United States Patent
`Oshlack et al.
`
`[19]
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005508042A
`[11] Patent Number:
`[451 Date of Patent:
`
`5,508,042
`Apr. 16, 1996
`
`[54] CONTROLLED RELEASE OXYCODONE
`COMPOSITIONS
`
`[75]
`
`Inventors: Benjamin Oshlack, New York, N.Y.;
`Mark Chasin, Manalpan, N.J.; John J,
`Minogue, Mount Vernon, N.Y.; Robert
`F. Kaiko, Weston, Conn.
`
`[73] Assignee: Euro-Celtigue, S.A., Luxembourg,
`Luxembourg
`
`[21] Appl. No.: 467,584
`[22] Filed:
`Jun. 6, 1995
`
`Related U.S. Application Data
`
`[60] Division of Ser. No. 81,302, Jun. 18, 1993, which is a
`continuation-in-part of Ser. No. 800,549, Nov. 27, 1991, Pat.
`No. 5,266,331.
`Int. Cl.6
`................................ A61K 9/22; A61K 9/26
`[51]
`[52] U.S. Cl . .......................... 424/468; 424/469; 424/470;
`424/486; 424/487; 424/488; 424/494; 424/496;
`424/497; 424/498; 424/501; 424/502; 424/495
`[58] Field of Search ..................................... 424/486, 464,
`424/465, 468-469, 470, 487-488, 49-98,
`494
`
`[56]
`
`4,862,598
`4,990,341
`
`References Cited
`U.S. PATENT DOCUMENTS
`8/1989 Oshlack .................................. 424/470
`2/1991 Goldie et al ............................ 424/484
`
`5,266,331 1111993 Oshlack et al. ......................... 424/468
`Primary Examiner-Edward J. Wehman
`Attorney, Agent, or Firm-Steinberg, Raskin & Davidson
`
`[57]
`ABSTRACT
`A method for substantially reducing the range in daily
`dosages required to control pain in approximately 90% of
`patients is disclosed whereby an oral solid controlled release
`dosage formulation having from about 10 to about 40 mg of
`oxycodone or a salt thereof is administered to a patient. The
`formulation provides a mean maximum plasma concentra-
`tion of oxycodone from about 6 to about 60 ng/ml from a
`mean of about 2 to about 4.5 hours after administration, and
`a mean minimum plasma concentration from about 3 to
`about 30 ng/rnl from about I 0 to about 14 hours after
`repeated "q12h" (i.e. every 12 hour) administration through
`steady-state conditions. Another embodiment is directed to
`a method for substantially reducing the range in daily
`dosages required to control pain in substantially all patients
`by administering an oral solid controlled release dosage
`formulation comprising up to about 160 mg of oxycodone or
`a salt thereof, such that a mean maximum plasma concen-
`tration of oxycodone up to about 240 ng/rnl from a mean of
`up to about 2 to about 4.5 hours after administration, and a
`mean minimum plasma concentration up to about 120 ng/ml
`from about 10 to about 14 hours after repeated "q12h" (i.e.,
`every 12 hour) administration through steady-state condi-
`tions are achieved. Controlled release oxycodone formula-
`tions for achieving the above are also disclosed.
`
`2 Claims, 5 Drawing Sheets
`
`PAIN
`INTENSITY
`3.00-
`
`2.75
`
`2.50
`
`2.25
`
`2.00
`
`1.75
`
`1.50
`
`1.25
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`0.00
`
`0
`
`7
`6
`5
`4
`OBSERVATION TIME ( hrl
`
`8
`
`9
`
`10
`
`11
`
`12
`
`TREATMENT GROUP ...,_.._._ IR OXY 15mg
`-<>-¢4 CR OXY 2Dmg
`
`-cR OXY 10mg
`-cHJ--0. PLACEBO
`~ CR OXY 30mg ...- PERCOCET
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Apr. 16, 1996
`
`Sheet 1 of 5
`
`5,508,042
`
`PAIN
`INTENSITY
`3.00-
`
`2.75
`
`2.50
`
`2.25
`
`2.00
`
`1.75
`
`1.50
`
`1.25
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`0.00
`
`0
`
`2
`
`3
`
`6
`5
`4
`1
`OBSERVATION TIME ( hr>
`
`8
`
`9
`
`10
`
`11
`
`12
`
`TREATMENT GROUP
`
`~ j( * CR OXY tOmg
`-o-o-o PLACEBO
`• 1 1 IR OXY 15mg
`-¢-<>-<>- CR OXY 20mg
`-6--&-Cr CR OXY 30mg ~-u- PERCOCET
`F/6. I
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Apr. 16, 1996
`
`Sheet 2 of 5
`
`5,508,042
`
`PAIN
`INTENSITY
`DIFFERENCE
`3.00
`
`2.75
`
`2.50
`
`2.25
`
`2.00
`
`1.75
`
`1.50
`
`1.25
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`0.00
`
`0
`
`2
`
`3
`
`7
`6
`5
`4
`OBSERVATION TIME {hr)
`
`8
`
`9
`
`10
`
`11
`
`12
`
`TREATMENT GROUP
`
`" ~ K= CR OXY 10mg
`-ooo- PLACEBO
`+-+-+ IR OXY 15mg
`-<:H>-0- CR OXY 20mg ~ CR OXY 30mg ~ PERCOCET
`
`F/6.2
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Apr. 16, 1996
`
`Sheet 3 of 5
`
`5,508,042
`
`4.0
`
`3.5
`
`3.0
`
`2.5
`
`PAIN
`RELIEF
`
`TREATMENT GROUP
`
`2
`
`3
`
`4 56 7
`OBSERVATION TIME { hr)
`
`8
`
`9
`
`10
`
`11
`
`12
`
`• • • CR OXY 10mg
`-o-o-o- PLACEBO
`• • ' IR OXY 15mg
`-<>-<>-<>- CR OXY 20mg
`-6--l::r-C'r CR OXY 30mg ~ PERCOCET
`F/6.3
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Apr. 16, 1996
`
`Sheet 4 of 5
`
`5,508,042
`
`100
`
`90
`
`80
`
`70
`
`PAIN 60
`RELIEF
`(mm)
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`2
`
`3
`
`7
`6
`5
`4
`OBSERVATION TIME (hr)
`
`8
`
`9
`
`10
`
`II
`
`12
`
`TREATMENT GROUP
`
`'* ll' *CR OXY IOrng
`1 1 1 lR OXY 15mg -o-o-o PLACEBO
`-<>--<>-0- CR OXY 20mg
`-es-cr-6 CR OXY 30mg ~PERCOCET
`
`FIG. 4
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`.... = ... N
`UJ = QO
`
`....
`UJ
`
`f.lt e,
`~
`\I) ;
`
`f.lt
`
`\C)
`~
`
`\C) ="
`
`~ !"
`~
`
`~
`
`~ a. a
`0 • 00. •
`
`7
`
`j .J
`
`FIG.5
`
`12
`
`10
`!
`
`8
`I
`
`-4--OCAcr -+-ROX
`TIME FROM LAST DOSE (HRS)
`
`6
`I
`
`3.2
`1.4
`99.1
`i03. 5
`15.6
`15 . I
`OCAcr Rox Sol
`
`T( max)
`AUG (0, 12)
`C(max)
`
`4
`
`I
`
`2
`
`I
`
`0
`Q I
`
`7 ~
`
`8
`
`2
`;J
`5
`0
`,..
`
`I
`~~~~~D~NE guJ I
`
`(no /ml)
`
`.I
`
`I
`
`14
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`5,508,042
`
`1
`CONTROLLED RELEASE OXYCODONE
`COMPOSITIONS
`
`This is a divisional of application Ser. No. 08/081,302,
`filed Jun. 18, 1993, which is a continuation-in-part of U.S.
`application Ser. No. 07/800,549, filed Nov. 27, 1991, now
`U.S. Pat. No. 5,266,331.
`
`BACKGROUND OF THE INVENTION
`Surveys of daily dosages of opioid analgesics required to
`control pain suggest that an approximately eight-fold range
`in daily dosages is required to control pain in approximately
`90% of patients. This extraordinary wide range in the 15
`appropriate dosage makes the titration process particularly
`time consuming and resource consuming, as well as leaving
`the patient without acceptable pain control for an unaccept-
`ably long duration.
`In the management of pain with opioid analgesics, it has 20
`been commonly observed and reported that there is consid-
`erable inter-individual variation in the response to a given
`dose of a given drug, and, therefore, considerable variability
`among patients in the dosage of opioid analgesic required to
`control pain without unacceptable side effects. This neces- 25
`sitates considerable effort on the part of clinicians in estab-
`lishing the appropriate dose in an individual patient through
`the time consuming process of titration, which requires
`careful assessment of both therapeutic and side effects and
`dosage adjustments over a period of days and sometimes 30
`longer before the appropriate dosage is determined. The
`American Pain Society's 3rd Edition of Principles of Anal-
`gesic Use in the Treatment of Acute Pain and Cancer Pain
`explains that one should "be aware that the optimal analge-
`sic dose varies widely among patients. Studies have shown 35
`that in all age groups, there is enormous variability in doses
`of opioids required to provide relief, even among opioid
`naive patients with identical surgical lesions .... This great
`variability underscores the need to write analgesic orders
`that include provision for supplementary doses, and to use 40
`intravenous boluses and infusions to provide rapid relief of
`severe pain .... Give each analgesic an adequate trial by
`dose titration ... before switching to another drug."
`An opioid analgesic treatment which acceptably controls
`pain over a substantially narrower daily dosage range would, 45
`therefore, substantially improve the efficiency and quality of
`pain management.
`It has previously been known in the art that controlled
`release compositions of opioid analgesics such as morphine,
`hydromorphone or salts thereof could be prepared in a 50
`suitable matrix. For example, U.S. Pat. No. 4,990,341
`(Goldie), also assigned to the,assignee of the present inven-
`tion, describes hydromorphone compositions wherein the
`dissolution rate in vitro of the dosage form, when measured
`by the USP Paddle Method at 100 rpm in 900 ml aqueous
`buffer (pH between 1.6 and 7.2) at 37° C., is between 12.5
`and 42.5% (by wt) hydromorphone released after 1 hour,
`between 25 and 55% (by wt) released after 2 hours, between
`45 and 75% (by wt) released after 4 hours and between 55
`and 85% (by wt) released after 6 hours.
`
`55
`
`2
`It is another object of the present invention to provide an
`opioid analgesic formulation which substantially improves
`the efficiency and quality of pain management.
`It is another object of the present invention to provide a
`5 method and formulation(s) which substantially reduce the
`approximately eight-fold range in daily dosages required to
`control pain in approximately 90% of patients.
`It is another object of the present invention to provide a
`method and formulation(s) which substantially reduce the
`10 variability in daily dosages and formulation requirements
`necessary to control pain in substantially all patients.
`It is yet another object of the present invention to provide
`a method for substantially reducing the time and resources
`need to titrate patients requiring pain relief on opioid anal-
`gesics.
`It is yet another object of the present invention to provide
`controlled release opioid formulations which have substan-
`tially less inter-individual variation with regard to the dose
`of opioid analgesic required to control pain without unac-
`ceptable side effects.
`The above objects and others are attained by virtue of the
`present invention, which is related to a solid controlled
`release oral dosage form, the dosage form comprising from
`about 10 to about 40 mg of oxycodone or a salt thereof in a
`matrix wherein the dissolution rate in vitro of the dosage
`form, when measured by the USPPaddle Method at 100 rpm
`in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C.
`is between 12.5 and 42.5% (by wt) oxycodone released after
`1 hour, between 25 and 56% (by wt) oxycodone released
`after 2 hours, between 45 and 75% (by wt) oxycodone
`released after 4 hours and between 55 and 85% (by wt)
`oxycodone released after 6 hours, the in vitro release rate
`being substantially independent of pH, such that the peak
`plasma level of oxycodone obtained in vivo occurs between
`2 and 4.5 hours after administration of the dosage form.
`USP Paddle Method is the Paddle Method described, e.g.,
`in U.S. Pharmacopoeia XXII (1990).
`In the present specification, "substantially independent of
`pH" means that the difference, at any given time, between
`the amount of oxycodone released at, e.g., pH 1.6, and the
`amount released at any other pH, e.g., pH 7.2 (when
`measured in vitro using the USP Paddle Method at 100 rpm
`in 900 ml aqueous buffer), is 10% (by weight) or less. The
`amounts released being, in all cases, a mean of at least three
`experiments.
`The present invention is further related to a method for
`substantially reducing the range in daily dosages required to
`control pain in approximately 90% of patients, comprising
`administering an oral solid controlled release dosage for-
`mulation comprising from about 10 to about 40 mg of
`oxycodone or a salt thereof, said formulation providing a
`mean maximum plasma concentration of oxycodone from
`about 6 to about 60 ng/ml from a mean of about 2 to about
`4.5 hours after administration, and a mean minimum plasma
`concentration from about 3 to about 30 ng/ml from a mean
`of about 10 to about 14 hours after repeated "q12h" (i.e.,
`every 12 hour) administration through steady-state condi-
`tions.
`The present invention is further related to a method for
`substantially reducing the range in daily dosages required to
`control pain in substantially all patients, comprising admin-
`istering an oral solid controlled release dosage formulation
`comprising up to about 160 mg of oxycodone or a salt
`thereof, said formulation providing a mean maximum
`plasma concentration of oxycodone up to about 240 ng/ml
`from a mean of up to about 2 to about 4.5 hours after
`
`60
`
`SUMMARY OF THE INVENTION
`It is an object of the present invention to provide a method
`for substantially improving the efficiency and quality of pain
`management.
`
`65
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`5,508,042
`
`3
`administration, and a mean minimum plasma concentration
`up to about 120 ng/ml from a mean of about 10 to about 14
`hours after repeated "q12h" (i.e., every 12 hour) adminis-
`tration through steady-state conditions.
`The present invention is further related to controlled
`release oxycodone formulations comprising from about 10
`to about 40 mg oxycodone or a salt thereof, said formula-
`tions providing a mean maximum plasma concentration of
`oxycodone from about 6 to about 60 ng/ml from a mean of
`about 2 to about 4.5 hours after administration, and a mean
`minimum plasma concentration from about 3 to about 30
`ng/ml from about 10 to about 14 hours after repeated q12h
`administration through steady-state conditions.
`The present invention is further related to controlled
`release oxycodone formulations comprising up to about 160
`mg oxycodone or a salt thereof, said formulations providing
`a mean maximum plasma concentration of oxycodone up to
`about 240 ng/ml from a mean of about 2 to about 4.5 hours
`after administration, and a mean minimum plasma concen-
`tration up to about 120 ng/ml from about 10 to about 14
`hours after repeated q12h administration through steady-
`state conditions.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`The following drawings are illustrative of embodiments
`of the invention and are not meant to limit the scope of the
`invention as encompassed by the claims.
`FIGS. 1-4 are graphs showing the time-effect curves for
`pain intensity differences and pain relief for Example 17;
`FIG. 5 is a graph showing the mean plasma oxycodone
`concentration for a 10 mg controlled release oxycodone
`formulation prepared in accordance with the present inven-
`tion and a study reference standard.
`
`5
`
`25
`
`4
`Morphine, which is considered to be the prototypic opioid
`analgesic, has been formulated into a 12 hour controlled-
`release formulations (i.e., MS Contin® tablets, commer-
`cially available from Purdue Pharma, L.P.). Despite the fact
`that both controlled-release oxycodone and controlled
`release morphine administered every 12 hours around-the-
`clock possess qualitatively comparable clinical pharmaco-
`kinetic characteristics, the oxycodone formulations of the
`presently claimed invention can be used over approximately
`10 Y2 the dosage range as compared to commercially available
`controlled release morphine formulations (such as MS Con-
`tin®) to control 90% of patients with significant pain.
`Repeated dose studies with the controlled release oxyc-
`odone formulations administered every 12 hours in com-
`15 parison with immediate release oral oxycodone adminis-
`tered every 6 hours at the same total daily dose result in
`comparable extent of absorption, as well as comparable
`maximum and minimum concentrations. The time of maxi-
`mum concentration occurs at approximately 2-4.5 hours
`after oral administration with the controlled-release product
`20 as compared to approximately 1 hour with the immediate
`release product. Similar repeated dose studies with MS
`Contin® tablets as compared to immediate release morphine
`provide for comparable relative results as with the controlled
`release oxycodone formulations of the present invention.
`There exists no substantial deviation from parallelism of
`the dose-response curves for oxycodone either in the forms
`of the controlled release oxycodone formulations of the
`present invention, immediate release oral oxycodone or
`parenteral oxycodone in comparison with oral and parenteral
`30 opioids with which oxycodone has been compared in terms
`of dose-response studies and relative analgesic potency
`assays. Beaver, et al., "Analgesic Studies of Codeine and
`Oxycodone in Patients with Cancer. II. Comparisons of
`Intramuscular Oxycodone with Intramuscular Morphine and
`35 Codeine", J. Pharmacol. and Exp. Ther., Vol. 207, No.1, pp.
`101-108, reported comparable dose-response slopes for
`parenteral oxycodone as compared to parenteral morphine
`and comparable dose-response slopes for oral as compared
`to parenteral oxycodone.
`A review of dose-response studies and relative analgesic
`assays of mu-agonist opioid analgesics, which include oxy-
`codone, morphine, hydromorphone, levorphanol, metha-
`done, meperidine, heroin, all indicate no significant devia-
`tion from parallelism in their dose response relationships.
`45 This is so well established that it has become an underlining
`principal providing for establishing relative analgesic
`potency factors and dose ratios which are commonly utilized
`when converting patients from one m!l-agonist analgesic to
`another regardless of the dosage of the former. Unless the
`dose-response curves are parallel, conversion factors would
`not be valid across the wide range of dosages involved when
`substituting one drug for another.
`The clinical significance provided by the controlled
`release oxycodone formulations of the present invention at
`a dosage range from about 10 to about 40 mg every 12 hours
`for acceptable pain management in approximately 90% of
`patients with moderate to severe pain, as compared to other
`opioid analgesics requiring approximately twice the dosage
`range provides for the most efficient and humane method of
`managing pain requiring repeated dosing. The expertise and
`time of physicians and nurses, as well as the duration of
`unacceptable pain patients must endure during the opioid
`analgesic titration process is substantially reduced through
`the efficiency of the controlled release oxycodone formula-
`tions of the present invention.
`It is further clinically significant that a dose of about 80
`mg controlled release oxycodone administered every 12
`
`DETAILED DESCRIPTION
`It has now been surprisingly discovered that the presently
`claimed controlled release oxycodone formulations accept-
`ably control pain over a substantially narrower, approxi- 40
`mately four-fold (10 to 40 mg every 12 hours-around-the-
`clock dosing) in approximately 90% of patients. This is in
`sharp contrast to the approximately eight-fold range required
`for approximately 90% of patients for opioid analgesics in
`general.
`The use of from about 10 mg to about 40 mg of 12-hourly
`doses of controlled-release oxycodone to control pain in
`approximately 90% of patients relative to a wider dosage
`range of other m!l-agonist analgesics, indicated for moderate
`to severe pain, is an example of the unique characteristics of 50
`the present invention. It should also be appreciated that the
`remaining 10% of patients would also be successfully man-
`aged with 12-hourly controlled-release oxycodone over a
`relatively narrower dosage range than with the use of other
`similar analgesics. Substantially all of those remaining 10% 55
`of patients not managed with controlled release oxycodone,
`10 mg to 40 mg every 12 hours, would be managed using
`dosages of greater than 40 mg every 12 hours through 160
`mg every 12 hours utilizing any one of a number or
`multiples of formulation strengths such as 10, 20, 40, 80 and 60
`160 mg unit dosages or combinations thereof. In contrast,
`the use of other similar analgesics such as morphine would
`require a wider range of dosages to manage the remaining
`10% of patients. For example, daily dosages of oral mor-
`phine equivalents in the range of 1 gram to more than 20 65
`grams have been observed. Similarly, wide dosage ranges of
`oral hydromorphone would also be required.
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`5,508,042
`
`55
`
`5
`hours will provide acceptable pain relief management in,
`e.g., approximately 95% of patients with moderate to severe
`pain, and that about 160 mg controlled release oxycodone
`administered every 12 hours will provide acceptable pain
`relief management in, e.g., approximately all patients with 5
`moderate to severe pain.
`In order to obtain a controlled release drug dosage form
`having at least a 12 hour therapeutic effect, it is usual in the
`pharmaceutical art to produce a formulation that gives a
`peak plasma level of the drug between about 4-8 hours after 10
`administration (in a single dose study). The present inven-
`tors have surprisingly found that, in the case of oxycodone,
`a peak plasma level at between 2-4.5 hours after adminis-
`tration gives at least 12 hours pain relief and, most surpris-
`ingly, that the pain relief obtained with such a formulation 15
`is greater than that achieved with formulations giving peak
`plasma levels (of oxycodone) in the normal period of up to
`2 hours after administration.
`A further advantage of the present composition, which
`releases oxycodone at a rate that is substantially independent
`of pH, is that it avoids dose dumping upon oral administra-
`tion. In other words, the oxycodone is released evenly
`throughout the gastrointestinal tract.
`The present oral dosage form may be presented as, for
`example, granules, spheroids or pellets in a capsule or in any
`other suitable solid form. Preferably, however, the oral
`dosage form is a tablet.
`The present oral dosage form preferably contains between
`1 and 500 mg, most especially between 10 and 160 mg, of 30
`oxycodone hydrochloride. Alternatively, the dosage form
`may contain molar equivalent amounts of other oxycodone
`salts or of the oxycodone base.
`The present matrix may be any matrix that affords in vitro
`dissolution rates of oxycodone within the narrow ranges
`required and that releases the oxycodone in a pH indepen-
`dent manner. Preferably the matrix is a controlled release
`matrix, although normal release matrices having a coating
`that controls the release of the drug may be used. Suitable
`materials for inclusion in a controlled release matrix are
`(a) Hydrophilic polymers, such as gums, cellulose ethers,
`acrylic resins and protein derived materials. Of these poly-
`mers, the cellulose ethers, especially hydroxyalkylcelluloses
`and carboxyalkylcelluloses, are preferred. The oral dosage
`form may contain between 1% and 80% (by weight) of at 45
`least one hydrophilic or hydrophobic polymer.
`(b) Digestible, long chain (C8-C50, especially C12-C40),
`substituted or unsubstituted hydrocarbons, such as fatty
`acids, fatty alcohols, glyceryl esters of fatty acids, mineral
`and vegetable oils and waxes. Hydrocarbons having a melt- 50
`ing point of between 25° and 90° C. are preferred. Of these
`long chain hydrocarbon materials, fatty (aliphatic) alcohols
`are preferred. The oral dosage form may contain up to 60%
`(by weight) of at least one digestible, long chain hydrocar-
`bon.
`(c) Polyalkylene glycols. The oral dosage form may
`contain up to 60% (by weight) of at least one polyalkylene
`glycol.
`One particular suitable matrix comprises at least one 60
`water soluble hydroxyalkyl cellulose, at least one C12-C36,
`preferably C14-C22, aliphatic alcohol and, optionally, at
`least one polyalkylene glycol.
`The at least one hydroxyalkyl cellulose is preferably a
`hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropy-
`lcellulose, hydroxypropylmethylcellulose and, especially,
`hydroxyethyl cellulose. The amount of the at least one
`
`6
`hydroxyalkyl cellulose in the present oral dosage form will
`be determined, inter alia, by the precise rate of oxycodone
`release required. Preferably however, the oral dosage form
`contains between 5% and 25%, especially between 6.25%
`and 15% (by wt) of the at least one hydroxyalkyl cellulose.
`The at least one aliphatic alcohol may be, for example,
`lauryl alcohol, myristyl alcohol or stearyl alcohol. In par-
`ticularly preferred embodiments of the present oral dosage
`form, however, the at least one aliphatic alcohol is cetyl
`alcohol or cetostearyl alcohol. The amount of the at least one
`aliphatic alcohol in the present oral dosage form will be
`determined, as above, by the precise rate of oxycodone
`release required. It will also depend on whether at least one
`polyalkylene glycol is present in or absent from the oral
`dosage form. In the absence of at least one polyalkylene
`glycol, the oral dosage form preferably contains between
`20% and 50% (by wt) of the at least one aliphatic alcohol.
`When at least one polyalkylene glycol is present in the oral
`dosage form, then the combined weight of the at least one
`aliphatic alcohol and the at least one polyalkylene glycol
`20 preferably constitutes between 20% and 50% (by wt) of the
`total dosage.
`In one preferred embodiment, the controlled release com-
`position comprises from about 5 to about 25% acrylic resin
`25 and from about 8 to about 40% by weight aliphatic alcohol
`by weight of the total dosage form. A particularly preferred
`acrylic resin comprises Eudragit® RS PM, commercially
`available from Rohm Pharma.
`In the present preferred dosage form, the ratio of, e.g., the
`at least one hydroxyalkyl cellulose or acrylic resin to the at
`least one aliphatic alcohol/polyalkylene glycol determines,
`to a considerable extent, the release rate of the oxycodone
`from the formulation. A ratio of the at least one hydroxyalkyl
`cellulose to the at least one aliphatic alcohol/polyalkylene
`35 glycol of between 1:2 and 1:4 is preferred, with a ratio of
`between 1:3 and 1:4 being particularly preferred.
`The at least one polyalkylene glycol may be, for example,
`polypropylene glycol or, which is preferred, polyethylene
`glycol. The number average molecular weight of the at least
`40 one polyalkylene glycol is preferred between 1000 and
`15000 especially between 1500 and 12000.
`Another suitable controlled release matrix would com-
`prise an alkylcellulose (especially ethyl cellulose), a c!2 to
`c36 aliphatic alcohol and, optionally, a polyalkylene glycol.
`In addition to the above ingredients, a controlled release
`matrix may also contain suitable quantities of other mate-
`rials, e.g. diluents, lubricants, binders, granulating aids,
`colorants, flavorants and glidants that are conventional in the
`pharmaceutical art.
`As an alternative to a controlled release matrix, the
`present matrix may be a normal release matrix having a coat
`that controls the release of the drug. In particularly preferred
`embodiments of this aspect of the invention, the present
`dosage form comprises film coated spheroids containing
`active ingredient and a non-water soluble spheronising
`agent. The term spheroid is known in the pharmaceutical art
`and means a spherical granule having a diameter of between
`0.5 mm and 2.5 mm especially between 0.5 mm and 2 mm.
`The spheronising agent may be any pharmaceutically
`acceptable material that, together with the active ingredient,
`can be spheronised to form spheroids. Microcrystalline
`cellulose is preferred.
`A suitable microcrystalline cellulose is, for example, the
`65 material sold as Avicel PH 101 (Trade Mark, FMC Corpo-
`ration). According to a preferred aspect of the present
`invention, the film coated spheroids contain between 70%
`
`KASHIV1016
`IPR of Patent No. 9,492,392
`
`

`

`5,508,042
`
`8
`(b) extruding the blended mixture to give an extrudate,
`(c) spheronising the extrudate until spheroids are formed,
`and
`(d) coating the spheroids with a film coat.
`The present solid, controlled release, oral dosage form
`and processes for its preparation will now be described by
`way of example only.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`The following examples illustrate various aspects of the
`present invention. They are not meant to be construed to
`limit the claims in any manner whatsoever.
`
`EXAMPLE 1
`
`7
`and 99% (by wt), especially between 80% and 95% (by wt),
`of the spheronising agent, especially microcrystalline cellu-
`lose.
`In addition to the active ingredient and spheronising
`agent, the spheroids may also contain a binder. Suitable 5
`binders, such as low viscosity, water soluble polymers, will
`be well known to those skilled in the pharmaceutical art.
`However, water soluble hydroxy lower alkyl cellulose, such
`as hydroxy propyl cellulose, are preferred. Additionally (or
`alternatively) the spheroids may contain a water insoluble 10
`polymer, especially an acrylic polymer, an acrylic copoly-
`mer, such as a methacrylic acid-ethyl acrylate copolymer, or
`ethyl cellulose.
`The spheroids are preferably film coated with a material
`that permits release of the oxycodone (or salt) at a controlled 15
`rate in an aqueous medium. The film coat is chosen so as to
`achieve, in combination with the other ingredients, the
`in-vitro release rate outlined above (between 12.5% and
`42.5% (by wt) release after 1 hour, etc.).
`The film coat will generally include a water insoluble 20
`material such as
`(a) a wax, either alone or in admixture with a fatty
`alcohol,
`(b) shellac or zein,
`(c) a water insoluble cellulose, especially ethyl cellulose,
`(d) a polymethacrylate, especially Eudragit®.
`Preferably, the film coat comprises a mixture of the water
`insoluble material and a water soluble material. The ratio of
`water insoluble to water soluble material is determined by, 30
`amongst other factors, the release rate required and the
`solubility characteristics of the materials selected.
`The water soluble material may be, for example, polyvi-
`nylpyrrolidone or, which is preferred, a water soluble cel-
`lulose, especially hydroxypropylmethyl cellulose.
`Suitable combinations of water insoluble and water
`soluble materials for the film coat include shellac and
`polyvinylpyrrolidone or, which is preferred, ethyl cellulose
`and hydroxypropylmethyl cellulose.
`In order to facilitate the preparation of a solid, controlled 40
`release, oral dosage form according to this invention there is
`provided, in a further aspect of the present invention, a
`process for the preparation of a solid, controlled release, oral
`dosage form according to the present invention comprising
`incorporating hydromorphone or a salt thereof in a con- 45
`trolled release matrix. Incorporation in the matrix may be
`effected, for example, by
`(a) forming granules comprising at least one water soluble
`hydroxyalkyl cellulose and oxycodone or a oxycodone
`salt,
`(b) mixing the hydroxyalkyl cellulose containing granules
`with at least one C12-C36 aliphatic alcohol, and
`(c) optionally, compressing and shaping the granules.
`Preferably, the granules are formed by wet granulating 55
`the hydroxyalkyl cellulose/oxycodone with water. In a
`particularly preferred embodiment of this process, the
`amount of water added during the wet granulation step
`is preferably between 1.5 and 5 times, especially
`between 1.75 and 3.5 times, the dry weight of the 60
`oxycodone.
`The present solid, controlled release, oral dosage form
`may also be prepared, in the form of film coated spheroids,
`by
`(a) blending a mixture comprising oxycodone or a oxy- 65
`codone salt and a non-water soluble spheronising
`agent,
`
`Controlled Release Oxycodone HCl 30 mg
`Tablets-Aqueous Manufacture
`The required quantities of oxycodone hydrochloride,
`spray-dried lactose, and Eudragit® RS PM are transferred
`into an appropriate-size mixer, and mixed for approximately
`5 minutes. While the powders are mixing, the mixture is
`25 granulated with enough water to produce a moist granular
`mass. The granules are then dried in a fluid bed dryer at 60°
`C., and then passed through an 8-mesh screen. Thereafter,
`the granules are redried and pushed through a 12-mesh
`screen. The required quantity of stearyl alcohol is melted at
`approximately 60°-70° C., and while the granules are mix-
`ing, the melted stearyl alcohol is added. The warm granules
`are returned to the mixer.
`The coated granules are removed from the mixer and
`allowed to cool. The granules are then passed through a
`35 12-mesh screen. The granulate is then lubricated by mixing
`the required quantity of talc and magnesium stearate in a
`suitable blender. Tablets are compressed to 375 mg in weight
`on a suitable tableting machine. The formula for the tablets
`of Example 1 is set forth in Table 1 below:
`
`50
`
`TABLE 1
`Formula of Oxycodone HCl 30-mg Tablets
`
`Component
`
`mgffablet
`
`% (bywt)
`
`Oxycodone Hydrochloride
`Lactose (spray-dried)
`Eudragit ® RS PM
`Purified Water
`Stearyl Alcohol
`Talc
`Magnesium Stearate
`
`30.0
`. 213.75
`45.0
`q.s*
`75.0
`7.5
`3.75
`
`Total:
`
`375.0
`
`8
`57
`12
`
`20
`2
`1
`
`100
`
`*Used in manufacture and remains in final product as residual quantity only.
`
`The tablets of Example 1 are then tested for dissolution
`via the USP Basket Method, 37° C., 100 RPM, first hour 700
`rnl gastric fluid at pH 1.2, then changed to 900 rnl at 7 .5. The
`results are set forth in Table 2 below:
`
`TABLE 2
`Dissolutio