(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(43) International Publication Date
`8 February 2001 (08.02.2001)
`
`PCT
`
`(10) International Publication Number
`WO 01/08661 A2
`
`(51) International Patent Classification7:
`
`A61K 9/00
`
`(21) International Application Number: PCTIUS00/20413
`
`(22) International Filing Date:
`
`27 July 2000 (27.07.2000)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`601146,298
`
`English
`
`English
`
`29 July 1999 (29.07.1999) US
`
`(71) Applicant:
`INC.
`ROXANE LABORATORIES,
`[US/US]; 1809 Wilson Road, Columbus, OH 43228
`(US).
`
`(72) Inventor: MALONEY, Ann, M.; 6383 Norshire Court,
`Dublin, OH 43228 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA. MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL. PT. RO, RU, SD, SE, SG, SI, SK, SL. TJ, TM,
`TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARJPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM. AZ, BY, KG, KZ, MD, RU, TJ. TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, Fl. FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG,
`CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`Without international search report and to be republished
`upon receipt of that report.
`
`(74) Agents: RAYMOND, Robert, P. et al.; Boehringer In(cid:173)
`gelheim Corporation, 900 Ridgebury Road, P.O. Box 368.
`Ridgefield, CT 06877-0368 (US).
`
`For two-letter codes and other abbreviations, reftr to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`-=
`iiiiiiiiiiiii -iiiiiiiiiiiii
`
`iiiiiiiiiiiii
`
`iiiiiiiiiiiii
`
`~
`\C
`\C
`
`QO = -......
`= (54) Title: OPIOID SUSTAINED-RELEASED FORMULATION
`~ -------------------------------------------------------------------------
`0 > (57) Abstract: A solid, oral, controlled release dosage form comprising a therapeutically effective amount of an opioid compound,
`
`~ or a salt thereof, a matrix-forming polymer and an ionic exchange resin.
`
`

`

`wo 01/08661
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`PCTIUS00/20413
`
`OPIOID SUSTAINED-RELEASED FORMULATION
`
`BACKGROUND OF THE INVENTION
`
`Field of Invention
`
`The present invention relates to an improved pharmaceutical drug
`
`delivery composition. More particularly, the present invention is directed to a
`
`controlled release formulation, capable of providing sustained, prolonged, repeat and/or
`
`delayed release, and methods for preparing the same. Such formulations have
`
`improved delivery characteristics.
`
`Background of the Related Art
`
`It is well known in the art that the maximum time of effectiveness of
`
`many pharmaceutical formulations, including conventional opioid formulations, is only
`
`a few hours because of biological modification or elimination of the drug from the
`
`body. Consequently, doses of such pharmaceutical formulations must be taken at
`
`frequent intervals to obtain long term therapeutic levels of active drug component.
`
`Many attempts have been made
`
`to design
`
`sustained-release
`
`pharmaceutical preparations to provide a more constant level of the drug in the blood
`
`over a set period of time. Many sustained-release preparations were originally
`
`contemplated as "convenience dosage forms," that is, dosage forms designed to
`
`improve QOL (that is, the "quality of life") of a patient by eliminating the necessity of
`
`dosing a patient several times during the day and by proffering the advantage of
`
`decreased missed doses which might result from the forgetfulness of a patient. A
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`number of such preparations, however, have subsequently been shown to provide clear
`
`therapeutic benefits which cannot be obtained by multiple dosing of their active drug
`
`component (especially those drugs which display high water solubility).
`
`Among the many possible therapeutic benefits provided by sustained(cid:173)
`
`release dosage forms are: (1) the allowance of more constant blood levels over time
`
`(thus avoiding large spike and trough levels not infrequently seen with rapidly
`
`dissolving dosage forms) leading to a more consistent therapeutic effect; (2) delay of
`
`the release of drug such that significant absorption of the drug may occur at more
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`1
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`wo 01/08661
`desirable sites (e.g., causing the bulk of the absorption to occur in a more desirable pH
`
`PCT!US00/20413
`
`milieu and thus reducing decomposition of the drug); (3) reduction in concentration
`
`dependent gastrointestinal irritation (owing to reduction in the concentration of drug in
`
`contact with a particular surface of the gastrointestinal tract); and (4) improvement of
`
`drug safety with respect to acute toxicity owing to lower concentrations of drug being
`
`released at a particular time as compared to readily available dosage forms of similar
`
`dose.
`
`Numerous methods have been described to prepare sustained release
`
`formulations of drugs.
`
`One of the most common techniques for delaying release of a drug from
`
`a pharmaceutical preparation is to incorporate the drug into a continuous matrix which
`
`is resistant to rapid dissolution by aqueous body fluids. The release of the drug in such
`
`matrix-based sustained-release preparations is driven by the drug concentration
`
`gradient resulting from diffusion of fluid into the dosage form. The matrices may be
`
`comprised of either erodable polymers (i.e., polymers that break down in the body) or
`
`non-erodable polymers (polymers that are substantially unchanged upon passage
`
`through the gastrointestinal tract). While commonly employed, an intrinsic problem
`
`with many matrix release preparations is that at the later stage of release the rate of
`
`release is disadvantageously diminished as a result of decrease in the concentration
`
`gradient across the surface of the tablet, and an increase in the distance of diffusion (a
`
`problem which is particularly associated with non-erodable polymers).
`
`In one type of matrix system, sustained release is effectuated by mixing
`
`the active drug product with one or more hydrophilic hydrocolloids such that when the
`
`hydrocolloids are contacted with gastric fluid at body temperature, a sustained
`
`gelatinous mix is formed on the surface of the dosage form. The gelatinous layer
`
`reduces the dissolution rate and eventuates in slow release of the drug from the surface
`
`of the dosage form. For example, U.S. Patent Nos. 3,965,256 and 4,235,870 teach slow
`
`release pharmaceutical compositions employing hydroxyalkyl cellulose and a higher
`
`aliphatic alcohol, while U.S. Patent No. 4,140,755 to Sheth et al. discloses sustained
`
`release tablets utilizing hydroxypropylmethylcellulose having a viscosity of 4000 cps.
`
`An advantage of hydroxypropylmethylcellulose (a series of compounds designated as
`
`2
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`

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`wo 01/08661
`PCT/US00/20413
`Methocel E, F, J and K, each of which has a different chemical composition with a
`
`methoxyl content within the range of 16.5 to 30 weight percent, and a hydroxypropyl
`
`content within the range of 4 to 32 weight percent) matrix formulations is that drug
`
`release rates are generally independent of processing variables such as compaction
`
`pressure, drug particle size and the incorporation of lubricant (See, Feely et al., Int. J
`
`Pharmaceutics 41 (1988) 83 - 90). Admixture of hydroxypropylmethylcellulose with
`
`anionic surfactants is reported to improve prolongation of drug release (See, Alli et al.,
`
`J. Applied Polymer Science 42 (1991) 947 956; U.S. Patent No. 4,795,327). Drug
`
`release kinetics in swellable matrices can be described by a second order equation in
`
`which polymer chain relaxation and drug diffusion influence the release behavior (See,
`
`Colombo et al., Int.
`
`J. Pharmaceutics 88 (1992) p. 99 - 109). Release kinetics,
`
`however, can be changed towards linearity by slowing matrix swelling achieved
`
`through adjusting the external matrix surface. !d.
`
`Another common approach to form sustained-release preparations is to
`
`microencapsulate the drug in a polymeric composition thus providing a slower
`
`dissolution rate. Microcapsules are designed such that the gastric fluids slowly diffuse
`
`through the capsule walls, dissolving the active drug. The dissolved drug slowly
`
`diffuses or leaches out through the microcapsule wall into the body. U.S. Patent Nos.
`
`3,155,590, 3,341,416, 3,488,418 and 3,531,418 are representative of early work
`
`involving microencapsulation
`
`techniques. While microencapsulation
`
`is used
`
`extensively in sustained-release formulations, microencapsulation of drugs frequently
`
`fails to provide a desired sustained-release profile in that the dissolution rate often
`
`decreases rapidly over time.
`
`Efforts to adjust the rate of dissolution from
`
`microcapsules and, thus, control the timing of sustained release, are disclosed, for
`
`example, in U.S. Patent No. 3,492,397 wherein the dissolution rate is said to be
`
`controlled by adjusting the wax/ethyl cellulose ratio, U.S. Patent No. 4,752,470
`
`wherein the controlled release characteristics are varied by altering the ratio of ethyl
`
`cellulose to hydroxypropyl cellulose in the coating, and U.S. Patent No. 4,205,060
`
`wherein it is disclosed that the rate of dissolution of various drugs can be controlled by
`
`varying the thickness of the coating applied to those drugs.
`
`31
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`wo 01/08661
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`PCT/US00/20413
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`It is also known in the art to prepare sustained release formulations of
`
`medicaments by applying rupturable, relatively water-insoluble, water permeable films
`
`over an insoluble swelling type release matrix (such as a blend of polyvinylpyrrolidone
`
`and carboxyvinyl hydrophilic polymer) which contains the medicament (See, e.g., U.S.
`
`Patent No. 4,252,786 to Weiss). Sustained release formulations containing actives in a
`
`coated core material are also known (See, e.g., U.S. Patent Nos. 4,248,857 and
`
`4,309,405)
`
`Multilayering is also used to prepare solid dosage forms with sustained
`
`release profiles. Such technique involves incorporating into the dosage form two or
`
`more separate layers of granulation which are designed to release drug at different
`
`rates. By compounding each layer differently, the rate of dissolution of the layer may
`
`be controlled in a desired manner.
`
`Controlled drug release may also be effectuated by taking advantage of
`
`charge-charge interactions, such as reacting basic drugs with polymers having acidic
`
`moieties (See, e.g. U.S. Patent No. 3,608,063). For example, extended action has been
`
`obtained by loading drugs onto ion-exchange resins (See, Remington's Pharmaceutical
`
`Sciences, 15th Ed. 1975). Such extended action is presumed to result from the slow
`
`rate of the displacement reaction when drug-resin complex contacts gastrointestinal
`
`fluids and ionic constituents are displaced from the resin, essentially by other ions.
`
`Sorption of the drug to the resin is believed to be primarily due to ionic electrostatic
`
`interactions (See, Jenquin et al., Int. J. of Pharmaceutics 101 (1994) 23- 34). Thus for
`
`example, amine containing drugs (such as codeine (See, e.g. Amsel et al., Pharm.
`
`Tech. 8 (1984) 28) and propanolol (Burke et al., Drug DeveL Indust. Pharmacy 12
`
`(1986) 713 - 732)) may be bound to strong cationic exchange resins yielding restricted
`
`elution of the drug from the resinates (See, Sanghvai et al., Indian Drugs 26 (1988) 27-
`
`32). Uncoated ion exchange resin-drug complexes which delay release of a drug in the
`
`gastrointestinal tract are described in U.S. Patent Nos. 2,990,332, 3,138,525, 3,499,960,
`
`3,594,470, Belgian Pat. No. 729,827, German Pat. No. 2,246,037 and Brodkins et al.,
`
`Journal of Pharmaceutical Science, Vol. 60, pages 1523- 1527 (1971).
`
`The problem with early ion exchange resin-drug compositions was that
`
`the drug complexes were often too rapidly released in the gastrointestinal tract.
`
`4
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`wo 01/08661
`Attempts to reduce the release rate by use of diffusion barrier coatings were frequently
`
`PCT IUS00/20413
`
`found to be ineffective as the coatings were often found to peel rapidly from the
`
`complex as the complex swelled upon exposure to biological fluids. Numerous
`
`proposals have been proffered in the context of barrier-coated ion exchange resin-drug
`
`formulations to decrease the release rate including the incorporation of solvating
`
`agents, such as polyethylene glycol, higher aliphatic alcohols, and matrix-forming
`
`cellulose ethers in formulation of the resin-drug complex (See, e.g., U.S. Patent No.
`
`4,221,778, U.S. Patent No. 4,861,598 and Feely et al., Int. J. Pharmaceutics 44 (1988)
`
`131 - 139 and Pharmaceutical Research 6 (1989) 274- 278, respectively).
`
`There is a growing recognition in the medical community that a large
`
`number of patients suffer from the undertreatment of pain. Among the reasons
`
`frequently cited as causative of undertreatment are: ( 1) the failure to prescribe enough
`
`drug at the right dosage interval to reach a steady-state threshold commensurate with
`
`the pain relief needed; (2) failure of patients to comply with a given dosage regimen;
`
`and
`
`(3) the reluctance of many physicians to prescribe analgesics categorized as
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`controlled drugs based on often unfounded concerns of future addiction and fear of
`
`regulatory review of the physician's prescribing habits. For example, it has been
`
`reported that with respect to cancer pain, a large percentage of cancer patients suffer
`
`debilitating pain despite treatment with analgesics (Cleeland et al., N Eng. J. Med. 330
`
`(1994) 592- 596).
`
`Opioid analgesics comprise the major class of drugs used in the
`
`management of moderate to severe pain. Until recently most opioid analgesics were
`
`available only in rapid dissolution forms. Because opioid drugs typically are
`
`metabolized and/or excreted relatively rapidly, dosing of rapid dissolution opioid
`
`preparations is typically frequent so that steady state blood levels may be maintained.
`
`Due to rapid dissolution and absorption which results in a relatively large peak to
`
`trough differential with regard to active drug concentrations, pain relief from rapid
`
`dissolution opioids is frequently found to be quite variable.
`
`Several manufacturers presently market sustained-release opioid
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`analgesic formulations to overcome one or more of the problems associated with the
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`administration of rapid dissolution opioids. Sustained-release opioid formulations
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`5
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`wo 01/08661
`promise relief from pain with, in theory, minimal addiction liability owing to a
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`PCT/US00/20413
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`substantially lower Cmax without compromise of analgesic efficacy. The approach taken
`
`by many manufacturers has been to develop sustained-release opioid formulations
`
`which provide zero order pharmacokinetics (thereby providing very slow opioid
`
`absorption and a generally flat serum concentration curve over time) to mimic a steady(cid:173)
`
`state level. However, it has been reported that greater analgesic efficacy is achieved by
`
`formulations designed to provide more rapid initial opioid release within two to four
`
`hours, and which follow first order pharmacokinetics (See, e.g., U.S. Patent No.
`
`5,478,577). Numerous sustained-release opioid analgesic formulations have been
`
`proposed, employing, for example, granulation and coating of the opioid drug (e.g.,
`
`with a water insoluble cellulose), to control the release of the drug (See, e.g., U.S.
`
`Patent Nos. 5,478,577, 5,580,578, 5,639,476, and 5,672,360), standard release matrices
`
`(See, e.g., U.S. Patent No. 5,226,331), drug loading onto a resin utilizing wet
`
`granulation (See, e.g., U.S. Patent Nos. 4,990,131 and 5,508,042) and hydrophilic
`
`matrices in conjunction with one or more aliphatic alcohols (See, e.g., U.S. Patent Nos.
`
`4,844,909, 4,990,341, 5,508,042, and 5,549,912).
`
`While
`
`presently
`
`available
`
`sustained-release
`
`opioid
`
`analgesic
`
`formulations have improved therapeutic efficacy (i.e., dosing is less frequent and hence
`
`dosing compliance by patients is believed to be achieved over rapid dissolution-type
`
`dosage forms
`
`incorporating the same opioid analgesic)
`
`in practice, consistent
`
`amelioration of pain between administration of doses is often less than adequate.
`
`Further, manufacture of presently available sustained-release opioid analgesic
`
`formulations is complex, requiring specialized granulation and coating equipment,
`
`cumbersome techniques, and expensive excipients.
`
`There is therefore a need for an improved sustained-release formulation
`
`for the release of opioid compounds, and opioid analgesics in particular.
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`BRIEF SUMMARY OF THE INVENTION
`
`The present invention provides an
`
`improved solid, oral dosage
`
`formulation for the in vivo sustained-release of opioid compounds, and salts thereof,
`
`and in particular for the sustained-release of opioid analgesics. The formulation
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`6
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`wo 01/08661
`comprises a simple mixture of a hydrophilic matrix-forming agent, ionic exchange
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`PCT/US00/20413
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`resin, and one or more opioid compound(s). Such formulation may be prepared
`
`without the need for wet granulation of the mixture, drug loading of the resin, or the
`
`application of coating materials over the active component. However, wet granulation
`
`may be employed. Significantly improved formulations employ ionic exchange resins
`
`which are processed such that the particle size distribution of the resin is less than or
`
`equal to about 325 mesh, U.S. Standard mesh size, and the mean particle size of the
`
`resin particles is less than about 50 J.lm.
`
`In particular, the present invention provides an improved formulation for
`
`the sustained release of oxycodone. An oxycodone formulation of the present
`
`invention comprises a therapeutically effective amount of oxycodone, or salt thereof, in
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`a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the
`
`USP Basket Method at 100 rpm in 900 mL aqueous buffer (pH 1.2 for the first hour and
`
`7.5 for hours 2 through 12) at 37 o C is between about 5 and 25% (by weight)
`
`oxycodone released over the first hour, between about 16 and 36% (by weight)
`
`oxycodone released after the second hour, between about 40 and 60% (by weight)
`
`oxycodone released after six hours, and between about 60 and 80% (by weight)
`
`oxycodone released after twelve hours. The release rate is independent of pH between
`
`about 1.2 and 7.5. Additionally, the peak plasma level of oxycodone obtained in vivo
`
`occurs between five and six hours after administration of the dosage form.
`
`It has surprisingly been found that formulations having from about 5 to
`
`about 100 mg oxycodone may be manufactured to have such release rates when the
`
`formulation comprises between about 30 and 65% matrix-forming polymer, more
`
`preferably between 50 - 60% matrix-forming polymer, and between about 1 and 20%
`
`ion exchange resin. Significantly improved formulations containing approximately 10
`
`mg - 30 mg of oxycodone hydrochloride contain between about 50 to about 60%
`
`matrix-forming polymer and between about 5 and about 15% ion exchange resin.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention overcomes many of the prior art problems
`
`associated with
`
`sustained-release opioid
`
`formulations.
`
`After considerable
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`7
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`

`wo 01108661
`experimentation, with numerous conventional sustained-release modalities and
`
`PCT/US00/20413
`
`techniques (and combinations thereof), the present inventor has discovered a unique
`
`sustained-release formulation and process for opioid compounds, and in particular
`
`opioid analgesics, which does not require polymeric coatings to be applied to the
`
`active, does not require wet granulation procedures in the preparation of the
`
`formulation (although wet granulation can be used if desired), and does not require
`
`drug loading onto exchange resins, and yet which provides an advantageous release
`
`profile of the active.
`
`In a first aspect of the invention, there is disclosed a solid, oral,
`
`controlled release dosage form comprising a therapeutically effective amount of opioid
`
`compound, or a salt thereof, between about 30 and 65% of a matrix-forming polymer,
`
`more preferably between about 50 - 60% matrix-forming polymer, and between 5 and
`
`15% of a ionic exchange resin. Preferably the opioid compound included in the
`
`formulation is an opioid analgesic. It has been surprisingly found that a simple mixture
`
`of the matrix-forming agent with the opioid compound and ion-exchange resin, in the
`
`proportions disclosed, results in a formulation with improved opioid release kinetics
`
`without the need for, or recourse to, expensive coating procedures or wet granulation
`
`techniques. Coating and wet granulation may be used in conjunction with the present
`
`invention in order to obtain desired tablet configurations, but such procedures and
`
`techniques are optional. Such discovery is taught away from by presently available
`
`opioid analgesic sustained-release preparations, and goes against conventional thought
`
`with respect to highly water soluble drugs (such as the opioid analgesics) which points
`
`toward the desirability of drug loading onto the resin, of coating drug-resin complexes,
`
`and which suggests that uncoated complexes provide only a relatively short delay of
`
`drug release (See, e.g., U.S. Patent No. 4,996,047 to Kelleher et al.). The present
`
`invention also provides a pharmaceutical preparation with a different pharmacokinetic
`
`profile. Peak plasma levels of, for example, oxycodone, five to six hours after
`
`administration presents a unique profile for an analgesic.
`
`By the term "opioid," it is meant a substance, whether agonist,
`
`antagonist, or mixed agonist-antagonist, which reacts with one or more receptor sites
`
`bound by endogenous opioid peptides such as the enkephalins, endorphins and the
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`8
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`wo 01/08661
`dynorphins. By the term "opioid analgesic" it is meant a diverse group of drugs, of
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`PCT/US00/20413
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`natural, synthetic, or semi-synthetic origin, that displays opium or morphine-like
`
`properties.
`
`Opioid analgesics
`
`include, without
`
`limitation, morphine, heroin,
`
`hydromorphone, oxymorphone, buprenorphine, levorphanol, butorphanol, codeine,
`
`dihydrocodeine, hydrocodone, oxycodone, meperidine, methadone, nalbulphine,
`
`opium, pentazocine, propoxyphene, as well as less widely employed compounds such
`
`as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,
`
`clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,
`
`dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
`
`butyrate,
`
`dipipanone,
`
`eptazocine,
`
`ethoheptazine,
`
`ethylmethylthiambutene,
`
`ethylmorphine, etonitazene, fentanyl, remifentanil, hydroxypethidine, isomethadone,
`
`ketobemidone, levallorphan, levophenacylmorphan, lofentanil, meptazinol, metazocine,
`
`metopon, myrophine, narceine, nicomorphine, norpipanone, papvretum, phenadoxone,
`
`phenomorphan, phenazocine, phenoperidine, piminodine, propiram,
`
`sufentanil,
`
`tramadol, tilidine, and salts and mixtures thereof.
`
`Matrix-forming polymers useful in the present invention may comprise
`
`any polymer not readily degradable by the body. Typical matrix-forming polymers
`
`useful in the present invention, include, without limitation, hydroxypropylmethyl
`
`cellulose (in particular having a molecular weight range of 50,000 to 1,250,000
`
`daltons), ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl
`
`cellulose,
`
`carboxymethyl
`
`cellulose
`
`calcium,
`
`sodium
`
`carboxymethylcellulose,
`
`hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, camauba wax and
`
`stearyl alcohol, carbomer, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, guar
`
`gum, hydrogenated castor oil, magnesium aluminum silicate, maltodextrin, polyvinyl
`
`alcohol, polyvinyl chloride, polyethylene glycol, polyethylene glycol alginate,
`
`polymethacrylates, polyesters, polysaccharides, poloxamer, povidone, stearyl alcohol,
`
`glyceryl stearate, gelatin, acacia, dextran, alginic acid and sodium alginate, tragacanth,
`
`xanthan gum and zein. A preferred matrix-forming polymer is alkylcellulose-based,
`
`more particularly hydroxyalkylcellulose-based.
`
`Alkylcellulose matrix-forming
`
`polymers were found unexpectedly to improve the release profile of opioids when used
`
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`

`wo 01108661
`in conjunction with numerous types of ionic exchange resins. The most efficacious
`
`PCT /US00/20413
`
`matrix-forming polymers were found to be hydrophilic in nature.
`
`Among the ionic exchange resins useful in the present invention,
`
`without limitation, are styrene-divinylbenzene copolymers (e.g. IRP-69, IR-120, IRA-
`
`400 and IRP- 67 -- Rohm & Haas), copolymers of methacrylic acid and divinylbenzene
`(e.g. IRP-64 and IRP-88 -- Rohm & Haas), phenolic polyamines (e.g., IRP-58 -- Rohm
`
`& Haas), and styrene-divinylbenzene (e.g., colestyramine resin U.S.P.). The drug and
`
`resin should be oppositely charged such that the drug will bind to the resin when
`
`solubilized in the matrix formed by the matrix-former. As most opioid compounds are
`
`basic in nature, it is preferred that the ionic exchange resin be cationic in nature, and
`
`most preferably be strongly acidic in nature.
`
`It has been surprisingly found that micronization of the ionic resin
`
`particles, such that about 90% or more of the particles are less than about 325 mesh,
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`U.S. Standard mesh size, or such that the particles have an mean particle size of less
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`than about 50j..tm, significantly improves the sustained release profile of a wide array of
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`opioid compounds incorporated into a polymeric matrix, in particular a hydrophilic
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`matrix. A further aspect of the present invention therefore comprises a novel solid,
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`oral, controlled release dosage form comprising a therapeutically effective amount of
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`an opioid compound, or a salt thereof, between about 30 and 65% of a matrix-forming
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`polymer and between 5 and 15% ionic exchange resin having a mean particle size of
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`less than about 50 j..tm and a particle size distribution such that not less than 90% of the
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`particles pass through a 325 mesh sieve, US. Standard Sieve Size. In particular, the
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`present inventor has found that strongly acidic cationic exchange resins, such as IRP-69
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`(Rohm & Hass), having a particle size of less than about 325 mesh (U.S. Standard mesh
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`size) and/or a mean particle size of less than about 50j..tm, more preferably less than
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`about 44j..tm, are particularly useful in formulating improved slow-release oxycodone
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`preparations, particularly when an alkylcellulose matrix-former is utilized.
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`The formulations of the present invention may include diluents,
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`lubricants, glidants and additives, as known to those of ordinary skill in the art to
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`improve compaction, augment swallowability, decrease gastrointestinal irritation, and
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`wo 01/08661
`generally to improve the pharmaceutical elegance of the final product. Among the
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`PCT/US00/20413
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`diluents which may find application in the present formulations are, without limitation,
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`lactose, microcrystalline cellulose, starch and pregelatinized starch, sucrose,
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`compressible sugar and confectioner's sugar, polyethylene glycol, powdered cellulose,
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`calcium carbonate, calcium sulfate, croscarmellose sodium, crospovidone, dextrates,
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`dextrin, dextrose, fructose, glyceryl palmitostearate, kaolin, magnesium aluminum
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`silicate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, dibasic
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`calcium phosphate, tribasic calcium phosphate, sodium strach glycolate, sorbitol, and
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`hydrogenated vegetable oil (type 1). Among the lubricants which may find application
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`in the present formulations are, without limitation, stearic acid, calcium stearate,
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`glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
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`vegetable oil (type 1), magnesium stearate, sodium stearyl fumarate, talc and zinc
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`stearate. Suitable glidants, which may find application in the present formulations, are,
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`without limitation, colloidal silicon dioxide, magnesium trisilicate, starch, talc, and
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`tribasic calcium phosphate. Among the many additives that may find application in the
`
`present formulations are, without
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`limitation, colorants,
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`flavorants, sweetners,
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`granulating agents, and coating agents such as cellulose acetate phthalate. A
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`formulation of the present invention may comprise from about 0.1 - 500 mg opioid
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`compound, a matrix-forming polymer from about 10- 95% w/w, an ion exchange resin
`
`from about 0.1-50% w/w, a diluent from about 0 -100% w/w, a glidant from about 0-
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`5% w/w and a lubricant from about 0-20% w/w.
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`An advantage of the present formulations is that preparation of the
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`formulations typically requires only industry standard equipment.
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`Another aspect of the present invention is a process for the preparation
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`of a solid, controlled release, oral dosage form comprising the step of incorporating an
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`analgesically effective amount of an opioid analgesic, or salt thereof, in a bulk mixture
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`comprising about 30 to about 65% of a matrix-forming polymer and about 5 to about
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`15% of a ionic exchange resin, thereby forming an admixture. Further disclosed is a
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`process for the preparation of a solid, controlled release, oral dosage form comprising
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`the step of incorporating an analgesically effective amount of oxycodone, or a salt
`
`thereof, in a bulk mixture comprising about 30 to about 65% of a matrix-forming
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`wo 01108661
`polymer and about 5 to about 15% of an ionic exchange resin, wherein the dissolution
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`PCT /US00/20413
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`rate in vitro, when measured by the USP Basket Method at 100 rpm in 900 mL aqueous
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`buffer (pH 1.2 for the first hour and 7.5 for hours 2 through 12) at 37 o C is between
`
`about 5 and 25% (by weight) oxycodone released over the first hour, between about 16
`
`and 36% (by weight) oxycodone released after the second hour, between about 40 and
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`60% (by weight) oxycodone released after six hours, and between about 60 and 80%
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`(by weight) oxycodone released after twelve hours. The release rate is independent of
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`pH between about 1.2 and 7.5. Additionally, the peak plasma level of oxycodone
`
`obtained in vivo occurs between five and six hours after administration of the dosage
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`form.
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`Yet another aspect of the present invention relates to methods for
`
`reducing the range in daily dosages required to control pain in a human using the
`
`formulations described. One method comprises administering an oral controlled
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`release dosage form comprising a therapeutically effective amount of an opioid
`
`compound, or salt thereof, between 30 and 65% of a matrix-forming polymer and
`
`between 5 and 15% ionic exchange resin. Another method comprises administering a
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`solid, oral, controlled release dosage form comprising a therapeutically effective
`
`amount of oxycodone, or a salt thereof, a matrix-forming polymer and a ionic exchange
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`resin comprising a copolymerization of divinylbenzene.
`
`DETAILED DESCRIPTION OF THE
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`PREFERRED EMBODIMENTS
`
`Certain preferred embodiments of the present invention have been
`
`elucidated after numerous experiments. The preferred matrix-forming polymer of the
`
`present
`
`formulations
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`hydroxyalkylcellulose.
`
`is
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`an
`
`C6
`alkylcellulose, more preferably a C1
`In a preferred dosage form the hydroxyalkylcellulose is
`
`selected from the group consisting of: hydroxypropylcellulose, hydroxypropylmethyl
`
`cellulose and hydroxyethylcellulose. While the ionic exchange resin of the present
`
`invention may be phenolic-based polyamine condensates or styrene-divinylbenzene co(cid:173)
`
`polymers, it is preferred that the ionic exchange resin comprise a cationic exchange
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`resin, in particular one which is sulfonated, to maximize charge-charge interactions
`
`between the resin and the opioids. Cationic exchange resins particularly useful in the
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`wo 01108661
`present invention may comprise divinylbenzene co-polymers, such as a copolymer of
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`PCT/US00/20413
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`divinylbenzene and styrene, or co-polymer of divinylbenzene and methacrylic acid, and
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`the like. It is preferred that the ionic exchange resin comprise between 5 and 15% of
`
`the final dosage form, more preferably between about 7 and 10%. Preferably the final
`
`dosage form contains between about 30 - 65% matrix-f