(12) United States Patent
`Burnside et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,605,300 B1
`Aug. 12, 2003
`
`US006605300B1
`
`(54)
`
`(75)
`
`ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`
`Inventors: Beth A. Burnside, Silver Spring, MD
`(US); Xiaodi Guo, DerWood, MD (US);
`Kimberly Fiske, Alexandria, VA (US);
`Richard A. Couch, Bethesda, MD
`(US); Donald J. Treacy, Arnold, MD
`(US); Rong-Kun Chang, Hockessin,
`DE (US); Charlotte M. McGuinness,
`Bethesda, MD (US); Edward M.
`Rudnic, North Potomac, MD (US)
`
`(73)
`
`Assignee: Shire Laboratories, Inc., Rockville,
`MD (US)
`
`( * )
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`(22)
`(86)
`
`Appl. No.:
`
`09/807,462
`
`PCT Filed:
`
`Oct. 20, 1999
`
`PCT No.:
`
`PCT/US99/24554
`
`§ 371 (9X1),
`(2), (4) Date:
`
`Jul. 19, 2001
`
`(87)
`
`PCT Pub. No.: WO00/23055
`
`PCT Pub. Date: Apr. 27, 2000
`
`(63)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Related U.S. Application Data
`
`Continuation-in-part of application No. 09/176,542, ?led on
`Oct. 21, 1998, now Pat. NO. 6,322,819.
`
`Int. Cl.7 ...................... .. A61K 33/22; A61K 33/24;
`A61K 33/36; A61K 31/135
`U.S. Cl. ..................... .. 424/452; 424/458; 424/468;
`424/469; 424/470; 424/471; 424/472; 424/514;
`424/649
`Field of Search ............................... .. 424/457, 458,
`424/468, 469, 470, 471, 472; 514/649
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2/1988 Pope et al. ............ .. 604/8901
`4,723,958 A
`8/1988 Wong et al.
`424/473
`4,765,989 A
`4,871,549 A 10/1989 Veda et al. ..... ..
`424/494
`4,891,230 A
`1/1990 Geoghegan et al. .
`424/461
`4,894,240 A
`1/1990 Geoghegan et al. .
`424/497
`4,902,516 A
`2/1990 Korsatko et al.
`424/497
`4,917,899 A
`4/1990 Geoghegan et al. .
`424/461
`5,002,776 A
`3/1991 Geoghegan et al. .
`424/497
`5,011,692 A
`4/1991 Fujioka et al. ..... ..
`424/426
`5,011,694 A
`4/1991 Nuernberg et al.
`424/464
`5,051,262 A
`9/1991 PanoZ et al. ....... ..
`.. 424/468
`5,093,200 A
`3/1992 Watanabe et al. .
`428/407
`5,226,902 A
`7/1993 Bae et al. ....... ..
`604/8921
`5,229,131 A
`7/1993 Amidon et al.
`424/451
`5,275,819 A
`1/1994 Amer et al. .... ..
`424/408
`5,312,388 A * 5/1994 Wong et al. .... ..
`604/8921
`5,364,620 A 11/1994 Geoghegan et al.
`424/497
`5,395,628 A
`3/1995 Noda et al. ..... ..
`424/490
`5,407,686 A
`4/1995 Patel et al.
`424/468
`5,474,786 A 12/1995 Kotwal et al. .
`424/472
`5,616,345 A
`4/1997 Geoghegan et al. ...... .. 424/497
`
`5,800,836 A
`
`9/1998 Morella et al. ........... .. 424/489
`
`. . . .. 424/473
`5,824,341 A 10/1998 Segh et al. . . . . . . . . .
`424/484
`5,824,342 A 10/1998 Cherukuri et al. ..
`5,824,343 A 10/1998 Na et al. ............... .. 424/486
`5,837,284 A 11/1998 Mehta et al.
`424/459
`
`5,840,329 A 11/1998 Bai . . . . . . . . . . . . .
`
`. . . .. 424/458
`
`5,885,616 A
`3/1999 Hsiao et al. . . . . . . . .
`5,885,998 A * 3/1999 Bencherif et al. ..
`5,891,474 A
`4/1999 Busetti et al. . . . . . .
`
`. . . .. 424/472
`514/256
`. . . .. 424/490
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`W087/00044
`W090/09168
`
`1/1987
`8/1990
`
`.......... .. A61K/9/22
`.......... .. A61K/9/22
`
`OTHER PUBLICATIONS
`GaZZaniga, et al., S. TR Pharma Sciences, vol. 5, No. 1, gs.
`83—88 (1995), Time dependent oral delivery for colon tar
`geting.
`Modern Pharmaceutics, Banker, et al., eds., Marcel Dekker,
`Inc., NeW York, p. 350 (1996).
`Walia, et al., Pharm. Dev. Tech., vol. 3, No. 1, pp. 103—113
`(1998), Preliminary Evaluation of an Aqueous Wax Emul
`sion for Controlled—Release Coating.
`Wilding, et al., Pharmaceutical Research, vol. 9, No. 5, pp.
`654—657 (1992), Gastrointestinal Transit and Systemic
`Absorption of Captopil from Pulsed—Release Formulation.
`Xu, et al., Pharmaceutical Research, vol. 10, No. 8, pp.
`1144—1152 (1993), Programmable Drug Delivery from an
`Erodible Association Polymer System.
`Conte, et al., Biomaterials, vol. 14, No. 13, pp. 1017—1023
`(1993), Press—coated tablets for time—programmed release
`of drugs.
`GaZZaniga, et al., Eur J. Pharm. Biopharm, vol. 40, No. 4,
`pp. 246—250 (1994), Oral Chronotopic Drug Delivery Sys
`tem: Achievement of Time and/or Site Speci?city.
`PoZZi, et al., J. Controlled Release, vol. 31, pp. 99—108
`(1994), The Time Clock System: a neW oral dosage form for
`fast and complete release of drug after a predetermined lag
`time.
`Snire Laboratory Inc’s Complaint against Barr Laboratories
`based on Parent U.S. patent 6,322,815 in U S District Court
`for the Southern District of NeW York (Case No
`03—CV—1219(VM)(DFE)) 2003.
`Barr Laboratories’ AnsWer. Af?rmative Defenses and Coun
`terclaim in Case No. 03—CV—1219(VM)(DFE) (S D N Y)
`2003.
`Barr’s Paragraph IV Certi?cation against Parent U S Patent
`6,322,819 on Jan. 14, 2003.
`* cited by examiner
`Primary Examiner—Russell Travers
`(74) Attorney, Agent, or Firm—Millen, White, Zelano &
`Branigan, PC.
`(57)
`
`ABSTRACT
`
`A multiple pulsed dose drug delivery system for pharma
`ceutically active amphetamine salts, comprising an
`immediate-release component and an enteric delayed
`release component Wherein (1) the enteric release coating
`has a de?ned 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.
`
`18 Claims, 7 Drawing Sheets
`
`KVK-TECH EXHIBIT 1002
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 1 0f 7
`Sheet 1 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`50
`
`45
`
`4o
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`0
`0
`
`4
`4
`
`a
`8
`
`12
`12
`TIME (HOURS)
`TIME (HOURS)
`FIG. 1
`FIG. 1
`
`16
`16
`
`2o
`20
`
`24
`24
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 2 0f 7
`Sheet 2 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`Overcoating
`Drug
`
` Overcoati ng
`
`Seed Core
`
`Polymeric
`Layer
`
`FIG. 2A
`FIG. 2A
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 3 0f 7
`Sheet 3 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`
`
`FIG. 2B
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 4 0f 7
`Sheet 4 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`FIG.20
`
`FIG. 2C
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 5 0f 7
`Sheet 5 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`8282a
`
`PercentDissolved
`861
`
`100
`
`90
`
`80
`
`70
`
`60
`50
`
`4o
`
`30
`
`20
`
`10
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`Time (min)
`Time (min)
`FIG. 3
`FIG. 3
`
`H D.
`,_U n_, nr 0 0 _ o
`2 mm 8 6 4 N 0
`
`D.
`
`0. 6
`
`H 2
`
`5. m
`% I6
`
`D. l5
`
`0 I8
`
`%Released
`umwmm?mxv
`
`0
`
`1
`
`2
`
`3
`3
`
`I?
`
`7
`
`8
`
`I9
`
`9
`
`6
`
`l4
`4
`5
`Time (hrs)
`Time (hrs)
`FIG. 4
`FIG. 4
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 6 0f 7
`Sheet 6 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`120
`
`100
`
`80
`
`60
`
`%Released
`00000
`x. 882mm
`
`8642
`
`40
`
`20
`
`____ q_
`
`Time (hrs)
`Time (hrs)
`FIG. 5
`FIG. 5
`
`%Released
`
`O
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Time (hrs)
`Time (hrs)
`FIG. 6
`FIG. 6
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 2003
`Aug. 12, 2003
`
`Sheet 7 0f 7
`Sheet 7 0f 7
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`Dataset subject 3 phase 4 (Extravascular)
`Dataset subject 3 phase 4 (Extravascular)
`
`50
`
`40
`
`30
`
`rag
`f8
`
`g,
`
`X Data
`
`C(ng/ml)
`
`10
`J
`
`0
`
`O
`
`10
`
`\K‘
`\x\
`N
`
`20
`30
`T (hours)
`T (hours)
`
`40
`
`50
`
`FIG. 7
`
`Dataset subject 18 phase 2 (Extravascular)
`Dataset subject 18 phase 2 (Extravascular)
`
`25
`
`x
`
`20 A f!
`I
`5%
`
`i‘ 15
`g
`0 10
`
`0
`
`0
`
`C(ng/ml)
`
`\
`\
`\\
`
`X Data
`
`\k
`
`N
`
`1O
`
`20
`
`30
`
`40
`
`50
`
`T (hours)
`FIG. 8
`
`

`

`1
`1
`ORAL PULSED DOSE DRUG DELIVERY
`ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`SYSTEM
`
`US 6,605,300 B1
`US 6,605,300 B1
`
`5
`
`2
`2
`sustained release preparations. These same factors are also
`sustained release preparations. These same factors are also
`problematic in pulsed dose formulation development. For
`problematic in pulsed dose formulation development. For
`example, gastrointestinal transit times vary not only from
`eXample, gastrointestinal transit times vary not only from
`patient to patient but also within patients as a result of food
`patient to patient but also Within patients as a result of food
`intake, stress, and illness; thus a single-unit pulsed-release
`intake, stress, and illness; thus a single-unit pulsed-release
`system may give higher variability compared to a multiple
`system may give higher variability compared to a multiple
`unit system. Additionally, drug layering or core making for
`unit system. Additionally, drug layering or core making for
`multiple unit systems is a time-consuming and hard-to-
`multiple unit systems is a time-consuming and hard-to
`optimize process. Particularly challenging for formulation
`optimiZe process. Particularly challenging for formulation
`scientists has been overcoming two conflicting hurdles for
`scientists has been overcoming tWo con?icting hurdles for
`pulsatile formulation development, i.e., lag time and rapid
`pulsatile formulation development, i.e., lag time and rapid
`release.
`release.
`Various enteric materials, e. g., cellulose acetate phthalate,
`Various enteric materials, e. g., cellulose acetate phthalate,
`hydroXypropyl methylcellulose phthalate, polyvinyl acetate
`hydroxypropyl methylcellulose phthalate, polyvinyl acetate
`phthalate, and the EUDRAGIT® acrylic polymers, have
`phthalate, and the EUDRAGIT® acrylic polymers, have
`been used as gastroresistant, enterosoluble coatings for
`been used as gastroresistant, enterosoluble coatings for
`single drug pulse release in the intestine
`The enteric
`single drug pulse release in the intestine (3). The enteric
`materials, which are soluble at higher pH values, are fre-
`materials, Which are soluble at higher pH values, are fre
`quently used for colon-specific delivery systems. Due to
`quently used for colon-speci?c delivery systems. Due to
`their pH-dependent attributes and the uncertainty of gastric
`their pH-dependent attributes and the uncertainty of gastric
`retention time, in-vivo performance as well as inter- and
`retention time, in-vivo performance as Well as inter- and
`intra-subject variability are major issues for using enteric,
`intra-subject variability are major issues for using enteric,
`coated systems as a time-controlled release of drugs.
`coated systems as a time-controlled release of drugs.
`A retarding swellable hydrophilic coating has been used
`A retarding sWellable hydrophilic coating has been used
`for oral delayed release systems (4,5). It was demonstrated
`for oral delayed release systems (4,5). It Was demonstrated
`that lag time was linearly correlated with coating weight
`that lag time Was linearly correlated With coating Weight
`gain and drug release was pH independent.
`gain and drug release Was pH independent.
`Hydroxypropyl methylcellulose barriers with erodible
`HydroXypropyl methylcellulose barriers With erodible
`and/or gellable characteristics formed using press coating
`and/or gellable characteristics formed using press coating
`technology for tablet dosage forms have been described to
`technology for tablet dosage forms have been described to
`achieve time-programmed release of drugs
`Barrier for
`achieve time-programmed release of drugs (6). Barrier for-
`mulation variables, such as grade of hydroxypropyl
`mulation variables, such as grade of hydroXypropyl
`methylcellulose, water-soluble and water-insoluble
`methylcellulose, Water-soluble and Water-insoluble
`excipients, significantly altered the lag time and the release
`eXcipients, signi?cantly altered the lag time and the release
`rate from the center cores.
`rate from the center cores.
`Special grades of hydroXypropyl methylcellulose, e.g.,
`Special grades of hydroxypropyl methylcellulose, e.g.,
`METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and
`METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and
`METHOCEL® F4M (Dow Chemical Company, USA), as a
`METHOCEL® F4M (DoW Chemical Company, USA), as a
`hydrophilic matrix material have been used to achieve
`hydrophilic matriX material have been used to achieve
`bimodal drug release for several drugs,
`i.e., aspirin,
`bimodal drug release for several drugs, i.e., aspirin,
`ibuprofen, and adinazolam (7). Bimodal release is charac-
`ibuprofen, and adinaZolam
`Bimodal release is charac
`terized by a rapid initial release, followed by a period of
`teriZed by a rapid initial release, folloWed by a period of
`constant release, and finalized by a second rapid drug
`constant release, and ?naliZed by a second rapid drug
`release.
`release.
`Tablets or capsules coated with a hydrophobic wax-
`Tablets or capsules coated With a hydrophobic Wax
`surfactant layer, made from an aqueous dispersion of car-
`surfactant layer, made from an aqueous dispersion of car
`nauba wax, beeswax, polyoxyethylene sorbitan monooleate,
`nauba Wax, beesWaX, polyoXyethylene sorbitan monooleate,
`and hydroxypropyl methylcellulose have been used for rapid
`and hydroXypropyl methylcellulose have been used for rapid
`drug release after a predetermined lag time. However, even
`drug release after a predetermined lag time. HoWever, even
`though a two-hour lag time was achieved for the model drug
`though a tWo-hour lag time Was achieved for the model drug
`theophylline at a higher coating level (60%), three hours
`theophylline at a higher coating level (60%), three hours
`were required for a complete release of theophylline after
`Were required for a complete release of theophylline after
`the lag time. (8)
`the lag time. (8)
`A sustained-release drug delivery system is described in
`A sustained-release drug delivery system is described in
`US. Pat. No. 4,871,549. When this system is placed into
`US. Pat. No. 4,871,549. When this system is placed into
`dissolution medium or the gastrointestinal tract, water influx
`dissolution medium or the gastrointestinal tract, Water in?uX
`and the volume expansion of the swelling agent cause the
`and the volume expansion of the sWelling agent cause the
`explosion of the water permeable membrane. The drug thus
`eXplosion of the Water permeable membrane. The drug thus
`releases after a predetermined time period. The OROS®
`releases after a predetermined time period. The OROS®
`push-pull system (AlZa Company) has been developed for
`push-pull system (Alza Company) has been developed for
`pulsatile delivery of water-soluble and water-insoluble drugs
`pulsatile delivery of Water-soluble and Water-insoluble drugs
`(9,10), e.g.
`the OROS-CT® system and is based on the
`(9,10), eg the OROS-CT® system and is based on the
`swelling properties of an osmotic core compartment which
`sWelling properties of an osmotic core compartment Which
`provides a pH-independent, time-controlled drug release.
`provides a pH-independent, time-controlled drug release.
`The PULSINCAP® dosage form releases its drug content
`The PULSINCAP® dosage form releases its drug content
`at either a predetermined time or at a specific site (e.g.,
`at either a predetermined time or at a speci?c site (e.g.,
`colon) in the gastrointestinal tract (11). The drug formula-
`colon) in the gastrointestinal tract (11). The drug formula
`
`This application is a 371 of PCT/US99/24554 filed Oct.
`This application is a 371 of PCT/US99/24554 ?led Oct.
`20, 1999, which is continuation-in-part of application Ser.
`20, 1999, Which is continuation-in-part of application Ser.
`No. 09/176,542, filed Oct. 21, 1998, now US. Pat. No.
`No. 09/176,542, ?led Oct. 21, 1998, now US. Pat. No.
`6,322,819 the contents of which are incorporated herein by
`6,322,819 the contents of Which are incorporated herein by
`reference.
`reference.
`This invention pertains to a multiple unit dosage form
`This invention pertains to a multiple unit dosage form
`delivery system comprising one or more amphetamine salts
`delivery system comprising one or more amphetamine salts
`for administering the amphetamine salts to a recipient.
`for administering the amphetamine salts to a recipient.
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`Traditionally, drug delivery systems have focused on
`Traditionally, drug delivery systems have focused on
`constant/sustained drug output with the objective of mini-
`constant/sustained drug output With the objective of mini
`miZing peaks and valleys of drug concentrations in the body
`mizing peaks and valleys of drug concentrations in the body
`to optimize drug efficacy and to reduce adverse effects. A
`to optimiZe drug ef?cacy and to reduce adverse effects. A
`reduced dosing frequency and improved patient compliance
`reduced dosing frequency and improved patient compliance
`can also be expected for the controlled/sustained release
`can also be eXpected for the controlled/sustained release
`drug delivery systems, compared to immediate release
`drug delivery systems, compared to immediate release
`preparations. However, for certain drugs, sustained release
`preparations. HoWever, for certain drugs, sustained release
`delivery is not suitable and is affected by the following
`delivery is not suitable and is affected by the folloWing
`factors:
`factors:
`First pass metabolism: Some drugs, such as [3 blockers,
`First pass metabolism: Some drugs, such as [3 blockers,
`B-estradiol, and salicylamide, undergo extensive first
`[3-estradiol, and salicylamide, undergo eXtensive ?rst
`pass metabolism and require fast drug input to saturate
`pass metabolism and require fast drug input to saturate
`metabolizing enzymes in order to minimize pre-
`metaboliZing enZymes in order to minimiZe pre
`systemic metabolism. Thus, a constant/sustained oral
`systemic metabolism. Thus, a constant/sustained oral
`method of delivery would result in reduced oral bio-
`method of delivery Would result in reduced oral bio
`availability.
`availability.
`Biological tolerance: Continuous release drug plasma
`Biological
`tolerance: Continuous release drug plasma
`profiles are often accompanied by a decline in the
`pro?les are often accompanied by a decline in the
`pharmacotherapeutic effect of the drug, e.g., biological
`pharmacotherapeutic effect of the drug, e.g., biological
`tolerance of transdermal nitroglycerin.
`tolerance of transdermal nitroglycerin.
`Chronopharmacology and circadian rhythms: Circadian
`Chronopharmacology and circadian rhythms: Circadian
`rhythms in certain physiological functions are well
`rhythms in certain physiological functions are Well
`established. It has been recognized that many symp-
`established. It has been recogniZed that many symp
`toms and onset of disease occur during specific time
`toms and onset of disease occur during speci?c time
`periods of the 24 hour day, e.g., asthma and angina
`periods of the 24 hour day, e.g., asthma and angina
`pectoris attacks are most frequently in the morning
`pectoris attacks are most frequently in the morning
`hours (1,2).
`hours (1,2).
`Local therapeutic need: For the treatment of local disor-
`Local therapeutic need: For the treatment of local disor
`ders such as inflammatory bowel disease, the delivery
`ders such as in?ammatory boWel disease, the delivery
`of compounds to the site of inflammation with no loss
`of compounds to the site of in?ammation With no loss
`due to absorption in the small
`intestine is highly
`due to absorption in the small intestine is highly
`desirable to achieve the therapeutic effect and to mini-
`desirable to achieve the therapeutic effect and to mini
`mize side effects.
`miZe side effects.
`Gastric irritation or drug instability in gastric fluid: For
`Gastric irritation or drug instability in gastric ?uid: For
`compounds with gastric irritation or chemical instabil-
`compounds With gastric irritation or chemical instabil
`ity in gastric fluid,
`the use of a sustained release
`ity in gastric ?uid, the use of a sustained release
`preparation may exacerbate gastric irritation and
`preparation may eXacerbate gastric irritation and
`chemical instability in gastric fluid.
`chemical instability in gastric ?uid.
`Drug absorption differences in various gastrointestinal
`Drug absorption differences in various gastrointestinal
`segments: In general, drug absorption is moderately
`segments: In general, drug absorption is moderately
`slow in the stomach, rapid in the small intestine, and
`sloW in the stomach, rapid in the small intestine, and
`sharply declining in the large intestine. Compensation
`sharply declining in the large intestine. Compensation
`for changing absorption characteristics in the gas-
`for changing absorption characteristics in the gas
`trointestinal tract may be important for some drugs. For
`trointestinal tract may be important for some drugs. For
`example, it is rational for a delivery system to pump out
`eXample, it is rational for a delivery system to pump out
`the drug much faster when the system reaches the distal
`the drug much faster When the system reaches the distal
`segment of the intestine, to avoid the entombment of
`segment of the intestine, to avoid the entombment of
`the drug in the feces.
`the drug in the feces.
`Pulsed dose delivery systems, prepared as either single
`Pulsed dose delivery systems, prepared as either single
`unit or multiple unit formulations, and which are capable of
`unit or multiple unit formulations, and Which are capable of
`releasing the drug after a predetermined time, have been
`releasing the drug after a predetermined time, have been
`studied to address the aforementioned problematic areas for
`studied to address the aforementioned problematic areas for
`
`10
`10
`
`15
`15
`
`20
`20
`
`25
`25
`
`30
`30
`
`35
`35
`
`40
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`60
`
`65
`65
`
`

`

`US 6,605,300 B1
`US 6,605,300 B1
`
`3
`3
`tion is contained within a water-insoluble capsule body and
`tion is contained Within a Water-insoluble capsule body and
`is sealed with a hydrogel plug. Upon oral administration, the
`is sealed With a hydrogel plug. Upon oral administration, the
`capsule cap dissolves in the gastric juice and the hydrogel
`capsule cap dissolves in the gastric juice and the hydrogel
`plug swells. At a controlled and predetermined time point,
`plug sWells. At a controlled and predetermined time point,
`the swollen plug is ejected from the PULSINCAP® dosage
`the sWollen plug is ejected from the PULSINCAP® dosage
`form and the encapsulated drug is released. A pulsatile
`form and the encapsulated drug is released. A pulsatile
`capsule system containing captopril with release after a
`capsule system containing captopril With release after a
`nominal 5-hr period was found to perform reproducibly in
`nominal 5-hr period Was found to perform reproducibly in
`dissolution and gamma scintigraphy studies. However, in
`dissolution and gamma scintigraphy studies. HoWever, in
`the majority of subjects, no measurable amounts of the drug
`the majority of subjects, no measurable amounts of the drug
`were observed in the blood, possibly due to instability of the
`Were observed in the blood, possibly due to instability of the
`drug in the distal intestine. (12)
`drug in the distal intestine. (12)
`ADDERALL® comprises a mixture of four amphetamine
`ADDERALL® comprises a miXture of four amphetamine
`salts, deXtroamphetamine sulfate, deXtroamphetamine
`salts, dextroamphetamine sulfate, dextroamphetamine
`saccharate, amphetamine aspartate monohydrate and
`saccharate, amphetamine aspartate monohydrate and
`amphetamine sulfate, which in combination, are indicated
`amphetamine sulfate, Which in combination, are indicated
`for treatment of Attention Deficit Hyperactivity Disorder in
`for treatment of Attention De?cit Hyperactivity Disorder in
`children from 3—10 years of age. One disadvantage of
`children from 3—10 years of age. One disadvantage of
`current treatment is that a tablet form is commonly used
`current treatment is that a tablet form is commonly used
`which many young children have difficulty in swallowing.
`Which many young children have dif?culty in sWalloWing.
`Another disadvantage of current treatment is that two sepa-
`Another disadvantage of current treatment is that tWo sepa
`rate dose are administered, one in the morning and one
`rate dose are administered, one in the morning and one
`approximately 4—6 hours later, commonly away from home
`approximately 4—6 hours later, commonly aWay from home
`under other than parental supervision. This current form of
`under other than parental supervision. This current form of
`treatment, therefore, requires a second treatment which is
`treatment, therefore, requires a second treatment Which is
`time-consuming, inconvenient and may be problematic for
`time-consuming, inconvenient and may be problematic for
`those children having difficulty in swallowing table formu-
`those children having dif?culty in sWalloWing table formu
`lations.
`lations.
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`Accordingly, in view of a need for successfully adminis-
`Accordingly, in vieW of a need for successfully adminis
`tering a multiple unit pulsed dose of amphetamine salts and
`tering a multiple unit pulsed dose of amphetamine salts and
`mixtures thereof,
`the present
`invention provides an oral
`miXtures thereof, the present invention provides an oral
`multiple unit pulsed dose delivery system for amphetamine
`multiple unit pulsed dose delivery system for amphetamine
`salts and mixtures thereof. FIG. 1 illustrates the desired
`salts and mixtures thereof. FIG. 1 illustrates the desired
`target plasma level profile of the pharmaceutical active
`target plasma level pro?le of the pharmaceutical active
`contained within the delivery system.
`contained Within the delivery system.
`In accordance with a preferred embodiment of the present
`In accordance With a preferred embodiment of the present
`invention, there is provided a pharmaceutical composition
`invention, there is provided a pharmaceutical composition
`for delivering one or more pharmaceutically active amphet-
`for delivering one or more pharmaceutically active amphet
`amine salts that includes:
`amine salts that includes:
`(a) one or more pharmaceutically active amphetamine
`(a) one or more pharmaceutically active amphetamine
`salts that are covered with an immediate release
`salts that are covered With an immediate release
`coating, and
`coating, and
`(b) one or more pharmaceutically active amphetamine
`(b) one or more pharmaceutically active amphetamine
`salts that are covered with an enteric release coating
`salts that are covered With an enteric release coating
`wherein (1) the enteric release coating has a defined
`Wherein (1) the enteric release coating has a de?ned
`minimum thickness and/or (2) there is a protective
`minimum thickness and/or (2) there is a protective
`layer between the at least one pharmaceutically active
`layer betWeen the at least one pharmaceutically active
`amphetamine salt and the enteric release coating and/or
`amphetamine salt and the enteric release coating and/or
`(3) there is a protective layer over the enteric release
`(3) there is a protective layer over the enteric release
`coating.
`coating.
`In one embodiment, the immediate release and enteric
`In one embodiment, the immediate release and enteric
`release portions of the composition are present on the same
`release portions of the composition are present on the same
`core.
`core.
`In another embodiment, the immediate release and enteric
`In another embodiment, the immediate release and enteric
`release components are present on different cores.
`release components are present on different cores.
`It is also contemplated that the composition may include
`It is also contemplated that the composition may include
`a combination of the hereinabove referred to cores (one or
`a combination of the hereinabove referred to cores (one or
`more cores that include both components on the same core
`more cores that include both components on the same core
`and one or more cores that include only one of the two
`and one or more cores that include only one of the tWo
`components on the core).
`components on the core).
`The present invention provides a composition in which
`The present invention provides a composition in Which
`there is immediate release of drug and enteric release of drug
`there is immediate release of drug and enteric release of drug
`wherein the enteric release is a pulsed release and wherein
`Wherein the enteric release is a pulsed release and Wherein
`the drug includes one or more amphetamine salts and
`the drug includes one or more amphetamine salts and
`mixtures thereof.
`miXtures thereof.
`
`10
`10
`
`15
`15
`
`20
`20
`
`25
`25
`
`30
`30
`
`35
`35
`
`40
`40
`
`45
`45
`
`50
`
`55
`55
`
`60
`60
`
`65
`65
`
`4
`4
`The immediate release component releases the pharma-
`The immediate release component releases the pharma
`ceutical agent in a pulsed dose upon oral administration of
`ceutical agent in a pulsed dose upon oral administration of
`the delivery system.
`the delivery system.
`The enteric release coating layer retards or delays the
`The enteric release coating layer retards or delays the
`release of the pharmaceutical active or drug for a specified
`release of the pharmaceutical active or drug for a speci?ed
`time period (“lag time”) until a predetermined time, at which
`time period (“lag time”) until a predetermined time, at Which
`time the release of the drug is rapid and complete, i.e., the
`time the release of the drug is rapid and complete, i.e., the
`entire dose is released within about 30—60 minutes under
`entire dose is released Within about 30—60 minutes under
`predetermined environmental conditions,
`i.e. a particular
`predetermined environmental conditions, ie a particular
`location within the gastrointestinal tract.
`location Within the gastrointestinal tract.
`The delay or lag time will take into consideration factors
`The delay or lag time Will take into consideration factors
`such as transit
`times, food effects,
`inflammatory bowel
`such as transit times, food effects, in?ammatory boWel
`disease, use of antacids or other medicaments which alter the
`disease, use of antacids or other medicaments Which alter the
`pH of the GI tract.
`pH of the GI tract.
`In a preferred embodiment, the lag time period is only
`In a preferred embodiment, the lag time period is only
`time-dependent, i.e., pH independent. The lag time is pref
`time-dependent, i.e., pH independent. The lag time is pref-
`erably within 4 to 6 hours after oral administration of the
`erably Within 4 to 6 hours after oral administration of the
`delivery system.
`delivery system.
`In one aspect,
`the present
`invention is directed to a
`In one aspect, the present invention is directed to a
`composition that provides for enteric release of at least one
`composition that provides for enteric release of at least one
`pharmaceutically active amphetamine salt, including at least
`pharmaceutically active amphetamine salt, including at least
`one pharmaceutically active amphetamine salt that is coated
`one pharmaceutically active amphetamine salt that is coated
`with an enteric coating wherein (1)
`the enteric release
`With an enteric coating Wherein (1) the enteric release
`coating has a defined minimum thickness and/or (2) there is
`coating has a de?ned minimum thickness and/or (2) there is
`a protective layer between the at least one pharmaceutically
`a protective layer betWeen the at least one pharmaceutically
`active amphetamine salt and the enteric release coating
`active amphetamine salt and the enteric release coating
`and/or (3) there is a protective layer over the enteric release
`and/or (3) there is a protective layer over the enteric release
`coating.
`coating.
`In attempting to provide for enteric release of an amphet-
`In attempting to provide for enteric release of an amphet
`amine salt, applicants found that use of an enteric release
`amine salt, applicants found that use of an enteric release
`coating as generally practiced in the art did not provide
`coating as generally practiced in the art did not provide
`effective enteric release.
`effective enteric release.
`Typical enteric coating levels did not meet the above
`Typical enteric coating levels did not meet the above
`requirements for the desired dosage profile of amphetamine
`requirements for the desired dosage pro?le of amphetamine
`salts. Using the typical amount of enteric coating (10—20p)
`salts. Using the typical amount of enteric coating (10—20y)
`resulted in undesired premature leakage of the drug from the
`resulted in undesired premature leakage of the drug from the
`delivery system into the upper gastrointestinal tract and thus
`delivery system into the upper gastrointestinal tract and thus
`no drug delivery at the desired location in the gastrointes-
`no drug delivery at the desired location in the gastrointes
`tinal tract after the appropriate lag time. Thus this coating
`tinal tract after the appropriate lag time. Thus this coating
`did not meet the requirements for the drug release profile to
`did not meet the requirements fo