the active agents therefrom.
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`DRL - EXHIBIT 1005
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`DRL007
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`DRL - EXHIBIT 1005
`DRL007
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`WO 2008/025791
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`PCT/EP2007/058978
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`In order to reduce of eliminate these problems, the present invention provides oral
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`pharmaceutical dosage forms which comprise the active agent buprenorphine and which
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`release buprenorphine instantly after oral, preferably sublingual, administration of the drug.
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`It is understood that if reference is made in the context of this invention to the term
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`“buprenorphine” this refers to the free base as well as to any pharmaceutically acceptable salt
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`thereof such as the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate,
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`phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate, succinate salts and the
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`like.
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`A particularly preferred pharmaceutically acceptable salt of buprenorphine is buprenorphine
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`hydrochloride.
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`The provision of a pharmaceutical dosage form comprising buprenorphine or a
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`pharmaceutically acceptable salt thereof in e.g. film— like or wafer—like shapes which allows
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`for instant release of the active agent upon oral, preferably sublingual, administration of the
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`dosage form should prevent the type of abuse resulting from illicit diversion of the tablets by
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`drug addicts participating in drug substitution therapy programmes.
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`In the context of the present invention instant release means that substantially the whole
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`amount of the buprenorphine or the respective pharmaceutically acceptable salt thereof will
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`be released in less than five minutes. Preferably, substantially all of the buprenorphine or its
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`pharmaceutically acceptable salt thereof will be released within less than four, within less
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`than three, within less than two and more preferably within less than one n1inute.
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`In a particularly preferred embodiment, instant release refers to the situation that substantially
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`all of the buprenorphine or the respective pharmaceutically acceptable salt thereof will be
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`released within less than thirty seconds, within less than twenty seconds, or within less than
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`DRL - EXHIBIT 1005
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`DRL008
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`DRL - EXHIBIT 1005
`DRL008
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`WO 2008/025791
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`PCT/EP2007/058978
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`ten seconds.
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`In an even more preferred embodiment, the term “instant release” means that
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`substantially all of the buprenorphine will be released from the dosage form within less than
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`five seconds or within less than three seconds.
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`The term “substantially all” means that approximately 95% of the drug will have been
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`released.
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`The term “approximately” in the context of the present invention describes a deviation from
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`the indicated value of 10% and preferably of 5%.
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`Such efficient release of the drug is hard to achieve with a sublingual tablet which generally
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`requires a greater amount of time to melt or to disintegrate.
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`Fast—dissolving or rapidly disintegrating dosage forms for other pharmaceutically active
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`compounds are known which disintegrate within seconds upon contact with the mucosal
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`saliva of the mouth and particularly the sublingual mucosa.
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`These pharmaceutical dosage forms and formulation principles are well known to the person
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`skilled in the art and will be described in more detail below.
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`As regards the dosage amount, the pharmaceutical compositions in accordance with the
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`present invention will typically comprise between approximately 0.1 mg and approximately
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`16 mg of buprenorphine or a pharmaceutically acceptable salt thereof such as buprenorphine
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`hydrochloride. Preferred dosage amounts will be in the range of between approximately 0.4
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`mg and approximately 12 mg or between approximately 2 mg and approximately 8 mg
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`buprenorphine or a pharmaceutically acceptable salt thereof.
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`DRL - EXHIBIT 1005
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`DRL009
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`DRL - EXHIBIT 1005
`DRL009
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`WO 2008/025791
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`PCT/EP2007/058978
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`The oral pharmaceutical dosage forms in accordance with the invention may have the further
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`characteristic of providing a Cmax of approximately 1.5 to 2.5 ng/n1l in the case of a dose of 4
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`mg buprenorphine hydrochloride being administered. A preferred Cmax in the case of a dose
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`of 4 mg of buprenorphine hydrochloride being administered may be approximately between
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`1.7 ng/ml to 2 ng/n1l.
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`In the case of a dose of 8 mg buprenorphine hydrochloride being administered, the Cmax may
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`be approximately between 2.5 and 3.5 ng/ml. In a preferred embodiment the Cmax may be
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`approximately between 2.75 ng/ml and 3.25 ng/ml in the case of a dose of 8 mg
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`buprenorphine hydrochloride being administered.
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`In case of a dose of 16 mg buprenorphine hydrochloride being administered, the Cmax may
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`preferably be in the range of approximately 5 to 7 ng/ml.
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`In a preferred embodiment the Cmax
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`may be between 5.5 and 6.5 ng/ml if 16 mg of buprenorphine hydrochloride are administered.
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`The AUCo-4s (i.e. the Area under the Curve for 48 hours after administration) may in the case
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`of administration of 4 mg of buprenorphine hydrochloride be in the range of approximately 10
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`to 15 hours x ng/ml.
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`In a preferred embodiment the AUC0_4g may be approximately 12 to 13
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`hours x ng/n1l. In the case of 8 mg buprenorphine hydrochloride being administered the
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`AUC()_4g may be approximately in the range of 15 to 25 hours x ng/ml. In a preferred
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`embodiment the AUC()_4g in this case may be between approximately 20 to 22 hours x ng/n1l.
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`In the case of 16 mg buprenorphine hydrochloride being administered, the AUC0_4g may be in
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`the range of 25 to 40 hours x ng/ml. In a preferred embodiment the AUC0_4g in this case may
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`be in the range of approximately 30 to 35 hours x ng/n1l.
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`The average Tmax values for such preparations will preferably be from approximately 45 to
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`approximately 90 minutes.
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`DRL - EXHIBIT 1005
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`DRL010
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`DRL - EXHIBIT 1005
`DRL010
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`WO 2008/025791
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`PCT/EP2007/058978
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`-10-
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`It is understood that the aforementioned pharmacokinetic parameters Cmax and AUC0_4g are
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`average values that are obtained by measuring the blood plasma levels in a group of eight to
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`approximately twenty— four patients. These patients will be selected according to inclusion
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`and exclusion criteria, as they are common for drug substitution programmes. It is understood
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`that such patients typically will be of average weight and Caucasian origin.
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`The pharmaceutical dosage form in accordance with the invention will be administered such
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`that the maximal dosage per day is 32 mg of buprenorphine. Once a patient is enrolled in
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`substitution therapy, the initial dosage will be typically between 2 mg to 4 mg of
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`buprenorphine. The formulations may be administered once a day, every two days, preferably
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`every three days or even less fequently.
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`In a preferred embodiment, the oral dosage forms of the invention will additionally comprise
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`an opioid antagonist. Such antagonists may be selected from the group comprising
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`naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone,
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`ketylcyclazocine, norbinaltorphimine, naltrindol, 6—B—naloxol and 6—B—naltrexol or the
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`pharmaceutically acceptable salts thereof.
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`Especially preferred antagonists comprise naltrexone, nalmefene and naloxone. Specifically
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`preferred as an antagonist is naloxone and its hydrochloride salt.
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`It is understood, that if in the context of the present invention reference is made to an opioid
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`antagonist, this also not only refers to the free base but also to pharmaceutically acceptable
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`salts thereof such as those mentioned for buprenorphine.
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`A particularly preferred antagonist is naloxone. Of the naloxone salts, naloxone
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`hydrochloride dihydrate may be particularly preferable in combination with buprenorphine
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`hydrochloride.
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`
`DRL - EXHIBIT 1005
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`DRL011
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`DRL - EXHIBIT 1005
`DRL011
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`WO 2008/025791
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`PCT/EP2007/058978
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`-11-
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`The pharmaceutical dosage forms in accordance with the invention will comprise
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`buprenorphine and the antagonist, which preferably is naloXone, in a weight ratio of from 1:1
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`to 10:1. A weight ratio of from 2:1 to 8:1 may be preferred, with a weight ratio of 4:1 being
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`particularly preferred.
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`Thus, if an oral dosage form in accordance with the present invention for example comprises
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`2 mg buprenorphine hydrochloride it will comprise approximately 0.5 mg naloxone. If the
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`dosage form comprises 0.4 mg buprenorphine hydrochloride, it will comprise 0.1 mg
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`naloxone and if the dosage form comprises 8 mg buprenorphine hydrochloride it will
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`comprise e.g. 2 mg naloxone hydrochloride.
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`A particularly preferred embodiment thus relates to an oral dosage form comprising
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`buprenorphine, preferably buprenorphine hydrochloride, and naloXone, preferably naloxone
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`hydrochloride, wherein the dosage form releases said active agents within less than one
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`minute, preferably within less than thirty seconds and more preferably within less than ten
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`seconds after sublingual application of the dosage form. In addition, the dosage forms may
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`provide the preferred values of the aforementioned pharrnacokinetic parameters Cmax, and
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`AUC0 -43 .
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`Thus, the person skilled in the art will have to ensure that indeed an oral dosage form is used
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`which is able to allow for incorporation of sufficient amounts of buprenorphine and
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`preferably also of naloxone and which at the same time disintegrates rapidly enough to release
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`the active agents instantly.
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`In one embodiment one may use non gelatin film materials, e.g. films of modified cellulose
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`materials as dosage forms. In this case, buprenorphine and optionally opioid antagonists such
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`DRL - EXHIBIT 1005
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`DRL012
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`DRL - EXHIBIT 1005
`DRL012
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`WO 2008/025791
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`PCT/EP2007/058978
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`-12-
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`as naloxone are incorporated into the film matrix and films thus prepared may be
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`administered orally.
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`In accordance with this aspect of the invention, the active ingredients may be dissolved in a
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`hydrophilic, organic system to form a homogenous solution or dispersion. The solution or
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`dispersion can then be applied to one or more surfaces of a non— gelatin polymeric film, e.g. a
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`dry cellulose ether film, resulting in the active ingredient(s) and/or liquid carrier phase being
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`transported through the surface of the “dry” film resulting in a new film composition.
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`The film substrate may remain completely intact or relatively physically unchanged
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`immediately following the incorporation process. It can, however, be converted to any size or
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`shape of unit dosage form. Alternatively, the film substrate may liquefy or dissolve partly or
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`fully during the incorporation process, but nevertheless finally forn1ing a single discrete film,
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`after curing. Films according to this aspect of the invention are typically made up of one or
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`more soluble polymer or polymers which will otherwise degrade at the intended site of release
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`after administration in the mouth, e.g. sublingual administration, in order to provide the
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`instant release of the active agents. Suitable cellulose ether film bases include e. g.
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`hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
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`hydroxyethylmethylcellulose (HEMC), hydroxyethylcellulose (HEC), methylcellulose (MC),
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`carboxymethylcellulose (CMC) and salts and derivates of all of the aforesaid materials. A
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`particularly suitable cellulose ether for forming the film is HPMC.
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`Optional ingredients may be added including colorants, emulsifiers, humectants, and anti-
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`blocking agents.
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`Once one has a film being based on a cellulose ether available, in a next step the active
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`ingredient(s) will be applied in the form of a liquid to the film. Appropriate means of liquid
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`application onto the film substrate include extrusion, roller application, pouring, spraying,
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`DRL - EXHIBIT 1005
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`DRL013
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`DRL - EXHIBIT 1005
`DRL013
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`WO 2008/025791
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`PCT/EP2007/058978
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`-13-
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`brush painting or whipping. Further details of the preparation of such films can be taken e.g.
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`from WO 2005/079750 A2 which is incorporated by reference herewith.
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`Another possible technology in order to provide the afore— described pharmaceutical dosage
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`forms of buprenorphine and preferably naloxone is described in WO 03/030883.
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`In this latter
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`embodiment of the present invention, a thin film drug delivery composition includes (i) a
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`flowabl