O
`
`(12) Ulllted States Patent
`(10) Patent N0.:
`US 9,173,857 B2
`" i
`‘
`.
`2
`‘
`‘
`:
`V. -
`I
`
`Sho ae et a]
`4s Date of Patent
`*No
`3, 2018
`
`USOO9173857B2
`
`(54) CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`.
`.
`(71) Applicant: Shire LLC, Florence, KY (US)
`.
`.
`(72)
`Inventors: Amir Shojaei, Phoenixyille, PA HIS):
`Stephanie Read, Philadelphia, PA (US);
`Richard A. Couch Brvn Mawr PA
`.
`.3
`"
`a
`A
`(US), Paul HOdgkms’ Emma PA (US)
`
`.
`_
`(73) Asmgnee: Shire LLC, Florence, KY (US)
`.
`‘
`.
`.
`.
`.
`( * ) Notice:
`Subiect to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`This patent is subject to a terminal dis-
`elaimer.
`
`.
`(21) Appl. No.. 14/498,130
`.
`(22) Filed:
`
`Sep. 26, 2014
`
`(65)
`
`Prior Publication Data
`US 2015/0080474 A1
`Mar. 19, 2015
`
`Related US. Application Data
`(63) Continuation of application No. 11/383,066, filed on
`May 12: 2006, HOW Pat. NO. 8,846,100.
`
`(51)
`
`(2006.01)
`(200601)
`(200601)
`(2006.01)
`
`Int. Cl.
`A61K 9/16
`A61K 31/13 7
`A61K 9/48
`AGIK 9/50
`(52) US. Cl.
`CFC
`A61K ”/1 {7 (2013’ 01). A61K 9/16
`'
`i """"""""""
`.
`7
`7
`’ i
`’
`.
`(201301), A61K 9/1676 (2013-01): 4461K
`9/4808 (201301)? A61K 9/5078 (201301)
`(58) Field of Classification Search
`cpc ..... A61K 9/1676: A61K 9/28: A61K 9/2806;
`A61K 9/284, A61K 91,2866, A61K 9/2886
`USPC .................................................. 424/4897502
`See application file for complete search history.
`
`(56)
`
`References ('lted
`us. PATENT DOCUMENTS
`
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`
`
`
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`....... 424/ 73
`
`AU
`EP
`JP
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`JP
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`WO
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`W0
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`WO
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`
`109438
`0640337 A2
`59-082311
`03-148215
`07-061922
`09-249557
`09237035
`10-081634
`87/00441 Al
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`
`OTHER PUBLICATIONS
`
`Apr. 30, 2014 OfficcAetion in US. Appl. No. 11/383,066 (now US.
`Pat. No. 8,866,100).
`Jun. 3, 2014 Amendment in US. Appl. No. ll/383,066.
`igbeéglflll/Etét31c56gf Allowance and Interv1ew Summary in US.
`International Search Report dated Nov. 21, 2006 issued for corre—
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`_
`'
`,
`d
`(Continue )
`
`Primary Examiner 7 Michael G Hartley
`Assistant Examiner 7 Micah-Paul Young
`(74) Attorney, Agent, or Firm 7 Blank Rome LLP
`
`(57)
`
`ABSTRACT
`,
`.
`A multiple pulsed dose drug delivery system for pharmaceu-
`tically active amphetamine salts, comprising a pharmaceuti—
`cally active amphetamine salt covered with an immediate-
`release coating and a pharmaceutically active amphetamine
`salt covered with an enteric coating wherein the immediate
`.
`.
`.
`.
`.
`release coating and the enteric coating prov1de for multiple
`pulsed dose delivery of the pharmaceutically active ainphet—
`amine salt. 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.
`
`29 Claims, 10 Drawing Sheets
`
`KVK-TECH EXHIBIT 1001
`
`KVK-TECH EXHIBIT 1001
`
`

`

`US 9,173,857 B2
`
`Page 2
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`(56)
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`

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`
`* cited by examiner
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 1 of 10
`
`US 9,173,857 B2
`
`FIG.1
`
`120
`
`110 -------------------------------------------------------------------------------------------------------
`
`100 ---—~——-~---——--——-—«——-~——-—-~~~--
`
`-—~—~—----——~~-——-—~~>—~——-~«~—~~—-«--—-~———~«-—----~--—-—~.~~~~~
`
`....................................................
`
`---
`
`-O- PD0149-120 Initial. HFs+0padry+Surelease
`+ PD0149~124 )nifiaI, HIR+SureleasehFS
`
`7c: ————————————————————————————————————————————————————————————————————————————————————————————————————— 8
`
`
`
`PercentDissoived 5e -----------------------------------------------------------------------------------------------------
`
`60 -----------------------------------------------------------------------------------------------------
`
`4o -----------------------------------------------------------------------------------------------------
`
`O
`
`2
`
`4
`
`6
`
`8
`Time (hours)
`
`10
`
`12
`
`14
`
`16
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 2 of 10
`
`US 9,173,857 B2
`
`FIG.2
`
`Protective coating
`
`
`
`Su release coating
`
`
`
`Drug layered
`core
`
`Eudragit FS—BOD
`coating
`
`FIG. 3
`
`SPD465 Sustained Release Capsule
`
`Immediate-Release
`Bead (IR)
`
`Delayed-Release
`Bead 1 (DR!)
`
`Delayed Release
`Bead 2 (DR2)
`
`Dru’g layer
`
`
`Overcoatin *‘
`:
`
`
`
`
`
`
`‘
`"éercoaflng
`
`Delayed-release
`polymer
`
`Delayeld-release
`90 ymer
`Drug layer
`Overcoafing
`
`
`
`
`33.3%
`
`33.3%
`
`Sustained-release
`33.3% WW“
`
`QD (morning)——>
`
`—~>TID dosing profile
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 3 of 10
`
`US 9,173,857 B2
`
`FIG.4
`
`Dissolution Profile of SPD465 1 2.5mg Capsules Low A03552A
`
`U)0
`
`
`
`
`
`100’m‘
`80V
`PercentDlssolved(%) bO
`20l0
`
`0
`
`Tlme (hr)
`
`F!G.5
`
`Dissolution Profile of SPD465 25mg Capsules Low A03547A
`
`l
`
`
`
`
`
`
`
`PercentDissolved(l6)..\E3388
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 4 of 10
`
`US 9,173,857 B2
`
`FIG.6
`
`Dissolution Profile of SPD465 37.5mg Capsules Low A0354BB
`
`G)0
`
`rI 2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`Time (hr)
`
`FIG; 7
`
`Dissolution Profile of SPD465 50mg Capsules Lot}: A035365
`
`' 2
`
`0
`
`100
`
`
`
`PercentDissolved
`
`(”M A.<3V"“
`
`20
`
`.7”
`PercentDissolved(92) O)O
`
`
`
`
`
`abO
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 5 of 10
`
`US 9,173,857 B2
`
`FIG. 8
`
` Percent
`Diasolvad0%)
`
`012 345678910111213141516
`
`Timemr)
`
`
`dAmphetanfineMeanPlasmaConcantmtion
`(ng/mL)
`
`50 ..._._..__._._____.____......__......_......»~WWVM.
`
`, + SPD465 37.5 mg
`~0- ADDERALL XR° 25 mg
`+ Mixed Amphetamine salts 12.5 mg
`
`
`
`.
`
`40
`
`r
`
`60
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 6 of 10
`
`US 9,173,857 B2
`
`FIG. 10
`
`.a. co
`
`a a:
`
`a-LNh
`
`—L O
`
`
`
`Concentration(ng/mL)
`
`
`
`
`WWW“:
`
`-~¢- AQQERALL KR“ 2§ mg
`
`
`
`4- Mixed Amphetamine saits 125 mg
`«9» SWBS 3?.Smg
`
`
`
`o
`
`10
`
`20
`
`30
`
`4o
`
`50
`
`60
`
`Time (hr)
`
`FIG. 11
`
`
`
`
`
`Meand—AmphetaminePlasma
`
`25
`
`
`
`
`wiw SSng¥e Dose {Day 1}
`-~£§3-~ Afiuifipw Dose (Day 3?}
`
`
`
`
` .AMCh0
`Concentration(ng/mL) 8
`
`T
`0 MMWWW WMMV~M\MTM“MWM“~~~~~~~~.,\\\\\\\\\\\\r\\\\\\\\\\\\\\\\\\\\\\\\\\3\\\\\\\\\\\\,...........-3
`o
`4
`s
`12
`1s
`20
`24
`
`Time (hr)
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 7 of 10
`
`US 9,173,857 B2
`
`1 60
`
`n.............~.........~..~..,.....u.“.......w.m.W.W.Mm.....-......h._.w.w...wm.w
`
`N“
`
`EM.“ 1;:5mg<f§ayfi1
`g 421» 2:3 mg may 2'}
`‘ «Ow 5:3 mg {Say ?3
`E “““m M W ’QSYW‘
`\K
`
`”MW
`
`‘
`
`xx
`
`\x
`
`f
`
`12’
`2*
`
`y
`/
`
`. .
`
`‘43»
`
`n
`
`WM WN‘RNQW‘E»
`
`\
`
`14°
`120
`3 100
`
`2E
`
`D. E
`23
`
`a)
`
`m .=
`33' .9
`.c ‘5
`8E
`i g
`g0
`E
`
`0
`
`60
`
`40
`
`20
`
`0
`
`0
`
`250
`
`
`
`NM».
`\MM
`f
`'V'.‘
`“Mg“
`”M MWMw—MW.W
`
`“*WWW“TW““TM“*”‘*M
`16
`20
`24
`
`4
`
`3
`
`12
`
`Time (hr)
`
`
`O
`lndividuaf Vatues
`
`I- Mean
`
`0
`
`20°
`
`'*-' Power Mode! Regression Line
`
`
`
`150
`
`100
`
`50
`
`0
`
`0
`
`1o
`
`20
`
`30
`
`4o
`
`50
`
`60
`
`7o
`
`80
`
`’3
`
`E 2
`
`’
`v“
`E
`
`0 £
`
`1E
`
`%.1:
`o.
`
`E 4
`
`.:
`'B
`
`Dose (mg)
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 8 of 10
`
`US 9,173,857 B2
`
`FIG. 14
`
`5000
`
`Individual Values
`0
`- Mean
`
`4000
`
`"A"
`
`Power Mode! Regression Line
`
`AUC(M4)(hr*ng/mL)
`d-Amphetamine
`
`3000
`
`2000
`
`1 000
`
`
`
`
`
`MeanI-AmphetammePlasma
`
`10WNW
`l
`
`
`mow Singie 8050 {Gay 1}
`
`1: MumpteEase{Day3’}
`
`“aw
`
`E
`
`‘%
`
`i
`
`/I
`
`'35x“
`
`,/
`
`
`
`Concentration(ng/mL)
`
`
`
`“W“Ww“ 0....
`
`'
`
`'S'" '
`
`"1“
`
`4
`
`8
`
`12
`
`Time (hr)
`
`MT”
`
`16
`
`-2
`
`"
`
`3
`
`'
`
`?
`
`20
`
`24
`
`

`

`U.S. Patent
`
`Nov. 3, 2015
`
`Sheet 9 of 10
`
`US 9,173,857 B2
`
`FIG. 16
`
`
`
`
`
`MeanI—AmphetaminePlasma
`
`
`
`Concentration(ng/mL)
`
`
`
`I-AmphetamineCm(ng/mL)
`
`
`
`l
`i
`l a» l2.5m9{l}ay?} g
`; -3§- 25 mg gnaw}
`;
`' ~+~ mmgmam l
`2 w- 75 ms may?)
`l
`l
`
`35“
`,5/
`/
`
`”NR
`Wk
`\
`\\
`
`.
`A»;MN
`
`/
`
`x\\
`
`“k
`
`\‘
`
`\\
`
`MN
`
`i
`
`g
`
`2
`i
`g
`
`
`
`MW” WWNN
`
`\‘mww
`jm
`J«W”M“‘Wom .
`WW“ “‘T”“‘““-1“"'" "PM "W‘WWW M
`4
`8
`12
`16
`20
`24
`
`“MN (
`‘
`
`Time (hr)
`
`
`O
`lndlvidual Values
`
`
`- Mean
`
`
`O
`
`A
`Power Model Regression Line
`
`."v
`
`‘—aa
`
`,v'v
`
`a"o_.
`
`,-
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`7O
`
`80
`
`100
`
`80
`
`60
`
`40
`
`20
`
`

`

`US. Patent
`
`Nov. 3, 2015
`
`Sheet 10 of 10
`
`US 9,173,857 B2
`
`FIG. 18
`
`!ndividual Values
`O
`-- Mean
`
`“A" Power Mode! Regression Line
`
`O
`
`8 Q
`
`"
`g
`
`o
`9 .......
`1‘ -,..
`
`.....
`
`_
`
`0
`0
`
`."a
`
`l"..
`
`..v,..
`
`.-
`
`fl
`
`1800
`
`1600
`
`1400
`
`1200
`
`1000
`
`803
`600
`
`400
`
`200
`
`GM
`
`Dose (mg)
`
`
`
`
`
`[AmphetamineAUCMQ(hr*ng/mL)
`
`

`

`US 9,173,857 B2
`
`1
`CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`
`CROSS REFERENCE TO PRIOR APPLICATIONS
`
`This application is a continuation of US. patent applica-
`tion Ser. No. 11/383,066, filed May 12, 2006, which is herein
`incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`Traditionally, drug delivery systems have focused on con-
`stant/sustained drug output with the objective of minimizing
`peaks and valleys of drug concentrations in the body to opti-
`mize drug efficacy and reduce adverse effects. Reduced dos-
`ing frequency and improved patient compliance can also be
`expected for constant/sustained release drug delivery sys-
`tems, 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 B-blockers,
`B-estradiol, and salicylamide, undergo extensive first pass
`metabolism and require fast drug input to saturate metaboliz-
`ing enzymes in order to minimize pre-systemic metabolism.
`Thus, a constant/sustained oral method of delivery would
`result in reduced oral bioavailability.
`Biological tolerance: Continuous release drug plasma pro-
`files are often accompanied by a decline in the pharmaco-
`therapeutic effect of the drug, e.g., biological tolerance of
`transdermal nitroglycerin.
`Chronopharmacology and circadian rhythms: Circadian
`rhythms in certain physiological functions are well estab-
`lished. It has been recognized that a symptom or disease onset
`can occur d