United States Patent [19J
`Stark et al.
`
`[54]
`
`[75]
`
`ORAL MORPHINE MULTIPARTICUIATE
`FORMUlATION
`
`Inventors: Paul Stark; Sean Cunningham;
`Jagathesan Moodley, all of Althone,
`Ireland
`
`[73]
`
`Assignee: Elan Corporation, pic, Dublin, Ireland
`
`[21]
`
`Appl. No.: 08/977,965
`
`[22]
`
`Filed:
`
`Nov. 25, 1997
`
`Related U.S. Application Data
`[60] Provisional application No. 60/062,525, Oct. 17, 1997.
`Int. Cl? ....................................................... A61K 9/14
`[51]
`[52] U.S. Cl. .......................... 424/489; 424/464; 424/468;
`424/469; 424/471; 424/472; 424/482; 424/484;
`424/487
`[58] Field of Search ..................................... 424/464, 468,
`424/469, 471, 472, 482, 484, 487, 489
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`9/1986 Panoz et al. .............................. 424/19
`4,609,542
`9/1986 Panoz et al. .............................. 424/80
`4,610,875
`5/1987 Panoz et al. ............................ 424/494
`4,663,150
`4,716,040 12/1987 Panoz et al. ............................ 424/459
`1!1988 Panoz et al. ............................ 424/459
`4,721,619
`2/1988 Panoz et al. ............................ 424/465
`4,726,951
`9/1988 Panoz et al. .............................. 424/80
`4,769,236
`4/1989 Panoz et al. ............................ 424/458
`4,820,521
`5/1989 Panoz et al. ............................ 424/458
`4,826,688
`9/1989 Panoz et al. ............................ 424/473
`4,863,742
`1!1990 Geoghegan et al. .................... 424/461
`4,891,230
`1!1990 Geoghegan et al. .................... 424/497
`4,894,240
`2/1990 Panoz et al. ............................ 424/468
`4,898,737
`4/1990 Geoghegan et al. .................... 424/461
`4,917,899
`4,970,075 11/1990 Oshlack .................................. 424/451
`3/1991 Geoghegan et al. .................... 424/497
`5,002,776
`1/1993 Malmquist-Granlund et al. .... 424/490
`5,178,868
`4/1993 Morella et al. ......................... 424/469
`5,202,128
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006066339A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,066,339
`May 23,2000
`
`6/1993 Geoghegan et al. ....................
`5,219,621
`7/1993 Amidon et al. .........................
`5,229,131
`5,273,760 12/1993 o~hlack et al. .........................
`2/1994 Oshlack et al. .........................
`5,286,493
`7/1994 Morella et al. .........................
`5,330,766
`8/1994 Geoghegan et al. ....................
`5,336,504
`5,364,620 11/1994 Geoghegan et al. ....................
`1/1995 Morella et al. .........................
`5,378,474
`5/1995 Oshlack et al. .........................
`5,411,745
`5,478,577 12/1995 Sadder et al. ..........................
`5/1996 Persson et al. .........................
`5,520,931
`1/1997 Hayashida et al. .....................
`5,593,694
`1/1997 Merrill et al. ..........................
`5,593,695
`4/1997 Geoghegan et al. ....................
`5,616,345
`8/1997 Olsson et al. ...........................
`5,656,291
`9/1997 Merrill et al. ..........................
`5,667,805
`4/1998 Staniforth et al. ......................
`5,741,524
`
`424/462
`424/451
`424/480
`424/468
`424/490
`424/462
`424/497
`424/469
`424/456
`424/489
`424/473
`424/468
`424/480
`424/497
`424/458
`424/473
`424/489
`
`FOREIGN PATENT DOCUMENTS
`
`5/1990 European Pat. Off ..
`0 365 947
`7/1990 European Pat. Off ..
`0 377 518
`8/1994 European Pat. Off ..
`0 609 961
`1/1995 European Pat. Off ..
`0 631 781
`1/1995 European Pat. Off ..
`0 636 370
`4/1995 European Pat. Off ..
`0 647 448
`2/1994 WIPO.
`wo 94/03161
`wo 94/22431 10/1994 WIPO.
`wo 95/14460
`1/1995 WIPO.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner--Lakshmi Channavajjala
`Attorney, Agent, or Firm-Marla J. Church
`ABSTRACT
`
`[57]
`
`An oral morphine multiparticulate formulation for once(cid:173)
`daily administration to a patient, comprising sustained
`release particles each having a core containing water soluble
`morphine and an osmotic agent, the core being coated with
`a rate-controlling polymer coat comprised of ammonio
`methacrylate copolymers in an amount sufficient to achieve
`therapeutically effective plasma levels of morphine over at
`least 24 hours in the patient.
`
`27 Claims, 4 Drawing Sheets
`
`lOOt
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`
`26
`
`TIME
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 1 of 16
`
`

`

`U.S. Patent
`
`May 23,2000
`
`Sheet 1 of 4
`
`6,066,339
`
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`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 2 of 16
`
`

`

`U.S. Patent
`
`May 23,2000
`
`Sheet 2 of 4
`
`6,066,339
`
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`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 3 of 16
`
`

`

`U.S. Patent
`
`May 23,2000
`
`Sheet 3 of 4
`
`6,066,339
`
`_,'t i
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`
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`oo ~ ~ N
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`ID ~ N
`d
`or- ~ ~ ~ .,;--
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 4 of 16
`
`

`

`FIGURE 4
`
`0 •
`IJ).
`•
`~
`~
`~
`
`~ = ~
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`~ = ~
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`N = = =
`1!"1' .. Q -., ..
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`rJl =(cid:173)!'t
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`
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`
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`
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`
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`
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`
`PLASMA
`CONCENTRATION
`
`o.ooa+------+-------;-------;--------r------~-------r-------r-------+------~
`8.00
`12.00
`16.00
`20.00
`24.00
`28.00
`0.00
`4.00
`36.00
`32.00
`TIME
`
`~ -... = ~
`
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`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 5 of 16
`
`

`

`6,066,339
`
`1
`ORAL MORPHINE MULTIPARTICUIATE
`FORMUlATION
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/062,525, filed Oct. 17, 1997.
`
`FIELD OF THE INVENTION
`This invention relates to an oral morphine formulation
`which is suitable for once-daily administration and which
`minimises the risk of side effects caused by morphine
`attributable to fluctuations in plasma morphine levels.
`
`5
`
`2
`constipation, sedation, confusion and loss of appetite. It has
`been suggested that the use of modified release morphine
`formulations, apart from their convenience and their ability
`to provide continuous analgesia, may also result in a lower
`incidence and severity of morphine-related side effects
`(Gourlay, G. K. et al., Pain (1997) 69, 295-302.
`U.S. Pat. No. 5,478,577, describes and claims a method
`for providing effective pain management in humans for a
`time period of about 24 hours using an opioid analgesic such
`10 as morphine in a solid, controlled-release oral dosage form.
`This dosage form following administration provides a rapid
`rate of initial rise of the plasma concentration of the opioid,
`such that peak plasma levels thereof occur from about 2 to
`about 8 hours and which provides large peak to trough
`15 fluctuations in opioid levels even after repeated dosing. Such
`large peak to trough fluctuations would be expected to
`maximise attendant morphine-related side effects.
`In order to minimise morphine-related side effects, which
`are a distinct disadvantage and which add to the suffering of
`those experiencing long-term pain such as cancer patients,
`what is required is a formulation which exhibits minimal
`peak to trough fluctuations, namely a substantially fiat
`plasma profile over the dosage period.
`A further requirement of a therapeutically effective mor(cid:173)
`phine sustained release formulation is one which maintains
`a high plasma concentration of morphine over the dosage
`period.
`In case of U.S. Pat. No. 5,478,577 mentioned above peak
`plasma levels occur from about 2 to about 8 hours after
`administration.
`EP 631,781 discloses morphine formulations having
`extended controlled release with peak plasma levels in vitro
`occurring from about 2 to about 6 hours after administration.
`Likewise, EP 636,370 discloses morphine-containing sus(cid:173)
`tained release formulations which are described as giving in
`vivo peak plasma levels relatively early after administration,
`that is from 1.0 to 6 hours after administration and a W 50 (a
`parameter defined therein as the width of the plasma profile
`at 50% CM->X i.e. the duration over which the plasma
`concentrations are equal to or greater than 50% of the peak
`concentration) for morphine of between 4 and 12 hours.
`EP 609,961 discloses sustained released compositions
`which can contain morphine as active ingredient and which
`45 can maintain an active ingredient blood level at steady state
`of at least 75% of maximum blood level (t @0.75 em=) for
`approximately 3.5 hours or greater and so that the time at
`which the active ingredient reaches its maximum concen(cid:173)
`tration (tmaJ is 4.5 hours or greater.
`WO 94/22431 discloses an oral morphine preparation
`which achieves a mean serum concentration of morphine of
`at least 50% of the maximum serum concentration during at
`least 12 hours after administration of a single dose of the
`55 preparation.
`SUMMARY OF THE INVENTION
`
`40
`
`The invention provides an oral morphine multiparticulate
`formulation for once-daily administration to a patient, com(cid:173)
`prising sustained release particles each having a core con(cid:173)
`taining water soluble morphine and an osmotic agent, the
`core being coated with a rate-controlling polymer coat
`comprised of ammonia methacrylate copolymers in an
`amount sufficient to achieve therapeutically effective plasma
`65 levels of morphine over at least 24 hours in the patient.
`As demonstrated hereinbelow, the formulation according
`to the invention achieves therapeutically effective plasma
`
`BACKGROUND OF THE INVENTION
`Morphine is typically used in therapy in the form of
`morphine sulfate or a hydrate thereof.
`Morphine sulfate is an opioid compound with specific
`affinity for the receptors J.l, o and K. The principal actions of
`therapeutic value are analgesia and sedation. The precise
`mechanism of the analgesic action is unknown. Specific
`opioid receptors have been located in the brain and the spinal 20
`cord and are likely to play a role in the expression of
`analgesic effects.
`Following oral administration of a given dose of
`morphine, the amount eventually absorbed is essentially the
`same irrespective of the formulation. Morphine is subject to 25
`presystemic elimination (metabolism in the gut wall and
`liver) and therefore only 40% of the administered dose
`reaches systemic circulation. Virtually all morphine is con(cid:173)
`verted to glucuronide metabolites; morphine-3-glucuronide
`(present in highest concentrations but inactive) and 30
`morphine-6-glucuronide. A large body of evidence from
`animal experiments show that morphine-6-glucuronide is a
`potent 11-opioid agonist, with the potential to contribute to
`morphine's analgesic response.
`Morphine undergoes significant hepatic first pass metabo- 35
`lism to form morphine-6-glucuronide. About 90% of a dose
`of morphine is excreted in the urine mainly as either this
`conjugate or as morphine-3-glucuronide, while the remain(cid:173)
`der is excreted in the bile.
`Morphine sulphate is generally indicated for the relief of
`moderate to severe pain most particularly in palliative care,
`surgery and myocardial infarction. It is intended for use in
`patients who require repeated dosing with potent opioid
`analgesic over periods of more than a few days.
`Various slow/sustained release morphine formulations
`have been developed and are described in the literature.
`Extended release oral morphine sulphate preparations are
`considered to be clinically significant as they impart equiva(cid:173)
`lent to superior analgesia with respect to immediate release 50
`forms in addition to reducing the likelihood of morphine
`associated side effect<>. Morphine sulphate is currently avail(cid:173)
`able as a bd dosage form as MS Contin™ Tablets (Napp)
`available as 10 mg, 30 mg, 60 mg, 100 mg and 200 mg
`active per unit dose. Pain specialists have indicated the
`requirement for a once daily extended release preparation to
`avoid break-through pain. Once daily morphine products
`currently available are those sold under the Trade Marks
`MST Continus Long and Kapanol.
`Apart from achieving sustained release of morphine over 60
`extended periods of time, for true therapeutic efficacy a
`sustained release morphine formulation should achieve
`therapeutically effective plasma levels of morphine over at
`least 24 hours coupled with minimum fluctuations in plasma
`morphine levels.
`Morphine-related side effects are a feature of morphine
`therapy. These side effects include nausea and vomiting,
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 6 of 16
`
`

`

`6,066,339
`
`5
`
`3
`levels of morphine over at least 24 hours coupled \vith a
`substantially fiat plasma profile. Thus, the formulation
`according to the invention, which exhibits minimal fluctua(cid:173)
`tions in plasma levels of morphine over the dosage period,
`should serve to minimise the occurrence of morphine-related
`side effects and thus ensure more efficacious morphine
`therapy than sustained release formulations currently avail(cid:173)
`able and/or as described in the prior art set out above.
`Additionally, because of the substantially fiat morphine
`plasma bioprofile, titrating the formulation according to this 10
`invention to a particular patient's need is safer and easier
`than the formulations set out in the prior art above.
`The formulations according to the invention are also
`bioequivalent under single dosage and steady state condi(cid:173)
`tions to instant release oral solution (Q4hx6), twice daily
`and other once-daily formulations. This bioequivalence
`combined with the substantially flat plasma bioprofile for the
`formulations according to this invention allows the formu(cid:173)
`lations to be effective in preventing break-through pain.
`According to one embodiment a portion or all of the
`sustained release particles further comprise an immediate
`release coating applied onto the rate-controlling polymer
`coat, which immediate release coating comprises water
`soluble morphine and optionally an osmotic agent.
`Although frequently in on-going pain management
`therapy a patient will already by taking morphine as part of
`his/her medication when prescribed a formulation in accor(cid:173)
`dance with the invention, there will be occasions when an
`immediate release of morphine is required by such patient<;. 30
`However, the formulation according to the invention will
`also be suitable for use in managing pain in other situations,
`such as in post-operative pain, where it is also important to
`control morphine-related side effects. Thus, the formulation
`according to the invention may be characterized by both a 35
`fiat plasma profile and a rapid onset of action. Such a rapid
`onset of action is achieved by including an immediate
`release morphine component in the formulation.
`In an alternative embodiment, the formulation can contain
`a portion of immediate release particles each comprising a 40
`core of water soluble morphine and optionally an osmotic
`agent.
`The immediate release particles can comprise immediate
`release pellets or granulates.
`The formulation according to the invention may also
`comprise at least two populations of sustained release par(cid:173)
`ticles having different in vitro dissolution profiles.
`Preferably, the formulation releases morphine in vivo)
`following single dose administration such that the duration
`over which the plasma level of morphine is equal to or
`greater than 50% of the peak plasma concentration is 20
`hours or greater, more preferably 24 hours or greater,
`especially 30 hours or greater.
`Also, preferably the formulation releases morphine in 55
`vivo following single dose administration such that the
`duration over which the plasma level of morphine is equal
`to or greater than 75% of the peak plasma concentration is
`6 hours or greater, more preferably 12 hours or greater, most
`preferably 18 hours or greater.
`Further, preferably the formulation releases morphine in
`vivo at steady state such that the plasma level of morphine
`over the entire 24 hour dosing period is equal to or greater
`than 50% of the peak plasma concentration.
`Still further, preferably the formulation releases morphine 65
`in vivo at steady state such that the duration over which the
`plasma level of morphine over the 24 hour dosing period is
`
`4
`equal to or greater than 75% of the peak plasma concentra(cid:173)
`tion is 12 hours or greater.
`Also preferably, the formulation according to the inven(cid:173)
`tion provides a dissolution profile in aqueous media such
`that about 3 to 25% of the water soluble morphine is released
`after 1 hour; about 5 to 35% is released after 4 hours; about
`25 to 65% is released after 9 hours; about 35 to 75% is
`released after 12 hours and at least 70% is released after 24
`hours.
`In an alternative embodiment the formulation provides a
`dissolution profile in aqueous media such that about 10 to
`15% of the water soluble morphine is released after 1 hour;
`about 15 to 30% is released after 4 hours; about 35 to 50%
`is released after 9 hours; about 45 to 65% is released after
`15 12 hours and at least 80% is released after 24 hours.
`Also, in a preferred embodiment greater than 80% of the
`formulation is comprised of sustained release particles.
`In a preferred embodiment the rate-controlling polymer
`20 coat contains Ammonia Methacrylate Copolymer Type A
`and Ammonia Methacrylate Copolymer Type B as described
`in USP/NF in a ratio of 15:85 to 1:99, more especially about
`5:95.
`Such copolymers are manufactured and marketed by
`25 Rohm, GmbH, Darmstadt, Germany.
`Most preferably, the rate-controlling polymer coat con(cid:173)
`tains a 5:95 mixture of Eudragit RL:Eudragit RS most
`especially Eudragit RL 12.5:Eudragit RS 12.5.
`The osmotic agent according to the invention refers to a
`pharmaceutically acceptable material that enhances the pas(cid:173)
`sage of the water soluble morphine through the rate(cid:173)
`controlling polymer coat or through the tissue in the gas(cid:173)
`trointestinal tract (GIT). Without being limited to any
`particular theoretical mechanism, the osmotic agent may
`enhance the absorption of water soluble morphine by cre(cid:173)
`ating a local pH and/or chemical potential environment.
`Preferably, the osmotic agent is an organic acid, a phar(cid:173)
`maceutically acceptable salt, a GIT absorption enhancer or
`a combination thereof. Suitable osmotic agents include but
`are not limited to adipic acid, a5corbic acid, citric acid, malic
`acid, succinic acid, tartaric acid, lactic acid, monopotassium
`citrate, potassium acid tartrate, sodium fumarate, sodium
`dihydrogen phosphate, sodium bisulfate, sodium metabisul(cid:173)
`fate or combinations thereof.
`Further, preferably, the osmotic agent is an organic acid
`selected from fumaric acid, adipic acid, ascorbic acid, citric
`acid, tartaric acid, lactic acid, malic acid and succinic acid,
`more especially fumaric acid.
`Preferably, the water soluble morphine and osmotic agent
`are present in the cores in a ratio of 2.5:1 to 1:2.5, more
`especially about 1:1.
`Preferably, the water soluble morphine is morphine sul(cid:173)
`fate or a hydrate thereof, especially the pentahydrate.
`Morphine sulphate pentahydrate typically contains
`-9-12% bound water. A portion of this water is typically
`dried off during routine processing. However, loss of water
`of hydration can affect the dissolution profile and thus the
`efficacy of the formulation. Thus, we have found that it is
`60 benefi~ial to prevent the loss of water of hydration during the
`drying process involved in manufacturing the multiparticu(cid:173)
`late formulation according to the invention when morphine
`sulphate pentahydrate is used.
`It has been found that about 3--4% by weight moisture
`content is beneficial on the basis of the moisture level of
`morphine sulphate in the formulation. However, as other
`excipients in the formulation may absorb moisture, a range
`
`45
`
`50
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 7 of 16
`
`

`

`6,066,339
`
`5
`of about 3-6% by weight moisture content for the formu(cid:173)
`lation may be required. Preferably the cores for the sustained
`release particles are equilibrated at ambient conditions or
`dried at humidified conditions such as about 40-50° C. and
`about 30-60% relative humidity for 10-20 hours prior to
`being coated with the rate-controlling polymer coat so as to
`obtain a moisture content of about 3-6% by weight.
`Still further preferably, the sustained release particles
`following application of the rate-controlling polymer coat
`are dried at a temperature of about 40-50° C. and about
`30-60% relative humidity or are equilibrated at ambient
`conditions.
`Preferably, the formulation contains between 10 mg and
`200 mg of morphine sulfate or the equivalent amount of
`water soluble morphine.
`In a preferred embodiment, the formulation is
`encapsulated, for example in hard or soft gelatin capsules.
`The core, herein referred to as applied beads or IR beads,
`can be formed by building up the morphine active agent,
`osmotic agent, and, if desired, any pharmaceutically accept(cid:173)
`able excipient(s) such as binders, surfactants and lubricants
`on an inert core. The inert core is preferably a non-pareil
`seed of sugar/starch having an average diameter in the range
`0.2-1.4 mm, more especially, 0.3-0.8 mm, most especially 25
`0.5-0.6 mm.
`The morphine active agent, the osmotic agent and, if
`desired, pharmaceutically acceptable excipient(s) are
`blended to form a homogeneous powder herein referred to as
`the active blend. This blend can then be applied to the inert
`core using an application solution.
`The blend is optionally passed through an appropriate
`mesh screen using a milling machine. In the case of coating
`in a conventional coating pan, alternate layers of the appli(cid:173)
`cation solution and the powder are applied to the central
`inert core to build up the multi-layer arrangement of the
`core. In the case of an automatic coating system, the
`application solution and the powder are applied,
`simultaneously, in conventional manner. Conventional auto(cid:173)
`mated coating systems include for example a CF granulator
`or other suitable fluidized bed based systems.
`The application solution comprises one or more binder(s)
`dissolved/suspended in a suitable solvent or mixture of
`solvents. Suitable binding agents include
`polyvinylpyrrolidone, starch and gelatin. A preferred binder
`is polyvinylpyrrolidone. Preferably, between 5 and 50 parts
`of the central inert cores are used relative to the homoge(cid:173)
`neous powder.
`The completed cores preferably have an average diameter
`in the range 0.4-1.8 mm, more especially in the range
`0.7-1.5 mm.
`The pharmaceutically acceptable excipients can be homo(cid:173)
`geneously mixed with the water soluble morphine to form
`the active blend. These materials may include ingredients
`known to act as lubricants and surfactants. Representative
`excipients include: microcrystalline cellulose (such as that
`sold under the Trade Mark AVICEL); colloidal silicon
`dioxide (such as that sold under the Trade MarkAEROSIL);
`lactose; talc; starch; sorbitol; sodium lauryl sulphate; and
`cyclodextrin. These may be used singly or in combination
`with each other. Especially preferred excipients are talc and
`sodium lauryl sulphate.
`The sustained release particles are formed by coating the
`applied beads with a rate-controlling polymer coat com- 65
`prised of ammonia methacrylate copolymers such as those
`sold under the Trade Mark EUDRAGIT.
`
`45
`
`10
`
`6
`EUDRAGIT polymers are polymeric lacquer substances
`based on acrylates and/or methacrylates. The polymeric
`materials sold under the Trade Mark EUDRAGIT RL and
`EUDRAGIT RS are acrylic resins comprising copolymers of
`5 acrylic and methacrylic acid esters with a low content of
`quaternary ammonium groups and are described in the
`''EUDRAGIT" brochure of Messrs. Rohm Pharma GmbH
`(1984) wherein detailed physical-chemical data of these
`products is given. The ammonium groups are present as salts
`and give rise to the permeability of the lacquer films.
`EUDRAGIT RL and RS are freely permeable (RL) or
`slightly permeable (RS), respectively, independent of pH.
`The rate-controlling polymer coat may be built up by
`applying a plurality of coats of polymer solution or suspen(cid:173)
`sion to the core as hereinafter described. The polymer
`15 solution or suspension contains the polymer(s) dissolved or
`suspended, respectively, in a suitable aqueous or organic
`solvent or mixture of solvents, optionally in the presence of
`a lubricant. Suitable lubricants are talc, stearic acid, mag(cid:173)
`nesium stearate and sodium stearate. A particularly preferred
`20 lubricant is talc.
`The polymer solution or suspension may optionally
`include a plasticizing agent. Suitable plasticizing agents
`include polyethylene glycol, propylene glycol, glycerol,
`triacetin, dimethyl phthalate, diethyl phthalate, dibutyl
`phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate,
`triethyl acetyl citrate, castor oil and varying percentages of
`acetylated monoglycerides.
`Suitable organic solvents include isopropyl alcohol or
`acetone or a mixture thereof.
`The polymer solution or suspension may be applied to the
`30 active cores in a conventional coating pan as indicated or,
`alternatively, and preferably using an automated system
`such as a CF granulator, for example, a FREUND CF
`granulator, a GLATT fluidised bed processor, an
`AEROMATIC, a modified ACCELA-COTA or any other
`suitably automated bead coating equipment (FREUND,
`35 GLATT, AEROMATIC and ACCELA-COTA are all Trade
`Marks).
`Preferably 2-75 ml of polymer solution/suspension is
`applied per application per kilogram of cores. In an auto(cid:173)
`mated system the total amount of polymer solution/
`40 suspension applied to the cores is similar to that applied in
`a conventional coating pan, except that the polymer
`solution/suspension may be applied continuously.
`Preferably, when a coating pan is used the rate-controlling
`polymer coat is applied to a given target polymer coating
`weight.
`The method of manufacturing the oral morphine multi-
`particulate formulation in accordance with the invention is
`based upon coating drug loaded cores with rate controlling
`polymers to achieve a target dissolution rate. Drug release
`from these beads is diffusion controlled as the polymer
`50 swells and becomes permeable, thus, allowing for controlled
`release in the GIT. To achieve an appropriate dissolution
`profile, in addition to accommodating an efficient manufac(cid:173)
`turing process, the following critical parameters require
`consideration
`(a) drug solubility
`55 (b) drug and excipient particle size
`(c) drug: osmotic agent ratio
`(d) drug: coated bead surface area ratio
`(e) bead size
`(f) coating polymer
`60 (g) applied bead binding polymer
`(h) processing conditions
`as will be apparent from the following Examples.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 shows dissolution(%) vs time (h.) for the formu(cid:173)
`lations of Examples 1-3 and the reference product of
`Example 7 in aqueous media.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1019, Pg. 8 of 16
`
`

`

`~,
`
`7
`Curve ---o- corresponds to the reference product of
`Example 7,
`curve - - 0 - - corresponds to the product of Example
`3,
`curve - - l l - - corresponds to the product of Example 5
`1 and
`curve - - x - - corresponds to the product of Example
`ry.
`F1G. 2 shows mean morphine plasma concentration (ng/
`ml) vs time (h.) for the products described under FIG. 1
`following single dose administration. Curves - - 0 - - ,
`- - 0 - - , - - l l - - and - - x - - correspond to the
`same products as the corresponding curves of FIG. 1;
`F1G. 3 shows mean plasma morphine concentration (ng/
`ml) vs time (h.) for the formulations of Examples 1 and 2 15
`relative to the reference as described in Example 9 at steady
`state.
`Curve ---!•----corresponds to the product of Example
`1,
`curve --+-- corresponds to the product of Example
`2, and
`curve - - l l - - corresponds to the reference product of
`Example 9; and
`F1G. 4 shows morphine plasma concentrations (single 25
`dose) (ng/ml) vs time (h.) for the products of Examples 1 and
`2 relative to the reference products 1 and 2 of Example 11.
`Curve - - 0 - - corresponds to reference product: 1,
`curve
`•
`corresponds to reference product 2,
`curve - - l l - - corresponds to the product of Example
`1 and
`curve - - x - - corresponds to the product of Example
`2.
`
`6,066,339
`
`10
`
`8
`able fluidized bed system onto non pareil seeds using a
`suitable binder, such as Povidone, from a suitable organic or
`aqueous solution, such as isopropyl alcohol. The resultant
`immediate release beads were dried for 20 h at 55° C. to
`obtain a moisture content of between 3-6%. The dried beads
`were then screened and appropriate fractions retained for
`further processing.
`The applied beads were formed from:
`Active blend 75.3%
`Povidone solution (Solids) 6.1%
`Non pareil seeds 18.6%
`Sustained Release Beads (SR beads)
`Prior to coating, the applied beads (immediate release)
`from above were exposed on drying trays at ambient con(cid:173)
`ditions to allow equilibration of applied bead moisture
`content.
`To coat the applied beads (IR), a coating solution com(cid:173)
`prising a 6.25% solution of Eudragit RS (95% w/w) and
`Eudragit RL (5% w/w) dissolved in isopropyl alcohol/
`20 acetone was sprayed onto a fluidised bed of applied beads.
`Talc was also added simultaneously via an auger feeder to
`prevent agglomeration. The resulting product consisted of a
`core (applied beads) coated with a rate-controlling polymer
`coat having 30.1 mg of polymer coat per gram of applied
`beads.
`The coated beads were oven dried for 20 h. at 35° C. to
`remove residual solvent, then the coated beads were exposed
`at ambient conditions for 96 h. on drying trays to allow for
`moisture equilibration.
`Thus, the materials used for the SR beads were applied
`30 beads: 81.8%; Eudragit RS/RL coating solution (solids):
`2.5% and talc: 15.7%.
`Encapsulation (90% SR beads/10% IR beads)
`Morphine sulphate applied beads (10% w/w by potency)
`and the polymer coated beads (90% w/w by potency) from
`35 above were blended together using a tumble blender. The
`blended beads from above were filled into gelatin capsules
`to give a target strength of 60 mg per capsule.
`EXAMPLE 2
`
`DETAILED DESCRIPTION OF TilE
`INVENTION
`
`EXAMPLE 1
`
`Morphine Sulphate 60 mg Capsules
`Morphine sulphate capsules containing a blend of SR
`beads and IR beads and having the following composition:
`
`40
`
`Morphine Sulphate 60 mg Capsules
`Morphine sulphate capsules containing a blend of two
`populations of SR beads and IR beads having the following
`composition:
`
`IXGREDIENT
`
`ACriVE
`
`Morphine sulphate
`EXCIPIENTS
`
`Sugar spheres
`Fumaric acid
`Talc
`Sodium Iaury! sulphate
`Povidone (Kollidon 30)
`Ammonia Methacrylate
`Copolymer Type A (Eudragit RL)
`Ammonia Methacrylate
`Copolymer Type B (Eudragit RS)
`Isopropyl alcohol"
`Acetone*
`
`mg/cap.
`
`mg;g
`
`45
`
`60
`
`310.0
`
`30
`60
`29.1
`0.30
`9.8
`0.22
`
`4.15
`
`155.0
`310.0
`150.3
`1.5
`50.6
`1.1
`
`21.4
`
`INGREDIENT
`
`ACriVE
`
`50
`
`Morphine sulphate
`EXCIPIENTS
`
`Sugar spheres
`Fumaric acid
`Talc
`Sodium Iaury! sulphate
`Povidone (Kollidon 30)
`Ammonio Methacrylate
`Copolymer Type A (Eudragit RL)
`Ammonia ~1ethacrylate
`Copolymer Type B (Eudragit RS)
`Diethylphthalate
`Isopropyl alcohol*
`Acetone*
`
`55
`
`60
`
`mg/cap.
`
`mg/g
`
`60
`
`309.6
`
`30
`60
`29.1
`0.30
`9.8
`0.22
`
`4.15
`
`0.22
`
`154.8
`309.6
`150.2
`1.5
`50.6
`1.1
`
`21.4
`
`1.1
`
`*Used in processing, occurring in trace amounts in finished product.
`
`were manufactured as follows:
`Applied Beads (IR beads)
`Morphine sulphate (49.38% w/w), fumaric acid (49.38%
`w/w) talc (0.988% w/w) and sodium lauryl sulphate (0.25%) 65
`(collectively the active blend) were blended in a tumble
`blender and comminuted. The blend was applied in a suit-
`
`*Used in processing, occurring in trace amounts in finished product
`
`were manufactured as follows:
`Applied Beads (IR beads)
`The applied beads were prepared in the same way as for
`the applied beads of Example 1.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1