United States Patent [19]
`Mehta et al.
`
`[54]
`
`[76]
`
`DELIVERY OF MULTIPLE DOSES OF
`MEDICATIONS
`
`Inventors: Atul M. Mehta, 252 E. Cresent Ave.,
`Ramsey, NJ. 07446; Andrew L.
`Zeitlin, 1500 Whitebridge Rd.,
`Millington, NJ. 07946; Maghsoud M.
`Dariani, 11 Byron La., FanWood, NJ.
`07023
`
`Appl. No.: 892,190
`Filed:
`Jul. 14, 1997
`
`Related US. Application Data
`
`Continuation-in-part of Ser. No. 567,131, Dec. 4, 1995,
`abandoned, and a continuation-in-part of Ser. No. 583,317,
`Jan. 5, 1996, and a continuation-in-part of Ser. No. 647,642,
`May 15, 1996.
`
`Int. Cl.6 ............................. .. A61K 9/56; A61K 9/54;
`A61K 9/58; A61K 9/22; A61K 31/21
`US. Cl. ........................ .. 424/459; 424/458; 424/462;
`424/468; 514/317
`Field of Search ................................... .. 424/458, 459,
`424/462, 468; 514/317
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`US005837284A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,837,284
`Nov. 17, 1998
`
`7/1994 Rudnic et al. ........................ .. 424/458
`5,326,570
`5,478,573 12/1995 Eichel et al.
`424/480
`5,500,227
`3/1996 Oshlack et al. ....................... .. 424/476
`5,639,476
`6/1997 Oshlack et al. ....................... .. 424/658
`5,672,360
`9/1997 Sackler et al. ........................ .. 424/490
`
`OTHER PUBLICATIONS
`
`PDR, 46th ed. “Ritalin SR” pp. 880—881, 1992.
`
`Primary Examiner—Raymond Henley, III
`Attorney, Agent, or Firm—Woodcock Washburn KurtZ
`MackieWicZ & Norris LLP
`
`[57]
`
`ABSTRACT
`
`Dosage forms for oral administration of a methylphenidate
`drug are provided. The dosage forms provide a substantially
`immediate dose of methylphenidate upon ingestion, fol
`loWed by one or more additional doses at predetermined
`times. By providing such a drug release pro?le, the dosage
`forms eliminate the need for a patient to carry an additional
`dose for ingestion during the day. The dosage forms and
`methods provided are useful in administering methylpheni
`date and pharmaceutically acceptable salts thereof, Which
`generally require one or more doses throughout the day.
`
`4,794,001 12/1988 Mehta etal. .......................... .. 424/458
`
`30 Claims, 2 Drawing Sheets
`
`Page 1
`
`SHIRE EX. 2007
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`U.S. Patent
`
`Nov. 17,1998
`
`Sheet 1 of2
`
`5,837,284
`
`120
`
`100
`
`O 8
`
`O 6
`
`O 4
`
`%Dissolved
`
`//
`
`10
`Time ( hours )
`
`15
`
`2O
`
`FIG. 1
`
`Page 2
`
`

`

`U.S. Patent
`
`Nov. 17,1998
`
`Sheet 2 of2
`
`5,837,284
`
`’
`
`T1
`
`T2
`
`C1
`C 2
`
`.__|,._ T
`
`FIG. 2
`
`Page 3
`
`

`

`5,837,284
`
`1
`DELIVERY OF MULTIPLE DOSES OF
`MEDICATIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation in part of application
`Ser. No. 08/567,131, ?led Dec. 4, 1995, noW abandoned;
`application Ser. No. 08/583,317, ?led Jan. 5, 1996; and
`application Ser. No. 08/647,642, ?led May 15, 1996.
`
`FIELD OF THE INVENTION
`
`The present invention relates to improved dosing of
`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 forms 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 De?cit 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. Arelated disorder, termed Atten
`tion De?cit Hyperactivity Disorder (ADHD), 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 Immunode?ciency Syndrome
`(AIDS) or AIDS related conditions. See, e.g., BroWn, G.,
`Intl. J. Psych. Med. 25(1): 21—37 (1995); Holmes et al., J.
`Clin. Psychiatry 50:5—8 (1989).
`Methylphenidate eXists as four separate optical isomers as
`folloWs:
`
`(‘302cm
`
`CO2CH3
`
`l-threo
`
`d-erythro
`
`H
`
`R2
`
`CO2CH3
`
`H
`
`R2
`
`_
`EZOZCH3
`
`N
`H
`
`l-erythro
`
`N
`H
`
`d-threo
`
`Wherein R2 is phenyl. Pharmaceutically acceptable salts are
`generally administered clinically. Other phenidate drugs,
`
`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 R2 is optionally
`substituted With C1—C4 alkyl.
`Clinically, the threo 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 “methylphenidate” is used
`broadly herein to include methylphenidate and pharmaceu
`tically acceptable salts thereof, including methylphenidate
`hydrochloride.
`The threo racemate (pair of enantiomers) of methylpheni
`date is a mild central nervous system stimulant With phar
`macological activity qualitatively similar to that of amphet
`amines. Undesirable side effects associated With the use of
`the dl-threo racemate of methylphenidate include anorexia,
`Weight loss, insomnia, diZZiness and dysphoria.
`Furthermore, the racemate, 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-threo-,
`d-threo, and l-threo-methylphenidate to children suffering
`from ADHD, and reported that the pharmacodynamic activ
`ity of dl-threo-methylphenidate resides in the d-threo isomer
`(Clin. Pharmacol. Then, 52:561—568 (1992)). Therefore,
`While dl-threo-methylphenidate is generally used
`therapeutically, this racemate includes the l isomer Which
`apparently makes no signi?cant contribution to the pharma
`cological effectiveness of the drug, but likely contributes to
`the associated side effects. It is thus desirable to administer
`only the active d-threo form 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. Furthermore, children may be trauma
`tiZed by ridicule from peers When they must take medication
`at school.
`Sustained release formulations of dl-threo methylpheni
`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 ef?cacy 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 effective meth
`ylphenidate. This Will eliminate the risk of theft or loss of the
`second dose, While minimiZing undesirable side effects and
`maXimiZing ease of administration. The present invention is
`directed to these, as Well as other, important ends.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 depicts an in vitro time-concentration relationship
`(release pro?le) 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 pro?le shoWn in FIG. 1.
`
`65
`
`Page 4
`
`

`

`3
`SUMMARY OF THE INVENTION
`
`The present invention provides, in one embodiment, a
`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 ?rst group of particles
`provides a substantially immediate dose of the methylpheni
`date drug upon ingestion by a mammal. The ?rst group of
`particles can also comprise a coating and/or 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 suf?
`cient to provide a delay of from about 2 hours to about 7
`hours folloWing ingestion before release of the second dose.
`If desired, one or more additional doses may be delivered by
`additional particles, coated in a similar manner, but With a
`sufficient 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.
`In one embodiment of the present invention, the ?rst
`group of particles comprises a methylphenidate drug and
`provides a substantially immediate dose of the methylpheni
`date drug upon ingestion by a mammal. The ?rst group of
`particles may comprise a coating and/or 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 20%, by Weight of the particles of the methylphenidate
`drug in admixture With one or more binders. The coating
`comprises a pharmaceutically acceptable ammonio meth
`acrylate copolymer in a quantity suf?cient to provide a dose
`of methylphenidate delayed by from about 2 hours to about
`7 hours folloWing ingestion.
`For example, the ?rst group of particles can comprise a
`pharmaceutically acceptable salt of methylphenidate, such
`as methylphenidate hydrochloride, in poWder form, or
`coated or uncoated particles 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 for methylphenidate
`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 and/or 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 ?rst group of
`particles. In addition to the methylphenidate drug, the sec
`ond group of particles comprises a ?ller, such as a hydro
`phobic ?ller, one or more ammonio methacrylate
`copolymers, and optional excipients and other additives. The
`?ller 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
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5,837,284
`
`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 ?rst 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 ?rst group may comprise a
`coating and/or sealant. The second group of particles 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 from about 5% to about
`20%, by Weight of the second group of particles, and a
`coating comprising an ammonio methacrylate copolymer in
`a quantity suf?cient 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 forms 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 suf?cient to delay release of the
`d-threo-methylphenidate 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 pro?les for methylphenidate
`having tWo maxima, temporally separated from each other
`by from about 2 hours to about 7 hours. Preferably, the
`magnitude of said maxima differs 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 pharmaceutically
`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 “threo ” and the erythro isomers as “erythro ”. 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 differ
`generally in producing unWanted side effects. The present
`invention provides dosage forms Which maximiZe therapeu
`
`Page 5
`
`

`

`5,837,284
`
`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 methylphenidate drugs, in at
`least tWo doses. Most preferably, the dosage forms provide
`tWo doses of a d-threo methylphenidate drug such as d-threo
`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 ADD, to carry
`a second dose for ingestion several hours after ingestion of
`a ?rst 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 effects and/or reduced effectiveness.
`The temporal separation of the tWo doses provided
`according to the present invention can be represented
`graphically as in FIG. 1. FIG. 1 is an in vitro drug release
`pro?le 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 ?rst 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 “pulses”, and
`such a release pro?le can be referred to as “pulsatile”.
`FIG. 2 is a schematic representation of the plasma con
`centration of drug resulting from a release pro?le according
`to FIG. 1. The maximum concentration due to the ?rst dose,
`C1, occurs at t1, preferably from about 1 hour to about 3
`hours after ingestion, most preferably about 2 hours after
`ingestion. The release of the ?rst 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, C2, at t2, 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 pro?le 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:
`
`15
`
`25
`
`35
`
`45
`
`55
`
`In such embodiments is most preferred that the maxima
`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 relative amounts of drug in each release can be readily
`determined by one skilled in the art.
`Dosage forms of the present invention provide controlled
`release of a methylphenidate drug, including pharmaceuti
`
`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.
`“Immediate 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 drug release pro?le 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 forms 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 forms 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 doses being
`more preferred. For example, the ?rst 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
`drug. If desired, the ?rst 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 effect 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 ?rst 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 pro?le as illustrated in FIG. 1.
`The initial dose of methylphenidate drug in the dosage
`forms of the present invention can be provided by incorpo
`rating the methylphenidate drug into a form Which alloWs
`
`Page 6
`
`

`

`5,837,284
`
`7
`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 dose. 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 and/or 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
`of certain copolymers referred to as “ammonio methacrylate
`copolymers”. Ammonio methacrylate copolymers comprise
`acrylic and/or methacrylic 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 and/or 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 C1—C6 alkyl esters of acrylic
`acid and C1—C6 alkyl esters of methacrylic acid. Preferred
`are C1—C4 alkyl esters of acrylic acid and methacrylic acid.
`Suitable monomers include, for example, methyl acrylate,
`ethyl acrylate, methyl methacrylate, and ethyl methacrylate.
`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 forms of the present
`invention can be derived from monomers comprising qua
`ternary ammonium groups. Preferably, the monomers are
`alkyl esters of acrylic or methacrylic acid, comprising alkyl
`groups having from 1 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-dibutylamino)ethyl acrylate,
`2-(N,N-dibutylamino)ethyl methacrylate, 4-diethylamino-1
`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 (TAMCl).
`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 drug, it has been surprisingly and unexpectedly
`found that dosage forms comprising a methylphenidate drug
`and a coating prepared from one or more ammonio meth
`acrylate copolymers and certain ?llers, can provide delayed
`or pulsatile release of the drug, a very distinct phenomenon.
`Methylphenidate drugs are amine-containing, rely upon
`body or membrane loading for ef?cacy, and are psychotro
`pic. The ability to provide delayed release of a methylpheni
`date drugs using ammonio methacrylate copolymers is due
`to a combination of factors, including the composition of the
`ammonio methacrylate copolymers used, and the amount
`and composition of ?ller.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`The ratio of acrylic groups to quaternary ammonium
`groups in the ammonio methacrylate copolymers in?uences
`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 methacrylate copolymers are used: a ?rst copolymer
`comprising acrylic groups and quaternary ammonium
`groups in a ratio of from about 30:1 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 TAMCl, in ratios of
`2:1:0.1 for the ?rst copolymer and 2:1:0.2 for the second
`copolymer.
`When tWo such ammonio methacrylate 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 ?rst polymer, most
`preferably having an acrylic group/quaternary ammonium
`group ratio of from about 30:1 to about 40:1, and the second
`polymer, most preferably having an acrylic group/
`quaternary ammonium group ratio of from about 15:1 to
`about 20:1, be from about 93:7 to about 97:3. More
`preferably, the ratio of the ?rst 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 US. 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 Hiils America
`under the Eudragit® trademarks. The Eudragit® 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 Coatings for Pharmaceutical Dosage
`Forms, 2nd. Ed., pp. 101—174, James Mc Ginity, Ed., Marcel
`Dekker, Inc., NeW York (1996), the disclosure of Which is
`incorporated herein by reference.
`The coatings of the present invention also preferably
`include a ?ller. The ?ller is preferably in poWder form and
`is preferably hydrophobic. Exemplary ?llers include talc,
`colloidal silica, fumed silica, gypsum, and glycerine
`monostearate. Talc is a particularly preferred ?ller.
`The quantity of ?ller used in preparing coatings for the
`dosage forms of the present invention should be suf?cient to
`minimiZe agglomeration of the particles. Agglomeration is
`highly undesirable because the agglomerates, rather than
`discrete particles, Will become coated. Agglomerates are
`
`Page 7
`
`

`

`5,837,284
`
`susceptible to breaking into discrete particles, Which Will be
`partially uncoated, resulting in unwanted variability in
`release rates. Preferably, the amount of ?ller 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 ?ller 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, aZelates, benZoates, citrates, stearates,
`isoebucates, sebacates, propanetriol acetate, polyethylene
`glycols, diethyl phthalate, dibutyl sebacate, propylene glycol
`and ethylene glycol. Citric acid esters are preferred, and
`triethyl citrate is particularly preferred. The amount of
`plasticiZer to be used in the coating is preferably from about
`10 percent