(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`21 June 2007 (21.06.2007)
`
` (10) International Publication Number
`
`WO 2007/070632 A2
`
`(51) International Patent Classification:
`A61K 9/00 (2006.01)
`A61K 31/4468 (2006.01)
`A61K 45/06 (2006.01)
`A61K 31/485 (2006.01)
`
`(21) International Application Number:
`PCT/US2006/047686
`
`(22) International Filing Date:
`13 December 2006 (13.12.2006)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/750,191
`60/764,619
`
`13 December 2005 (13.12.2005)
`2 February 2006 (02.02.2006)
`
`US
`US
`
`Applicant (for all designated States except US): BIODE-
`LIVERY SCIENCES
`INTERNATIONAL,
`INC.
`[US/US]; 2501 Aerial Center Parkway, Suite 205, More
`risville, NC 27560 (US).
`
`Inventors; and
`Inventors/Applicants (for US only): FINN, Andrew
`
`[US/US]; 317 West Morgan Street, Unit 405, Raleigh,
`NC 27601 (US). VASISHT, Niraj [
`/US]; 230 Shillings
`Chase Drive, Apex NC 27539 (GB).
`
`(71)
`
`(72)
`(75)
`
`(74)
`
`(81) Designated States (unless otherwise indicated, for ever
`kind ufnational protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, 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, LV, LY, MA, MD, 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 ever
`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, 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:
`
`without international search report and to be republished
`upon receipt of that report
`
`Agent: HANI.EY, Elizabeth, A.; LAHIVE & COCK—
`FIELD, LLP, One Post Office Square, Boston, MA 02109—
`2127 (US).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: ABUSE RESISTANT TRANSMUCOSAL DRUG DELIVERY DEVICE
`
`IVFentanyl + IVNaloxone
`
`
`100—
`
`
`
`
`VAS
`my
`SC0re
`
`
` w
`
`
`
`
`
`4 [Placebo ‘
`Positive effect
`
`F
`
`Negative effect
`
`9W 37’
`F + 25°loN
`
`j,“
`F+ 50°/oN
`
`F = fentanyl
`N = naloxoue
`
`
`
`007/070632A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`(57) Abstract: The present invention relates to a solid pharmaceutical dosage form for abusable drug delivery with reduced illicit
`N abuse potential. The dosage form is presented as a bioerodable transmucosal delivery device that includes an abusable drug and an
`O antagonist to the abusable drug associated with an abuse—resistant matrix. The devices of the invention may be in the form of a layered
`film or a tablet. Upon application in a non—abusive manner, the device adheres to the mucosal surface, providing transmucosal drug
`W
`delivery of the drug with minimal absorption of the antagonist into systemic circulation.
`
`

`

`WO 2007/070632
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`PCT/US2006/047686
`
`ABUSE RESISTANT TRANSMUCOSAL DRUG DELIVERY DEVICE
`
`RELATED APPLICATIONS
`
`[001]
`
`This application claims the benefit of and priority to US. Provisional
`
`Application No. 60/750,191, filed on December 13, 2005 and US. Provisional
`
`Application No. 60/764,619, filed on February 2, 2006. The contents of these
`
`applications are hereby incorporated by this reference in their entireties.
`
`BACKGROUND OF THE INVENTION
`
`[002]
`
`Opioids, or opioid agonists, refer generally to a group of drugs that exhibit
`
`opium or morphine-like properties. Opioids can be employed as moderate to strong
`
`analgesics, but have other pharmacological effects as well, including drowsiness,
`
`respiratory depression, changes in mood and mental clouding without a resulting loss of
`
`consciousness. Opium contains more than twenty distinct alkaloids- Morphine, codeine
`
`and papaverine are included in this group. With the advent of totally synthetic entities
`
`with morphine—like actions, the term "opioid" was generally retained as a generic
`
`designation for all exogenous substances that bind stereo—specifically to any of several
`
`subspecies of opioid receptors and produce agonist actions.
`
`[003]
`
`The potential for the development of tolerance and physical dependence with
`
`repeated opioid use is a characteristic feature of all the opioid drugs, and the possibility
`
`of developing psychological dependence (z‘.e., addiction) is one of the major concerns in
`
`the treatment of pain with opioids. Another major concern associated with the use of
`
`opioids is the diversion of these drugs from the patient in pain to another (non—patient)
`
`for recreational purposes, e.g., to an addict.
`
`[004]
`
`While opioids are highly successful in relieving and preventing moderate to
`
`severe pain, they are subject to abuse to achieve a state of narcosis or euphoria. Oral
`
`intake of such drugs by abusers, however, does not usually give rise to the euphoric
`
`result desired by the abuser, even when taken in an abusively large quantity, because of
`
`poor uptake of such drugs through the GI tract.
`
`'
`
`[005]
`
`Because a particular dose of an opioid analgesic is typically more potent
`
`when administered parenterally as compared to the same dose administered orally, one
`
`mode of abuse of oral medications involves the extraction of the opioid from the dosage
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`

`

`WO 2007/070632
`
`PCT/US2006/047686
`
`form, and the subsequent injection of the opioid (using any suitable vehicle for injection)
`
`in order to achieve a "high." Such extraction is generally as easy as dissolving the
`
`dOSage form using an aqueous liquid or a suitable solvent. Oral opioid formulations,
`
`however, are not only being abused by the parenteral route, but also via the oral route
`
`when the patient or addict orally self-administers more than the prescribed oral dose
`
`during any dosage interval. In another mode of abuse, the corresponding dosage forms
`
`are comminuted, for example ground, by the abuser and administered, for example, by
`
`inhalation. In still another form of abuse, the opioid is extracted from the powder
`
`obtained by comminution of the dosage form (optionally dissolving in a suitable liquid)
`
`and inhaling the (dissolved or powdered) opioid. These forms of administration give
`
`rise to an accelerated rise in levels of the abusable drug, relative to oral administration,
`
`providing the abuser with the desired result.
`
`‘
`
`[006]
`
`Some progress has been made in the attempt to alleviate or lessen the
`
`problem of opioid abuse. For example, U.S. Patent No. 5,866,164 proposes an oral
`
`'
`
`osmotic therapeutic system with a two—layer core, wherein the first layer of the core,
`
`facing towards the opening of the system comprises an opioid analgesic and the second
`
`layer comprises an antagonist for this opioid analgesic and simultaneously effects the
`
`push function, i. e., expelling the analgesic item the corresponding layer out of the
`
`opening of the system. U.S. Patent No. 6,228,863 describes an oral dosage form
`
`containing a combination of an opioid agonist and an opioid antagonist, the formulation
`of which has been selected such that the two compounds can in each case only be
`
`extracted together from the dosage form and then an at least two-stage process is
`
`required to separate them.
`
`[007]
`
`U.S. Patent No. 4,582,835 describes a method of treating pain by
`
`administering a sublingually effective dose of buprenorphine with naloxone. U.S. Patent
`
`No. 6,277,384 also discloses a dosage form containing a combination of an opioid
`
`agonist and an opioid antagonist in a specific ratio that brings about a negative effect on
`
`administration to an addicted person. U.S. Application Publication No. 2004/0241218
`
`discloses a transdermal system which includes an inactivating agent, e.g., a substance
`which crosslinks the opioid drug, to prevent abuse. Such transdermal formulations may
`
`also include an antagonist.
`
`

`

`WO 2007/070632
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`PCT/US2006/047686
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`SUMMARY OF THE INVENTION
`
`[008]
`
`The present invention provides a bioerodable abuse resistant transmucosal
`
`drug delivery device and method of treatment using such devices. The drug delivery
`
`devices of the present invention provide reduced illicit abuse potential and are
`
`particularly useful in, e.g., opioid transmucosal drug delivery. The transmucosal drug
`
`delivery devices of the present invention generally include a drug and its antagonist
`
`contained within the device such that abuse of the drug is impeded.
`
`[009]
`
`Thus, for example, illicit use efforts to extract an abusable drug from the
`
`transmucosal devices of the present invention for parenteral injection (e.g. , by extraction
`
`of the drug by dissolving some or all of the transmucosal device in water or other
`
`solvent), are thwarted by the co-extraction of an antagonist. The amount of antagonist
`
`contained in the product is chosen to block any psychopharmacological effects that
`
`would be expected from parenteral administration of the drug alone. The antagonist is
`
`generally associated with an abuse-resistant matrix, and does not interfere with the
`
`transmucosal delivery of the drug.
`
`[0010]
`
`One of the advantages of the devices of the present invention is that the
`
`devices generally include an abuse-resistant matrix that does not effectively release the
`
`antagonist when the device is used in a non-abusive manner. The dosage forms
`
`described in US. Patent No. 4,582,384 and US. Patent No. 6,227,384, even when
`
`correctly administered, release the corresponding antagonist into the mucosa along with
`
`the opioid. This impairs the activity of the opioid analgesic and it ofizen becomes
`
`necessary to increase the quantity thereof required in the dosage form for satisfactory
`
`treatJnent of the patient. The risk of the occurrence of undesirable accompanying
`
`symptoms is also increased in comparison to dosage forms which contain no opioid
`antagonists. Moreover, it is desirable not to fiirther increase the stress on the patient by
`
`releasing a large proportion of opioid antagonist when such a dosage fonn is correctly
`
`administered.
`
`[0011]
`
`One of the advantages of the devices of the present invention is that the
`
`devices are bioerodable, such that the devices do not have to be removed after use.
`
`[0012]
`
`Accordingly, in one aspect, the present invention includes a bioerodable
`
`abuse-resistant drug delivery device. The device generally includes transmucosal drug
`
`delivery composition and an abuse-resistant matrix. The transmucosal drug delivery
`
`composition includes an abusable drug and the abuse-resistant matrix includes an
`
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`WO 2007/070632
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`PCT/US2006/047686
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`antagonist to the abusable drug. The delivery device can be, for example, a
`
`mucoadhesive drug delivery device, a buccal delivery device, and/or a sublingual
`
`delivery device. In some embodiments, the antagonist is substantially transmucosally
`
`unavailable. In other embodiments, the device is substantially free of inactivating
`
`agents.
`
`[0013]
`
`In some embodiments, the abuse—resistant matrix is a layer or coating, e.g., a
`
`water—erodable coating or layer at least partially disposed about the antagonist. In some
`
`embodiments, the abuse—resistant matrix is a water-hydrolysable, water-erodable or
`
`water-soluble matrix, e.g., an ion exchange polymer. In some embodiments, the
`
`delivery device is in the form of a tablet, a lozenge, a film, a disc, a capsule or a mixture
`of polymers.
`.
`
`[0014]
`
`In some embodiments, the device includes a mucoadhesive layer. In some
`
`embodiments, the device includes a mucoadhesive layer and a non-adhesive backing
`
`layer. In other embodiments, the device includes a third layer disposed between the
`
`mucoadhesive layer and the backing layer. In some embodiments, either or both of the
`
`abusable drug and the abuse-resistant matrix are incorporated into a mucoadhesive layer.
`
`In some embodiments, the abuse-resistant matrix is incorporated into the backing layer.
`
`In some embodiments, either or both of the abusable drug and the abuse-resistant matrix
`
`are incorporated into the third layer. In some embodiments, the abuse-resistant matrix is
`
`the third layer. In some embodiments, either or both of the abusable drug and the abuse—
`
`resistant mattix are incorporated into any combination of layers discussed herein. In
`
`some embodiments, the abusable drug is incorporated into the mucoadhesive layer and
`
`the abuse-resistant matrix is incorporated into the backing layer.
`
`[0015]
`
`In some embodiments, the abuse—resistant matrix erodes at a slower rate than
`
`the backing layer, the mucoadhesive layer, the third layer, or any combination thereof.
`
`[0016]
`
`In some embodiments, the abusable drug can be, but is not limited to opiates
`
`and opioids, e.g., alfentanil, allylprodine, alphaprodine, apomorphine, anileridine,
`
`apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,
`
`codeine, cyclorphan, cyprenorphine, desomorphine, dextromoramide,
`dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine,
`
`dihydromorphine, dimenoxadol, eptazocine, ethylmorphine, etonitazene, etorphine,
`
`fentanyl, fencamfamine, fenethylline, hydrocodone, hydromorphone,
`
`hydroxymethylmorphinan, hydroxypethidine, isomethadone, levomethadone,
`
`

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`WO 2007/070632
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`levophenacylmorphan, levorphanol, lofentanil, mazindol, meperidine, metazocine,
`
`methadone, methylmorphine, modafinil, morphine, nalbuphene, necomorphine,
`
`normethadone, normorphine, opium, oxycodone, oxymorphone, pholcodine, profadol
`remifentanil, sufentanil, tramado], corresponding derivatives, physiologically acceptable
`
`compounds, salts and bases.
`
`[0017]
`
`In some embodiments, the antagonist includes, but is not limited to opiate or
`
`opioid antagonists, e.g., naloxone, naltrexone, nalmefene, nalide, nalmexone,
`
`nalorphine, naluphine, cyclazocine, levallorphan and physiologically acceptable salts
`
`and solvates thereof.
`
`[0018]
`
`In some embodiments, the abuse—resistant matrix includes, but is not limited
`
`to, partially crosslinlced polyacrylic acid, polycarbophilTM, providoneTM, cross—linked
`
`sodium carboxymethylcellulose,’ gelatin, chitosan, AmberliteTM IRP69, DuoliteTM
`
`AP143, AMBERLITETM IRP64, AlVIBERLITETM IRP88, and combinations thereof. In
`
`other embodiments, the abuse-resistant matrix includes, but is not limited to, alginates,
`
`polyethylene oxide, poly ethylene glycols, polylactide, polyglycolide, lactide-glycolide
`
`copolymers, poly-epsilon-caprolactone, polyoithoesters, polyanhydrides and derivatives,
`
`methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
`
`hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, polyacrylic acid, and
`
`sodium carboxymethyl cellulose, poly vinyl acetate, poly vinyl alcohols, polyethylene
`
`glycol, polyethylene oxide, ethylene oxide-propylene oxide co-polymers, collagen and
`
`derivatives, gelatin, albumin, polyarninoacids and derivatives, polyphosphazenes,
`
`polysaccharides and derivatives, chitin, or chitosan bioadhesive polymers, polyacrylic
`
`acid, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, and combinations thereof.
`
`[0019]
`
`In some embodiments, the device is less susceptible to abuse than an
`
`abusable drug alone. In other embodiments, less than 30% of the efficacy of the
`
`abusable drug is retained when used in an abusive manner. In some embodiments, the
`
`antagonist and the abusable drug are released at substantially the same rate when
`
`abusively dissolved. In some embodiments, the antagonist and the abusable drug are
`
`released at substantially the same rate when dissolved in water. In other embodiments,
`
`the ratio of released antagonist to released abusable drug is not less than about 1:20.
`
`[0020]
`
`In some aspects, the present invention provides a method for treating pain in
`
`a subject. The method includes administering any device described herein such that pain
`
`is treated. In some embodiments, the extent of the absorption into systemic circulation
`
`

`

`WO 2007/070632
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`PCT/US2006/047686
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`of the antagonist by the subject is less than about 15% by weight. In some
`
`embodiments, the dosage of the abusable drug is between about SOug and about 10 mg-
`
`[0021]
`
`In some aspects, the bioerodable abuse-resistant drug delivery device
`
`comprising: a layered film having at least one bioerodable, mucoadhesive layer to be
`
`placed in contact with a mucosal surface, and at least one bioerodable non—adhesive
`
`backing layer, wherein at least one abusable drug is incorporated in at least the
`
`mucoadhesive layer, and an abuse-resistant matrix comprising an antagonist to the
`
`abusable drug is incorporated in any or all of the layers.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0022]
`
`Figure 1 graphically depicts the measure of positive and negative effects felt
`
`by a subject who was administered placebo, fentanyl only, and varying ratios of fentanyl
`
`and naloxone.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0023]
`
`Subjects with pain, e.g., cancer pain, are typically opioid tolerant because of
`
`the chronic narcotic use required to control such pain. Moreover, the dose of
`
`transmucosal opioid drug, e.g., fentanyl, required to treat breakthrough pain (for
`
`example, pain associated with unusual movement) can be high because of the opioid
`
`tolerance. In fact, doses in excess of one mg, a dose that would be fatal for a subject that
`
`was not opioid tolerant, are often used. This amount of a potent narcotic in a device
`
`makes it potentially subject to diversion and abuse by the intended route of
`administration as well as through extraction of the fenitanyl for injection or inhalation.
`
`[0024]
`
`Abuse by injection can be prevented or reduced by the inclusion of an
`
`antagonist, such as naloxone, in the formulation, which would block any
`
`psychophannacologic effect of injected opioid drug.
`
`[0025]
`
`Accordingly, the present invention relates to novel drug delivery devices that
`
`provide for the transmucosal delivery of an abusable drug while reducing, and, in some
`
`embodiments, eliminating abuse potential. The drug delivery devices generally include
`
`an abusable drug and at least one antagonist for the drug incorporated into a device (e.g.,
`
`a multilayered transmucosal delivery device) that impedes abuse of the drug. Abuse of
`
`the drug can be impeded by use of the present invention in many, non-limiting ways. In
`
`some embodiments, the antagonist impedes abuse of the drug because attempts to extract
`
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`WO 2007/070632
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`PCT/US2006/047686
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`the drug from the transmucosal delivery device results in co—extraction of the antagonist
`
`which blocks the expected effect of the drug. In other embodiments, the abusable drug
`
`and the antagonist are incorporated into the same layer or indistinguishable layers of a
`
`delivery device of the present invention, so that they can not be separated from one
`
`another, e.g., by peeling one layer off of the device.
`
`[0026]
`
`When used as intended, however, the abusable drug will be delivered through
`
`the mucosa, e. g., by application to the mucous membrane of the mouth, and thus into the
`
`systemic circulation. The antagonist is associated with an abuse—resistant matrix, e.g. ,
`
`dispersed within coated—microparticles or chemicallyLbound to a polymer that impedes
`
`or prevents mucoabsorption, e. g., a high molecular weight polymer or an ion exchange
`
`polymer. In some embodiments, the antagonist is substantially transmucosally
`
`unavailable when used in a non-abusive manner. Without wishing to be bound by any
`
`particular theory, it is believed that when used in a non-abusive manner, the opioid
`
`antagonist will be swallowed, e.g., as an unbound antagonist in a layer or matrix not
`
`contacting the mucosa and/or as an intact microcapsule, polymer bound particle or in
`
`some other form not amenable to mucosa] administration. Because the opioid antagonist
`
`is poorly absorbed from the gastrointestinal tract, the amount in the systemic circulation
`
`is below a level that would produce a significant pharmacologic effect against the drug,
`
`and therefore it is relatively inactive under these conditions.
`
`[0027]
`
`In order to more clearly and concisely describe the subject matter of the
`
`claims, the following definitions are intended to provide guidance as to the meaning of
`
`terms used herein.
`
`[0028]
`
`The terms “abusable drug” or “drug” as used interchangeably herein, refers
`
`to any pharmaceutically active substance or agent that has the ability to promote abuse,
`
`high tolerance with extended use, and/or chemical or physical dependency. Abusable
`
`drugs include, but are not limited to, drugs for the treatment of pain such as an opioid
`
`analgesic, e.g., and opioid or an opiate.
`
`[0029]
`
`As used herein, the term “antagonist” refers to a moiety that renders the
`
`active agent unavailable to produce a pharmacological effect, inhibits the function of an
`
`agonist, e.g., an abusable drug, at a specific receptor, or produces an adverse
`
`pharmacological effect. For example, in some embodiments, when used in an abusive
`
`manner, the antagonist is released in an amount effective to attenuate a side effect of
`
`said opioid agonist or to produce adverse effect such as anti-analgesia, hyperalgesia,
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`hyperexcitability, physical dependence, tolerance, or any combination thereof. Without
`
`wishing to be bound by any particular theory, it is believed that antagonists generally do
`
`not alter the chemical structure of the abusable drug itself, but rather work, at least in
`
`part, by an effect on the subject, e.g., by binding to receptors and hindering the effect of
`
`the agonist. Antagonists can compete with an agonist for a specific binding site
`
`(competitive antagonists) and/or can bind to a different binding site from the agonist,
`
`hindering the effect of the agonist via the other binding site (non-competitive
`
`antagonists). Non—limiting examples of antagonists include opioid—neutralizing
`
`antibodies; narcotic antagonists such as naloxone, naltrexone and nalmefene; dysphoric
`
`or imitating agents such as scopolarnine, ketamine, atropine or mustard oils; or any
`
`combinations thereof. In one embodiment, the antagonist is naloxone or naltrexone.
`
`[0030] The term "bioerodable" as used herein refers to the property of the devices of the
`present invention which allow the solid or semisolid portion of the device to sufficiently ‘
`
`degrade by surface erosion, bioerosion, and/or bulk degradation such that it is small
`
`enough to be swallowed. Bulk degradation is the process in which a material, e.g., a
`
`polymer, degrades in a fairly uniform manner throughout the matrix. This results in a
`
`reduction of molecular weight (Mn) without immediate change in physical properties,
`
`followed by fragmentation due to faster penetration of saliva or water into the device
`
`than conversion of the device into saliva— or water-soluble form. Bioerosion or surface
`
`erosion generally occurs when the rate at which saliva or water penetrates the material is
`
`slower than the rate of the conversion of the material into saliva- or water—soluble
`
`substances. Bioerosion generally results in a thinning of the material over time, though
`
`the bulk integrity is maintained. It is to be understood that “bioerodable” refers to the
`
`device as a whole, and not necessarily to its individual components. For example, if the
`
`antagonist is microencapsulated or coated, the microcapsules or coating may or may not
`
`be bioerodable, but the device as a whole may be bioerodable such that as the device is
`
`eroded the intact microcapsules or coated antagonist is swallowed. This can be
`
`advantageous because the device will erode and the microcapsules or coated antagonist
`
`can be delivered to the GI tract intact, i.e., without crossing the mucosa. The ten-n
`
`“bioerodable” is intended to encompass many modes of material removal, such as
`
`enzymatic and non—enzymatic hydrolysis, oxidation, enzymatically—assisted oxidation,
`
`wear, degradation and/or dissolution.
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`[0031]
`
`Bioerodable materials are generally selected on the basis of their degradation
`
`characteristics to provide a sufficient fimctional lifespan for the particular application.
`
`In the case of applications of the present invention, a functional lifespan of between 1
`
`minute and 10 hours may be suitable. In some embodiments, the functional lifespan is
`
`about 2 minutes. In some embodiments, the functional lifespan is about 5 minutes. In
`
`some embodiments, the functional lifespan is about 10 minutes. In some embodiments,
`
`the functional lifespan is about 15 minutes. In some embodiments, the functional
`
`lifespan is about 20 minutes. In some embodiments, the functional lifespan is about 30
`
`minutes. In some embodiments, the functional lifespan is about 45 minutes. In some
`
`embodiments, the functional lifespan is about 60 minutes. In some embodiments, the
`
`functional lifespan is about 2 hours. In some embodiments, the functional lifespan is
`
`about 3 hours. In some embodiments, the functional lifespan is about 4 hours. In some
`
`embodiments, the fimctional lifespan is about 5 hours. In some embodiments, the
`
`functional lifespan is about 10 hours. All ranges and values which fall between the .
`
`ranges and values listed herein are meant to be encompassed by the present invention.
`
`For example, lifespans of between about 5 minutes and about 45 minutes, between about
`
`6 minutes and about 53 minutes, between about 13 minutes and about 26 minutes, etc.
`
`are all encompassed herein. Shorter or longer periods may also be appropriate.
`
`[0032]
`
`Bioerodable materials include, but are not limited to, polymers, copolymers
`
`and blends of polyanhydrides (e.g., those made using melt condensation, solution
`
`polymerization, or with the use of coupling agents, aromatic acids, aliphatic diacids,
`amino acids, e.g., aspartic. acid and glutamic acid, and copolymers thereof); copolymers
`
`of epoxy terminated polymers with acid anhydrides; polyorthoesters; homo— and
`
`copolymers of oz—hydroxy acids including lactic acid, glycolic acid, e-caprolactone, 1&-
`
`butyrolactone, and 8-va1erolactone; homo- and copolymers of a—hydroxy alkanoates;
`
`polyphosphazenes; polyoxyalkylenes, e. g., where alkene is 1 to 4 carbons, as
`
`homopolymers and copolyrners including graft copolymers; poly(amino acids),
`
`including pseudo poly(amino acids); polydioxanones; and copolymers of polyethylene
`
`glycol with any of the above.
`
`{0033]
`
`As used herein, the articles “a” and “an” mean “one or more” or “at least
`
`one,” unless otherwise indicated. That is, reference to any element of the present
`
`invention by the indefinite article "a" or “an” does not exclude the possibility that more
`
`than one of the element is present.
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`WO 2007/070632
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`PCT/US2006/047686
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`[0034]
`
`The term “abuse-resistant matrix” refers generally to a matrix with which an
`
`antagonist to an abusable drug is associated. An abuse resistant matrix is a matrix that
`
`effectively releases the antagonist when the device is used in an abusive manner (e.g.,
`
`dissolved in water in an attempt to extract the drug, solubilized, opened, chewed and/or
`
`cut apart) so that, e.g., the antagonist is co—extracted and alters or blocks the effect the
`
`drug. However, when used as intended, e.g., in a non—abusive manner, the abuse—
`
`resistant matrix does not effectively release the antagonist. E.g., the antagonist instead is
`
`retained within the matrix and is delivered to the gastrointestinal tract where it is not
`
`readily absorbed such that any amount of antagonist delivered systemically through the
`
`mucosa and/or the GI tract does not significantly block or alter the effect of the drug.
`
`[0035]
`
`When used in reference to the antagonist, the phrase “substantially
`
`transmucosally unavailable” refers to the fact that the antagonist in the compositions and
`
`devices of the present invention is available transmucosally in amounts that do not
`
`effect, or negligibly effect, the efficacy of the abusable drug when employed in a non—
`
`abusive manner. Without wishing to be bound by any particular theory, it is believed
`
`that the antagonist is prevented or slowed from entering the system transmucosally while
`
`still being available for other routes of administration (e.g., swallowing or dissolution),
`
`thus allowing the abusable drug to act efficaciously in a transmucosal composition, but
`
`hindering the use of the composition in an abusive manner. That is, it is to be
`
`understood that the antagonist effects the efficacy of the abusable drug when the
`
`compositions of the present invention are abused. In non-abusive situations, the
`
`antagonist provides no or negligible effect, e. g., is swallowed. In some embodiments,
`
`less than about 25% antagonist (by weight versus abusable drug) can be delivered non—
`
`abusively, e.g., transmucosally. In other embodiments, less than about 15% antagonist
`
`is delivered transmucosally- In still other embodiments, less than 5% of antagonist is
`
`delivered transmucosally. In some embodiments, less than 2% antagonist is delivered
`
`transmucosally. In still other embodiments, less than 1% antagonist is delivered
`
`transmucosally.
`
`[0036]
`
`Accordingly, in some embodiments, when the device is a multilayer disc or
`
`film, the abuse-resistant matrix is a layer or is incorporated into a layer which is
`
`disposed between a mucoadhesive layer and a backing layer. In other embodiments, the
`
`abuse—resistant matrix is incorporated into a backing layer. Without wishing to be bound
`
`by any particular theory, it is believed that the antagonist would not able to enter
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`10
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`WO 2007/070632
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`PCT/US2006/047686
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`systemic circulation through the mucosa in any significant amount because it would be
`
`washed into the GI tract, e.g., swallowed. In some embodiments, the abuse resistant
`
`matrix is a coating or water—hydrolysable matrix, e. g., an ion—exchange polymer. The
`
`coating or water—hydrolysable matrix can be chosen such that it dissolves more slowly
`
`than a backing layer as described above. The coating or water—hydrolysable matrix can
`
`additionally or alternatively be chosen such that they dissolve slowly enough not to
`
`release the antagonist at all. Without limiting the invention, it is believed that the
`
`antagonist would be washed into the GI tract as either free-antagonist or as a coated or
`
`otherwise entrapped, e.g., by the ion—exchange polymer, moiety. It is to be understood
`
`that layers, coatings, and water—hydrolyzable matrices are exemplary, and that additional
`
`abuse-resistant matrices can be envisioned using the teachings of the present invention.
`
`[0037]
`
`As used herein, the term “abusive manner” refers to the use of the delivery
`
`device in amanner not intended, e.g., in a non-transmucosal manner or in a manner not
`
`otherwise prescribed by a physician. In some embodiments, the abusive manner
`
`includes extraction of the drug from the delivery device for oral or parenteral
`
`administration. As used herein, “non-abusive manner” refers to the use of the delivery
`
`device for its intended purpose, e.g., transmucosal administration of the drug. In some
`
`cases, a portion of the drug will unintentionally be delivered non—transmucosally, e.g.,
`
`orally through the dissolution of a portion of the device. Such inadvertent or
`
`unintentional delivery is not indicative of use in an abusive manner.
`
`[0038]
`
`Accordingly, in some embodiments, the devices of the present invention are
`
`less susceptible to abuse than an abusable drug alone. For example, when used in an
`
`abusive manner, the abusable drug may only retain about 50%, 40%, 30%, 20%, 10%,
`
`5%, 2%, 1% or 0% of its efficacy, e.g., as a pain reliever. Accordingly, when used in an
`
`abusive manner, it is believed that the effectiveness of the abusable drug, e.g., the ability
`
`to produce a “high” in an addict, would be reduced by a corresponding amount, e.g., by
`
`50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 100%.
`
`[0039]
`
`As used herein, “treatment” of a subject includes the administration of a drug
`
`to a subject with the purpose of preventing, curing, healing, alleviating, relieving,
`
`altering, remedying, ameliorating, improving, stabilizing or affecting a disease or
`
`disorder, or a symptom of a disease or disorder (e.g., to alleviate pain).
`
`[0040]
`
`The term “subject” refers to living organisms such as humans, dogs, cats, and
`
`other mammals. Administration of the drugs included in the devices of the present
`
`11
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`

`WO 2