`United States Patent
`
`[19]
`
`Mehta et al.
`
`I|||||||||||l||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`US00583 728-4A
`
`[11] Patent Number:
`
`5,837,284
`
`[45] Date of Patent:
`
`Nov. 17, 1998
`
`[54]
`
`Dl'*lL1VI*}RY OF MULTIPLE DOSES OF
`NIl"J)IC/\TI()NS
`
`[76]
`
`Inventors: Atul M. Mehta, 252 1:‘. Crcsem Avc.,
`Ramsey. N.J. U744-6; Andrew L.
`Zeitlin, 1500 Whitcbridgc Rd.,
`Millinglun, NJ. (17945; Mug-hsoud M.
`Dariani, 11 Byron La., Fanwood, NJ.
`07023
`
`‘£51094 Rudnic ct al.
`5.326,5?(I
`12.31995 Eichel el :11.
`5.47-‘8_.573
`5_,5[]'l'J,22'? M19816 Oshlack et all.
`S_,r:3U_,4?o
`5:199?‘ Oshlack el al.
`5_.G?2_.36(l WIIJQT Sacklcr cl al.
`
`........................ .. 424x458
`.. 424F430
`
`....................... .. 424,."4?6
`....................... .. 424.-“(:58
`........................ _. 424f4-‘J0
`
`OTHER 1)UBL1CA1"IONS
`
`PDR, 46111 cd. "Ritalin SR" pp. 880-881, 1992.
`
`[21] Appl. No.: 892,190
`
`[23]
`
`1:iIcd:
`
`Jul_ 14’ 1997
`
`Related U.S. Application Data
`
`[63]
`
`[51|
`
`1‘.i")5__
`Conlinualion—in—pam of Ser. No. 561131. Dec. 4,
`abandoned, and a continuation—in—part of Scr. No. 583.317.
`-Tm 5.. 1996.. and 5' W|1linU«1li0|1-i|1-PflI1 UT 5t'f- N0- 047-042,
`May 15‘ 19%‘
`Int. Cl." ............................. .. A6lK 9156; AGIK 9154;
`A61K EH58; A61K 9393: /\51K 31331
`.......................... 424.1459; 42’:lf458; 424_e’:lé3;
`[52] U.S. Ci.
`4-414589 514-"317
`_
`424,"-5i-5E8, 459,
`[53] Held {If Search ..............................
`4"4’46“ 468; 314-817
`References Cited
`U.S. l’A’l‘l£N'1‘ DOCUML-LN’l'S
`
`[56,
`
`Primrtry :‘.'.mrm'ner—Raymond I'Icni::.y. III
`mrorney,
`/lgem, or 1"':’m:—Woodcock Washlaum Kurtz
`Mac-kiewicz & Norris LLP
`
`i-vii
`
`ABSTRACT
`
`Dosagc forms for oral administration of a mcthylphcniclatc
`drug are provided. The dosage forms provide a suhstanlially
`immcdiatc close of mcthylphcnidatc upon ingcstion, fol-
`lowcd by one or more additional doses al prcdelcrmins.-d
`limes. B)’ llroviding such a drug release profile, the dosage
`forms eliminate the need for a palicnl to carry an additional
`dose for ingestion during [he day The dosage forms and
`mclhods provided are useful in adnlinislcriflg mc1hvlphcni-
`dale and pharrnaceutically acceptable salts thereof, winch
`generally rcqmrc one or more doses throughout the day.
`
`4__?94_.crm1
`
`12.11988 Mchla el :11.
`
`.......................... .. 424x458
`
`30 Claims, 2 Drawing Slmts
`
`Amerigen Ex. 1027, p. 1
`Amerigen Ex. 1027, p. 1
`
`
`
`U.S. Patent
`
`Nov. 17,1998
`
`Sheet 1 of 2
`
`5,837,284
`
`120
`
`100
`
`so
`
`so
`
`40
`
`20
`
`0
`
`o
`
`5
`
`10
`
`15
`
`20
`
`Time ( hours )
`
`FIG.
`
`1
`
`Amerigen Ex. 1027, p. 2
`Amerigen Ex. 1027, p. 2
`
`% D .
`
`1 S 5
`
`0 1 V
`
`e d
`
`
`
`U.S. Patent
`
`Nov. 17, 1993
`
`Sheet 2 of 2
`
`5,837,284
`
`FIG. 2
`
`Amerigen Ex. 1027, p. 3
`Amerigen Ex. 1027, p. 3
`
`
`
`5,837,284
`
`1
`DELIVERY OF MUI.'l‘lPLl£ DOSES OF
`MEDICATIONS
`
`CROSS—REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation in part of application
`Ser. No. (|8!56?,131, filed Dec. 4, 1995, now abandoned;
`application Ser. No. 08,583,317,
`liled Jan. 5, 1996; and
`application Ser. No. U8.»"64'!',642, filed May 15, 1996.
`
`FIELD OF THE INVENTION
`
`invention relates to improved dosing of
`The present
`medications. In particular, the present
`invention relates to
`improved dosing of a medication whereby two or more
`effective, time-separated doses may be provided by admin-
`istration of a single dosage unit. The second, and any later,
`dose is time-delayed following administration. Based on
`predictable in vitro release times, the dosage forms can be
`formulated to deliver delayed doses in vivo at desired times.
`The dosage fonns and methods of the present invention
`are particularly suitable for the administration of meth-
`ylphenidate hydrochloride, and especially for the adminis-
`tration of a single isomer, d—threo—methylphenidate hydro-
`chloride.
`
`The administration of dosage forms which contain an
`immediate dosage and a delayed second dosage provides for
`reduced abuse potential,
`improved convenience of
`administration, and better patient compliance, especially
`when methylphenidate is used to treat certain central ner-
`vous system disorders.
`BACKGROUND OF THE INVENTION
`
`Attention Deficit Disorder (ADD), a commonly diag-
`nosed nervous system illness in children, is generally treated
`with methylphenidate hydrochloride (available commer-
`cially as, e.g., Ritalin®). Symptoms of ADD include dis-
`tractibility and impulsivity. A related disorder, termed Atten-
`tion Delicit Ilyperactivity Disorder (ADIID),
`is
`further
`characterized by symptoms of hyperactivity, and is also
`treated with methylphenidate hydrochloride. Methylpheni-
`date drugs have also been used to treat cognitive decline in
`patients with Acquired Immunodeficiency Syndrome
`(AIDS) or AIDS related conditions. See, e.g., Brown, (3.,
`lrtrl. J. Psych. Med. 25(1): 21-37 (1995); Holmes et al..J.
`Ciirr. 1’5'_vci1irrtr'_v 50:5—8 (1989).
`Methylphcnidate exists as four separate optical isomers as
`follows:
`
`2
`which also can be administered according to the invention,
`include those in which the methyl group in the above
`structures is replaced by C2-C4 alkyl and R3 is optionally
`substituted with C,—C,, alkyl.
`Clinically. the three pair of enantiomers of methylpheni-
`date hydrochloride is generally administered for the treat-
`ment of ADD and ADHD. The hydrochloride salt is com-
`monly referred to simply as "methylphenidate”. Unless
`indicated otherwise,
`the term "me1hylphenidate” is used
`broadly herein to include methylphenidate and phanTtaceu-
`tieally acceptable salts thereof. including methylphenidate
`hydrochloride.
`The three racematc (pair of enantiomers) of methylpher1i—
`date is a mild central nervous system stimulant with phar-
`macological activity qualitatively similar to that of amphet-
`amines. Undesirable side elfects associated with the use of
`the dl-threo racemate cl" methylphenidate include anorexia,
`weight
`loss,
`insomnia, dizziness and dysphoria.
`Furthennore, the raccmate, which is a Schedule II controlled
`substance, produces a euphoric effect when administered
`intravenously or through inhalation or ingestion, and thus
`carries a high potential for abuse.
`Srinivas et al. studied the administration of dl-three-,
`d—threo, and 1-threo-methylphenidate to children sulfering
`from ADI II), and reported that the pharrnacodynamic activ-
`ity of dl-threo-methylphenidate resides in the d-threo isomer
`(Clirt. Pltartrracol. Titer, 521561-568 (l992)). Therefore,
`while dl-threo-methylphenidate is generally used
`therapeutically, this racemate includes the l
`isomer which
`apparently makes no significant contribution to the pharma-
`cological ellectivencss of the drug, but likely contributes to
`the associated side effects. It is thus desirable to administer
`only the active d-threo four: of the drug.
`An additional problem is that children being treated with
`dl-threo methylphenidate must generally take one or more
`doses during the day. This creates a problem for school
`administrators who must store a controlled substance on
`school premises, with the associated risk that
`it may be
`stolen for illicit use. Furtherrnore, children may be trauma-
`lined by ridicule from peers when they must take medication
`at school.
`Sustained release formulations of dl-threo methyIpheni-
`date have been developed, which provide for slow release of
`the drug over the course of the day. However, it has been
`observed that peak plasma concentrations of the drug are
`lower when sustained release formulations are used. In some
`studies, sustained release formulations of methylphenidate
`have been shown to have lower ellicacy than conventional
`dosage forms.
`There remains a need for methods for delivering meth-
`ylphenidate with maximum effectiveness and minimal
`potential for abuse. Furthermore, it has been determined that
`there is a need for a dosage form which provides,
`in one
`administration, an initial release followed, at a predictable
`delay, by a second release, of maximally efiective meth-
`ylphenidatc. This will eliminate the risk of theft or loss of the
`second dose, while minimizing undesirable side elfects and
`maximizing ease of administration. The present invention is
`directed to these, as well as other, important ends.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 depicts an in vitro time-concentration relationship
`(release profile) for certain preferred dosage forms in accor-
`dance with the invention.
`
`FIG. 2 depicts a schematic representation of in vivo
`plasma concentration of a drug released according to the
`release profile shown in FIG. 1.
`
`ill
`
`15
`
`30
`
`35
`
`40
`
`45
`
`60
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`65
`
`Amerigen Ex. 1027, p. 4
`Amerigen Ex. 1027, p. 4
`
` s‘ H
`
`N H
`
`d -e r y t h to
`
`R:
`
`cogs;
`
`H
`
`R:
`
`co,c1r3
`
`N
`H
`
`d—threo
`
`H
`
`R:
`
`_
`E:o;ct1,
`
`N
`H
`
`l-Cf}’ll'I1’O
`
`wherein R3 is phenyl. Pharmaoeutically acceptable salts are
`generally administered clinically. Other phenidate drugs,
`
`
`
`5,837,284
`
`3
`SUMMARY OF THE INVENTION
`
`invention provides, in one embodiment, a
`The present
`therapeutic composition for the oral administration of a
`methylphenidate drug comprising a dosage form containing
`two groups of particles, each containing the methylpheni-
`date drug. The term “particles", as used herein,
`includes
`pellets, granules, and the like. The first group of particles
`provides a substantially immediate dose of the methylpheni-
`date drug upon ingestion by a mammal. The lirst group of
`particles can also comprise a coating andior sealant. The
`second group of particles comprises coated particles, which
`comprise from about 2% to about 75%, preferably from
`about 2.5% to about 50%, and more preferably from about
`5% to about 20%, by weight of the second group of particles,
`of the methylphenidate drug, in admixture with one or more
`binders. The coating comprises a pharmaceutically accept-
`able ammonio methacrylate copolymer in an amount sulli-
`cient to provide a delay of from about 2 hours to about 7
`hours following ingestion before release of the second dose.
`lfdesired, one or more additional doses may be delivered by
`additional panicles, coated in a similar manner, but with a
`sufiicient amount of ammonio methacrylate copolymer coat-
`ing to provide the dosage after an additional delay. Meth-
`ylphenidate and pharmaceutically acceptable salts thereof,
`including methylphenidate hydrochloride, can be prepared
`into the dosage forms of the invention.
`the first
`invention,
`In one embodiment of the present
`group of particles comprises a methylphenidate drug and
`provides a substantially immediate dose of the methylpheni-
`date drug upon ingestion by a mammal. The first group of
`particles may comprise a coating andtor sealant. The second
`group of particles comprises coated particles, which com-
`prise from about 2% to about 75%, preferably from about
`2.5% to about 50%, and more preferably from about 5% to
`about 2[l%,by weight ofthc particlesofthe methylphenidate
`drug in admixture with one or more binders. The coating
`comprises a pharmaceutically acceptable ammonio meth-
`aerylate copolymer in a quantity sufiicient to provide a dose
`of methylphenidate delayed by from about 2 hours to about
`7 hours following ingestion.
`For example, the first group of particles can comprise a
`pharmaceutically acceptable salt of methylphenidate, such
`as methylphenidate hydrochloride,
`in powder
`form, or
`coated or uncoated panicles containing the methylphenidate
`salt. The amount of methylphenidate salt in each group of
`particles can vary, depending upon the dosage requirements
`of the patient
`to whom the drug is to be administered.
`Generally, the daily dosage requirement lhr methylphenid ate
`drugs is from about 1 mg to about 50 mg per day, preferably
`from about 2 mg to about 20 mg, and more preferably from
`about 2.5 to about 12 mg per day. The actual dosage to be
`administered will be determined by the attending physician
`as a matter of routine. Thus, depending upon the amounts of
`coating andfor and optional excipients and other additives,
`the amount of methylphenidate drug can be, for example,
`from about 2% to about 99% by weight of the first group of
`particles. In addition to the methylphenidate drug, the sec-
`ond group of particles comprises a filler, such as a hydro-
`phobic liller, one or more ammonio methacrylate
`copolymers, and optional excipients and other additives. The
`filler can be present in an amount of, for example, from
`about 35% to about 45%, by weight, based on the total
`weight of the second group of particles.
`Another embodiment of the present invention provides a
`method for treating disease, such as, for example, ADD,
`ADHD, or AIDS-related dementia. in a patient in need of
`
`ill
`
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`
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`
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`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`treatment. This treatment comprises administering to the
`patient a dosage form providing once-daily oral administra-
`tion of a methylphenidate drug such as methylphenidate
`hydrochloride. The dosage form comprises at
`least
`two
`groups of particles, each containing the methylphenidate
`drug. The first group of particles comprises from about 2%
`to about 99% by weight of the methylphenidate drug,
`depending upon desired the daily dosage, and provides a
`substantially immediate dose of methylphenidate upon
`ingestion by a mammal. The first group may comprise a
`coating andfor sealant. The second group of panicles com-
`prises coated particles. The coated particles comprise the
`methylphenidate drug in admixture with one or more
`binders, wherein the amount of methylphenidate drug is
`from about 2% to about 75%. preferably from about 2.5% to
`about 50%, and more preferably front about 5% to about
`20%, by weight of the second group of particles, and a
`coating comprising an ammonio rnethacrylate copolymer in
`a quantity sufficient to provide a dose of methylphenidate
`delayed by from about 2 hours to about 7 hours following
`ingestion. The components of the two groups of particles can
`vary as described hereinabove. The initial dose can be
`administered separately from the delayed dose, if desired.
`A further embodiment of the present invention provides
`dosage fonns for the oral administration, in a single dosage
`form, of two doses of a pharmaceutically acceptable salt of
`d-threo-methylphenidate. The dosage forms comprise par-
`ticles containing within their interiors from about 2% to
`about 75%, preferably from about 2.5% to about 50%, and
`more preferably from about 5% to about 20%, of the
`d-threo-methylphenidate salt, in admixture with one or more
`binders. The particles have a coating exterior to the meth-
`ylphenidate salt, which comprises an ammonio methacrylate
`copolymer in a quantity suflicient to delay release of the
`d—threo—rncthylphenidatc salt contained within by from
`about 2 hours to about 7 hours following administration. The
`dosage forms also comprise, exterior to the coating, an outer
`layer comprising from about 2% to about 99% by weight of
`the d-threo-methylphenidate salt, based on the weight of all
`components in the outer layer,
`to provide a substantially
`immediate dose of the d-threo-methylphenidate salt upon
`administration. The layer comprising the immediate dose of
`the d-threo-methylphenidate salt can,
`if desired,
`further
`comprise an outer sealant layer. If desired, the two doses of
`the d-threo-methylphenidate salt can be approximately
`equaL
`The present invention also provides dosage forms pro-
`viding plasma concentration profiles for methylphenidate
`having two maxima, temporally separated from each other
`by from about 2 hours to about 1" hours. Preferably, the
`magnitude of said maxirna ditfers by no more than about 30
`percent, more preferably by no more than about 20 percent,
`and most preferably by no more than about 10 percent.
`"Methylphenidate" as used herein, includes all four opti-
`cal
`isomers of the compound and all phannaceutically
`acceptable salts thereof. When one or more particular iso-
`mers is contemplated, the isomer is indicated, as in d-threo,
`l-threo, etc. The combined threo isomers may be indicated
`simply as "three ” and the erythro isomers as “erylhro
`For
`therapeutic use in treating conditions treatable by meth-
`ylphenidate drugs, dl-threo methylphenidate hydrochloride
`is generally used, while d-threo methylphenidate hydrochlo-
`ride is preferred according to the present invention.
`As discussed, the four isomers have exhibited varying
`levels of therapeutic activity, and have been shown to dilfer
`generally in producing unwanted side ell'ects. The present
`invention provides dosage forms which maximize therapeu-
`
`Amerigen Ex. 1027, p. 5
`Amerigen Ex. 1027, p. 5
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`5,837,284
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`ll!
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`15
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`-
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`30
`
`5
`tic effectiveness and minimize undesirable side effects. In
`certain preferred embodiments,
`the dosage forms of the
`present
`invention provide administration of the two threo
`forms of methylphenidate.
`In particularly preferred
`embodiments.
`the dosage forms of the present
`invention
`provide administration of a single isomer, d-threo-
`methylphenidate, albeit in two or more doses.
`The dosage forms of the present invention are intended
`for oral ingestion by a mammal, particularly a human. The
`dosage forms of the present invention are particularly suit-
`able for the administration of methylphcnidate drugs, in at
`least two doses. Most preferably, the dosage forms provide
`two doses of a d—threo methylphenidate drug such as d—tl1reo
`methylphenidate hydrochloride. The second dose can be
`delayed by from about 2 hours to about 7 hours, preferably
`from about 3 hours to about 6 hours, and most preferably
`from about 4 hours to about 5 hours, following ingestion of
`the dosage form by a mammal. This eliminates the need for
`a patient, for example a child being treated for/\DD, to carry
`a second dose for ingestion several hours after ingestion of
`a lirst dose. The exclusion of the l isomers and the d-erythro
`isomer eliminates the concurrent
`ingestion of forms of
`methylphenidate principally believed to be associated with
`adverse side elfects andlor reduced elfectiveness.
`The temporal separation of the two doses provided —
`according to the present
`invention can be represented
`graphically as in FIG. 1. FIG. I is an in vitro drug release
`profile of a dosage form of the present invention. The data
`were obtained by measuring the rate of dissolution of drug
`as a function of time. In this embodiment
`two doses are
`provided. The release of the first dose preferably occurs
`substantially immediately; for example, within about 30
`minutes following administration. Following a period of
`little or substantially no drug release.
`the second dose is
`released. The two releases can be referred to as "pulms”, and
`such a release profile can be referred to as "pulsatile".
`I~“lCu. 2 is a schematic representation of the plasma con-
`centration of drug resulting from a release profile according
`to FIG. 1. The maximum concentration due to the first dose,
`C1, occurs at t,, preferably from about 1 hour to about 3
`hours after ingestion, most preferably about 2 hours after
`ingestion. The release of the first dose is followed by a
`period during which substantially no drug is released, which
`lasts approximately 2-6 hours, preferably 3-5 hours, post
`ingestion. The second dose is then released, with the maxi-
`mum concentration, C:, at [2, which is preferably about 6
`hours post-ingestion. Preferably at least about 80% of the
`total drug has been released by about 6 hours following
`administration. In the embodiment represented by FIG. 2,
`the levels of drug released at the two maxima are nearly
`equal. Preferably,
`if two approximately equal doses are
`released, the release of the two doses provides a plasma
`concentration profile having two maxima, which differ from
`each other by no more than about 40 percent in magnitude,
`preferably by no more than about 30 percent, and more
`preferably by no more than about 25 percent. This is
`determined by the relationship:
`lCI‘C:l-lct
`
`35
`
`40
`
`45
`
`50
`
`55
`
`the maxima
`In such embodiments is most preferred that
`differ by no more than 20%. However, embodiments in
`which the maxima of the two releases differ by more than 40
`percent are within the scope of the invention. The appro-
`priate rclativc amounts ofdrug in each release can be readily
`determined by one skilled in the art.
`Dosage fonns of the present invention provide controlled
`release of a methylphenidate drug, including pharmaceuti-
`
`60
`
`65
`
`6
`cally acceptable salts of methylphenidate, whereby an initial
`dose for immediate release can be combined with a delayed
`release of one or more additional doses. Such dosage forms
`may alternatively be referred to as "pulsatile" dosage forms.
`"lmmcdiate release", as used herein. means release within
`about a half hour following ingestion, preferably about 15
`minutes, and more preferably within about 5 minutes fol-
`lowing ingestion. “Delayed release”, as used herein, refers to
`a dnig release profile which includes a period during which
`no more than about 10 percent of the drug in a particular
`dosage form is released, followed by a period of from about
`0.5 hour to about 2.5 hours, preferably about 1.5 hours, more
`preferably about
`1 hour, in which no less than about 70
`percent, preferably no less than about 80 percent, and more
`preferably no less than about 90 percent, of the drug is
`released. The terms "medication" and “drug" are used
`interchangeably herein.
`According to the present invention, delayed release dos-
`age fonns can be combined with forms which provide
`immediate release of a drug. Thus,
`two or more dosage
`forms can be combined, one dosage form providing a
`portion of a patient’s daily dosage needs of a drug and
`subsequent dosage forms providing additional portions of a
`patient’s daily dosage needs. For example, a drug can be
`administered to a patient
`in two dosage forms
`simultaneously, one providing, e.g., about 30-50 percent of
`the patient’s daily requirement of the drug and the second
`providing the remainder of the patient’s daily requirement.
`Alternatively, and preferably, a single dosage form can be
`administered which includes an immediate dose of some
`portion of a patient’s daily requirement and one or more
`delayed doses to provide the remaining portion or portions
`of the patient’s daily requirement.
`Dosage fonns of the present invention provide an initial
`dose of a drug such as, for example, a pharmaceutically
`acceptable salt of d-threo—methylphenidate (also referred to
`herein as d-MPD), followed by an interval wherein substan-
`tially no additional drug is released, followed in turn by
`release of a second dose. If desired, a second substantially
`release-free interval may be provided following the second
`release, followed in turn by a third dose. Thus, dosage forms
`providing 3 or more doses are contemplated by the present
`invention. However, dosage forms providing 2 or 3 doses are
`generally preferred for therapeutic use, with 2 (loses being
`more preferred. For example, the first dose can provide from
`about 30 percent
`to about 70 percent of a patient’s daily
`prescribed intake of the drug and the second dose provides
`from about 70 percent to about 30 percent. If two approxi-
`mately equal doses are desired, the initial dose preferably
`provides from about 40 percent to about 60 percent, and the
`second dose preferably provides from about 60 percent to
`about 40 percent, of a patient’s prescribed daily intake of the
`dmg. If desired, the first dose and the second dose can each
`provide about 50 percent of a patient’s prescribed daily
`intake of drug. However, as will be apparent to one skilled
`in the art, the elIect of drug metabolism in the body may
`require adjustment of the relative amounts of each dose, so
`that, for example, the second dose may have to be adjusted
`to provide more of the drug than the first dose, to compen-
`sate for any competition between drug release and drug
`metabolism. This can be observed in FIG. 2, which, as
`discussed above, represents the blood plasma level of a drug,
`such as a methylphenidate drug, delivered in a dosage form
`which provides a release profile as illustrated in FIG. 1.
`The initial dose of methylpltenidate drug in the dosage
`forms of the present invention can be provided by incorpo-
`rating the rnethylphenidate drug into a form which allows
`
`Amerigen Ex. 1027, p. 6
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`for substantially immediate release of the drug once the
`dosage form is ingested by a patient. Such forms include, for
`example, powders, coated and uncoated pellets, and coated
`and uncoated tablets. The dose for immediate release can be
`administered in a tablet or capsule form which may also
`include the delayed close. For example, two or more groups
`of pellets may be combined within a hard gelatin capsule or
`compressed into a tablet. Powders can be granulated and can
`be combined with pellets and excipients andfor other
`additives, and contained within a capsule or compressed into
`a tablet. These and other dosage forms will be familiar to
`those skilled in the art.
`The delayed dose of a methylphenidate drug in the dosage
`forms of the present invention is provided in part by the use
`ofcertain copolymers referred to as “ammonio methacrylate
`copolymers". Ammonio methacrylate copolymers comprise
`acrylic artdfor rnethacrylic ester groups together with qua-
`ternary ammonium groups. According to the present
`invention, the copolymers are incorporated into a formula-
`tion which is used to coat particles containing a medication.
`The “acrylic andtor methacrylic ester groups” in the -
`copolymers used in the compositions and methods of the
`present
`invention are referred to herein collectively as
`"acrylic groups”. The acrylic groups are preferably derived
`from monomers selected from C,—C,,- alkyl esters of acrylic
`acid and C1-C6 alkyl esters of methacrylic acid. Preferred _
`are C,—C, alkyl esters of acrylic acid and methacrylic acid.
`Suitable monomers include, for example, methyl acrylate,
`ethyl acrylate, methyl methacrylate, and ethyl rnethacrylate.
`Ethyl acrylate and methyl methacrylate are preferred, and
`copolymers containing ethyl acrylate and methyl methacry-
`late are highly preferred. Also preferably, the copolymers
`have a molecular weight of about 150,000.
`Quaternary ammonium groups in copolymers useful in
`forming coatings for use in the dosage fon'ns of the present
`invention can be derived from monomers comprising qua-
`ternary ammonium groups. Preferably, the monomers are
`al.kyl esters of acrylic or methacrylic acid, comprising alkyl
`groups having from I to 6 carbon atoms and a quaternary
`ammonium group in the alkyl portion. Monomers compris-
`ing quaternary ammonium groups can be prepared,
`for
`example, by reaction of monomers containing amino groups
`with alkylating agents such as, for example, alkyl halides,
`especially methyl chloride. Suitable monomers containing
`amino groups include 2-(N,N-dibutylamiuo)ethyl acrylate,
`2—(N,N—dibutylamino)ethyl methacrylate, 4—diethylamino—l~
`methyl-butyl acrylamide, and 4-diethylamino-1-methyl-
`butyl methacrylamide. Other useful monomers containing
`amino groups are disclosed in US. Pat. No. 5,422,121, the
`disclosure of which is incorporated herein by reference.
`Particularly preferred as a monomer comprising a quater-
`nary ammonium group is trimethylammonioethyl methacry—
`late chloride (TAMCI).
`While ammonio methacrylate copolymers such as those
`described herein have been used for sustained delivery of
`certain medicaments, i.e., for the relatively constant admin-
`istration of a dnig, it has been surprisingly and unexpectedly
`found that dosage forms comprising a ntethylphenidate drug
`and a coating prepared from one or more ammonio meth-
`acrylate copolymers and certain tillers, can provide delayed
`or pulsatile release of the drug, a very distinct phenomenon.
`Methylphcnidate drugs are amine-containing,
`rely upon
`body or membrane loading for efficacy, and are psychotro-
`pic. Thc ability to provide delayed release of a methylpheni—
`date drugs using ammonio mcthacrylate copolymers is due
`to a combination of factors, including the composition of the
`ammonio methacrylate copolymers used, and the amount
`and composition of filler.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`The ratio of acrylic groups to quaternary ammonium
`groups in the ammonio methacrylate copolymers inlluences
`the properties of the copolymers utilized in forming the
`coatings of the present
`invention. For use in the dosage
`forms and methods of the present
`invention, the ratio of
`acrylic groups to quaternary ammonium groups in the
`copolymers is preferably from about 10:1 to about 50:1,
`more preferably from about 15:1 to about 45:1. Preferably,
`in preparing a dosage form according to the present
`invention, two or more copolymers are used in combination.
`Also preferably, one of the copolymers comprises acrylic
`groups and quaternary ammonium groups in a ratio of from
`about 25:1 to about 45:1, more preferably from about 30:1
`to about 40:1, and another of the copolymers comprises
`acrylic groups and quaternary ammonium groups in a ratio
`of from about 10:1 to about 25:1, more preferably from
`about 15:1 to about 20:1. Even more preferably, two ammo-
`nio methacryiate copolymers are used: a first copolymer
`comprising acrylic groups and quaternary ammonium
`groups in a ratio of from about 30:} to about 40:1 and the
`second copolymer comprising acrylic groups and quaternary
`ammonium groups in a ratio of from about 15:1 to about
`20:1. Most preferably.
`the copolymers are copolymers of
`methyl methacrylate, ethyl acrylate, and TAMCI, in ratios of
`2:l:0.l for the lirst copolymer and 2:1:(l.2 for the second
`copolymer.
`When two such ammonio metltacrylate copolymers are
`used to form the coatings, the relative amounts of the two
`polymers is partly determinative of the delay and release
`properties of the dosage forms of the present invention. It is
`preferred that
`the ratio between the first polymer, most
`preferably having an acrylic grouptquaternary ammonium
`group ratio of from about 30:] to about 40:1, and the second
`polymer, most preferably having an acrylic groupf
`quaternary ammonium group ratio of from about 15:]
`to
`about 20:1, be from about 93:’? to about 97:3. More
`preferably,
`the ratio of the first polymer to the second
`polymer is from about 96:4 to about 94:6, and most pref-
`erably about 95:5.
`Ammonio methacrylate copolymers used in the coatings
`of the dosage forms of the present invention can be prepared
`by methods known to those skilled in the art. Exemplary
`methods include emulsion polymerization, bulk polymeriza-
`tion and suspension polymerization. A suitable procedure is
`described in U.S. Pat. No. 3,979,349, the disclosure of which
`is incorporated herein by reference. Suitable ammonio meth-
`acrylate copolymers are known per se, and can be purchased
`from commercial providers. For example, suitable ammonio
`methacrylate polymers are available from lltils America
`under the l:ludragit® trademarks. The l:ludragit® polymers
`and similar polymers, including methods for preparation, are
`described in Klaus O. R. Lehman, "Chemistry and Appli-
`cation Properties of Polymethacrylate Coating Systems",
`Aqueous Polymeric Contr’ng.s for Pitrrrmrrceiiricrrl Dosage
`Forms, 2nd. Ed, pp. t0t—l'r'4, James Me Ginity, Ed., Marcel
`Dekker, Inc., New York (1996), the disclosure of which is
`incorporated herein by reference.
`invention also preferably
`The coatings of the present
`include a filler. The filler is preferably in powder form and
`is preferably hydrophobic. Exemplary lillers include talc,
`colloidal silica,
`fumed silica. gypsum, and glyeerine
`monostearate. Tale is a particularly preferred filler.
`The quantity of filler used in preparing coatings for the
`dosage forms of the present invention should be suflieient to
`minimize agglomeration of the particles. Agglorneration is
`highly undesirable because the agglomerates, rather than
`discrete particles, will become coated. Agglomeratcs are
`
`Amerigen Ex. 1027, p. 7
`Amerigen Ex. 1027, p. 7
`
`
`
`5,837,284
`
`9
`susceptible to breaking into discrete particles, which will be
`partially uncoated,
`resulting in unwanted variability in
`release rates. Preferably. the amount of filler is from about
`30 percent to about 50 percent by weight, based on the total
`weight of the dry polymer, commonly referred to as "total
`solids". More preferably the amount of filler is from about
`35 percent
`to about 45 percent of total solids, and most
`preferably about 40 percent.
`Coatings used in the dosage forms of the present inven-
`tion also preferably include a material which improves. the
`processing of the copolymers. Such materials are generally
`referred to as “plasticizers” and include, for example, citric
`acid esters, adipates, azelatcs, benzoates, citrates, stearates,
`isoebucates. sehaeatcs, propanctriol acetate, polyethylene
`glycols, diethyl phthalate, dibu tyl sebacate, propylene glycol
`and ethylene glycol. Citric acid esters are preferred, and
`triethyl citrate is particularly preferred. The amount of
`plasticizicr to be used in the coating is preferably from about
`10 percent t