(12) United States Patent
`Burnside et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006322819Bl
`US 6,322,819 Bl
`*Nov. 27, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`
`(75)
`
`Inventors: Beth A. Burnside, Bethesda; Xiaodi
`Guo, Derwood; Kimberly Fiske,
`Bethesda; Richard A. Couch, Chevy
`Chase; Donald J. Treacy, Annapolis,
`all of MD (US); Rong-Kun Chang,
`Hockessin, DE (US); Charlotte
`McGuinness, Bethesda; Edward M.
`Rudnic, North Potomac, both of MD
`(US)
`
`(73) Assignee: Shire Laboratories, Inc., Rockville,
`MD (US)
`
`( *) Notice:
`
`This patent issued on a continued pros(cid:173)
`ecution application filed under 37 CFR
`1.53( d), and is subject to the twenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/176,542
`
`(22) Filed:
`
`Oct. 21, 1998
`
`(51)
`
`Int. Cl.7 ....................................................... A61K 9/16
`
`(52) U.S. Cl. ........................... 424/494; 424/472; 424/480
`
`(58) Field of Search ..................................... 424/494, 457,
`424/471, 472, 480, 497, 461, 462, 470,
`458, 459, 460, 468, 482
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,723,958
`4,871,549
`4,891,230
`
`2/1988 Pope et al. .. ... ... ... ... .... ... ... 604/890.1
`10/1989 Ueda et al. .
`1/1990 Geoghegan et al. ................. 424/461
`
`FOREIGN PATENT DOCUMENTS
`
`87/00044
`90/09168
`
`1/1987 (WO) .
`8/1990 (WO) .
`OTHER PUBLICATIONS
`Conte, et al., "Press-coated tablets for time-programmed
`release of drugs," Biomaterials, 14(13):1017-1023 (1993).
`Gazzaniga, et al., "Time-dependent oral delivery systems
`for colon targeting," S.T.P. Pharma Sciences, 5(1):83-88
`(1995).
`Gazzaniga, et al., "Oral Chronotopic Drug Delivery Sys(cid:173)
`tems: Achievement of Time and/or Site Specificity," Eur. J.
`Pharm. Biopharm, 40(4):246-250 (1994).
`Pozzi, et al., "The Time Clock system: a new oral dosage
`form for fast and complete release of drug after a predeter(cid:173)
`mined lag time," Journal of Controlled Release, 31:99-108
`(1994).
`Walia, et al., "Preliminary Evaluation of an Acqueous Wax
`Emulsion for Controlled-Release Coating," Pharmaceutical
`Development and Technology, 3(1):103-113 (1998).
`Wilding, et al., "Gastrointestinal Transit and Systemic
`Absorption of Captopril from a Pulsed-Release Formula(cid:173)
`tion," Pharmaceutical Research, 9(5):654-657 ((1992).
`Xin Xu and Pink I. Lee, "Programmable Drug Delivery from
`an Erodible Association Polymer System," Pharmaceutical
`Research, 10(8):1144--1152 (1993).
`Primary Examiner-Diana Dudash
`Assistant Examiner-Alysia Berman
`(74) Attorney, Agent, or Firm-Elliot M. Olstein; Raymond
`J. Lillie
`(57)
`
`ABSTRACT
`
`A multiple pulsed dose drug delivery system for pharma(cid:173)
`ceutically active amphetamine salts, comprising an
`immediate-release component and an enteric delayed(cid:173)
`release component wherein (1) the enteric release coating
`has a defined minimum thickness and/or (2) there is a
`protective layer between the pharmaceutically active
`amphetamine salt and the enteric release coating and/or (3)
`there is a protective layer over the enteric release coating.
`The product can be composed of either one or a number of
`beads in a dosage form, including either capsule, tablet, or
`sachet method for administering the beads.
`
`(List continued on next page.)
`
`24 Claims, 8 Drawing Sheets
`
`Seed Core
`
`Polymeric
`Layer
`
`Amerigen Ex. 1002, p. 1
`
`

`
`US 6,322,819 Bl
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`4,894,240
`4,902,516
`4,917,899
`5,002,776
`5,011,692
`5,011,694
`5,051,262
`5,093,200 *
`5,226,902
`
`1/1990 Geoghegan et al. ................. 424/497
`2/1990 Korsatko et al. .................... 424/497
`4/1990 Geoghegan et al. ................. 424/461
`3/1991 Geoghegan et al. ................. 424/497
`4/1991 Fujioka et al. ....................... 424/426
`4/1991 Nuernberg et al. .................. 424/464
`9/1991 Panoz et al. ......................... 424/468
`3/1992 Watanabe et al. ................... 428/407
`7 /1993 Bae et al. .... ... ... ... ... .... ... ... 604/892.1
`
`7/1993 Amidon et al. ...................... 424/451
`5,229,131
`1/1994 Amer et al. .......................... 424/408
`5,275,819
`11/1994 Geoghegan et al. ................. 424/497
`5,364,620
`3/1995 Noda et al. .......................... 424/490
`5,395,628
`5,407,686 * 4/1995 Patel et al. ........................... 424/468
`5,474,786 * 12/1995 Kotwal et al. ....................... 424/472
`5,616,345
`4/1997 Geoghegan et al. ................. 424/497
`5,840,329
`11/1998 Bai ....................................... 424/458
`
`* cited by examiner
`
`Amerigen Ex. 1002, p. 2
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 1 of 8
`
`US 6,322,819 Bl
`
`~ ::>
`
`-ti)
`0 = -
`
`~ ::e:
`t-1
`E-4
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`0
`N
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`-L
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`0 ~ 0 ~ 0 ~ 0 ~ 0 ~ 0
`~ ~ ~ M M N N
`-
`-
`
`AMPHETAMINE (NG/ML)
`
`Amerigen Ex. 1002, p. 3
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 2 of 8
`
`US 6,322,819 Bl
`
`F JG. 2A
`
`Overcoating
`
`Drug
`
`Seed Core
`
`Polymeric
`Layer
`
`Amerigen Ex. 1002, p. 4
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 3 of 8
`
`US 6,322,819 Bl
`
`F I G. 2 B
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`Amerigen Ex. 1002, p. 5
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`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 4 of 8
`
`US 6,322,819 Bl
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`Amerigen Ex. 1002, p. 6
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 5 of 8
`
`US 6,322,819 Bl
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`
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`
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`
`Amerigen Ex. 1002, p. 7
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 6 of 8
`
`US 6,322,819 Bl
`
`F I G. 4
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`pH7.5
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`
`Amerigen Ex. 1002, p. 8
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 7 of 8
`
`US 6,322,819 Bl
`
`F I G. 5
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`
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`
`Amerigen Ex. 1002, p. 9
`
`

`
`U.S. Patent
`
`Nov. 27, 2001
`
`Sheet 8 of 8
`
`US 6,322,819 Bl
`
`FI G. 6
`
`I
`
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`
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`
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`
`Amerigen Ex. 1002, p. 10
`
`

`
`US 6,322,819 Bl
`
`1
`ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`
`This invention pertains to a multiple dosage form deliv(cid:173)
`ery system comprising one or more amphetamine salts for 5
`administering the amphetamine salts to a recipient.
`
`BACKGROUND OF THE INVENTION
`
`Traditionally, drug delivery systems have focused on
`constant/sustained drug ouput with the objective of mini(cid:173)
`mizing peaks and valleys of drug concentrations in the body
`to optimize drug efficacy and to reduce adverse effects. A
`reduced dosing frequency and improved patient compliance
`can also be expected for the controlled/sustained release
`drug delivery systems, compared to immediate release
`preparations. However, for certain drugs, sustained release
`delivery is not suitable and is affected by the following
`factors:
`First pass metabolism: Some drugs, such as ~ blockers,
`~-estradiol, and salicylamide, undergo extensive first pass
`metabolism and require fast drug input to saturate metabo(cid:173)
`lizing enzymes in order to minimize pre-systemic metabo(cid:173)
`lism. Thus, a constant/sustained oral method of delivery
`would result in reduced oral bioavailability.
`Biological tolerance: Continuous release drug plasma
`profiles are often accompanied by a decline in the pharma(cid:173)
`cotherapeutic effect of the drug, e.g., biological tolerance of
`transdermal nitroglycerin.
`Chronopharmacology and circadian rhythms: Circadian
`rhythms in certain physiological functions are well estab(cid:173)
`lished. It has been recognized that many symptoms and
`onset of disease occur during specific time periods of the 24
`hour day, e.g., asthma and angina pectoris attacks are most
`frequently in the morning hours (1,2).
`Local therapeutic need: For the treatment of local disor(cid:173)
`ders such as inflammatory bowel disease, the delivery of
`compounds to the site of inflammation with no loss due to
`absorption in the small intestine is highly desirable to
`achieve the therapeutic effect and to minimize side effects.
`Gastric irritation or drug instability in gastric fluid: For
`compounds with gastric irritation or chemical instability in
`gastric fluid, the use of a sustained release preparation may
`exacerbate gastric irritation and chemical instability in gas(cid:173)
`tric fluid.
`Drug absorption differences in various gastrointestinal
`segments: In general, drug absorption is moderately slow in
`the stomach, rapid in the small intestine, and sharply declin(cid:173)
`ing in the large intestine. Compensation for changing
`absorption characteristics in the gastrointestinal tract may be
`important for some drugs. For example, it is rational for a
`delivery system to pump out the drug much faster when the
`system reaches the distal segment of the intestine, to avoid
`the entombment of the drug in the feces.
`Pulsed dose delivery systems, prepared as either single
`unit or multiple unit formulations, and which are capable of
`releasing the drug after a predetermined time, have been
`studied to address the aforementioned problematic areas for
`sustained release preparations. These same factors are also
`problematic in pulsed dose formulation development. For
`example, gastrointestinal transit times vary not only from
`patient to patient but also within patients as a result of food
`intake, stress, and illness; thus a single-unit pulsed-release
`system may give higher variability compared to a multiple
`unit system. Additionally, drug layering or core making for
`multiple unit systems is a time-consuming and hard-to-
`
`15
`
`20
`
`25
`
`2
`optimize process. Particularly challenging for formulation
`scientists has been overcoming two conflicting hurdles for
`pulsatile formulation development, i.e., lag time and rapid
`release.
`Various enteric materials, e.g., cellulose acetate phthalate,
`hydroxypropyl methylcellulose phthalate, polyvinyl acetate
`phthalate, and the EUDRAGIT® acrylic polymers, have
`been used as gastroresistant, enterosoluble coatings for
`single drug pulse release in the intestine (3). The enteric
`10 materials, which are soluble at higher pH values, are fre(cid:173)
`quently used for colon-specific delivery systems. Due to
`their pH-dependent attributes and the uncertainty of gastric
`retention time, in-vivo performance as well as inter- and
`intra-subject variability are major issues for using enteric
`coated systems as a time-controlled release of drugs.
`A retarding swellable hydrophilic coating has been used
`for oral delayed release systems ( 4,5). It was demonstrated
`that lag time was linearly correlated with coating weight
`gain and drug release was pH independent.
`Hydroxypropyl methylcellulose barriers with erodible
`and/or gellable characteristics formed using press coating
`technology for tablet dosage forms have been described to
`achieve time-programmed release of drugs (6). Barrier for(cid:173)
`mulation variables, such as grade of hydroxypropyl
`methylcellulose, water-soluble and water-insoluble
`excipients, significantly altered the lag time and the release
`rate from the center cores.
`Special grades of hydroxypropyl methylcellulose, e.g.,
`METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and
`30 METHOCEL® F4M (Dow Chemical Company, USA), as a
`hydrophilic matrix material have been used to achieve
`bimodal drug release for several drugs, i.e., aspirin,
`ibuprofen, and adinazolam (7). Bimodal release is charac(cid:173)
`terized by a rapid initial release, followed by a period of
`35 constant release, and finalized by a second rapid drug
`release.
`Tablets or capsules coated with a hydrophobic wax(cid:173)
`surfactant layer, made from an aqueous dispersion of car(cid:173)
`nauba wax, beeswax, polyoxyethylene sorbitan monooleate,
`40 and hydroxypropyl methylcellulose have been used for rapid
`drug release after a predetermined lag time. For example,.
`However, even though a two-hour lag time was achieved for
`the model drug theophylline at a higher coating level (60%),
`three hours were required for a complete release of theo-
`45 phylline after the lag time. (8)
`A sustained-release drug delivery system is described in
`U.S. Pat. No. 4,871,549. When this system is placed into
`dissolution medium or the gastrointestinal tract, water influx
`and the volume expansion of the swelling agent cause the
`50 explosion of the water permeable membrane. The drug thus
`releases after a predetermined time period.
`The OROS® push-pull system (Alza Company) has been
`developed for pulsatile delivery of water-soluble and water(cid:173)
`insoluble drugs ( a specific site (e.g., colon) in the gas-
`55 trointestinal tract (11). The drug formulation is contained
`within a water-insoluble capsule body and is sealed with a
`hydrogel plug. Upon oral administration, the capsule cap
`dissolves in the gastric juice and the hydrogel plug swells.
`At a controlled and predetermined time point, the swollen
`60 plug is ejected from the PULSINCAP® dosage form and the
`encapsulated drug is released. A pulsatile capsule system
`containing captopril with release after a nominal 5-hr period
`was found to perform reproducibly in dissolution and
`gamma scintigraphy studies. However, in the majority of
`65 subjects, no measurable amounts of the drug were observed
`in the blood, possibly due to instability of the drug in the
`distal intestine. (12)
`
`Amerigen Ex. 1002, p. 11
`
`

`
`US 6,322,819 Bl
`
`3
`ADDERAL® comprises a mixture of four amphetamine
`sulfate salts which, in combination is indicated for treatment
`of Attention Deficit of age. One disadvantage of current
`treatment is that a tablet form is commonly used which many
`young children have difficulty in swallowing. Another dis-
`advantage of current treatment is that two separate doses are
`administered, one in the morning and one approximately
`4-6 hours later, commonly away from home under other
`than parental supervision. This current form of treatment,
`therefore, requires a second treatment which is time(cid:173)
`consuming, inconvenient and may be problematic for those
`children having difficulties in swallowing table t formula-
`tions.
`
`SUMMARY OF THE INVENTION
`
`Accordingly, in view of a need for successfully adminis(cid:173)
`tering a multiple pulsed dose of amphetamine salts and
`mixtures thereof, the present invention provides an oral
`multiple pulsed dose delivery system for amphetamine salts
`and mixtures thereof. FIG. 1 illustrates the desired target
`plasma level profile of the pharmaceutical active contained
`within the delivery system.
`In accordance with a preferred embodiment of the present
`invention, there is provided a pharmaceutical composition
`for delivering one or more pharmaceutically active amphet(cid:173)
`amine salts that includes:
`(a) one or more pharmaceutically active amphetamine
`salts that are covered with an immediate release
`coating, and
`(b) one or more pharmaceutically active amphetamine
`salts that are covered with an enteric release coating
`wherein (1) the enteric release coating has a defined
`minimum thickness and/or (2) there is a protective
`layer between the at least one pharmaceutically active
`amphetamine salt and the enteric release coating and/or
`(3) there is a protective layer over the enteric release
`coating.
`In one embodiment, the immediate release and enteric
`release portions of the composition are present on the same
`core.
`In another embodiment, the immediate release and enteric
`release components are present on different cores.
`It is also contemplated that the composition may include
`a combination of the hereinabove referred to cores (one or
`more cores that include both components on the same core
`and one or more cores that include only one of the two
`components on the core).
`The present invention provides a composition in which
`there is immediate release of drug and enteric release of drug
`wherein the enteric release is a pulsed release and wherein
`the drug includes one or more amphetamine salts and
`mixtures thereof.
`The immediate release component releases the pharma(cid:173)
`ceutical agent in a pulsed dose upon oral administration of
`the delivery system.
`The enteric release coating layer retards or delays the
`release of the pharmaceutical active or drug for a specified
`time period ("lag time") until a predetermined time, at which
`time the release of the drug is rapid and complete, i.e., the
`entire dose is released within about 30--60 minutes under
`predetermined environmental conditions, i.e. a particular
`location within the gastrointestinal tract.
`The delay or lag time will take into consideration factors
`such as transit times, food effects, inflammatory bowel
`disease, use of antacids or other medicaments which alter the
`pH of the GI tract.
`
`5
`
`10
`
`30
`
`4
`In a preferred embodiment, the lag time period is only
`time-dependent, i.e., pH independent. The lag time is pref(cid:173)
`erably within 4 to 6 hours after oral administration of the
`delivery system.
`In one aspect, the present invention is directed to a
`composition that provides for enteric release of at least one
`pharmaceutically active amphetamine salt, including at least
`one pharmaceutically active amphetamine salt that is coated
`with an enteric coating wherein (1) the enteric release
`coating has a defined minimum thickness and/or (2) there is
`a protective layer between the at least one pharmaceutically
`active amphetamine salt and the enteric release coating
`and/or (3) there is a protective layer over the enteric release
`coating.
`In attempting to provide for enteric release of an amphet-
`15 amine salt, applicants found that use of an enteric release
`coating as generally practiced in the art did not provide
`effective enteric release.
`Typical enteric coating levels did not meet the above
`requirements for the desired dosage profile of amphetamine
`20 salts. Using the typical amount of enteric coating (10-20 µ)
`resulted in undesired premature leakage of the drug from the
`delivery system into the upper gastrointestinal tract and thus
`no drug delivery at the desired location in the gastrointes(cid:173)
`tinal tract after the appropriate lag time. Thus this coating
`25 did not meet the requirements for the drug release profile to
`provide full beneficial therapeutic activity at the desired
`time.
`Surprisingly, applicants found that using a thicker appli(cid:173)
`cation of enteric coating on the formulation allowed for the
`second pulsed dose to be released only and completely at the
`appropriate time in the desired predetermined area of the
`gastrointestinal tract, i.e., in the intestine.
`Th is was surprising because an increase in thickness of
`about 5-10 µof enteric coatings above a minimum thickness
`of about 10-20 µtypically does not have a significant effect
`35 on release of d rug from within such coatings. Enteric
`coatings typically are pH dependent and will only dissolve/
`disperse when exposed to the appropriate environment.
`Typically, application of a thicker coating (greater than 20 µ)
`will only marginally increase the time for complete release
`40 at the appropriate environmental condition i.e., for a brief
`period of time (20 minutes). Using the typical coating,
`applicants could not achieve the desired result-rather, the
`coating leaked before the predetermined time in an inap(cid:173)
`propriate environment resulting in significant loss of the
`45 therapeutic agent.
`Accordingly, in one aspect, the pulsed enteric release of
`the amphetamine salts is accomplished by employing a
`certain minimum thickness of the enteric coating .
`In one embodiment of the invention, the pulsed dose
`50 delivery comprises a composition which comprises one or
`more pharmaceutically active amphetamine salts; an enteric
`coating over the one or more pharmaceutically active
`amphetamine salts, wherein the thickness of the enteric
`coating layer is at least 25 µ; a further layer of one or more
`55 pharmaceutically active amphetamine salts over the enteric
`coating layer; and an immediate release layer coating. The
`thicker enteric coating surprisingly provides the required
`delayed i m mediate release of the pharmaceutically active
`amphetamine salt at the desire d time in the desired area of
`60 the gastrointestinal tract. FIG. 2 illustrates a model of this
`delivery system.
`In this aspect, the one or more pharmaceutically active
`amphetamine salts can be provided within or as a part of a
`core seed around which the enteric coating is applied.
`65 Alternatively, a core seed can be coated with one or more
`layers of one or more pharmaceutically active amphetamine
`salts.
`
`Amerigen Ex. 1002, p. 12
`
`

`
`US 6,322,819 Bl
`
`6
`of the environment around the enteric polymer layer. The
`acid layer may also be applied on the outer layer of the
`pH-sensitive enteric polymer layer, followed by a layer of
`low water-permeability polymer. The release of the active
`thus may be delayed and the dissolution rate may be
`increased in an alkaline environment.
`In a further embodiment, the protective coating may be
`used both over the drug and over the enteric coating.
`With respect to this embodiment of the invention, the one
`10 or more pharmaceutically active amphetamine salts can be
`provided within or as a part of a core seed, during the core
`seed manufacturing process, around which the enteric coat(cid:173)
`ing is applied. Alternatively, a core seed can be coated with
`one or more layers of one or more pharmaceutically active
`15 amphetamine salts.
`The drug delivery system of the present invention as
`described herein preferably comprises one or a number of
`beads or beadlets in a dosage form, either capsule, tablet,
`sachet or other method of orally administering the beads.
`
`5
`
`5
`It has further been discovered that a delayed immediate
`release drug delivery can also be accomplished by coating
`the drug first with a protective layer prior to applying the
`enteric coating.
`Thus, in another embodiment, the pulsed enteric release is
`accomplished by employing a protective layer between the
`drug and the enteric coating. When using a protective
`coating, the enteric coating may be of an increased thickness
`or may be of lower thickness.
`Thus, in another aspect, the object of the invention is met
`by providing a composition comprising one or more phar(cid:173)
`maceutically active amphetamine salts; a protective layer
`coating over the one or more pharmaceutically active
`amphetamine salt layer(s), and an enteric coating layer over
`the protective coating layer; a further pharmaceutically
`active amphetamine salt layer and an immediate release
`layer coating. In a preferred embodiment of this aspect, the
`thickness of the enteric coating is at least 25 µ, and the
`protective layer comprises an immediate release coating.
`With respect to this embodiment of the invention, the one 20
`or more pharmaceutically active amphetamine salts can be
`provided within or as a part of a core seed, during the core
`seed manufacturing process, around which the protective
`coating is applied. Alternatively, a core seed can be coated
`with one or more layers of one or more pharmaceutically 25
`active amphetamine salts.
`In another embodiment, the pulsed enteric release is
`accomplished by employing a protective layer over the
`enteric coating.
`Accordingly, in this embodiment of the present invention, 30
`there is provided a pulsed dose release drug delivery system
`comprising one or more pharmaceutically active amphet(cid:173)
`amine salts; an enteric coating layer over the pharmaceuti(cid:173)
`cally active amphetamine salt layer(s); and a protective layer
`over the enteric coating; a second pharmaceutically active 35
`amphetamine salt layer; and an immediate release layer
`coating.
`In one aspect of this embodiment, the protective layer is
`comprised of one or more components, which includes an
`immediate release layer and a modifying layer. The modi(cid:173)
`fying layer is preferably comprised of a semi water(cid:173)
`permeable polymer. Applicants have surprisingly found that
`a semi-permeable polymer coating used in combination with
`an immediate release layer coating provided a delayed
`pulsed release drug delivery profile when layered over the 45
`enteric coating.
`Thus, in this embodiment, the protective layer comprises
`a semi-permeable polymer and an immediate release coating
`layer. In a preferred embodiment, the modifying layer com(cid:173)
`prises a first layer of a semi-permeable polymer which is 50
`adjacent to the enteric coating layer and a second coating
`layer over the semi-permeable polymer coating layer com(cid:173)
`prising an immediate release polymer coating layer.
`In one aspect of this embodiment, a semi-permeable
`polymer, which may comprise a low water-permeable 55
`pH-insensitive polymer, is layered onto the outer surface of
`the enteric layer, in order to obtain prolonged delayed
`release time. This semi-permeable polymer coating controls
`the erosion of the pH-sensitive enteric polymer in an alka(cid:173)
`line pH environment in which a pH-sensitive polymer will 60
`dissolve rapidly. Another pH-sensitive layer may be applied
`onto the surface of a low water-permeability layer to further
`delay the release time.
`In a still further aspect of the invention, in addition to a
`protective layer, the composition comprises an acid which is 65
`incorporated into the pharmaceutical active layer or coated
`onto the surface of the active layer to reduce the pH value
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 illustrates a multiple pulse drug delivery system
`target plasma profile of the drug delivery system of the
`present invention. The profile reflects an immediate-release
`component followed by a delayed-release component.
`FIG. 2 schematically illustrates the delayed-release sys(cid:173)
`tem of the present invention.
`FIG. 2a graphically illustrates a pulsed dose delivery
`system.
`FIGS. 2b and c graphically illustrate the drug release
`mechanism from the proposed delivery system.
`FIG. 3 is a plot of the percent drug released versus time
`from the drug-loaded pellets described in Example 1 which
`exemplifies the immediate release component of the present
`invention.
`FIG. 4 is a plot of the percent drug released versus time
`from the coated pellets described in Example 2 which
`exemplifies the immediate release component and the
`40 delayed release components of the present invention.
`FIG. 5 is a plot of the percent drug released versus time
`from the coated pellets of Example 3 which exemplifies the
`immediate release component and the delayed release com(cid:173)
`ponents of the present invention.
`FIG. 6 illustrates the drug release profile of coated pellets
`described in Example 4 which exemplifies the immediate
`release component and the delayed release components of
`the present invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention comprises a core or starting seed,
`either prepared or commercially available product. The
`cores or starting seeds can be sugar spheres; spheres made
`from microcrystalline cellulose and any suitable drug crys(cid:173)
`tals.
`The materials that can be employed in making drug(cid:173)
`containing pellets are any of those commonly used in
`pharmaceutics and should be selected on the basis of com(cid:173)
`patibility with the active drug and the physicochemical
`properties of the pellets. The additives except active drugs
`are chosen below as examples:
`Binders such as cellulose derivatives such as
`methylcellulose, hydroxyethyl cellulose, hydroxypropyl
`cellulose, hydroxypropyl methylcellulose,
`polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate
`copolymer and the like.
`
`Amerigen Ex. 1002, p. 13
`
`

`
`US 6,322,819 Bl
`
`7
`Disintegration agents such as corn starch, pregelatinized
`starch, cross-linked carboxymethylcellulose (AC-DI(cid:173)
`SOL®), sodium starch glycolate (EXPLOTAB®), cross(cid:173)
`linked polyvinylpyrrolidone (PLASDONE® XL), and any
`disintegration agents used in tablet preparations.
`Filling agents such as lactose, calcium carbonate, calcium
`phosphate, calcium sulfate, microcrystalline cellulose,
`dextran, starches, sucrose, xylitol, lactitol, mannitol,
`sorbitol, sodium chloride, polyethylene glycol, and the like.
`Surfactants such as sodium lauryl sulfate, sorbitan
`monooleate, polyoxyethylene sorbitan monooleate, bile
`salts, glyceryl monostearate, PLURONIC® line (BASF),
`and the like.
`Solubilizer such as citric acid, succinic acid, fumaric acid,
`malic acid, tartaric acid, maleic acid, glutaric acid sodium
`bicarbonate and sodium carbonate and the like.
`Stabilizers such as any antioxidation agents, buffers,
`acids, and the like, can also be utilized.
`Methods of manufacturing the core include
`a. Extrusion-Spheronization-Drug(s) and other additives
`are granulated by addition of a binder solution. The wet mass
`is passed through an extruder equipped with a certain size
`screen. The extrudates are spheronized in a marumerizer.
`The resulting pellets are dried and sieved for further appli(cid:173)
`cations.
`b. High-Shear Granulation-Drug(s) and other additives
`are dry-mixed and then the mixture is wetted by addition of
`a binder solution in a high shear-granulator/mixer. The
`granules are kneaded after wetting by the combined actions
`of mixing and milling. The resulting granules or pellets are
`dried and sieved for further applications.
`c. Solution or Suspension Layering-A drug solution or
`dispersion with or without a binder is sprayed onto starting
`seeds with a certain particle size in a fluid bed processor or
`other suitable equipment. The drug thus is coated on the
`surface of the starting seeds. The drug-loaded pellets are
`dried for further applications.
`For purposes of the present invention, the core particles
`have a diameter in the range of about 500-1500 microns;
`preferably 100--800 microns.
`These particles can then be coated in a fluidized bed
`apparatus with an alternating sequence of coating layers.
`The core may be coated directly with a layer or layers of
`at least one pharmaceutically active amphetamine salts
`and/or the pharmaceutically active amphetamine salt may be
`incorporated into the core material. Pharmaceutical active
`amphetamine salts contemplated to be within the scope of
`the present invention include amphetamine base, all chemi(cid:173)
`cal and chiral derivatives and salts thereof; methylphenidate,
`all chemical and chiral derivatives and salts thereof; phe(cid:173)
`nylpropanolamine and its salts; and all other compounds
`indicated for the treatment of attention deficit hyperactivity
`disorder (ADHD).
`A protective layer may be added on top oft he pharma(cid:173)
`ceutical active containing layer and also may be provided
`between active layers. A separation or protective layer may
`be added onto the surface of the active-loaded core, and then
`the enteric layer is coated thereupon. Another active layer
`may also be added to the enteric layer to deliver an initial
`dose.
`A protective coating layer may be applied immediately
`outside the core, either a drug-containing core or a drug(cid:173)
`layered core, by conventional coating techniques such as
`pan coating or fluid bed coating using solutions of polymers
`in water or suitable organic solvents or by using aqueous
`
`10
`
`15
`
`8
`polymer dispersions. Suitable materials for the protective
`layer include cellulose derivatives such as hydroxyethyl
`cellulose, hydroxypropyl cellulose, hydroxypropyl
`me th ylce 11 ulo se,
`po 1 yvin ylp yrro lido ne,
`5 polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellu(cid:173)
`lose aqueous dispersions (AQUACOAT®,
`SURELEASE®), EUDRAGIT® RL 30D, OPADRY® and
`the like. The suggested coating levels are from 1 to 6%,
`preferably 2-4% (w/w).
`The enteric coating layer is applied onto the cores with or
`without seal coating by conventional coating techniques,
`such as pan coating or fluid bed coating using solutions of
`polymers in water or suitable organic solvents or by using
`aqueou