(72) Inventors: KUCZYNSKI, Anthony, L.; 777 West Middlefield Published
`Road #157, Mountain View, CA 94043 (US). CHILDERS,
`Without international search report and to be republished
`Jerry, D.; 1313 Socorro Avenue, Sunnyvale, CA 94089
`upon receipt of that report.
`(US). BARCLAY, Glen, E.; Unit C, 441 Mariposa Avenue,
`Mountain View, CA 94041 (US). ROGRIGUEZ, Susan;
`816 Lathrop Drive, Stanford, CA 94305 (US). MERRILL,
`Sonya; 5002 Paseo Olivos, San Jose, CA 95130 (US).
`
`(74) Agents: SABATINE, Paul, L. et al.; Alza Corporation, 950
`Page Mill Road, P.O. Box 10950, Palo Alto, CA 94303-
`0802 (US).
`
`(54) Title: COMPOSITION AND DOSAGE FORM COMPRISING OPIOID ANTAGONIST
`
`(57) Abstract
`
`A composition of matter is disclosed and claimed comprising an opioid antagonist and a high molecular weight poly(alkylene) or
`a poly(carboxymethylcellulose). A dosage form is disclosed and claimed comprising the composition of matter for displacing an opioid
`analgesic from the dosage form.
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intemauonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 6 =
`‘
`(11) International Publication Number:
`WO 97/33566
`A61K 9/20
`
`(43) International Publication Date:
`
`18 September 1997 (18.09.97)
`
`(2]) International Application Number:
`
`PCT/US97/03110
`
`(22) International Filing Date:
`
`28 February 1997 (28.02.97)
`
`(30) Priority Data:
`60/013,290
`
`12 March 1996 (12.03.96)
`
`US
`
`(71) Applicant: ALZA CORPORATION [US/US]; 950 Page Mill
`Road, P.0. Box 10950, Palo Alto, CA 94303-0802 (US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS,
`LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL,
`PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA,
`U6, U2, VN, ARIPO patent (GI-I, KE, LS, MW, SD, 82,
`UG), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European patent (AT, BE, CH, DE, DK, ES, FI, FR,
`GB, GR, IE, 1T, LU, MC, NL, PT, SE), OAPI patent (BF,
`BJ. CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Viet Nam
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`8]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Armenia
`Austria
`Auaralia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d‘lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`
`

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`WO 97/33566
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`1
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`PCT/USQ7/031 10
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`SITI
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`F
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`M CO PRI
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`Pl D ANTA
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`N ST
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`Fl
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`D FTHEINVENT N
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`This invention pertains to a novel composition comprising an opioid
`
`antagonist. This invention also concerns a novel dosage form comprising an
`
`opioid antagonist. The invention further concerns a method of administering
`
`a dosage form comprising an opioid antagonist for lessening the incidence of
`
`drug abuse.
`
`WW
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`Analgesics are drugs which relieve pain and they act to relieve pain by
`elevating the pain threshold of a patient in need of pain relief. One group of
`
`analgesic drugs are the opiates. The opiate group of analgesics are among
`
`the most powerfully acting and clinically useful drugs for the relief of pain.
`
`The term opiate was once used to designate analgesic drugs derived from
`
`opium including morphine, codeine and synthetic congeners of morphine.
`
`V\fith the development of totally synthetic drugs with morphine-like actions,
`
`the word opioid is used to refer to all drugs, both natural and synthetic,
`
`with morphine-like actions. The term narcotic as associated with the opioids,
`
`refers to the physical dependence accompanying the use of these drugs and
`with their increasing use it refers to opioid substances that cause
`
`dependence.
`
`In addition to their many important medical uses, the opioid drugs are
`
`employed commonly for illicit purposes, including emotional, psychological,
`
`euphoric, hallucinogenic, depressive, and psychedelic experiences. These
`
`purposes and the physical dependence accompanying the administration of
`
`these drugs has led to drug abuse. Drug abuse has become for many
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`WO 97/33566
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`PCT/U597/03 1 l0
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`habituates a way of life. To a rapidly growing segment of the world
`
`population, use of these drugs is a vogue often seen as fashionable.
`
`While these drugs are a necessary part of modern medicine, it would be
`
`highly desirable to provide a novel drug delivery system and a novel
`
`composition of matter that do not possess drug abuse potential, and thereby
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`seek to lessen the incidence of their abuse and their illicit use.
`
`SU
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`A
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`OF T
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`I
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`Tl
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`In view of the foregoing, it is apparent that a pressing need exists for
`
`an improved delivery of opioids for their therapeutic effects, while
`
`concomitantly substantially lessening or substantially preventing opioid
`
`abuse. Thus, it is an object of this invention to provide a composition of
`
`matter indicated for use in a dosage form comprising an abusable opioid,
`
`which composition imparts a low potential for abuse of both the composition
`
`and the dosage form comprising same. Another object of the invention is to
`
`provide a dosage form comprising a first composition containing an opioid
`
`and a second composition separate and distinct from the first composition
`
`containing an antagonist for lessening opioid abuse.
`
`TAI
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`C
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`Tl
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`OF
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`T
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`The term opioid as used for the purpose of this invention represents an
`
`opioid member selected from the group consisting of alfentanil, allylprodine,
`
`alphaprodine, apomorphine, anileridine, apocodeine, benzylmorphine,
`
`bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclorphan,
`
`cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide,
`
`dihydrocodeine. dehydromorphine, diminoxadol, eptazocine, ethylmorphine,
`
`fentanyl, hydrocodone, hydroxymethylmorphian. hydromorphone,
`
`hydroxypethidine, Ievophenacylmorphan, levorphanol, Iofentanil,
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`WO 97/33566
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`PCT/US971031 10
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`methylmorphine, morphine, necomorphine, normethadone, normorphine,
`
`opium, oxycodone, oxymorphone, pholcodine, profadol, and sufentanil.
`
`The opioid can be present as a member selected from the opioid base and
`
`the opioid pharmaceutically acceptable salt. The pharmaceutically
`
`acceptable salt embraces the inorganic and the organic salt. Representative
`
`salts include a member selected from the group consisting of hydrobromide,
`
`hydrochloride, mucate, succinate, n-oxide, sulfate, malonate, acetate,
`
`phosphate dibasic, phosphate monobasic, acetate trihydrate,
`
`bi(heplafluorobutyrate), maleate, bi(methylcarbamate),
`
`bi(pentafluoropropionate), mesyiate, bi(pyridine-S—carboxylate),
`
`bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate, and sulfate
`
`pentahydrate. The dose of opioid, in the first or opioid composition,
`
`is 75 ng to 750 mg.
`
`The antagonist present in the second, or antagonist composition, is an
`
`effective amount to attenuate, that is to lessen and/or reduce the effect of the
`
`opioid present in the first composition. The antagonist is present in 10 ng to
`
`275 mg, or 0.75 to 10 wt%, in the second or antagonist composition that is
`
`separate and distinct from the first or opioid composition. The antagonist is
`
`an opioid antagonist selected from the group consisting of naltrexone,
`
`naloxone, nalmefene, naiide, nalmexone, nalorphine, nalpuphine, nalorphine
`
`dinicotinate, and the pharmaceutically acceptable base, the pharmaceutically
`
`acceptable salt thereof. The pharmaceutically acceptable addition salt
`
`embraces those presented earlier in the specification.
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`WO 97/33566
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`PCT/US97/03l 10
`
`4
`
`F R
`
`N
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`EXAMPLE 1
`
`A novel dosage form for delivering hydrocodone to a patient in need
`
`of pain relief is prepared as follows:
`
`first, 24.89 of hydrocodone bitratrate
`
`hemipentahydrate, 70.39 of poly(ethylene oxide) of 200,000 average number
`
`1
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`2 3
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`4 5
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`5
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`7
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`a molecular weight, available from Union Carbide Institute, West Virginia, and
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`9
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`10
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`5.0 mg of hydroxypropylmethylcellulose possessing a 11,200 average
`
`number molecular weight available from Dow Chemical Co., Midland,
`
`11 Michigan, are dry blended for 5 minutes using a roll mill. Then, 50 ml of
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`denatured ethyl alcohol are added to the dry blend, and slowly mixed together
`
`for 5 minutes. After drying at room temperature, the mass is pressed through
`
`a 0.0331 inch (0.85 mm) screen, and then dried further at room temperature
`
`overnight. Next, 0.5 mg of magnesium stearate is blended with the
`
`granulation for 2 minutes to produce a homogenous blend.
`
`Next, a second or antagonist composition is prepared as follows:
`
`first, 30.89 of poly(ethylene oxide) of 7,000,000 number average molecular
`
`weight, 15.09 of sodium chloride, and 3.09 of hydroxypropylmethylcellulose of
`
`11,200 number average molecular weight, and 0.49 of naloxone, and 1.09 of
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`ferric oxide are blended homogeneously in the presence of denatured
`
`alcohol. The homogenous mass is pressed through a 0.0469 inch (1.19 mm)
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`screen and dried overnight at room temperature, and then pressed through a
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`0.0331 inch (0.85 mm) screen. Then, 1.0 m9 of lubricant is added to the
`
`9rar,1lation. Then, 450 m9 of the first composition and 250 mg of the second
`
`composition are pressed in a standard tablet press into a bilayer core with
`
`the first composition and the second composition in bilayered arrangement.
`
`The bilayered core comprises an oval shape 0.700 inches (1.78 cm) by
`
`0.375 inches (0.95 cm).
`
`

`

`WO 97133566
`
`PCT/U897/03l 10
`
`The bilayered core is coated with a semipermeable membrane
`
`consisting of 40 mg of cellulose acetate of 39.8% acetyl and 2 mg of
`polyethylene glycol 3350. The membrane-forming composition is dissolved
`
`in acetonezwater (95:5 wtzwt), and the wall-forming composition is sprayed
`around the bilayered core in a coater. Next. two 30 mil (0.762 mm) exit
`
`passageways are drilled through the semipermeable membrane to connect
`the opioid drug layer with the exterior of the dosage form. Finally, the dosage
`form is dried for 48 hours at 50° to remove excess moisture.
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`EXAMBLEg
`
`A dosage form is provided by the invention by first preparing a
`morphine composition wherein 17.289 of morphine sulfate pentahydrate,
`38.529 of poly(ethylene oxide) possessing a 200,000 number-average
`molecular weight, and 3.609 of poly(vinyl pyrrolidone) having a number-
`
`average molecular weight of 40,000 available from lSP Technologies,
`Texas City, Texas, are added to a planetary mixing bowl. Next, the dry
`materials are mixed for 10 minutes. Then, 169 of denatured anhydrous
`ethyl alcohol is slowly added to the blended materials with continuous mixing
`for 15 minutes. Then. the freshly prepared wet granulation is passed through
`a 20 mesh screen (0.841 mm sieve opening) allowed to dry at room
`
`temperature for 20 hours and then is passed through a 16 mesh screen
`
`(1.00 mm sieve opening). Next, the granulation is transferred to a planetary
`mixer, mixed and lubricated with 0.69 of magnesium stearate.
`
`Next, a push composition is prepared as follows: first, a binder
`
`solution is prepared by dissolving 39 of hydroxypropymethylcellulose
`
`possessing a number-average molecular weight of 11,200 in 33.79 of water.
`Next 0.19 of butylated hydroxytoluene is dissolved in 29 of denatured
`
`anhydrous alcohol. Approximately 59 of the
`
`hydroxypropylmethylceliulose/water solution is added to the butylated
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`

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`WO 97/33566
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`PCT/US97/031 10
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`hydroxytoluene/alcohol solution with continuous mixing for 2 to 3 minutes.
`
`Next, the binder solution preparation is completed by adding the remaining
`
`hydroxypropylmethylcellulose/water solution to the butylated
`
`hydroxytoluenelalcohol solution, again with continuous mixing thereof.
`
`Next, 369 of osmagent sodium chloride is sized using a Quadro
`
`Co-mil® mill, to reduCe the particle size of the sodium chloride. Next, 1.29
`
`of ferric oxide is passed through a 40 mesh screen (0.387 mm opening).
`
`Then, all the screened materials and 1.29 of naloxone are added to 75.29
`
`of pharmaceutically acceptable poly(ethylene oxide) comprising a 7,000,000
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`number-average molecular weight and to 39 of hydroxypropylmethylcellulose
`
`comprising a number—average molecular weight of 11,200 in a fluid bed
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`granular bowl, and the granulation process is initiated to effect granulation.
`
`Next, the dry powders are air suspended and mixed for 3 minutes.
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`Then, all the binder solution is sprayed from 3 nozzles onto the
`
`powder. The granulating conditions are monitored during the process.
`
`Then, a fluid air mill is used to size the coated granules with an 8 mesh
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`screen (2.38 mm opening screen) and lubricated with 0.289 of magnesium
`
`stearate.
`
`Next, the morphine sulfate pentahydrate composition and the
`
`displacement antagonist composition are compressed into a bilayer tablet.
`
`First, 434 mg of the morphine sulfate pentahydrate composition is added to
`
`the die cavity and compressed, then, 260 mg of the displacement antagonist
`
`composition is added and the layers pressed under a pressure of
`
`approximately 3 tons into a 0.700 inch (1 .78cm) x 0.375 inch (0.95 cm)
`
`contacting bilayer core with the antagonist separate from the opioid.
`
`The bilayered core arrangement is coated with a semipermeable wall.
`
`The wall forming composition comprises 95% cellulose acetate having a
`
`39.8% acetyl content, and 5% polyethylene glycol having a 3350 number—
`
`average molecular weight. The semipermeable wall-forming composition is
`
`dissolved in an acetonezwater (95:5 wt:wt) cosolvent to make a 4% solids
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`

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`WO 97/33566
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`PCT/US97/03l 10
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`solution. The wall—forming composition is sprayed onto and around the
`bilayer tablets in a coater. Next, two 30 mil (0.762 mm) exit passageways are
`drilled through the semipermeable wall to connect the opioid-drug layer with
`the exterior of the dosage system. The residual solvent is removed by drying
`for 48 hours at 50°C and 50° humidity. The osmotic dosage forms are dried
`further for 4 hours to 50°C to remove the excess moisture. The dosage form
`produced by this manufacture comprises in the first composition 28.8%
`morphine sulfate pentahydrate, 64.2% poly(ethylene oxide) possessing a
`200,000 molecular weight, 6% poly(vinyl pyrrolidone) possessing a 40,000
`molecular weight, and 1% magnesium stearate. The second composition
`comprises 62.895% poly(ethylene oxide) comprising a 7,000,000 molecular
`weight, 30% sodium chloride, 5% hydroxypropylmethylcellulose of 11,200
`molecular weight, 0.78% antagonist naloxone, 1% ferric oxide, 0.075
`butylated hydroxylotuene, and 0.25% magnesium stearate. The
`
`semipermeable wall comprises 95% cellulose acetate comprising a 39.8%
`acetyl content and 5.0 wt polyethylene glycol of 3350 molecular weight.
`The dosage form comprises two passageways, 30 mil (0.762 mm) and it has
`a morphine sulfate mean release rate of 5mg/hr.
`
`EXAMELEA
`
`A dosage form prepared according to the above example is
`manufactured and further comprises a wall of 60 wt% to 100 wt% of a
`
`cellulose polymer which polymer comprises a member selected from the
`
`group consisting of a cellulose ester, cellulose diester, cellulose triester,
`cellulose ether, cellulose ester-ether, cellulose acylate, cellulose diacylate,
`cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate,
`cellulose acetate butyrate, and the like. The wall can also comprise from
`0 wt% to 40 wt% of a cellulose ether member selected from the group
`consisting of hydroxypropylcellulose, hydroxypropylbutylcellulose, and
`
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`WO 97133566
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`PCT/US97/03l 10
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`hydroxypropylmethylceIlulose and from 0 wt% to 20 wt% of polyethylene
`
`glycol. The total amount of all components comprising the wall is equal to
`
`100 wt%.
`
`The wall in other manufactures, comprises the selectively permeable
`
`cellulose ether, ethyl cellulose. The ethyl cellulose comprises an ethoxy
`
`group with a degree of substitution, D8, of about 1.4 to 3, equivalent to
`
`40% to 50% ethoxy content, and a viscosity range of 7 to 100 centipoise,
`
`or higher. More specifically, the wall comprises 40 wt% to 95 wt% ethyl
`
`cellulose, from 5 wt% to 60 wt% polyethylene glycol with the total weight
`
`percent of all components comprising the wall equal to 100 wt%.
`
`In another
`
`manufacture the wall comprises 45 wt% to 80 wt% of ethylcellulose, from
`
`5 wt% to 30 wt% hydroxypropylcellulose, from 2 wt% to 20 wt% of polyvinyl
`
`pyrrolidone, with the total amount of all components comprising the wall equal
`
`to 100 wt%.
`
`EKAMELEA
`
`The antagonist composition according to the above examples wherein
`
`the naloxone is replaced by a member selected from the group consisting of
`
`naltrexone, nalmefene, nalide, nalmexone, nalorphine, nalpuphine.
`
`naiorphine dinicotinate, and the pharmaceutically acceptable salt.
`
`ElAMELEj
`
`,
`
`In the dosage forms provided by the invention, the first composition
`
`can comprises 0.1 to 98 wt% opioid base, opioid salt, or opioid derivative;
`
`10 to 95 wt% poly(alky|ene oxide) possessing a 100,000 to 650,000
`
`molecular weight or 10 to 95 wt % of a carboxymethylcellulose, such as
`
`sodium carboxymethylcellulose,
`
`lithium carboxymethylcellulose, or potassium
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`carboxymethylcellulose possessing a 10,000 to 400,000 molecular weight;
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`WO 97133566
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`PCT/US97/03 l 10
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`1 to 20 wt% poly(vinyl pyrrolidone) of 40,000 to 75,000 molecular weight,
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`or hydroxypropylcellulose or hydroxypropylmethylcellulose; and 0.10 to
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`10 wt% lubricant such as magnesium stearate.
`
`in the dosage form,
`
`the composition comprising the antagonists comprises 30 to 99 wt%
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`poly(a|kylene oxide) exemplified by poly(ethylene oxide) comprising a
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`3,000,000 to 10,000,000 molecular weight, or 20 to 99 wt % of alkali
`
`carboxymethylcellulose comprising a 450,000 to 2,500,000 molecular weight
`
`available from Aqualon Co., Hopewell, Virginia; 0 to 80 wt% of an osmagent,
`
`aiso known as osmotic effective solute, represented by magnesium sulfate,
`
`sodium chloride, sodium bicarbonate, sodium succinate, sodium succinate
`
`hexahydrate, lithium chloride, potassium sulfate, sodium sulfate, lithium
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`sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium
`
`succinate, tartaric acid, carbohydrates like raffinose, sucrose, glucose,
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`lactose, fructose, sodium chloride, fructose, and potassium chloride dextrose;
`
`0.25 to 25 wt% of a hydroxyalkylcellulose selected from the group consisting
`
`of hydroxyethylcellulose, hydroxypropylcellulose, hydroxyisopropylcellulose,
`
`hydroxybutylcellulose. hydroxypropylmethylcellulose,
`
`hydroxypropylethylcellulose, hydroxypropylbutylcellulose, which
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`hydroxyalkylcellulose comprises a 7,500 to 75,000 molecular weight;
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`0 to 5 wt% ferric oxide; 0 to 3 wt% antioxidant represented by d-alpha
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`tocopherol, di-alpha tocopherol, d-alpha tocopherol acetate, dI-alpha—
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`tocopherol acetate, d-alpha tocopherol acid succinate, dl—alpha tocopherol
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`acid succinate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
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`butylated hydroxytoluene, and propyl gallate; 0.50 to 10 wt% of an
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`antagonists, selected from the group consisting of naloxone, naltrexone,
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`nalmefene, nalide, nalmexone, nalorphine, naluphine, nalorphine dinicotinate,
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`and the pharmaceutically acceptable salts thereof; and 0 to 3 wt% lubricant
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`represented by magnesium stearate, calcium stearate, corn starch, potato
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`starch, bentonite, citrus pulp, and stearic acid; and with all ingredients in the
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`push composition equal to 100 wt%, weight percent.
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`WO 97133566
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`PCTfUS97/03 l l 0
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`1O
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`EXAMPLE 6
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`The therapeutic compositions manufactured by following the above
`
`examples and substituting hydromorphone as the opioid and substituting
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`hydromorphone as the opioid provides a hydromorphone drug composition
`
`consisting of 1 to 1000 mg of hydromorphone, hydromorphone base,
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`hydromorphone salt, or hydromorphone derivative; at least one of 25 to
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`500 mg poly(alkylene oxide) of 100,000 to 750,000 molecular weight, or 25 to
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`500 mg of an alkali carboxymethylcellulose of 10,000 to 300,000 molecular
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`weight; at least one of 1 to 50 mg of poly(vinylpyrrolidone) of 10,000 to
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`300,000 molecular weight or 1 to 50 mg of hydroxypropylcellulose or
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`hydroxypropylalkylcellulose of 7,500 to 75,000 molecular weight; 0 to 10 mg
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`of a lubricant such as magnesium stearate; and 0 to 50 mg of a colorant such
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`as ferric oxide.
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`The dosage form, provided by the example, comprises a push
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`composition that forms a second layer consisting of at least one of 15 to
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`750 mg of a poly(alkylene oxide) of 3,000,000 to 7,750,000 molecular weight,
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`or 15 to 750 mg of a carboxymethylcellulose such as sodium
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`carboxymethylcellulose, and potassium carboxymethylceilulose of 450,000
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`to 2,500,000 molecular weight; 0 to 75 mg of an osmagent, also known as
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`osmotically solute represented by magnesium sulfate, sodium chloride,
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`sodium bicarbonate, sodium succinate, sodium succinate hexahydrate,
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`lithium chloride. potassium sulfate, sodium sulfate, lithium sulfate, potassium
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`acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,
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`carbohydrates like raffinose, sucrose, glucose, lactose, fructose, sodium
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`chloride, and fructose, potassium chloride and dextrose; 1 to 50 mg of a
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`hydroxyalkylcellulose selected from the group consisting of
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`hydroxyethylcellulose, hydroxypropylcellulose, hydroxyisopropylcellulose,
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`hydroxybutylcellulose, hydroxypropylmethyl-cellulose,
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`1O
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`WO 97/33566
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`11
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`PCT/US97/03l 10
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`1
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`hydroxypropylethylcellulose, hydroxypropylbuitylcellulose which
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`hydroxyalkylcellulose comprises a 7,500 to 75,000 molecular weight;
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`0 to 10 mg and more preferred 0.05 to 7.5 mg of an antioxidant represented
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`by d—alpha tocopherol acetate. dl-alpha tocopherol, ascorbyl palmitate,
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`butylated hydroxyanidole, butylated hydroxytoluene and propyl gallate;
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`0 to 10 mg of a lubricant represented by magnesium stearate, calcium
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`stearate, corn starch, potato starch, bentonite, citrus pulp, and stearic acid;
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`0 to 10 mg of a colorant; and 0.01 to 20 mg of an antagonist selected from
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`the group consisting of naloxone, naltrexone, nalmefene, nalide, nalmexone,
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`nalorphine. and naluphine.
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`EXAMM
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`The dosage form, further provided by the invention, comprises a push—
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`displacement composition for pushing the hydromorphone composition from
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`the dosage form consisting of at least one of 15 to 500 mg of a poly(alkylene
`
`oxide) of 3,000,000 to 10,000,000 molecular weight, or 15 to 750 mg of an
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`alkali carboxymethylcellulose such as sodium carboxymethylcellulose, and
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`potassium carboxymethylcellulose of 450,000 to 2,500,000 molecular weight;
`0 to 500 mg and more preferred 5 mg to 350 mg of an osmagent, also known
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`as osmotically solute represented by magnesium sulfate, sodium chloride,
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`sodium bicarbonate, sodium succinate, sodium succinate hexahydrate,
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`iithlum chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium
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`acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,
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`carbohydrates like raffinose, sucrose, glucose, lactose, fructose, sodium
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`chloride and fructose. potassium chloride and dextrose; 0.01 to 20 mg of an
`antagonist for an opioid; 1 to 50 mg of a hydroxyalkylcellulose selected from
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`the group consisting of hydroxyethylcellulose, hydroxypropylcellulose,
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`hydroxyisopropylcellulose, hydroxybutylcellulose,
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`hydroxypropylmethylcellulose. hydroxypropylethylcellulose,
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`WO 97/33566
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`PCT/US97/03 l 1 0
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`12
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`hydroxypropylbuitylcellulose which hydroxyalkylcellulose comprises a 7,500 to
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`75,000 molecular weight; 0 to 10 mg of an antioxidant represented by d-alpha
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`tocopherol acetate, dl-alpha tocopherol, ascorbyl palmitate, ascorbic acid,
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`butylated hydroxyanidole, butylated hydroxytoluene and propyl gallate;
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`0 to 10 mg of a lubricant represented by magnesium stearate, calcium
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`stearate, corn starch, potato starch, bentonite, citrus pulp, and stearic acid;
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`and 0 to 10 mg of a colorant.
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`EXAMELE§
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`The dosage form, as described in Example 2, except no colorant is
`
`present in the push composition. Also, rather than two 30 mil exit
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`passageways drilled through the semipermeable wall on the opioid—drug
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`layer, one 30 mil exit passageway is drilled on the opioid-drug layer and one
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`30 mil exit passageway is drilled on the push layer.
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`EXAMBLEfi
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`Same as Example 8, except the poly(ethylene oxide) comprising a
`
`5,000,000 to 15,000,000 number-average molecular weight in the push
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`composition.
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`T N
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`FT
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`INV
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`The expression, "exit means," for the dosage form as used, comprises
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`means and methods suitable for the metered release of beneficial drug
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`morphine from the dosage form. The exit means comprises at least one
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`passageway, orifice, or the like, through the wall for communicating with
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`morphine in the dosage form. The expression, “at least one passageway,"
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`comprises aperture, orifice, bore, micropore, porous composition, porous
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`WO 97/33566
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`13
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`PCT/US97/031 10
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`element through which the drug can migrate, hollow fiber, capillary tube,
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`porous overlay, porous insert, and the like. The expression also includes a
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`material that erodes or is leached from the wall in the fluid environment of use
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`to produce least one passageway in the dosage form. Representative
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`materials suitable for forming at least one passageway, or a multiplicity of
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`passageways, include an erodible poly(glycolic) acid, or poly(lactic) acid
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`member in the'wall, a gelatinous filament, poly(vinyl alcohol), leachable
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`materials such as fluid removable pore forming polysaccharides, salts, oxides,
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`or the like. A passageway or a plurality of passageways can be formed by
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`leaching a material such as sorbitol, lactose, fructose, maltose, mannose,
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`glucose, and the like from the wall. The passageway can have any shape
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`such as round, triangular, square, elliptical, and the like, for assisting in the
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`metered release of the opioid-drug from the dosage form. The dosage from
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`can be constructed with one or more passageways in spaced apart relations,
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`or more than one passageway on a single surface of a dosage form.
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`Passageways and equipment for forming passageways are disclosed
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`in US. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864.
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`Passageways of govern size formed by leaching are disclosed in
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`US. Pat. Nos. 4,200,098 and 4,285,987.
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`Exemplary solvents used for the present purpose comprise inorganic
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`and organic solvents that do not adversely harm the materials and the final
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`wall or the final compositions in the dosage form. The solvents broadly
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`include members selected from the group consisting of aqueous solvents,
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`alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated
`
`solvents, cycloaliphatics, aromatics, heterocyclic solvents, and mixtures
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`thereof. Typical solvents include acetone, diacetone alcohol, methanol,
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`ethanol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl
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`acetate, methyl isobutyl ketone, methyl propyl ketone, n—hexane, n-heptane,
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`ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate,
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`methylene dichloride, ethylene dichloride, propylene d ichloride, carbon
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`1 4
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`PCT/US97/03l 10
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`tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl
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`ether, isopropyl ether, cycle—hexane, cycle-octane, benzene, toluene,
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`naphtha, 1,4—dioxane, tetrahydrofuran, diglyme, aqueous and nonaqueous
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`mixtures thereof, such as acetone and water, acetone and methanol, acetone
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`and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride
`
`and methanol.
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`DISCLO
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`R
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`I
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`HE IN
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`T
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`The invention concerns a method for administering an opioid analgesic
`
`to a patient, from a dosage form characterized by a separate composition
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`comprising an antagonist for an opioid to substantially lessen opioid abuse.
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`The method provides administering 10 ng to 750 mg of an opioid
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`analgesic to the patient from a dosage form comprising a semipermeable
`
`wall permeable to aqueous-biological fluid and impervious to an opioid; an
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`opioid composition, which dosage form comprises 10 to 98 wt% opioid,
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`10 to 80 wt% poly(a|kylene oxide) possessing a 100,000 to 650,000
`
`molecular weight, and 1 to 20 wt% poly(vinyl pyrrolidone) of 40,000 to
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`75,000 molecular weight, and a push—displacement composition comprising
`
`40 to 90 wt% poly(a|kylene oxide) comprising a 3,000,000 to 15,000,000
`
`molecular weight, 0 to 80 wt% of an osmagent, and 0.25 to 25 wt% of a
`
`hydroxyalkylcellulose possessing a 7,500 to 75,000 molecular weight, and
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`0.01 to 10% of an antagonist maintained in the antagonist composition;
`
`and 0 to 5% of a colorant which opioid composition and push-displacement
`
`com :ositions are surrounded by the semipermeable wall; and exit means in
`
`the wall for delivering the opioid from the dosage form, by imbibing fluid
`
`through the wall into the dosage from causing the opioid composition, and
`
`causing the push-displacement composition to expand and push the opioid
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`drug composition through the exit means, whereby through the combined
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`WO 97/33566
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`15
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`PCT/US97/03l 10
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`operations of the dosage form, the opioid analgesic is delivered at a
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`therapeutically effective dose at a controlled rate over a sustained period
`of time.
`
`The invention is characterized additionaiiy by the invention's ability to
`administer an opioid analgesic to a patient in need of an opioid analgesic
`from a dosage form while simultaneously maintaining an opioid antagonist
`in the dosage form to prevent opioid abuse. Thus, the dosage form of the
`
`present invention provides the following advantages: (1) a therapeutic opioid
`analgesic effect that is essentially constant; (2) smoothness and consistency
`in the level of opioid analgesic delivered to the blood of the patient;
`(3) reduced potential for misuse or abuse of the opioid-containing dosage
`form; (4) maintaining the opioid and antagonist separate in the dosage form;
`(5) decrease the risk of overdosing and resulting toxic reactions;
`
`(6) improvement in patient compliance accompanied by a recommended
`therapy program; (7) eliminate undesirable interactions and reactions
`
`between the opioid and the opioid antagonist contained in the dosage form;
`(8) administering a drug opioid composition free of an antagonist; and
`(9) improve the treatment of an opioid addict to correctly and safely use
`opioid maintenance as both clinical inpatient and clinical outpatient treatment.
`
`Inasmuch as the foregoing specification comprises disclosed
`
`embodiments, it is understood what variations and modifications may be
`made herein, in accordance with the principles disclosed, without departing
`from the invention.
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`WO 97/33566
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`PCT[U597/03 1 10
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`16
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`We claim:
`
`1. A dosage form comprising:
`
`(1) a wall comprising a semipermeable composition, which wall
`
`surrounds:
`
`(2) a bilayer core comprising:
`
`(a) a first layer comprising an analgesic opioid;
`
`(b) a second layer in contact with the first layer,
`
`comprising 40 to 99 wt% of a poly(alkylene oxide) possessing a 3,000,000 to
`
`10,000,000 number average molecular weight, and 0.25 to 25 wt% of a
`
`hydroxyalkylcellulose possessing a number average mole