(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization _
`International Bureau
`
`' |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`
`
`(43) International Publication Date
`6 March 2008 (06.03.2008)
`
`(10) International Publication Number
`
`WO 2008/025791 A1
`
`(51) International Patent Classification:
`A61K 31/485 (2006.01)
`A61K 9/20 (2006.01)
`A6IP 25/04 (2006.01)
`A61K 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:
`061198396
`
`30 August 2006 (30.08.2006)
`
`EP
`
`(71) Applicant (for all designated States except US): EURO-
`CELTIQUE S.A. [LU/LU]; 122, Boulevard de la Pétrusse,
`L—2330 Luxembourg (LU).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): OKSCHE, Alexan-
`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/o Napp Pharmaceuticals Limited, Cambridge Sci—
`ence Park, Milton Road, Cambridge, CB4 OGW (GB).
`PRATER, Derek A. [GB/GB]; c/o Mundipharma Re—
`search Limited, Cambridge Science Park, Milton Road,
`Cambridge, CB4 OGW (GB). SACKLER, Richard S.
`
`(74)
`
`(81)
`
`[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).
`
`Agent: BUEHLER, Dirk; Elisenhof, Elisenstrasse 3,
`80335 Miinchen (DE).
`
`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,
`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,
`ZM, ZW.
`
`(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).
`
`Published:
`
`with international search report
`
`(54) Title: BUPRENOPHINE—WAFER FOR DRUG SUBSTITUTION THERAPY
`
`
`
`008/025791A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`N (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
`
`W0 subjects.
`
`Page 1
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`BDSI EXHIBIT 1018
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`Page 1
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`

`

`WO 2008/025791
`
`PCT/EP2007/058978
`
`EURO-CELTIQUE S.A.
`Our Reference: E 9665 / DB
`
`Munich, 29 August 2007
`
`EURO-CELTIQUE SA.
`
`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 / Dstch
`
`Page 2
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`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
`
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`formulated for sublingual administration is that this the preferred route of administration for
`
`buprenorphine. Furthermore, if a patient swallows such tablets they will not provide
`
`euphorigenic activity.
`
`One example of sublingual tablets for drug substitution therapy is the preparation SubuteX®
`
`(being marketed in Germany by Essex Pharma).
`
`Nevertheless, drug addicts 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.
`
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`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.
`
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`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 pharmaceutically acceptable salt thereof.
`
`In yet a further preferred embodiment, the pharmaceutical dosage form will comprise
`
`buprenorphine and the opioid antagonist, which preferably is naloxone, in a weight ratio of
`
`from approximately 1:1 to approximately 10:1.
`
`One embodiment of the present invention also relates to oral pharmaceutical dosage forms,
`
`which may have 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
`
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`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.
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`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 minute.
`
`In a particularly preferred embodiment, instant release refers to the situation that substantially
`
`all of the buprenorphine or the respective pharmaceutically acceptable salt thereof will be
`
`released within less than thirty seconds, within less than twenty seconds, or within less than
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`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.
`
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`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/ml in the case of a dose of 4
`
`mg buprenorphine hydrochloride being administered. A preferred Cmax in the case of a dose
`
`of 4 mg of buprenorphine hydrochloride being administered may be approximately between
`
`1.7 ng/ml to 2 ng/ml.
`
`In the case of a dose of 8 mg buprenorphine hydrochloride being administered, the Cmax may
`
`be approximately between 2.5 and 3.5 ng/ml. In a preferred embodiment the Cmax may be
`
`approximately between 2.75 ng/ml and 3.25 ng/ml in the case of a dose of 8 mg
`
`buprenorphine hydrochloride being administered.
`
`In case of a dose of 16 mg buprenorphine hydrochloride being administered, the Cmax may
`
`preferably be in the range of approximately 5 to 7 ng/ml.
`
`In a preferred embodiment the Cmax
`
`may be between 5.5 and 6.5 ng/ml if 16 mg of buprenorphine hydrochloride are administered.
`
`The AUCo-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_48 may be approximately 12 to 13
`
`hours x ng/ml. In the case of 8 mg buprenorphine hydrochloride being administered the
`
`AUC0_48 may be approximately in the range of 15 to 25 hours x ng/ml. In a preferred
`
`embodiment the AUC0_48 in this case may be between approximately 20 to 22 hours x ng/ml.
`
`In the case of 16 mg buprenorphine hydrochloride being administered, the AUC0_48 may be in
`
`the range of 25 to 40 hours x ng/ml. In a preferred embodiment the AUC0_48 in this case may
`
`be in the range of approximately 30 to 35 hours x ng/ml.
`
`The average Tmax values for such preparations will preferably be from approximately 45 to
`
`approximately 90 minutes.
`
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`-10-
`
`It is understood that the aforementioned pharmacokinetic parameters Cmax and AUC0_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.
`
`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.
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`-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 pharmacokinetic parameters Cmax, and
`
`AUC() -48 .
`
`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
`
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`-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 forming 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,
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`-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 WC 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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`flowable water— soluble film forming matrix and (ii) the active agent(s) uniformly stationed
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`therein. Optionally a taste— masking agent may be coated or intimately associate with the
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`active agent(s) to provide taste masking of the active agent(s). The flowable water— soluble
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`film forming matrix together with the active agent(s) is formable into a dry film of less than
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`about 380 microns in thickness, for example less than about 250 microns in thickness.
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`The matrix may be a cellulosic material, a gum, a protein, a starch, a glucan and combinations
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`thereof. For example one may use the already aforementioned methylcellulose, HMC, HEC,
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`HC, HPC, HPMC, HMPC, gum Arabic, xanthan gum etc. The films are prepared according
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`to standard technology and the active agents are displaced thereon and therein as described in
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`WC 03/030883.
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`Yet another interesting technology relates to immediate release drug delivery forms as
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`described in W0 99/ 17744, which is also incorporated by reference herein as far as it
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`describes fast releasing oral dosage forms. The person skilled in the art will understand that
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`the processes and dosage forms in W0 99/ 17744 may be used to obtain the aforementioned
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`described pharmaceutical dosage forms of buprenorphine and preferably also naloxone.
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`One may of course also use fast disintegrating tablets that disintegrate upon contacting the
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`saliva, e.g. under the tongue, following oral administration. Such fast—disintegrating tablets
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`are described e.g. in WO 99/44580 and are well known to the person skilled in the art.
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`WO 2008/025791
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`PCT/EP2007/058978
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`-14-
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`A particularly interesting technology for fast—releasing dosage forms that may be used for the
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`purpose of the present invention to provide an oral dosage form of buprenorphine and
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`preferably an opioid antagonist such as naloxone can be taken from WO 96/26720.
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`Therein it is described how the active agent selegiline is formulated into a rapidly releasing
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`dosage form that can be used e. g. for sublingual administration. WO 96/26720 describes in
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`detail a “fast—dispersing dosage form” with the term encompassing all types of dosage forms
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`being described in US patent 5,120,549, US 5,079,018, WO 93/12769, US 5,298,261 and WO
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`91/04757.
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`As for WO 96/26720 in the case of the active agent selegiline, the present invention
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`contemplates particularly using fast—dispersing dosage forms as described in UK patent
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`number 1548022, that is, a solid fast—dispersing dosage form comprising a network of the
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`active ingredient(s) and a water— soluble or water—dispersible carrier which is inert towards the
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`active ingredient, the network having been obtained by subliming solvent from a composition
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`in the solid state, that composition comprising the active ingredient and a solution of the
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`carrier in a solvent.
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`It is preferred that such a composition in accordance with the invention disintegrates within
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`one to ten seconds, and particularly within two to eight seconds of being placed in the oral
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`cavity and particularly sublingually.
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`The composition will preferably contain in addition to the active ingredient, matrix forming
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`agents and secondary components.
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`Matrix forming agents suitable for use in this aspect of the present invention include materials
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`derived from animal or vegetable proteins, such as gelatins, dextrins and soy, wheat and
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`psyllium seed proteins, gums such as acacia, guar, agar, and xanthan, polysaccharides,
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`WO 2008/025791
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`PCT/EP2007/058978
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`-15-
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`alginates, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such
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`as polyvinylpyrrolidone, and polypeptide/protein or polysaccharide complexes such as
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`gelatin— acacia complexes.
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`Other matrix forming agents suitable for use in the present invention include sugars such as
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`mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin;
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`inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and
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`amino acids having from 2 to 12 carbon atoms such as a glycine, L— alanine, L— aspartic acid,
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`L—glutamic acid, L—hydroxyproline, L— isoleucine, L— leucine and L—phenylalanine.
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`One or more matrix forming agents may be incorporated into the solution or suspension prior
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`to solidification. The matrix forming agent may be present in addition to a surfactant or to the
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`exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid
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`in maintaining the dispersion of any active ingredient within the solution or suspension.
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`Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers,
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`colouring agents, flavouring agents, pH modifiers, sweeteners or taste—masking agents may
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`also be incorporated into the composition. Suitable colouring agents include red, black and
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`yellow iron oxides. Suitable flavouring agents include mint, raspberry, liquorice, orange,
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`lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these.
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`Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and
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`maleic acid. Suitable sweeteners include aspartame and thaumatin. Suitable taste— masking
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`agents include sodium bicarbonate, ionexchange resins, cyclodextrin inclusion compounds,
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`adsorbates or microencapsulated actives.
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`Such fast—dispersing dosage forms containing buprenorphine and preferably an opioid
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`antagonist such as naloxone may be similarly obtained as described in GB 1548022B or
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`WO 2008/025791
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`PCT/EP2007/058978
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`—l6—
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`WO 96/26720, in particular Example 1 of the latter, which are incorporated herein in their
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`entirety.
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`A particularly preferred embodiment of the present invention relates to dosage forms, which
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`are produced along the lines described in WC 03/070227 Al.
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`This prior art reference describes taste— masked, film type or wafer— type medicinal
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`preparations.
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`It is to be understood that the dosage forms in accordance with the present
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`invention may preferably be such film type or wafer—type medicinal preparations with the
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`taste— masking being only an optional feature.
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`Flat active agent carriers that have a film type or wafer—type structure provide for various
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`advantages. As a consequence of the low thickness in comparison to the surface area, there is
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`only a short diffusion pathway if such a dosage form is applied e.g. to the mucosa of the oral
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`cavity. This typically leads to a very rapid release of the active agents which can then be
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`quickly, efficiently and directly absorbed by the mucosa of the oral cavity and particularly
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`sublingually if the active agent is absorbable at all via that route. Thus, in case of
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`buprenorphine such very flat film— type or wafer—type dosage forms are highly desirable as
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`they will allow for the provision of an instant release of active ingredient, thereby minimising
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`the abuse problems encountered with the formulations of the prior art.
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`Flat active agent carriers have been developed for different purposes. One of the basic prior
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`art references in this context is DE 27 46 414 in which active agent, binding agent and
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`additional excipients