throbber
(12) IN'I'ERNA'I'IONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Pmperty Organization
`
`Intemationai Bureau
`
`(43) International Publication Date P (10) International Publication Number
`6 March 2008 (06.03.2008)
`W0 2003/025791 A1
`
`(51) International Patent Classification:
`A61K 31/485 (2006.01)
`A6IK 9/20 (2006.01)
`A61P 25/04 (2006.01)
`A6IK 9/70 (2006.01)
`
`(21) International Application Number:
`PCT/EP2007/058978
`
`(22) International Filing Date: 29 August 2007 (29.08.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`06l19839.6
`
`30 August 2006 (30.08.2006)
`
`EP
`
`[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
`
`
`
`008/025791A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`(‘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
`subjects.
`
`W0
`
`DRL - EXHIBIT 1005
`
`DRL001
`
`DRL - EXHIBIT 1005
`DRL001
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`EURO—CELTIQUE S.A.
`
`
`
`
`Our Reference: E 9665 / DB
`
`
`
`
`
`
`Munich, 29 August 2007
`
`
`
`
`EURO— CELTIQUE S .A.
`
`
`
`
`
`
`
`
`
`
`122, Boulevard de la Pétrusse, 2330 Luxembourg, Luxembourg
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention relates to oral pharmaceutical dosage forms comprising buprenorphine
`
`
`
`
`
`
`
`
`
`
`
`
`
`with the dosage form releasing 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Chronic pain, which may be due to idiopathic reasons, cancer or other diseases such as
`
`
`
`
`
`
`
`
`
`rheumatism and arthritis, is typically treated with strong opioids.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Over the last decades prejudices in the medical community as to the use of strong opioids for
`
`
`
`
`
`
`
`
`
`
`
`
`
`treating chronic pain in patients has significantly decreased. Many of the se prejudices were
`
`
`
`
`
`
`
`
`
`
`
`
`due to some of the characteristics being inherent to opioids.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 dependence.
`
`
`
`E 9047 / DB:sch
`
`
`
`
`
`DRL - EXHIBIT 1005
`
`DRL002
`
`
`
`DRL - EXHIBIT 1005
`DRL002
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`These usually undesired characteristics of opioids can however become important in certain
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`scenarios such as drug substitution therapies for drug addicts. One of the fundamental
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`problems of illicit drug abuse by drug addicts (“junkies”) who are dependent on the constant
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`intake of illegal drugs such as heroin is the drug—related criminal activities resorted to by such
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`addicts in order to raise enough money to fund their addiction. The constant pressures upon
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`addicts to procure money for buying drugs and the concomitant criminal activities have been
`
`
`
`
`
`
`
`
`
`
`
`
`
`increasingly recognised as a major factor that counteracts efficient and long— lasting
`
`
`
`
`
`
`
`withdrawal and abstinence from drugs.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Therefore, programmes have been developed, particularly in the United States and western
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`European countries, in which drug addicts are allowed to take prescription drugs 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 because of their legal
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`character and prescription by medical practitioners do not lead to the aforementioned
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`described drug—related criminal 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 particularly suitable drug for that purpose is the
`
`
`
`
`
`
`
`
`
`
`opioid buprenorphine, which is a mixed opioid agonist/antagonist.
`
`
`
`
`
`
`
`
`
`
`
`
`Nowadays, buprenorphine preparations are administered in drug substitution programmes in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the form of a tablet for sublingual administration. One of the reasons that the tablets are
`
`
`
`DRL - EXHIBIT 1005
`
`DRL003
`
`
`
`DRL - EXHIBIT 1005
`DRL003
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 Pharrna).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Nevertheless, drug addicts sometimes still try to divert these sublingual buprenorphine tablets
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`by removing them from the mouth when the supervising healthcare professional’s attention is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`directed to other activities. Later the tablets may be sold or the active agent buprenorphine
`
`
`
`
`
`
`
`isolated/extracted to apply it parenterally.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Another buprenorphine preparation aimed at preventing this potential possibility of abuse has
`
`
`
`
`
`
`
`
`
`
`
`
`
`recently gained administrative approval in the United States (SuboXone®). The SuboXone®
`
`
`
`
`
`
`
`
`
`
`
`preparation comprises buprenorphine hydrochloride and the opioid antagonist naloxone
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hydrochloride dihydrate. The presence of naloxone is intended to prevent parenteral abuse of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`buprenorphine as parenteral co—administration of buprenorphine and naloxone in e. g. an
`
`
`
`
`
`
`
`
`opioid—dependent addict will lead to serious withdrawal symptoms.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`However, there remains a need for other diversion and / or abuse—resistant dosage forms of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`buprenorphine, which can be used in drug substitution therapy as described above.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Additionally, it would be desirable to have a buprenorphine preparation available which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`diversion and / or abuse—resistant in cases where the preparation is used for drug substitution
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`therapy and which could also provide efficient analgesia in cases where the preparation is
`
`
`
`
`
`
`
`
`administered to alleviate pain in a patient.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL004
`
`
`
`DRL - EXHIBIT 1005
`DRL004
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`Object and Summary of the Invention
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 pharmaceutically acceptable salt thereof instantly upon
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or oral, preferably sublingual, application of the dosage form. It is, however, understood that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the invention and its various embodiments 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`An instant release of buprenorphine or a pharmaceutically acceptable salt thereof upon oral,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`preferably sublingual, application means that substantially all of the buprenorphine or said
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable salt 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 buprenorphine or said pharmaceutically acceptable salt thereof will be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`released within less than thirty seconds, twenty seconds, ten seconds or even within less than
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`five seconds after 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 buprenorphine or the equivalent amounts of a pharmaceutically
`
`
`
`
`
`acceptable salt thereof.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL005
`
`
`
`DRL - EXHIBIT 1005
`DRL005
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In a further preferred embodiment these oral pharmaceutical dosage forms will achieve an
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`average Cmax of between 1.5 ng/ml and approximately 2.25 ng/ml in the case of a dose of 0.4
`
`
`
`
`
`
`
`
`
`
`
`
`mg buprenorphine hydrochloride being administered. In the case of a dose of 8 mg
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`buprenorphine HC1 being administered, the 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 Tmax of
`
`
`
`
`
`
`
`
`
`from approximately 45 to approximately 90 minutes.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In a particularly preferred embodiment the dosage forms will additionally comprise an opioid
`
`
`
`
`
`
`
`
`
`
`antagonist, preferably naloxone or a pharrnaceutically 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 some or all of the aforementioned characteristics and wherein the dosage
`
`
`
`
`
`
`
`
`
`form has a film— like or wafer— like shape.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Another embodiment relates to a method of manufacturing the afore— mentioned described
`
`
`
`
`
`dosage forms.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 medicament for
`
`DRL - EXHIBIT 1005
`
`DRL006
`
`
`
`DRL - EXHIBIT 1005
`DRL006
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`treating pain in a human or animal and/or for drug substitution therapy in drug—dependent
`
`
`
`
`human subjects.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`One aspect of the invention also relates to a method of drug substitution therapy in drug-
`
`
`
`
`
`
`
`
`
`
`
`dependent human subjects wherein the aforementioned oral pharmaceutical dosage forms are
`
`
`
`
`
`
`
`
`
`
`administered to a drug— dependent subject in need thereof.
`
`
`
`
`
`
`
`Detailed description of the invention
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`From the prior art, sublingual tablets are known under the trade names SubuteX® or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SuboXone® both of which comprise the active agent buprenorphine hydrochloride for drug
`
`
`
`
`substitution therapy.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The suitability of particularly buprenorphine for drug substitution therapy had been
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`recognised early on in view of buprenorphine’s very long elimination half— life (reported as
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`approximately 20 to 37 hours), which allows a reduced frequency of administration. 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Furthermore, the sublingual absorption of bup renorphine 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administration and typically disintegrate over a time period of five 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.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL007
`
`
`
`DRL - EXHIBIT 1005
`DRL007
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In order to reduce of eliminate these problems, the present invention provides oral
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical dosage forms which comprise the active agent buprenorphine and which
`
`
`
`
`
`
`
`
`
`
`
`
`
`release buprenorphine instantly after oral, preferably sublingual, administration of the drug.
`
`
`
`It is understood that if reference is made in the context of this invention to the term
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“buprenorphine” this refers to the free base as well as to any pharmaceutically acceptable salt
`
`
`
`
`
`
`
`
`
`
`
`
`
`thereof such as the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate,
`
`
`
`
`
`
`
`
`
`
`
`
`phosphate, malate, 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 buprenorphine or a
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable salt thereof in e.g. film— like or wafer—like shapes which allows
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for instant release of the active agent 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 means that substantially the whole
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`amount of the buprenorphine or the respective pharmaceutically acceptable salt thereof will
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be released in less than five minutes. Preferably, substantially all of the buprenorphine or its
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable salt thereof will be released within less than four, within less
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`than three, within less than two and more preferably within less than one n1inute.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`DRL - EXHIBIT 1005
`
`DRL008
`
`
`
`DRL - EXHIBIT 1005
`DRL008
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`ten seconds.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In an even more preferred embodiment, the term “instant release” means that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`substantially all of the buprenorphine will be released from the dosage form within less than
`
`
`
`
`
`
`
`
`
`
`five seconds or within less than three seconds.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The term “substantially all” 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%.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Such efficient release of the drug is hard to achieve with a sublingual tablet which generally
`
`
`
`
`
`
`
`
`
`
`
`
`
`requires a greater amount of time to melt or to disintegrate.
`
`
`
`
`
`
`
`
`
`
`
`
`Fast—dissolving or rapidly disintegrating dosage forms for other pharmaceutically active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`compounds are known which disintegrate within seconds upon contact with the mucosal
`
`
`
`
`
`
`
`
`
`
`
`saliva of the mouth and particularly the sublingual mucosa.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`These pharmaceutical dosage forms and formulation principles are well known to the person
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`skilled in the art and will be described in more detail 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 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.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL009
`
`
`
`DRL - EXHIBIT 1005
`DRL009
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The oral pharmaceutical dosage forms in accordance with the invention may have the further
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`characteristic of providing a Cmax of approximately 1.5 to 2.5 ng/n1l 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/n1l.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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-4s (i.e. the Area under the Curve for 48 hours after administration) may in the case
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of administration of 4 mg of buprenorphine hydrochloride be in the range of approximately 10
`
`
`
`
`
`
`
`
`to 15 hours x ng/ml.
`
`
`
`
`
`
`
`
`
`
`
`
`In a preferred embodiment the AUC0_4g may be approximately 12 to 13
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hours x ng/n1l. In the case of 8 mg buprenorphine hydrochloride being administered the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`AUC()_4g may be approximately in the range of 15 to 25 hours x ng/ml. In a preferred
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`embodiment the AUC()_4g in this case may be between approximately 20 to 22 hours x ng/n1l.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In the case of 16 mg buprenorphine hydrochloride being administered, the AUC0_4g may be in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the range of 25 to 40 hours x ng/ml. In a preferred embodiment the AUC0_4g in this case may
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be in the range of approximately 30 to 35 hours x ng/n1l.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The average Tmax values for such preparations will preferably be from approximately 45 to
`
`
`
`approximately 90 minutes.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL010
`
`
`
`DRL - EXHIBIT 1005
`DRL010
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`-10-
`
`
`
`
`
`
`
`
`
`
`
`
`It is understood that the aforementioned pharmacokinetic parameters Cmax and AUC0_4g 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The pharmaceutical dosage 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 formulations may be administered once a day, every two days, preferably
`
`
`
`
`
`
`
`
`
`
`every three days or even less fequently.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In a preferred embodiment, the oral dosage forms of the invention will additionally comprise
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`an opioid antagonist. Such antagonists may be selected from the group comprising
`
`
`
`
`
`
`
`
`
`naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone,
`
`
`
`
`
`
`
`
`
`
`ketylcyclazocine, norbinaltorphimine, naltrindol, 6—B—naloxol and 6—B—naltrexol or the
`
`
`
`
`
`
`pharmaceutically acceptable salts thereof.
`
`
`
`
`
`
`
`
`
`
`
`Especially preferred antagonists comprise naltrexone, nalmefene and naloxone. Specifically
`
`
`
`
`
`
`
`
`
`
`
`
`preferred as an antagonist is naloxone and its hydrochloride salt.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 naloxone salts, naloxone
`
`
`
`
`
`
`
`
`
`
`
`
`hydrochloride dihydrate may be particularly preferable in combination with buprenorphine
`
`
`
`hydrochloride.
`
`
`
`DRL - EXHIBIT 1005
`
`DRL011
`
`
`
`DRL - EXHIBIT 1005
`DRL011
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`
`-11-
`
`
`
`
`
`
`
`
`
`
`
`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 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 dosage form. In addition, the dosage forms may
`
`
`
`
`
`
`
`
`
`
`
`
`
`provide the preferred values of the aforementioned pharrnacokinetic parameters Cmax, and
`
`
`
`
`AUC0 -43 .
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 sufficient amounts of buprenorphine and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`preferably also of naloxone and which at the same time disintegrates rapidly enough to release
`
`
`
`
`
`
`the active agents instantly.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In one embodiment one may use non gelatin film materials, e.g. films of modified cellulose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`materials as dosage forms. In this case, buprenorphine and optionally opioid antagonists such
`
`
`
`DRL - EXHIBIT 1005
`
`DRL012
`
`
`
`DRL - EXHIBIT 1005
`DRL012
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`-12-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 homogenous solution or dispersion. The solution or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dispersion can then be applied to one or more surfaces of a non— gelatin polymeric film, e.g. a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dry cellulose ether film, resulting in the active ingredient(s) and/or liquid carrier phase being
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`transported through the surface of the “dry” film resulting in a new film composition.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The film substrate may remain completely intact or relatively physically unchanged
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`immediately following the incorporation process. It can, however, be converted to any size or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`shape of unit dosage form. Alternatively, the film substrate may liquefy or dissolve partly or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`fully during the incorporation process, but nevertheless finally forn1ing a single discrete film,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 film bases include e. g.
`
`
`
`
`
`
`hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
`
`
`
`
`
`
`
`
`hydroxyethylmethylcellulose (HEMC), hydroxyethylcellulose (HEC), methylcellulose (MC),
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`carboxymethylcellulose (CMC) and salts and derivates of all of the aforesaid materials. A
`
`
`
`
`
`
`
`
`
`
`
`
`particularly suitable cellulose ether for forming the film is HPMC.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Optional ingredients may be added including colorants, emulsifiers, humectants, and anti-
`
`
`blocking agents.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Once one has a film being based on a cellulose ether available, in a next step the active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ingredient(s) will be applied in the form of a liquid to the film. Appropriate means of liquid
`
`
`
`
`
`
`
`
`
`
`
`
`
`application onto the film substrate include extrusion, roller application, pouring, spraying,
`
`
`
`DRL - EXHIBIT 1005
`
`DRL013
`
`
`
`DRL - EXHIBIT 1005
`DRL013
`
`

`
`
`WO 2008/025791
`
`
`
`PCT/EP2007/058978
`
`
`
`
`
`-13-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Another possible 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`flowabl

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket