(12) Unlted States Patent
`(10) Patent No.:
`US 8,206,740 B2
`
`Chang et al.
`(45) Date of Patent:
`*Jun. 26, 2012
`
`USOO8206740B2
`
`(54) ONCE DAILY FORMULATIONS OF
`TETRACYCLINES
`
`(75)
`
`.
`Inventors: Rong-Kun Chang, RockVille, MD (US);
`Arash Raoufinia, Splmgfielda VA (US);
`Niraj Shah, Owings Mills, MD (US)
`
`.
`( * ) Notice:
`
`(73) Assignee: Supernus Pharmaceuticals, Inc.,
`ROCkVille MD (US)
`’
`.
`.
`.
`.
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 626 days.
`This patent is subject to a terminal dis-
`Clalmer'
`
`.
`(21) Appl.No.. 12/155,676
`
`4,704,383 A
`4,837,030 A
`4,935,411 A
`4,935,412 A
`5,045,538 A
`5,122,519 A
`5,167,964 A
`5,188,836 A
`
`5,223,248 A
`5,238,686 A
`5,258,371 A
`5,260,292 A
`5,277,916 A
`5,283,065 A
`5,286,497 A
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`FOREIGN PATENT DOCUMENTS
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`EP
`
`(Continued)
`
`(22)
`
`Filed:
`
`Jun. 6, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2009/0011006 A1
`
`Jan. 8, 2009
`
`D t
`t'
`R1 th.S.A l'
`a a
`e a e
`pp 1ca lon
`(63) Continuation of application No. 10/819,620, filed on
`Apr. 7, 2004, now Pat. No. 7,749,532.
`.
`.
`.
`.
`Prov1s1onal application No. 60/460,963, filed on Apr.
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`on Feb. 26, 2004.
`
`(60)
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 9/54
`(52) U.S. Cl.
`....................................................... 424/458
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
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`Primary Examiner 7 Paul Dickinson
`.
`.
`(74) Attorney, Agent, or Firm iFoley & Lardner LLP’
`Stephen B. Maebius; Sumt Talapatra
`
`ABSTRACT
`(57)
`Disclosed are once—daily fonnulations containing tetracy—
`clines, especially doxycycline. Such formulations are useful,
`for instance, for the treatment of collagenase destructive
`enzyme-dependent diseases, such as periodontal disease and
`acne, and acute and chronic inflammatory disease states, such
`as rosacea and arthritis.
`
`29 Claims, 6 Drawing Sheets
`
`Doxycycline Maunnydrale IR Pellets, 40 mg
`Report ll: Amams
`Let #: 301027 (CTM)
`
`110
`100
`90-
`007
`70*
`
`10- ——o— Vessel 1
`
`
`
`PercentDissolved
`
`5.),
`40—
`30-
`20-
`
`+Vessel 2
`+Vessel 3
`—-)(-—Vessel 4
`+ Vessel 5
`—e— Vessel 6
`
`Time (Minutes)
`
`Dissolution profile for doxycycline monohydrale 1R beads
`
`AMNEAL 1001
`
`1
`
`

`

`US 8,206,740 B2
`
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`* cited by examiner
`
`5
`
`

`

`US. Patent
`
`Jun. 26, 2012
`
`Sheet 1 0f6
`
`US 8,206,740 B2
`
`Doxycycline Monohydrate IR Pe Hats, 40 m 9
`
`Lot {3: 801027 (CTM)
`
`Report #: AW3A16
`
`Percent
`
`——e—Ve55el1
`
`—B—Vesse|2
`
`+Vessel 3
`
`Dissolved
`
`——>€-—Vessel4
`
`+Vesset 5
`
`——9—Vessel 6
`
`Time (Minutes)
`
`Figure 1
`
`Dissolution profile for doxycycline monohydrate IR beads
`
`6
`
`

`

`US. Patent
`
`Jun. 26, 2012
`
`Sheet 2 0f6
`
`US 8,206,740 B2
`
`Doxycycline Monohydrate XR Pellets. 40 mg
`
`Lot #1 301029 (CTM)
`
`Report 0: AR03A17
`
`.
`;
`I
`
`
`
`—-o—Vessel 1
`-El——Vesse| 2
`+Vessel 3
`—>(—-—Vesse| 4
`
`+Vessel 5
`—9—Vesse| 6
`
`110
`
`100
`
`90
`
`80
`
`E 70
`g 60
`a
`E 50
`II
`§ 40
`“-
`30
`
`20
`1°
`
`0
`
`0.5
`
`1
`
`1.5
`
`2
`
`2.5
`
`3
`
`3.5
`
`4
`
`Time (Hours)
`
`Figure 2
`
`Dissolution profile for doxycycline monohydrate DR beads
`
`7
`
`

`

`US. Patent
`
`Jun. 26, 2012
`
`Sheet 3 0f6
`
`US 8,206,740 B2
`
`Doxycycline Monohydrate IR! DR1. 40mg Capsules, DISSOLUTION PROFILE
`Sample Number: RRDSAOS
`
`Lot Number: PD-0126-104
`
`110
`
`100
`
`90
`
`an
`
`8 7o
`
`2 g
`
`a
`o
`.5
`
`g
`n.
`
`so
`
`50
`
`40
`30
`
`20
`10 .
`
`o R:
`o
`
`
`
`:
`I
`;
`
`'
`
`‘
`
`.
`
`'
`
`+Vessel1
`
`+Vessel 2
`+Vessel 3
`-)(—-Vessel 4
`
`—)K—Vessel 5
`—o——Vessel 6
`
`0.5
`
`1
`
`1.5
`
`2
`
`2.5
`Time (Hours)
`
`3
`
`3.5
`
`4
`
`4.5
`
`5
`
`Figure 3
`
`Dissolution profile for doxycycline monohydrate composite capsules
`containing 75% IR and 25% DR beads
`
`8
`
`

`

`US. Patent
`
`Jun. 26, 2012
`
`Sheet 4 0f6
`
`US 8,206,740 B2
`
`Mean (n =12)
`
`—4— 20m 9 IR bid
`
`—a—40mg IR qd
`
`+40mg IRIDR(70:30)
`
`——°—-—40mg IRIDNBOQD)
`
`_
`
`Conc.(uglml)
`
`' 192
`
`198
`
`204
`Time (Hours)
`
`210
`
`216
`
`Figure 4
`
`Simulated steady state blood level profiles for various treatments
`
`9
`
`

`

`U.S. Patent
`
`Jun