(12) United States Patent
`Burnside et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,605,300 Bl
`Aug. 12, 2003
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006605300B 1
`
`(54) ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`
`(75)
`
`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) Appl. No.:
`
`09/807,462
`
`(22) PCT Filed:
`
`Oct. 20, 1999
`
`(86) PCT No.:
`
`PCT/US99/24554
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jul. 19, 2001
`
`(87) PCT Pub. No.: W000/23055
`
`PCT Pub. Date: Apr. 27, 2000
`
`Related U.S. Application Data
`
`(51)
`
`( 63) Continuation-in-part of application No. 09/176,542, filed 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
`(52) U.S. Cl. ....................... 424/452; 424/458; 424/468;
`424/469; 424/470; 424/471; 424/472; 424/514;
`424/649
`(58) Field of Search ................................. 424/457, 458,
`424/468, 469, 470, 471, 472; 514/649
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,723,958 A
`4,765,989 A
`4,871,549 A
`4,891,230 A
`4,894,240 A
`4,902,516 A
`4,917,899 A
`5,002,776 A
`5,011,692 A
`5,011,694 A
`5,051,262 A
`5,093,200 A
`5,226,902 A
`5,229,131 A
`5,275,819 A
`5,312,388 A *
`5,364,620 A
`5,395,628 A
`5,407,686 A
`5,474,786 A
`5,616,345 A
`
`2/1988
`8/1988
`10/1989
`1/1990
`1/1990
`2/1990
`4/1990
`3/1991
`4/1991
`4/1991
`9/1991
`3/1992
`7/1993
`7/1993
`1/1994
`5/1994
`11/1994
`3/1995
`4/1995
`12/1995
`4/1997
`
`. . . . . . . . . . . . . . 604/890.1
`Pope et al.
`Wong et al. ................ 424/473
`Veda et al.
`................. 424/494
`Geoghegan et al.
`........ 424/461
`Geoghegan et al.
`........ 424/497
`Korsatko et al.
`........... 424/497
`Geoghegan et al.
`........ 424/461
`Geoghegan et al.
`........ 424/497
`Fujioka et al. .............. 424/426
`Nuernberg et al.
`......... 424/464
`Panoz et al. ................ 424/468
`Watanabe et al. ........... 428/407
`Bae et al. . . . . . . . . . . . . . . . . 604/892.1
`Amidon et al. ............. 424/451
`Amer et al.
`................ 424/408
`Wong et al. ............. 604/892.1
`Geoghegan et al.
`........ 424/497
`Noda et al. ................. 424/490
`Patel et al.
`................. 424/468
`Kotwal et al. .............. 424/472
`Geoghegan et al.
`........ 424/497
`
`............. 424/489
`9/1998 Morella et al.
`5,800,836 A
`10/1998 Segh et al.
`................. 424/473
`5,824,341 A
`10/1998 Cherukuri et al. .......... 424/484
`5,824,342 A
`10/1998 Na et al.
`.................... 424/486
`5,824,343 A
`11/1998 Mehta et al.
`............... 424/459
`5,837,284 A
`11/1998 Bai ............................ 424/458
`5,840,329 A
`3/1999 Hsiao et al.
`................ 424/472
`5,885,616 A
`5 ,885 ,998 A * 3/1999 Bencherif et al.
`. . . . . . . . . . 514/256
`.............. 424/490
`5,891,474 A
`4/1999 Busetti et al.
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`A61K/9/22
`A61K/9/22
`
`1/1987
`W087/00044
`8/1990
`W090/09168
`OTHER PUBLICATIONS
`Gazzaniga, et al., S.T.P. Pharma Sciences, vol. 5, No. 1, gs.
`83-88 (1995), Time dependent oral delivery for colon tar(cid:173)
`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(cid:173)
`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(cid:173)
`tem: Achievement of Time and/or Site Specificity.
`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 US District Court
`the Southern District of New York (Case No
`for
`03-CV-1219(VM)(DFE)) 2003.
`Barr Laboratories' Answer. Affirmative Defenses and Coun(cid:173)
`terclaim in Case No. 03-CV-1219(VM)(DFE) (SD NY)
`2003.
`Barr's Paragraph IV Certification against Parent US Patent
`6,322,819 on Jan. 14, 2003.
`* cited by examiner
`Primary Examiner-Russell Travers
`(74) Attorney, Agent, or Firm-Millen, White, Zelano &
`Branigan, P.C.
`(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.
`
`18 Claims, 7 Drawing Sheets
`
`Amerigen Ex. 1003, p. 1
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 1 of 7
`
`US 6,605,300 Bl
`
`50-r-,__,__,__,__,__,__,__,__,__,__,__,__,__,__,__,__,__,____,
`
`45
`40
`35
`30
`25
`20
`15
`10
`5
`0--..--..--~.--.--~~,__,__~,__,__ __ ,_ _ ,_ __ _ , ,_ _ ,__ - - -1
`24
`20
`
`0
`
`4
`
`8
`
`12
`TIME (HOURS)
`
`16
`
`FIG. 1
`
`Amerigen Ex. 1003, p. 2
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 2 of 7
`
`US 6,605,300 Bl
`
`Seed Core
`
`Polymeric
`Layer
`
`FIG. 2A
`
`Amerigen Ex. 1003, p. 3
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 3 of 7
`
`US 6,605,300 Bl
`
`0
`
`Q)
`
`0
`
`0
`0
`oO
`0 0
`
`0
`0
`
`0
`
`0 0
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`f!J
`
`0
`~o
`0 o U""o
`0
`0
`0
`0
`
`0
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`0
`
`0
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`0
`
`0
`
`0
`
`0
`0
`
`FIG. 28
`
`Amerigen Ex. 1003, p. 4
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 4 of 7
`
`US 6,605,300 Bl
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`e o
`
`0
`0 0
`
`0
`(\I
`•
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`C) -LI-
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Amerigen Ex. 1003, p. 5
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 5 of 7
`
`US 6,605,300 Bl
`
`"'C
`Q.l
`>
`0
`Cl)
`Cl)
`
`c
`Q.l
`.....
`(.)
`Q.) a..
`
`i:5 - 50
`
`100
`90
`80
`70
`60
`
`40
`30
`20
`10
`0
`
`0
`
`10
`
`20
`
`50
`
`60
`
`70
`
`40
`30
`Time (min)
`
`FIG. 3
`
`pH1.1
`
`pH7.5
`
`120
`
`100
`80
`60
`40
`
`20
`
`"'C
`Q.)
`Cl)
`ctl
`Q.)
`
`Qj er:
`'#.
`
`0
`
`0
`
`1
`
`2
`
`3
`
`6
`
`7
`
`8
`
`9
`
`4
`5
`Time (hrs)
`
`FIG. 4
`
`Amerigen Ex. 1003, p. 6
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 6 of 7
`
`US 6,605,300 Bl
`
`120
`
`100
`
`pH1.1
`
`pH6.0
`
`pH7.5
`
`Q)
`
`Q)
`
`'C 80
`Vl ro
`60 &
`40
`20
`
`~ 0
`
`0
`
`0
`
`1
`
`2
`
`3
`
`6
`
`7
`
`8
`
`9
`
`4
`5
`Time (hrs)
`FIG. 5
`
`Q)
`
`'C
`
`90
`80
`70
`Q) 60
`Cl) ro 50
`Q) 40
`er:
`30
`~ 0
`20
`10
`0
`
`I
`pH6.0
`
`pH1.1
`
`pH7.5
`
`0
`
`1
`
`2
`
`3
`
`6
`
`7
`
`8
`
`9
`
`4
`5
`Time (hrs)
`FIG. 6
`
`Amerigen Ex. 1003, p. 7
`
`

`
`U.S. Patent
`
`Aug. 12, 2003
`
`Sheet 7 of 7
`
`US 6,605,300 Bl
`
`Dataset subject 3 phase 4 (Extravascular}
`50--~~....-~--r~~-r-~~r-~-,
`
`E -C'l
`c: -u
`
`X Data
`
`o--~~--~-+-~~--~--t--~-
`o
`20
`10
`50
`40
`30
`T (hours)
`
`FIG. 7
`
`Dataset subject 18 phase 2 (Extravascular)
`25--~~.--~---~~--~~.--~~
`
`-C'l c: -
`
`E" 1s----w---~--~~--~~--~­
`
`X Data
`u 10-i-+-~+-~-+~~-4-~~'--~-1
`
`0
`
`10
`
`40
`
`50
`
`20
`
`30
`T (hours)
`
`FIG. 8
`
`Amerigen Ex. 1003, p. 8
`
`

`
`US 6,605,300 Bl
`
`1
`ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM
`
`This application is a 371 of PCT/US99/24554 filed Oct.
`20, 1999, which is continuation-in-part of application Ser.
`No. 09/176,542, filed Oct. 21, 1998, now U.S. Pat. No.
`6,322,819 the contents of which are incorporated herein by
`reference.
`This invention pertains to a multiple unit dosage form
`delivery system comprising one or more amphetamine salts
`for administering the amphetamine salts to a recipient.
`
`BACKGROUND OF THE INVENTION
`
`Traditionally, drug delivery systems have focused on
`constant/sustained drug output 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
`metabolizing enzymes in order to minimize pre(cid:173)
`systemic metabolism. Thus, a constant/sustained oral
`method of delivery would result in reduced oral bio(cid:173)
`availability.
`Biological tolerance: Continuous release drug plasma
`profiles are often accompanied by a decline in the
`pharmacotherapeutic effect of the drug, e.g., biological
`tolerance of transdermal nitroglycerin.
`Chronopharmacology and circadian rhythms: Circadian
`rhythms in certain physiological functions are well
`established. It has been recognized that many symp(cid:173)
`toms 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 45
`due to absorption in the small intestine is highly
`desirable to achieve the therapeutic effect and to mini(cid:173)
`mize side effects.
`Gastric irritation or drug instability in gastric fluid: For
`compounds with gastric irritation or chemical instabil(cid:173)
`ity in gastric fluid, the use of a sustained release
`preparation may exacerbate gastric irritation and
`chemical instability in gastric 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 declining in the large intestine. Compensation
`for changing absorption characteristics in the gas(cid:173)
`trointestinal 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 65
`releasing the drug after a predetermined time, have been
`studied to address the aforementioned problematic areas for
`
`5
`
`2
`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(cid:173)
`optimize process. Particularly challenging for formulation
`10 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
`15 phthalate, and the EUDRAGIT® acrylic polymers, have
`been used as gastroresistant, enterosoluble coatings for
`single drug pulse release in the intestine (3). The enteric
`materials, which are soluble at higher pH values, are fre(cid:173)
`quently used for colon-specific delivery systems. Due to
`20 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
`25 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
`30 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
`35 rate from the center cores.
`Special grades of hydroxypropyl methylcellulose, e.g.,
`METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and
`METHOCEL® F4M (Dow Chemical Company, USA), as a
`hydrophilic matrix material have been used to achieve
`40 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
`constant release, and finalized by a second rapid drug
`release.
`Tablets or capsules coated with a hydrophobic wax-
`surfactant layer, made from an aqueous dispersion of car(cid:173)
`nauba wax, beeswax, polyoxyethylene sorbitan monooleate,
`and hydroxypropyl methylcellulose have been used for rapid
`drug release after a predetermined lag time. However, even
`50 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 theophylline after
`the lag time. (8)
`A sustained-release drug delivery system is described in
`55 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
`explosion of the water permeable membrane. The drug thus
`releases after a predetermined time period. The OROS®
`60 push-pull system (Alza Company) has been developed for
`pulsatile delivery of water-soluble and water-insoluble drugs
`(9,10), e.g. the OROS-CT® system and is based on the
`swelling properties of an osmotic core compartment which
`provides a pH-independent, time-controlled drug release.
`The PULSINCAP® dosage form releases its drug content
`at either a predetermined time or at a specific site (e.g.,
`colon) in the gastrointestinal tract (11). The drug formula-
`
`Amerigen Ex. 1003, p. 9
`
`

`
`US 6,605,300 Bl
`
`3
`tion 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 plug is ejected from the PULSINCAP® dosage 5
`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 subjects, no measurable amounts of the drug 10
`were observed in the blood, possibly due to instability of the
`drug in the distal intestine. (12)
`ADDERALL® comprises a mixture of four amphetamine
`salts, dextroamphetamine sulfate, dextroamphetamine
`saccharate, amphetamine aspartate monohydrate and 15
`amphetamine sulfate, which in combination, are indicated
`for treatment of Attention Deficit Hyperactivity Disorder in
`children from 3-10 years of age. One disadvantage of
`current treatment is that a tablet form is commonly used
`which many young children have difficulty in swallowing. 20
`Another disadvantage of current treatment is that two sepa(cid:173)
`rate dose 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 25
`time-consuming, inconvenient and may be problematic for
`those children having difficulty in swallowing table formu(cid:173)
`lations.
`
`SUMMARY OF THE INVENTION
`Accordingly, in view of a need for successfully adminis(cid:173)
`tering a multiple unit pulsed dose of amphetamine salts and
`mixtures thereof, the present invention provides an oral
`multiple unit 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 65
`the drug includes one or more amphetamine salts and
`mixtures thereof.
`
`4
`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.
`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-
`30 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
`35 salts. Using the typical amount of enteric coating (10-20µ)
`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
`40 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
`45 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.
`This was surprising because an increase in thickness of
`about 5-10µ of enteric coatings above a minimum thickness
`50 of about 10-20µ typically does not have a significant effect
`on release of drug 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 20µ)
`55 will only marginally increase the time for complete release
`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-
`60 propriate environment resulting in significant loss of the
`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
`delivery comprises a composition which comprises one or
`more pharmaceutically active amphetamine salts; an enteric
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`US 6,605,300 Bl
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`10
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`6
`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
`5 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
`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
`incorporated into the pharmaceutical active layer or coated
`15 onto the surface of the active layer to reduce the pH value
`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
`20 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
`25 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
`30 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.
`
`35
`
`5
`coating over the one or more pharmaceutically active
`amphetamine salts, wherein the thickness of the enteric
`coating layer is at least 25µ; a further layer of one or more
`pharmaceutically active amphetamine salts over the enteric
`coating layer; and an immediate release layer coating. The
`thicker enteric coating surprisingly provides the required
`delayed immediate release of the pharmaceutically active
`amphetamine salt at the desired time in the desired area of
`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.
`Alternatively, a core seed can be coated with one or more
`layers of one or more pharmaceutically active amphetamine
`salts.
`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 25µ, and the
`protective layer comprises an immediate release coating.
`With respect to this embodiment of the invention, the one
`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 40
`with one or more layers of one or more pharmaceutically
`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,
`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 50
`over the enteric coating; a second pharmaceutically active
`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
`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
`adjacent to the enteric coating layer and a second coating
`
`45
`
`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. 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
`delayed release components of the present invention.
`FIG. 5 is a plot of the percent drug released versus time
`55 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
`60 release component and the delayed release components of
`the present invention.
`FIG. 7 is a plot of a profile of plasma amphetamine
`concentration after administration of a composite capsule
`containing the immediate release pellets and delayed release
`65 pellets from Examples 1 and 2, respectively.
`FIG. 8 is a plot of a profile of plasma amphetamine
`concentration after administration of a composite capsule
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`7
`containing the immediate release pellets and delayed release
`pellets from Examples 1 and 3, respectively.
`
`US 6,605,300 Bl
`
`DETAILED DESCRIPTION OF IBE
`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
`me thy lcellulose, hydroxyethy 1 cellulose, hydroxypropy 1
`cellulose, hydroxypropyl methylcellulose,
`polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate
`copolymer and the like.
`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.
`Solubilizers such as citric acid, succinic acid, fumaric 35
`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 applications.
`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(cid:173)
`loaded pellets are dried for further applications.
`For purpos