`
`US006555136B2
`
`(12)United States Patent
`
`
`Midha
`
`B2 (10)Patent No.:US 6,555,136
`
`
`(45)Date of Patent:
`*Apr. 29, 2003
`
`(54)PHARMACEUTICAL DOSAGE FORM FOR
`
`PULSATILE DELIVERY OF
`METHYLPHENIDATE
`
`
`
`
`
`(75)Inventor: Kamal K. Midha, Hamilton (BM)
`
`
`(73)Assignee:
`
`
`
`PharmaQuest, Ltd., Hamilton (BM)
`
`( *) Notice: Subject to any disclaimer, the term of this
`
`
`
`
`
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis
`
`
`
`
`
`claimer.
`
`(21)Appl. No.: 09/992,353
`
`
`
`(22)Filed:Nov. 13, 2001
`
`(65)
`
`Prior Publication Data
`
`
`
`
`
`US 2002/0058061 Al May 16, 2002
`
`
`
`
`
`Related U.S. Application Data
`
`5,260,069 A 11/1993 Chen
`
`
`5,300,304 A 4/1994 Sheth et al.
`
`5,308,348 A 5/1994 Balaban et al.
`
`5,312,390 A 5/1994 Wong
`
`5,340,590 A 8/1994 Wong et al.
`
`5,348,748 A 9/1994 Sheth et al.
`
`
`5,391,381 A 2/1995 Wong et al.
`
`5,407,686 A 4/1995 Patel et al.
`
`5,445,828 A 8/1995 Pozzi et al.
`
`5,456,679 A 10/1995 Balaban et al.
`5,472,708 A 12/1995 Chen
`
`5,498,255 A 3/1996 Wong
`
`5,499,979 A 3/1996 Wong et al.
`
`5,508,040 A 4/1996 Chen
`
`5,531,736 A 7/1996 Wong et al.
`
`5,773,478 A 6/1998 Richards et al.
`
`5,801,271 A 9/1998 Seido et al.
`
`5,837,284 A 11/1998 Mehta et al.
`
`5,859,249 A 1/1999 Seido et al.
`
`
`5,874,090 A 2/1999 Baker et al.
`
`5,914,129 A 6/1999 Mauskop
`
`
`
`6,150,376 A 11/2000 Kozikowski et al.
`
`
`6,217,904 Bl * 4/2001 Midha et al. ............... 424/468
`
`
`
`6,340,476 Bl * 1/2002 Midha et al. ............... 424/469
`
`FOREIGN PATENT DOCUMENTS
`
`
`
`WO 98/06380 2/1998
`
`OTHER PUBLICATIONS
`
`on Apr. 6,( 63)Continuation of application No. 09/544,732, filed
`
`
`
`
`WO
`2000, now Pat. No. 6,340,476.
`
`
`
`
`(60)Provisional application No. 60/127,984, filed on Apr. 6,
`1999.
`
`
`
`
`
`Conte et al. (2000), "A Flexible Technology for the Linear,
`
`(51)Int. Cl.7 .................................................. A61K 9/26
`
`
`
`
`
`Pulsatile and Delayed Release of Drugs, Allowing for Easy
`
`....................... 424/469; 424/451; 424/452; (52)U.S. Cl.
`
`
`
`
`
`Accommodation of Difficult In Vitro Targets," Journal of
`
`
`424/457; 424/458; 424/459; 424/463; 424/464;
`
`
`Controlled Release 64:263-268.
`
`
`
`424/465; 424/468; 424/474; 424/475; 424/481;
`*cited by examiner
`424/482
`(58)Field of Search .................................
`
`424/451, 452,
`
`Primary Examiner-Thurman K. Page
`
`
`
`
`
`424/457, 458, 459, 463, 464, 465, 468,
`Assistant Examiner-Liliana Di Nola-Baron
`
`
`469,474,475,481,482
`
`
`(74)Attorney, Agent, or Firm-Dianne E. Reed; Karen
`
`Canaan; Reed & Associates
`
`(56)
`
`
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`
`Novel pharmaceutical dosage forms provide for pulsatile
`
`
`4,627,850 A 12/1986 Deters et al.
`
`
`
`
`
`
`delivery of methylphenidate, i.e., release encapsulated drug
`
`
`
`4,713,247 A 12/1987 Sakamoto et al.
`
`
`
`
`in spaced apart "pulses. " The dosage forms are comprised of
`
`4,728,512 A 3/1988 Mehta et al.
`
`
`first, second and optionally third dosage units, with each
`
`
`4,777,049 A 10/1988 Magruder et al.
`
`
`4,874,388 A 10/1989 Wong et al.
`
`
`dosage unit having a different drug release profile. The
`
`
`4,957,494 A 9/1990 Wong et al.
`
`
`
`dosage forms may comprise capsules housing compressed
`
`
`4,971,805 A 11/1990 Kitanishi et al.
`
`
`tablets or drug-containing beads or particles, or may com
`
`
`5,023,088 A 6/1991 Wong et al.
`
`
`
`
`
`
`prise a single tablet with the first, second and optionally third
`
`
`5,110,597 A 5/1992 Wong et al.
`
`
`
`dosage units each representing an integral and discrete
`
`
`
`5,204,116 A 4/1993 Edgren et al.
`
`
`
`segment thereof. Methods of treatment using the pharma
`5,209,746 A 5/1993 Balaban et al.
`
`
`ceutical dosage forms are provided as well.
`
`
`
`5,221,278 A 6/1993 Linkwitz et al.
`
`
`5,236,689 A 8/1993 Wong et al.
`
`
`5,260,068 A 11/1993 Chen
`
`
`
`45 Claims, No Drawings
`
`KVK-TECH EXHIBIT 1018
`
`
`
`US 6,555,136 B2
`
`2
`
`zaniga et al. (1994), “Chronotopic Drug Delivery Systems
`for Pulsatile and/or Site-Specific Release,” 215‘. Proc. Int.
`Symp. Controlled Release Bioact. Mater, pp. 744—745.
`The present
`invention is directed in part
`to a novel
`pulsatile drug delivery system which is straightforward to
`manufacture and provides precisely timed drug release
`“pulses” at desired intervals.
`Methylphenidate hydrochloride (HCl), the hydrochloride
`salt of ot-phenyl-2-piperidine-acetic acid methyl ester
`(available commercially as Ritalin®), is a central nervous
`system stimulant that is used in the treatment of Attention
`Deficit Disorder (“ADD”), a commonly diagnosed nervous
`system illness in children that
`is characterized by both
`distractability and impulsivity. Methylphenidate HCl is also
`used to treat a related disorder, Attention Deficit Hyperac-
`tivity Disorder (“ADHD”), in which symptoms of hyperac-
`tivity are present along with the symptoms of ADD. The
`drug is additionally used in the symptomatic treatment of
`narcolepsy, depression, and the cognitive decline associated
`with Acquired Immunodeficiency Syndrome (“AIDS”) or
`AIDS-related conditions, as well as for mood elevation,
`particularly in terminally ill patients with diseases such as
`cancer. Methylphenidate exists as four distinct isomers, as
`follows:
`
`1
`PHARMACEUTICAL DOSAGE FORM FOR
`PULSATILE DELIVERY OF
`METHYLPHENIDATE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This is a continuation of US. Ser. No. 09/544,732, filed
`Apr. 6, 2000, now US. Pat. No. 6,340,476, which claims
`priority under 35 U.S.C. §119(e)(1) to US. Provisional
`Patent Application Serial No. 60/127,984, filed Apr. 6, 1999.
`The disclosures of the aforementioned patent applications
`are incorporated by reference in their entireties.
`The present invention relates generally to drug delivery,
`and more specifically relates to novel pharmaceutical dosage
`forms that provide pulsatile delivery of methylphenidate.
`The invention additionally relates to methods for adminis-
`tering methylphenidate using the novel dosage forms.
`
`BACKGROUND
`
`Pharmaceutical dosage forms are known which provide a
`variety of drug release profiles, including immediate release,
`sustained release, and delayed release. That is, it may be
`desirable, for a particular drug, to prevent drug release after
`drug administration until a certain amount of time has
`passed (so-called “timed release”), to provide substantially
`continuous release over a predetermined time period (so-
`called “sustained release”) or to provide release immediately
`following drug administration (i.e., “immediate release”).
`For some types of drugs, it is preferred to release the drug
`in “pulses,” wherein a single dosage form provides for an
`initial dose of drug followed by a release-free interval, after
`which a second dose of drug is released, followed by one or
`more additional
`release-free intervals and drug release
`“pulses.” Pulsatile drug delivery is useful, for example, with
`active agents that have short half-lives and must be admin-
`istered two or three times daily, with active agents that are
`extensively metabolized presystemically, and with active
`agents which lose the desired therapeutic effect when con-
`stant blood levels are maintained. These types of agents have
`pharmacokinetic-pharmacodynamic relationships that are
`best described by a clockwise “hysteresis loop.” A drug
`dosage form that provides a pulsatile drug release profile is
`also useful for minimizing the abuse potential of certain
`types of drugs, i.e., drugs for which tolerance, addiction and
`deliberate overdose can be problematic.
`Because a precise and effective pulsatile drug delivery
`system is difficult to formulate and manufacture, there are
`few such dosage forms that have been commercialized.
`There are, however, several patents and literature references
`pertaining to pulsatile drug delivery. See, for example, US.
`Pat. No. 5,413,777 to Sheth et al., directed to a pulsatile
`once-a-day delivery system for the administration of
`minocycline; US. Pat. No. 5,260,068 to Chen, directed to a
`multiparticulate pulsatile drug delivery system; US. Pat.
`No. 4,777,049 to Magruder et al., directed to an osmotic
`delivery system for constant release of a drug with inter-
`mittent release “pulses”; US. Pat. No. 5,391,381 to Wong et
`al., directed to a drug dispenser for delivering individual
`drug-containing units in a “pulsatile” manner; PCT Publi-
`cation No. WO 98/32424, pertaining to pulsatile delivery of
`diltiazem hydrochloride; US. Pat. Nos. 5,472,708 and
`5,260,069 to Chen; Ishino et al. (1992) “Design and Prepa-
`ration of Pulsatile Release Tablet as a New Oral Drug
`Delivery System,” Chem. Pharm. Bull. 40(11):3036—3041;
`Cohen et al. (1994), “Pulsatile Release from Microencap-
`sulated Liposomes,” J. Liposome Res. 349—360; and Gaz-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`"d-threo"
` H
`
`E2
`
`COZCH3
`
`COZCH3
`"d-erythro "
`
`N
`
`.
`
`COZCH3
`"l-erythro "
`
`The drug as used in therapy is a racemic mixture of the d-
`and l-threo enantiomers, which have been acknowledged as
`more active than the erythro pair.
`Because of its potential for tolerance (loss of clinical
`efficacy when constant blood levels are maintained), short-
`half life and potential for abuse, methylphenidate is a
`primary candidate for use in conjunction with the drug
`delivery systems of the invention.
`Accordingly, the present invention provides novel phar-
`maceutical dosage forms for the administration of meth-
`ylphenidate in its conventional form,
`i.e., as a racemic
`mixture of the d-threo and l-threo enantiomers. The novel
`
`thereby
`dosage forms provide for pulsatile drug release,
`maximizing efficacy (i.e., the loss of clinical efficacy over
`time), reducing the potential for abuse or noncompliance.
`The invention thus represents a significant advance in the
`art, particularly in the administration of drugs such as
`methylphenidate that have short half-lives, tend to be exten-
`sively metabolized presystemically, have pharmacokinetic-
`pharmacodynamic relationships which are best described by
`positive (clockwise) hysteresis loops (hence resulting in
`tolerance when constant blood levels are maintained), or are
`likely candidates for drug abuse. No art of which applicants
`are aware describes pulsatile drug delivery systems as now
`provided herein.
`To the best of applicants’ knowledge, the pharmaceutical
`dosage forms of the invention are previously unknown and
`completely unsuggested by the art.
`
`
`
`US 6,555,136 B2
`
`3
`SUMMARY OF THE INVENTION
`
`Accordingly, it is a primary object of the invention to
`address the above-mentioned need in the art by providing a
`pharmaceutical dosage form for pulsatile delivery of meth-
`ylphenidate.
`It is another object of the invention to provide such a
`dosage form comprising at
`least
`two individual drug-
`containing dosage units, each of which has a different drug
`release profile.
`It is another object of the invention to provide such a
`dosage form wherein the dosage units are housed in a closed
`capsule.
`It is still another object of the invention to provide such
`a dosage form wherein the dosage units are compressed
`tablets.
`
`It is yet another object of the invention to provide such a
`dosage form wherein the dosage units are drug-containing
`particles or beads.
`It is a further object of the invention to provide such a
`dosage form comprised of a single tablet of which the
`drug-containing dosage units represent integral but discrete
`segments.
`It is a further object of the invention to provide such a
`dosage form for administering methylphenidate optionally
`in combination with one or more other active agents such as
`CNS stimulants (including analeptic agents and
`psychostimulants), antidepressant drugs, antianxiety agents
`and the like.
`
`is an additional object of the invention to provide
`It
`methods for administering methylphenidate using the novel
`dosage forms.
`Additional objects, advantages and novel features of the
`invention will be set forth in part in the description which
`follows, and in part will become apparent to those skilled in
`the art upon examination of the following, or may be learned
`by practice of the invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Definitions and Nomenclature
`
`Before the present formulations and methods of use are
`disclosed and described, it is to be understood that unless
`otherwise indicated this invention is not limited to specific
`pharmacologically active agents, specific pharmaceutical
`carriers, or to particular administration regimens, as such
`may vary. It is also to be understood that the terminology
`used herein is for the purpose of describing particular
`embodiments only and is not intended to be limiting.
`It must be noted that, as used in the specification and the
`appended claims, the singular forms “a,” “an” and “the”
`include plural referents unless the context clearly dictates
`otherwise. Thus, for example, reference to “an active agent”
`includes mixtures of active agents, reference to “a pharma-
`ceutical carrier” includes combinations of two or more
`carriers, and the like.
`In this specification and in the claims which follow,
`reference will be made to a number of terms which shall be
`
`defined to have the following meanings:
`“Optional” or “optionally” means that the subsequently
`described circumstance may or may not occur, so that the
`description includes instances where the circumstance
`occurs and instances where it does not.
`
`The terms “active agent,” “drug” and “pharmacologically
`active agent” are used interchangeably herein to refer to a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`chemical material or compound which, when administered
`to an organism (human or animal, generally human) induces
`a desired pharmacologic effect. In the context of the present
`invention, the terms refer to a compound that is capable of
`being delivered orally.
`The term “methylphenidate” as used herein refers to a
`racemic mixture of d-threo methylphenidate and l-threo
`methylphenidate, also referred to herein as “d,l-
`methylphenidate.”
`By the terms “effective amount” or “pharmaceutically
`effective amount” of an agent as provided herein are meant
`a nontoxic but sufficient amount of the agent to provide the
`desired therapeutic effect. The exact amount required will
`vary from subject to subject, depending on age, general
`condition of the subject, the severity of the condition being
`treated, and the particular active agent administered, and the
`like. Thus, it is not possible to specify an exact “effective
`amount.” However, an appropriate “effective” amount in
`any individual case may be determined by one of ordinary
`skill in the art using routine experimentation.
`By “pharmaceutically acceptable” carrier is meant a car-
`rier comprised of a material
`that
`is not biologically or
`otherwise undesirable, i.e., the material may be administered
`to an individual along with the selected active agent without
`causing any undesirable biological effects or interacting in a
`deleterious manner with any of the other components of the
`pharmaceutical composition in which it is contained. The
`term “carrier” is used generically herein to refer to any
`components present
`in the pharmaceutical formulations
`other than the active agent or agents, and thus includes
`diluents, binders, lubricants, disintegrants, fillers, coloring
`agents, wetting or emulsifying agents, pH buffering agents,
`preservatives, and the like.
`Similarly, a “pharmaceutically acceptable” salt or a “phar-
`maceutically acceptable” ester of a compound as provided
`herein is a salt or ester which is not biologically or otherwise
`undesirable.
`
`In the chemical structures drawn herein, the use of bold
`and dashed lines to denote particular conformation of sub-
`stituents follows IUPAC convention. The symbols “0t” and
`“[3” indicate the specific stereochemical configuration of a
`substituent at an asymmetric carbon atom in a chemical
`structure as drawn. Thus “0t,” denoted by a broken line,
`indicates that the group in question is below the general
`plane of the molecule as drawn, and “[3” denoted by a bold
`line, indicates that the group at the position in question is
`above the general plane of the molecule as drawn.
`“Pulsatile Release” Dosage Forms
`In a first embodiment, the invention features pharmaceu-
`tical dosage forms that provide for pulsatile delivery of
`methylphenidate. By “pulsatile” is meant that a plurality of
`drug doses are released at spaced apart
`time intervals.
`Generally, upon ingestion of the dosage form, release of the
`initial dose is substantially immediate, i.e., the first drug
`release “pulse” occurs within 1—2 hours of ingestion. This
`initial pulse is followed by a first time interval during which
`substantially no drug is released from the dosage form, after
`which a second dose is then released. Typically, the second
`dose is released on the order of 3—5 hours following inges-
`tion of the dosage form. Preferably, release of the second
`dose is followed by a second non-release interval, which is
`again followed by a “pulse” of drug release. Ideally, release
`of a third dose occurs on the order of 7—9 hours following
`ingestion. In a preferred embodiment herein, either two or
`three release pulses are provided. However, the invention is
`also intended to encompass dosage forms that provide more
`
`
`
`US 6,555,136 B2
`
`5
`than three pulses, with non-release intervals therebetween of
`approximately 2—6 hours, preferably 3—5 hours.
`The aforementioned pulsatile release profile is achieved
`with dosage forms that, in one embodiment, are closed and
`preferably sealed capsules housing two or more drug-
`containing “dosage units.” In a preferred embodiment, each
`dosage unit comprises a compressed or molded tablet,
`wherein each of the tablets within the capsule provides a
`different drug release profile. That
`is, for an exemplary
`dosage form, a first tablet releases drug substantially imme-
`diately following ingestion of the dosage form, while a
`second tablet in the capsule releases drug approximately 3—5
`hours following ingestion, and an optional third tablet pro-
`vides drug release after approximately 7—9 hours. While the
`dosage form will not generally include more than three
`tablets, dosage forms housing four or more tablets are within
`the scope of the present invention.
`In an alternative embodiment, each dosage unit comprises
`a drug-containing particle or bead (drug-containing “beads”
`refer to drug-coated inert supports, e. g., lactose beads coated
`with drug). A first group of these particles or beads releases
`drug substantially immediately following ingestion of the
`dosage form, a second group releases drug approximately
`3—5 hours following ingestion, and an optional third group
`provides drug release after approximately 7—9 hours.
`In a further alternative embodiment, the individual dosage
`units are compacted in a single tablet, and represent integral
`but discrete segments thereof (e.g., layers). For example,
`drug-containing particles or drug-containing beads can be
`compressed together into a single tablet using conventional
`tabletting means.
`As will be appreciated by those skilled in the art and as
`described in the pertinent texts and literature, a number of
`methods are available for preparing drug-containing tablets
`or other dosage units which provide a variety of drug release
`profiles. Such methods include coating a drug or drug-
`containing composition, increasing the drug’s particle size,
`placing the drug within a matrix, and forming complexes of
`the drug with a suitable complexing agent.
`The delayed release dosage units in the present capsules
`can be prepared,
`for example, by coating a drug or a
`drug-containing composition with a selected membrane
`coating material, typically although not necessarily a poly-
`meric material. When a coating is used to provide delayed
`release dosage units, particularly preferred coating materials
`comprise bioerodible, gradually hydrolyzable and/or gradu-
`ally water-soluble polymers. The “coating weight,” or rela-
`tive amount of coating material per dosage unit, generally
`dictates the time interval between ingestion and drug
`release.
`
`Suitable membrane coating materials for effecting
`delayed release include, but are not limited to: cellulosic
`polymers such as hydroxypropyl cellulose, hydroxyethyl
`cellulose, hydroxypropyl methyl cellulose, methyl cellulose,
`ethyl cellulose, cellulose acetate, cellulose acetate phthalate,
`cellulose acetate trimellitate, hydroxypropylmethyl cellu-
`lose phthalate, cellulose ester-ether phthalate, hydroxypro-
`pylcellulose phthalate, alkali salts of cellulose acetate
`phthalate, alkaline earth salts of cellulose acetate phthalate,
`hydroxypropylmethyl cellulose hexahydrophthalate, cellu-
`lose acetate hexahydrophthalate, and carboxymethylcellu-
`lose sodium; acrylic acid polymers and copolymers prefer-
`ably formed from acrylic acid, methacrylic acid, acrylic acid
`alkyl esters, methacrylic acid alkyl esters, and the like, e.g.
`copolymers of acrylic acid, methacrylic acid, methyl
`acrylate, ethyl acrylate, methyl methacrylate and/or ethyl
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`methacrylate, with a terpolymer of ethyl acrylate, methyl
`methacrylate and trimethylammonioethyl methacrylate
`chloride (sold under the tradename Eudragit RS) particularly
`preferred; vinyl polymers and copolymers such as polyvinyl
`pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,
`vinylacetate crotonic acid copolymer, and ethylene-vinyl
`acetate copolymers; and shellac, ammoniated shellac,
`shellac-acetyl alcohol, and shellac n-butyl stearate.
`In some cases, it may be desirable for the third tablet or
`bead or particle fraction to provide for release of the active
`agent in the colon, in which case polymeric or other mate-
`rials are used that enable drug release within the colon.
`These may be selected from the aforementioned list, or other
`materials may be used as will be known to those skilled in
`the art of pharmaceutical formulation and drug delivery. For
`example, hydrocolloid gums may be effective to provide for
`colonic delivery, e.g., guar gum, locust gum, bena gum, gum
`tragacanth, and karaya gum (see, e.g., US. Pat. No. 5,656,
`294 to Friend). Other materials suitable for effecting colonic
`drug
`delivery
`include
`polysaccharides,
`mucopolysaccharides, and related compounds, e.g., pectin,
`arabinogalactose, chitosan, chondroitin sulfate, dextran,
`galactomannan, and xylan.
`Combinations of different coating materials may also be
`used to coat a single dosage unit.
`To bring about the desired pulsatile release profile for a
`dosage form comprised of encapsulated tablets,
`the first
`tablet is provided with little or no coating material, the
`second tablet
`is provided with some degree of coating
`material, the coating weight of a third tablet is still higher,
`and so on. Analogously, for encapsulated dosage forms in
`which the drug-containing dosage units are beads or
`particles, a first fraction of beads or particles is provided
`with little or no coating material, a second fraction is
`provided with some degree of coating material, the coating
`weight of a third fraction is still higher, etc. For example,
`when the dosage form contains three tablets (or,
`analogously, three groups of drug-containing particles or
`beads),
`the first tablet, which releases drug substantially
`immediately, may have a total coating weight of less than
`about 10%, preferably less than about 8%, the second tablet
`may have a total coating weight in the range of approxi-
`mately 10% to 30%, preferably 15% to 25%, and the third
`tablet, if present, may have a total coating weight in the
`range of approximately 15% to 65%, preferably 20% to
`65%. The preferred coating weights for particular coating
`materials may be readily determined by those skilled in the
`art by evaluating individual release profiles for dosage units
`prepared with different quantities of various coating mate-
`rials.
`
`Alternatively, the delayed release dosage units, i.e., tab-
`lets or particles, may be formulated by dispersing the drug
`within a matrix of a suitable material such as an insoluble
`
`plastic, a hydrophilic polymer, or a fatty compound. The
`insoluble plastic matrices may be comprised of, for example,
`polyvinyl chloride or polyethylene. Hydrophilic polymers
`useful for providing a matrix for a delayed release dosage
`unit include, but are not limited to, those described above as
`suitable coating materials. Fatty compounds for use as a
`matrix material
`include, but are not
`limited to, waxes
`generally (e.g., carnauba wax) and glyceryl tristearate. Once
`the active ingredient is mixed with the matrix material, the
`mixture can be compressed into tablets or processed into
`individual drug-containing particles.
`The individual dosage units may be provided with colored
`coatings, with a single color used to identify a tablet or bead
`
`
`
`US 6,555,136 B2
`
`7
`or particle fraction having a corresponding delayed release
`profile. That is, for example, a blue coating may be used for
`the immediate release tablet or bead or particle fraction, a
`red coating may be used for the “medium” release tablet or
`bead or particle fraction, and the like. In this way, errors
`during manufacture can be easily avoided. The color is
`introduced by incorporating a pharmaceutically acceptable
`colorant into the coating during coating preparation. The
`colorant may be either natural or synthetic. Natural colorants
`include pigments such as chlorophyll, anattenes, beta-
`carotene, alizarin, indigo, rutin, hesperidin, quercitin, car-
`minic acid, and 6,6'-dibromoindigo. Synthetic colorants are
`dyes, including both acidic dyes and basic dyes, such as
`nitroso dyes, nitro dyes, azo dyes, oxazines,
`thiazines,
`pyrazolones, xanthenes,
`indigoids, anthraquinones,
`acridines, rosanilines, phthaleins, quinolines. e.g., a dye or
`pigment, during preparation of the coating solution.
`For encapsulated tablets, the weight of each individual
`tablet in the capsule is typically in the range of about 10 mg
`to 150 mg, preferably in the range of about 25 mg to about
`100 mg, and most preferably is in the range of about 40 mg
`to 80 mg. The individual tablets are prepared using conven-
`tional means. Apreferred method for forming tablets herein
`is by direct compression of a powdered, crystalline or
`granular drug-containing composition, alone or in combina-
`tion with diluents, binders, lubricants, disintegrants, colo-
`rants or the like. As an alternative to direct compression,
`compressed tablets can be prepared using wet-granulation or
`dry-granulation processes. Tablets may also be molded
`rather than compressed, starting with a moist material con-
`taining a suitable water-soluble lubricant. Preferred tablets
`herein are manufactured using compression rather than
`molding, however. Drug-containing particles or beads are
`also prepared using conventional means, typically from a
`fluid dispersion.
`Conventional coating procedures and equipment may
`then be used to coat
`the dosage units,
`i.e.,
`the drug-
`containing tablets, beads or particles. For example, a
`delayed release coating composition may be applied using a
`coating pan, an airless spray technique, fluidized bed coating
`equipment, or the like. For detailed information concerning
`materials, equipment and processes for preparing tablets,
`beads, drug particles, and delayed release dosage forms,
`reference may be had to Pharmaceutical Dosage Forms:
`Tablets, eds. Lieberman et al. (New York: Marcel Dekker,
`Inc., 1989), and to Ansel et al., Pharmaceutical Dosage
`Forms and Drug Delivery Systems, 6’h Ed. (Media, Pa.:
`Williams & Wilkins, 1995).
`in the individual drug-
`Optional components present
`containing dosage units include, but are not
`limited to,
`diluents, binders,
`lubricants, disintegrants, stabilizers,
`surfactants, coloring agents, and the like. Diluents, also
`termed “fillers,” are typically necessary to increase the bulk
`of a tablet so that a practical size is provided for compres-
`sion. Suitable diluents include, for example, dicalcium phos-
`phate dihydrate, calcium sulfate, lactose, cellulose, kaolin,
`mannitol, sodium chloride, dry starch, hydrolyzed starches,
`silicon dioxide, titanium oxide, alumina, talc, microcrystal-
`line cellulose, and powdered sugar. Binders are used to
`impart cohesive qualities to a tablet formulation, and thus
`ensure that a tablet remains intact after compression. Suit-
`able binder materials include, but are not limited to, starch
`(including corn starch and pregelatinized starch), gelatin,
`sugars (including sucrose, glucose, dextrose, lactose and
`sorbitol), polyethylene glycol, waxes, natural and synthetic
`gums, e.g., acacia,
`tragacanth, sodium alginate,
`polyvinylpyrrolidone, celluloses, and Veegum, and synthetic
`
`8
`polymers such as polymethacrylates and polyvinylpyrroli-
`done. Lubricants are used to facilitate tablet manufacture;
`examples of suitable lubricants include, for example, mag-
`nesium stearate, calcium stearate, stearic acid, glyceryl
`behenate, and polyethylene glycol, and are preferably
`present at no more than approximately 1 wt. % relative to
`tablet weight. Disintegrants are used to facilitate tablet
`disintegration or “breakup” after administration, and are
`generally starches, clays, celluloses, algins, gums or
`crosslinked polymers. Stabilizers are used to inhibit or retard
`drug decomposition reactions which include, by way of
`example, oxidative reactions. Surfactants may be anionic,
`cationic, amphoteric or nonionic surface active agents, with
`anionic surfactants preferred. Suitable anionic surfactants
`include, but are not limited to, those containing carboxylate,
`sulfonate and sulfate ions, associated with cations such as
`sodium, potassium and ammonium ions. Particularly pre-
`ferred surfactants include, but are not limited to: long alkyl
`chain sulfonates and alkyl aryl sulfonates such as sodium
`dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates,
`such as sodium bis-(2-ethylhexyl)-sulfosuccinate; and alkyl
`sulfates such as sodium lauryl sulfate. If desired, the tablets
`may also contain minor amounts of nontoxic auxiliary
`substances such as wetting or emulsifying agents, pH buff-
`ering agents, preservatives, and the like.
`As noted earlier herein, the individual drug tablets, beads
`or particles are, in one embodiment, contained within a
`closed capsule. The capsule material may be either hard or
`soft, and as will be appreciated by those skilled in the art of
`pharmaceutical science, typically comprises a tasteless, eas-
`ily administered and water soluble compound such as
`gelatin, starch or cellulose. A preferred capsule material is
`gelatin. The capsules are preferably sealed, such as with
`gelatin bands or the like. See, for example, Remington: The
`Science and Practice of Pharmacy, Nineteenth Edition
`(Easton, Pa.: Mack Publishing Co., 1995), which describes
`materials and methods for preparing encapsulated pharma-
`ceuticals designed to dissolve shortly after ingestion.
`The novel dosage forms are used to administer meth-
`ylphenidate in a pulsatile release manner. As noted earlier
`herein, the drug is administered as a racemic mixture of the
`d-threo and l-threo enantiomers. For administration of race-
`
`mic methylphenidate, a dosage form of the invention com-
`prises a
`total of approximately 2 mg to 100 mg
`methylphenidate, preferably 2 mg to 50 mg
`methylphenidate, divided among the individual dosage
`units. Optimally,
`the first and second dosage units each
`contain approximately 2 mg to 20 mg methylphenidate, and
`preferably, the first and second methylphenidate doses are
`approximately the same. The third tablet should contain a
`lower dose of methylphenidate, preferably about half the
`dose in the first tablet, to avoid sleep disruption. Also, if an
`additional CNS stimulant such as d-amphetamine is incor-
`porated into the dosage form, it will be included in the first,
`immediate release dosage unit, will optionally be present in
`the second dosage unit, (and if present, at a lower dose than
`in the first dosage unit), and will not be included in the third
`dosage unit.
`It may be desirable to include one or more additional
`active agents in the dosage forms herein. These active agents
`may potentiate certain effects of methylphenidate, or vice
`versa. The additional active agent or agents may be com-
`bined with methylphenidate in a single dosage unit within
`the dosage form, or one or more dosage units within the
`dosage form may comprise the additional active agent
`without any methylphenidate. In the former case, the various
`active agents may be present as an admixture in a tablet, or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`US 6,555,136 B2
`
`9
`the agents may be physically segregated as in a bilayer
`tablet, a tablet having two or more active agent-containing
`coatings, or the like.
`Preferred additional active agents, i.e ., active agents for
`co-administration with methylphenidate, are CNS stimu-
`lants (including an