111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007749532B2
`
`c12) United States Patent
`Chang et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,749,532 B2
`Jul. 6, 2010
`
`(54) ONCE DAILY FORMULATIONS OF
`TETRACYCLINES
`
`(75)
`
`Inventors: Rong-Kun Chang, Rockville, MD (US);
`Arash Raoufinia, Springfield, VA (US);
`Niraj Shah, Owings Mills, MD (US)
`
`(73) Assignee: Supernus Pharmaceuticals, 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 1351 days.
`
`(21) Appl. No.: 10/819,620
`
`(22) Filed:
`
`Apr. 7, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2004/0228912 Al
`
`Nov. 18, 2004
`
`(51)
`
`Int. Cl.
`A61K 9154
`(2006.01)
`(52) U.S. Cl. ...................................................... 424/458
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,666,897 A
`4,704,383 A
`4,935,411 A
`4,935,412 A
`5,045,538 A
`5,223,248 A
`5,258,371 A
`5,283,065 A
`5,308,839 A
`5,321,017 A
`RE34,656 E
`5,459,135 A
`5,523,297 A
`5,532,227 A
`5,753,711 A
`5,770,588 A
`5,773,430 A
`5,789,395 A
`5,792,446 A
`5,827,503 A
`5,827,840 A
`5,834,449 A
`5,837,696 A
`5,908,838 A
`5,919,775 A
`5,929,055 A
`5,977,091 A
`
`5/1987 Golub eta!.
`1111987 McNamara eta!.
`6/1990 McNamara eta!.
`6/1990 McNamara eta!.
`9/1991 Schneider et a!.
`6/1993 McNamara eta!.
`1111993 Golub eta!.
`2/1994 Doyon eta!.
`5/1994 Golub eta!.
`6/1994 Golub eta!.
`7/1994 Golub eta!.
`10/1995 Golub eta!.
`6/1996 Pruzanski et a!.
`7/1996 Golub eta!.
`5/1998 Schwabe et a!.
`6/1998 McNamara eta!.
`6/1998 Simonet al.
`8/1998 Amin et al.
`8/1998 Ashley
`10/1998 Schwabe
`10/1998 Ramamurthy et a!.
`1111998 Thompson et a!.
`1111998 Golub eta!.
`6/1999 Gans
`7/1999 Amin et al.
`7/1999 Ryan eta!.
`1111999 Nieman eta!.
`
`5,998,390 A
`6,015,804 A
`6,043,231 A
`6,100,248 A
`6,114,316 A
`6,143,506 A
`6,455,583 B1
`6,506,740 B1
`6,610,274 B1
`6,638,922 B2
`6,730,320 B2
`7,211,267 B2
`7,232,572 B2
`2002/0136766 A1 *
`2004/0115261 A1
`
`12/1999 Ramamurthy eta!.
`112000 Golub et a!.
`3/2000 Pruzanski et a!.
`8/2000 Golub et a!.
`9/2000 Ramamurthy eta!.
`1112000 Golub et a!.
`9/2002 Pflugfelder eta!.
`112003 Ashley eta!.
`8/2003 Gardner
`10/2003 Ashley eta!.
`5/2004 Rudnic et al.
`5/2007 Ashley
`6/2007 Ashley
`9/2002 Rudnic et al ................ 424/457
`6/2004 Ashley
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`wo
`wo
`wo
`
`0 464 932 B2
`WO 98/05340 A1
`WO 01187823 A1
`WO 02/083106 A1
`
`111992
`2/1998
`1112001
`10/2002
`
`OTHER PUBLICATIONS
`
`Remington's Pharmaceutical Sciences, 181h Edition, Gennaro, Ed.,
`
`http://www.drugs.com/doxycycline.html, accessed Jul. 25, 2009.*
`Gunsel and Dusel, Chapter 5, "Compression-coated and layer tab(cid:173)
`lets," Pharmaceutical Dosage Forms: Tablets, Second Edition, vol. 1,
`Edited by H.A. Lieberman eta!., 1990.
`
`1990, Chapters 88-91.
`Elewski et a!., Journal of the American Academy of Dermatology,
`1983, vol. 8, pp. 807-812.
`Plewig eta!., Journal oflnvestigative Dermatology, 1975, vol. 65, p.
`532.
`Ryan et al., "Potential of Tetracycline to ModifY Cartilage Break(cid:173)
`down in Osteoarthritis," Current Opinion in Rheumatology, 1996,
`vol. 8, pp. 238-247.
`Wong et al., Journal of American Academy of Dermatology, 1984,
`vol. 1, pp. 1076-1081.
`ORACEA (doxycycline, USP) Capsules 40 mg brochure, Gal derma
`Laboratories, L.P., May 2008, 2 pages.
`* cited by examiner
`Primary Examiner-Michael G Hartley
`Assistant Examiner-Paul Dickinson
`(74) Attorney, Agent, or Firm-Foley & Lardner LLP;
`Stephen B. Maebius; Sunit Talapatra
`
`(57)
`
`ABSTRACT
`
`Disclosed are once-daily formulations containing tetracy(cid:173)
`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.
`
`21 Claims, 6 Drawing Sheets
`
`1
`
`

`

`U.S. Patent
`
`Jul. 6, 2010
`
`Sheet 1 of 6
`
`US 7,749,532 B2
`
`110
`
`100 -
`
`90-
`
`80-
`
`"C 70 -
`Ill
`>
`0
`60 -
`Ill
`Ill
`0 .... 50 -
`c
`Ill
`~ 40-
`II)
`0..
`
`30-
`
`20 ~
`
`10 -
`
`0
`
`0
`
`Doxycycline Monohydrate IR Pellets, 40 m g
`
`Lot#: 801027 (CTM)
`
`Report#: AR03A16
`
`~Vesse11
`
`-e-Vessel2
`--tr- Vessel 3
`----*-Vessel 4
`......_VesselS
`
`-e-Vessel6
`
`10
`
`Time (Minutes)
`
`20
`
`30
`
`Figure 1
`
`Dissolution profile for doxycycline monohydrate IR beads
`
`2
`
`

`

`U.S. Patent
`
`Jul. 6, 2010
`
`Sheet 2 of 6
`
`US 7,749,532 B2
`
`Doxycycline Monohydrate XRPellets, 40 mg
`
`lot#: 801029 (CTM)
`
`Report #:AR03A17
`
`pH1.1
`
`~Vessel1
`-e--- Vessel 2
`---A- Vessel 3
`
`-?E-Vessel4
`_._VesselS
`
`-e-Vessel6
`
`110
`
`100
`
`90
`
`80
`"C 70
`Q)
`~
`0
`Ill
`
`60
`
`Ill c - 50
`.. Q)
`
`c:
`Q)
`u 40
`0..
`
`30
`
`20
`
`10
`
`0
`
`0
`
`0.5
`
`1.5
`
`2
`Time (Hours)
`
`2.5
`
`3
`
`3.5
`
`4
`
`Figure 2
`
`Dissolution profile for doxycycline monohydrate DR beads
`
`3
`
`

`

`U.S. Patent
`
`Jul. 6, 2010
`
`Sheet 3 of 6
`
`US 7,749,532 B2
`
`Doxycycline Monohydrate IR/ DR1, 40mg Capsules, DISSOLUTION PRORLE
`Sample Number: RR03A05
`
`Lot Number: PD-0126-104
`
`110
`
`100
`
`90
`
`80
`
`70
`
`"0
`CD >
`0
`Ill
`Ill
`5 ...
`c
`Ql
`~ 40
`CD a.
`
`60
`
`50
`
`--+-Vessel1
`-Vessel2
`_._Vessell
`---*-Vesse14
`-*-VesselS
`_._Vessel&
`
`30
`
`20
`
`10
`
`0.5
`
`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
`
`4
`
`

`

`U.S. Patent
`
`Jul. 6, 2010
`
`Sheet 4 of 6
`
`US 7,749,532 B2
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`=[ 0.6 -Dl
`
`2. 0.5
`u
`1:
`0 0.4
`(J
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`192
`
`Mean {n = 12)
`
`----20mg IRbid
`--40mg IRqd
`---.!o-- 40mg IRIDR(70:30)
`-40mg IRJDR(80:20)
`
`198
`
`204
`Time (Hours)
`
`210
`
`216
`
`Figure 4
`
`Simulated steady state blood level profiles for various treatments
`
`5
`
`

`

`N = N
`\C u. w
`
`~
`~
`-....l
`rJl
`d
`
`0\
`0 ......
`Ul
`('D a
`rFJ =(cid:173)
`
`~
`
`0
`0 ......
`N
`0\
`~
`
`~
`
`24
`0~---------r---------+--------~----------r---------+-------~
`
`8
`
`4
`
`0
`
`20
`
`16
`
`12
`
`Timepoint (Hr)
`
`-a-75/25 Steady State
`-6-75125 Day 1
`
`100
`
`~ 200
`m
`c:
`8
`~ c:
`c 300
`i§
`.Q
`c:
`.s
`o,
`-g 400
`
`500
`
`600
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`(PK Curves from Mean Plasma Concentrations)
`
`Comparison of75/25 IRIDR at Day 1 and at Steady State (Day 7)
`
`Steady State Study
`
`Doxycycline
`
`Figure 5
`
`6
`
`

`

`N = N
`\C u. w
`
`~
`~
`-....l
`rJl
`d
`
`0\
`0 .....
`0\
`('D a
`rFJ =(cid:173)
`
`24
`
`20
`
`16
`
`12
`
`8
`
`4
`
`Timepoint (Hr)
`
`--£]
`
`R
`
`19
`
`0 ....
`
`0
`
`-i3-Perio Day 1
`-9-75/25 Day 1
`
`Comparison of 75/25 IRIDR (40 mg) to Periostat (20 mg BID) at Day 1
`
`(PK Curves from Mean Plasma Concentrations)
`
`Doxycycline Steady State Study
`
`Figure 6
`
`0
`
`0
`
`50
`
`100
`
`150
`
`~
`Q)
`ro
`c:
`(.) 200
`0
`~ c:
`~ 250
`0
`c:
`.s 300
`E -o,
`...J
`....... 350
`
`400
`
`450
`
`500
`
`~
`
`~
`
`N
`0\
`~
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`7
`
`

`

`US 7,749,532 B2
`
`1
`ONCE DAILY FORMULATIONS OF
`TETRACYCLINES
`
`FIELD OF THE INVENTION
`
`The present invention is concerned with once-daily com(cid:173)
`positions of tetracyclines, which can be used for the treatment
`of acute or chronic diseases, for instance those with inflam(cid:173)
`matory components. More specifically, the present invention
`is directed to a pharmaceutical composition of doxycycline
`for the treatment of diseases or conditions in which collagen
`destructive enzymes or molecules involved with such things
`as inflammation are contributing factors, and which is a once
`daily formulation. The compositions are especially useful for
`treating such common disease states as periodontal disease,
`rosacea, dry eye, acne and rheumatoid arthritis.
`
`2
`pill to the implant. However, Periostat® requires twice daily
`dosing and raises concerns about patient compliance. Thus, it
`would be highly beneficial to develop a once-a-day formula(cid:173)
`tion for doxycycline.
`While doxycycline is generally effective for treating infec(cid:173)
`tion, the use of doxycycline can lead to undesirable side
`effects. For example, the long-term administration of the
`antibiotic doxycycline can reduce or eliminate healthy biotic
`flora, such as intestinal flora, and can lead to the production of
`10 antibiotic resistance organisms or the overgrowth of yeast and
`fungi. Because of the undesirable side effects from its antibi(cid:173)
`otic properties, there is a need for a unique dose and an
`improved formulation to deliver doxycycline such that the
`anti-collagen destructive enzymes or other such beneficial
`15 effect of tetracyclines, especially doxycycline, is attained, but
`antibacterial effects are avoided.
`
`BACKGROUND OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`Conventionally, doxycycline and related tetracyclines are 20
`used as broad spectrum antibiotics to treat various bacterial
`infections. Tetracyclines interfere with the protein synthesis
`of Gram positive and Gram-negative bacteria by preventing
`the binding of aminoacyl-tRNA to the ribosome. Their action
`is bacteriostatic (preventing growth of bacteria) rather than 25
`killing (bactericidal). The doses commonly used for doxycy(cid:173)
`cline to achieve the antibiotic effect are 100 mg and 50 mg.
`Doxycycline, as well as other tetracyclines, also has other
`therapeutic uses in addition to its antibiotic properties. For
`example, doxycycline is known to inhibit the activity of col- 30
`lagen destruction enzymes such as collagenase, gelatinase,
`and elastase. Its collagenase inhibition activity has been used
`to treat periodontal disease. For another example, doxycy(cid:173)
`cline can inhibit lipase produced by the bacterium P. acnes
`and thus reduces the availability of free fatty acids that are 35
`involved in inflammation. Doxycycline may also reduce
`inflammation by reducing cytokine levels so that the integrity
`of the follicular wall is preserved. Thus, doxycycline also has
`the potential in treating skin diseases, such as acne.
`Investigators have found that sub-antimicrobial doses of 40
`tetracyclines are useful in the treatment of various ailments,
`although the mechanisms responsible for the effects are not
`entirely clear. For instance, U.S. Pat. No. 6,455,583 discloses
`treating meibomian gland disease by oral administration of
`non-antimicrobial amounts of a tetracycline to the patient. 45
`U.S. Pat. No. 6,100,248 teaches a method of inhibiting cancer
`growth by administering tetracyclines which have been
`chemically modified to attenuate or delete their antibacterial
`activity. Methods to reduce collagenolytic enzymes by
`administration of amounts of a tetracycline that are generally 50
`lower than the normal amounts used for antimicrobial therapy
`are disclosed in U.S. Pat. No. 4,666,897. The patents cited in
`this paragraph are hereby incorporated herein by reference.
`In the market, there are two implantable products for site(cid:173)
`specific use in the treatment of periodontal disease. The 55
`PerioChip® is a small, orange-brown chip, which is inserted
`into periodontal pockets. Each PerioChip® contains 2.5 mg
`of chlorhexidine gluconate in a biodegradable, resorbable
`matrix. It is recommended that PerioChip® treatment be
`administered once every three months in pockets that remain 60
`at 5 mm or deeper. A second product, Atridox®, is an inject(cid:173)
`able, resorbable gel, which provides the subgingival con(cid:173)
`trolled-release of 42.5 mg doxycycline for approximately one
`week. Additionally, there is now available a new oral medi(cid:173)
`cation called Periostat®, which delivers 20 mg doxycycline 65
`systemically as a collagenase inhibitor used in patients with
`adult periodontal disease. Most people would prefer to take a
`
`The present invention is in its broadest sense directed to
`pharmaceutical compositions of tetracyclines designed to
`provide an extended release profile in vivo of levels of active
`ingredient that at steady state are high enough to be effective
`to have a beneficial effect in the treatment of a disease or
`condition, but not as high as to exert an antibacterial effect.
`Such pharmaceutical compositions are formulated into dos(cid:173)
`age forms that can be taken once a day.
`One object of the present invention is to provide a pharma(cid:173)
`ceutical composition of doxycycline, which can be given
`once a day yet meet the steady state blood levels required for
`the treatment or prevention of diseases or conditions caused
`by overproduction of collagenase, such as periodontal dis(cid:173)
`ease, or other biochemicals associated with certain disease
`states which could be regulated with doxycycline, such as
`conditions involving inflammation, without the undesirable
`effects of long term antibiotic activity.
`One object of the present invention is to provide a once(cid:173)
`daily pharmaceutical composition containing doxycycline
`that will give steady state blood levels of doxycycline of a
`minimum of about 0.1 f.tg/ml and a maximum of about 1.0
`f.tg/ml.
`In one aspect of the invention is an immediate release
`formulation of doxycycline containing less than 50 mg but
`more than 25 mg, preferably about 40 mg. doxycycline base.
`In another aspect, the invention is directed to a pharmaceu(cid:173)
`tical composition of doxycycline that contains an immediate
`release (IR) component of the drug and a delayed release
`(DR) component of the drug, which are combined into one
`dosage unit for once-daily dosing. The components can be
`present in various ratios, although preferred are ratios of
`about 70:30 to about 80:20, and most preferred 7 5:25, IR:DR,
`with the total dosage of doxycycline being less than about 50
`mg. and preferably about 40 mg. The ratio refers to the dose
`breakdown between IR and DR, e.g., 80:20 means 80% of 40
`mg is from IR portion and 20% of 40 mg is from DR portion.
`Yet another object of the invention is to provide a method
`for treating diseases or conditions in which collagenase is
`produced in excessive amounts causing pathological destruc(cid:173)
`tion of tissues, such as periodontal disease, rheumatoid arthri(cid:173)
`tis, hyperparathyroidism, diabetes and acne, by administering
`the once-daily dosage of doxycycline. See, e.g., U.S. Pat. No.
`4,666,897 of Golub.
`Another object of the present invention is to provide a
`method for systemic treatment of rosacea, a dermatological
`condition of humans, by administering the once-daily dosage
`of doxycycline according to the present invention.
`
`8
`
`

`

`3
`Another object of the invention is to provide processes for
`preparing the once-daily compositions of the present inven(cid:173)
`tion.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows dissolution profiles for doxycycline mono(cid:173)
`hydrate immediate-release beads within the scope of the
`present invention, which were determined by utilizing a com(cid:173)
`puter algorithm that is based on a compartmental absorption
`and transit model to deconvolute in vivo release profiles from
`in vivo human plasma data. The in silica model was first
`validated and tested using human plasma data from immedi(cid:173)
`ate release dosage forms.
`FIG. 2 shows in silica dissolution profiles for doxycycline
`monohydrate delayed-release beads.
`FIG. 3 shows in silica dissolution profiles for the compos(cid:173)
`ite capsules with 7 5% of immediate-release beads and 25% of
`delayed-release beads.
`FIG. 4 shows predicted blood levels vs. time profiles at
`steady state for various treatments (i.e., 40 mg once-a-day IR
`formula, 40 mg once-a-day IR and DR combinations at 70:30
`and 80:20 ratios, and twice-a-day 20 mg doxycycline treat(cid:173)
`ment).
`FIG. 5 represents the pharmacokinetic profiles of 75:25
`IR:DR (40 mg.) formulation at day 1 and day 7 (steady state)
`in humans.
`FIG. 6 compares the pharmacokinetic curves of 75:25
`IR:DR ( 40 mg.) formulation with the Periostat® 20 mg. twice
`daily dosage form.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`US 7,749,532 B2
`
`4
`2003 Annual Edition, or available at www.usp.org, for
`amount of active pharmaceutical ingredients. With respect to
`blood levels, "about" means within FDA acceptable guide(cid:173)
`lines.
`By "immediate release" formulation is meant a dosage
`form that is intended to release substantially all of the active
`ingredient on administration with no enhanced, delayed or
`extended release effect. Such a composition of doxycycline
`can be in the form of a liquid suspension or solution, or as a
`10 solid such as a tablet, pellet (used interchangeably with bead
`or beadlet herein), particle, capsule or gel. Preferred in the
`present invention are tablets, or beadlets in a capsule.
`As pharmaceutically active ingredients, any form of the
`tetracycline compound can be used provided it will comply
`15 with the required blood serum levels of the present invention.
`Doxycycline, for instance, is commonly used in pharmaceu(cid:173)
`tical formulations under two chemical forms: the monohy(cid:173)
`drate form and the hyclate form. The monohydrate is the base
`molecule hydrated with one molecule of water and is used in
`20 the formulation of capsules and, in some markets, powder
`oral suspensions (to be reconstituted with water). The hyclate
`is a hydrochloric acid salt solvated with water and ethanol and
`is typically used in the formulation of capsules or tablets. The
`amount of doxycycline in the compositions of the present
`25 invention refers to doxycycline base. Also, in the composi(cid:173)
`tions of the present invention there may be more than one
`active ingredient. That is, the doxycycline can be combined
`with another therapeutic or nutritional substance in the dos(cid:173)
`age forms.
`
`While the following description is directed primarily to
`doxycycline, it is contemplated that the present invention is
`applicable to other tetracyclines, particularly other tetracy(cid:173)
`clines that have similar in vivo absorption profiles as doxy(cid:173)
`cycline, more specifically tetracyclines that have a similar
`region of absorption in the gastrointestinal tract as doxycy(cid:173)
`cline. Different kinds of tetracyclines and the beneficial
`effects on various disease states are disclosed in, for example,
`WO 02/083106 and U.S. Pat. No. 6,638,922, each of which
`are incorporated in their entireties herein by reference.
`The present invention can be accomplished by providing
`an orally administered composition of, as an example, doxy(cid:173)
`cycline which is designed to provide certain steady state
`blood levels of the drug, while in a formulation that requires
`that the mammal, preferably human, to take only one dosage
`a day. The compositions of the present invention are intended
`to be useful in lieu of multiple daily dosing, such as twice- 50
`daily dosing, of compositions that achieve the same effects.
`The preferred blood level of doxycycline, or other tetracy(cid:173)
`clines of comparable physiological and absorption proper(cid:173)
`ties, is between about 0.1 and about 1.0 flg/ml at the steady
`state. Preferably, the blood levels stay within the preferred 55
`blood level, with daily dosing, for the entire course of treat(cid:173)
`ment. More preferably, the blood levels are between about 0.3
`flg/ml and about 0.8 flg/ml.
`The above blood serum levels allow for the desired anti(cid:173)
`collagenase and anti-inflammatory activity of doxycycline,
`without being accompanied by undesirable antibiotic activity.
`It was surprisingly found that these levels can be accom(cid:173)
`plished with a single daily dose of an immediate release
`formulation containing below 50 mg. but more than 25 mg.,
`preferably about 40 mg. doxycycline base.
`"About" means within the pharmaceutically acceptable
`limits found in the United States Pharmacopia (USP-NF 21),
`
`30
`
`Immediate Release Dosage Forms
`There are many ways known in the art to formulate such
`immediate release dosage forms. For instance, an immediate
`release tablet can be prepared by mixing doxycycline with a
`35 bulking agent such as microcrystalline cellulose, for
`example, AVICEL® (FMC Corp.) or EMCOCEL® (Mendell
`Inc.); dicalcium phosphate, for example, EMCOMPRESS®
`(Mendell Inc.); calcium sulfate, for example, COMPAC(cid:173)
`TROL® (Mendell Inc.); and starches, for example, STARCH
`40 1500. Additionally, one can add a disintegrating agent, such
`as microcrystalline cellulose, starches, crospovidone, for
`example, POLYPLASDONE XL® (International Specialty
`Products);
`sodium
`starch glycolate,
`for
`example,
`EXPLOTAB® (Mendell Inc.); and croscarmellose sodium,
`45 for example, AC-DI-SOL® (FMC Corp.). Antiadherants and
`glidants employed herein can include talc, cornstarch, silicon
`dioxide, sodium Iaury! sulfate, colloidal silica dioxide, and
`metallic stearates.
`Lubricants may be employed, such as magnesium stearate,
`calcium stearate, sodium stearate, stearic acid, sodium stearyl
`fumarate, sterotex, talc, waxes and the like. Binding agents
`may be employed, such as polyvinyl pyrollidone, starch,
`methylcellulose, hydroxypropyl methylcellulose, carboxym(cid:173)
`ethyl cellulose, and the like.
`The present invention is preferably formulated into a tablet
`prepared using methods known in the art, including a wet
`granulation method and a direct compression method. The
`oral tablets are prepared using any suitable process known to
`the art. See, for example, Remington's Pharmaceutical Sci-
`60 ences, 18'h Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton,
`Pa. 1990), Chapters 88-91, the entirety of which is hereby
`incorporated by reference. Typically, the active ingredient,
`doxycycline, is mixed with pharmaceutically acceptable
`excipients (e.g., the binders, lubricants, etc. listed above) and
`65 compressed into tablets. Preferably, the dosage form is pre(cid:173)
`pared by a wet granulation technique or a direct compression
`method to form uniform granulates. Alternatively, the active
`
`9
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`

`US 7,749,532 B2
`
`5
`ingredient( s) can be mixed with the granulate after the granu(cid:173)
`late is prepared. The moist granulated mass is then dried and
`sized using a suitable screening device to provide a powder,
`which can then be filled into capsules or compressed into
`matrix tablets or caplets, as desired.
`In a preferred embodiment, the tablets are prepared using
`the direct compression method. The direct compression
`method offers a number of potential advantages over a wet
`granulation method, particularly with respect to the relative
`ease of manufacture. In the direct compression method, at
`least one pharmaceutically active agent and the excipients or
`other ingredients are sieved through a stainless steel screen,
`such as a 40 mesh steel screen. The sieved materials are then
`charged to a suitable blender and blended for 10 minutes with
`an intensifier bar for three minutes. The blend is then com(cid:173)
`pressed into tablets on a rotary press using appropriate tool(cid:173)
`ing.
`As mentioned above, another preferred dosage form for the
`immediate release composition is a capsule containing imme(cid:173)
`diate release beadlets or pellets. Methods for making such
`pellets are set forth in the section below (i.e., the IR pellets).
`The pellets are filled into capsules, for instance gelatin cap(cid:173)
`sules, by conventional techniques.
`Combination IR/DR Dosage Forms
`In another embodiment of the present invention is a com(cid:173)
`position having a substantially immediate release dose of
`doxycycline, followed by at least one additional dose at a
`predetermined time, in a unit dosage. The first immediate
`release dose of the composition can be in the form of powder,
`granule, beadlet, or tablet; the second delayed-release portion
`can be coated granular, coated beadlet, coated tablet, or
`uncoated matrix tablet. The ratio between the immediate(cid:173)
`release portion, or component, and the delayed-release por(cid:173)
`tion, or component, can be used to adjust the in vitro drug
`release profile and in vivo blood concentration profile. By 35
`providing such a drug release profile, the compositions elimi(cid:173)
`nate the need for a second dose for the day. Additionally, the
`total dose of doxycycline is below 50 mg. to avoid the unde(cid:173)
`sirable side effects from its antibiotic properties, but more
`than 25 mg. to achieve the anti-collagenase and/or anti-in(cid:173)
`flammatory effect.
`Several dosage form variations can be used to achieve a
`product with these attributes. For example, an immediate(cid:173)
`release powder blend can be encapsulated with a delayed(cid:173)
`release tablet or delayed-release pellets. A further example is
`an immediate-release tablet and a delayed-release tablet that
`are prepared separately and encapsulated into an appropriate
`sized capsule shell. Or, for example, a delayed-release tablet
`can be used as a core and the immediate-release portion can
`be compressed as an outer layer using a press coater or over- 50
`coated using a drug layering technique, both techniques of
`which can be found in Gunsel and Dusel, Chapter 5, "Com(cid:173)
`pression-coated and layer tablets", in Pharmaceutical Dosage
`Forms: Tablets, Second Edition, Volume 1, Edited by H. A.
`Lieberman, L. Lachman, and J. B. Schwartz, Marcel Dekker,
`Inc. New York and Basel (1990).
`Multiparticulate Capsules
`As a preferred embodiment, the IR/DR composition of
`doxycycline is in the form of a capsule containing beadlets. At
`present, it is preferred to have two different types of units in a
`single form multiple-unit dosage form.
`The first unit is an immediate release dosage form, prefer(cid:173)
`ably in pellet form. This component can also be a powder if
`desired or necessary. In either case, the dosage form may have
`a surface-active agent such as sodium Iaury! sulfate, sodium
`monoglycerate, sorbitan monooleate, polyoxyethylene sorbi(cid:173)
`tanmonooleate, glyceryl mono stearate, glyceryl monooleate,
`
`6
`glyceryl mono butyrate, any one of the Pluronic line of sur(cid:173)
`face-active polymers, or any other suitable material with sur(cid:173)
`face active properties or any combination of the above. Pref(cid:173)
`erably, the surface-active agent would be a combination of
`sodium monoglycerate and sodium Iaury! sulfate. The con(cid:173)
`centration of these materials in this component can range
`from about 0.05 to about 10.0% (W/W).
`Other excipient materials that can be employed in making
`drug-containing pellets are any of those commonly used in
`10 pharmaceutics and should be selected on the basis of com(cid:173)
`patibility with the active drug and the physicochemical prop(cid:173)
`erties of the pellets. These include, for instance: binders such
`as cellulose derivatives such as methylcellulose, hydroxy(cid:173)
`ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
`15 methylcellulose, polyvinylpyrrolidone, polyvinylpyrroli(cid:173)
`done/vinyl acetate copolymer and the like; disintegration
`agents such as cornstarch, pregelatinized starch, cross-linked
`carboxymethylcellulose (AC-DI-SOL®), sodium starch gly(cid:173)
`colate (EXPLOTAB®), cross-linked polyvinylpyrrolidone
`20 (PLASDONE® XL), and any disintegration agents used in
`tablet preparations, which are generally employed in imme(cid:173)
`diate release dosages such as the one of the present invention;
`filling agents such as lactose, calcium carbonate, calcium
`phosphate, calcium sulfate, microcrystalline cellulose, dext-
`25 ran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol,
`sodium chloride, polyethylene glycol, and the like; surfac(cid:173)
`tants such as sodium Iaury! sulfate, sorbitan monooleate,
`polyoxyethylene sorbitan monooleate, bile salts, glyceryl
`monostearate, the PLURONIC® line (BASF), and the like;
`30 solubilizers such as citric acid, succinic acid, fumaric acid,
`malic acid, tartaric acid, maleic acid, glutaric acid sodium
`bicarbonate and sodium carbonate and the like; and stabiliz(cid:173)
`ers such as any antioxidation agents, buffers, acids, and the
`like, can also be utilized.
`The pellet can be made by, for example, simple granula-
`tion, followed by sieving; extrusion and marumerization;
`rotogranulation; or any agglomeration process that results in
`a pellet of reasonable size and robustness. For extrusion and
`marumerization, the drug and other additives are granulated
`40 by addition of a binder solution. The wet mass is passed
`through an extruder equipped with a certain size screen, and
`the extrudates are spheronized in a marumerizer. The result(cid:173)
`ing pellets are dried and sieved for further applications. One
`may also use high-shear granulation, wherein the drug and
`45 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 com(cid:173)
`bined actions of mixing and milling. The resulting granules or
`pellets are dried and sieved for further applications.
`As stated earlier, it is also possible to have this immediate
`release component as a powder, although the preferred form
`is a pellet due to mixing and de-mixing considerations.
`Alternatively, the immediate release beadlets or pellets of
`the composition can be prepared by solution or suspension
`55 layering, whereby a drug solution or dispersion, with or with(cid:173)
`out a binder, is sprayed onto a core or starting seed (either
`prepared or a commercially available product) in a fluid bed
`processor or other suitable equipment. The cores or starting
`seeds can be, for example, sugar spheres or spheres made
`60 from microcrystalline cellulose. The drug thus is coated on
`the surface of the starting seeds. The drug-loaded pellets are
`dried for further applications.
`The second nnit should have a delayed release (DR) profile,
`and needs to be able to address the changing pH of the GI
`65 tract, and its effect on the absorption of doxycycline or other
`tetracycline. This pellet should have all of the ingredients as
`mentioned for the first unit pellet, as well as optionally some
`
`10
`
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`

`US 7,749,532 B2
`
`7
`organic acid that will be useful to reduce the pH of the
`microenvironment of the pellet, and thus facilitate dissolu(cid:173)
`tion. These materials are, but not limited to, citric acid, lactic
`acid, tartaric acid, or other suitable organic acids. These mate(cid:173)
`rials should be present in concentrations of from about 0 to 5
`about 15.0% (w/w); preferably these materials would be
`present in concentrations of from about 5.0 to about 10.0
`percent (w/w). The process for manufacturing these pellets is
`consistent with the process described above for the first unit
`pellet.
`Unlike the first unit pellet, the second unit delayed-release
`component has a controlling coat applied to the surface of the
`pellet such that the release of the drug from the pellet is
`delayed. This is accomplished by applying a coating of
`enteric materials. "Enteric materials" are polymers that are 15
`substantially insoluble in the acidic environment of the stom(cid:173)
`ach, but are predominantly soluble in intestinal fluids at spe(cid:173)
`cific pHs. The enteric materials are non-toxic, pharmaceuti(cid:173)
`cally acceptable polymers, and include, for example,
`cellulose acetate phthalate (CAP), hydroxypropyl methylcel- 20
`lulose phthalate (HPMCP), polyvinyl acetate phthalate
`(PVAP), hydroxypropyl methylcellulose acetate succinate
`(HPMCAS), cellulose acetate trimellitate, hydroxypropyl
`methylcellulose succinate, cellulose acetate succinate, cellu(cid:173)
`lose acetate hexahydrophthalate, cellulose propionate phtha- 25
`late, copolymer of methylmethacrylic acid and methyl meth(cid:173)
`acrylate, copolymer of methyl acrylate, methylmethacrylate
`and methacrylic acid, copolymer of methylvinyl ether and
`maleic anhydride (Gantrez ES series), ethyl methyacrylate(cid:173)
`methylmethacrylate-chlorotrimethylammonium ethyl aery- 30
`late copolymer, natural resins such as zein, shellac and copal
`collophorium, and several commercially available enteric
`EUDRAGIT® L30D55,
`dispersion
`systems
`(e.g.,
`EUDRAGIT® FS30D, EUDRAGIT® LlOO, KOLLI(cid:173)
`COAT® EMM30D, ESTACRYL® 30D, COATERIC®, and 35
`AQUATERIC® ). The foregoing is a list of possible materials,
`but one of skill in the art would recognize that it is not
`comprehensive and that there are other enteric materials that
`would meet the objectives of the present invention of provid(cid:173)
`ing for a delayed release profile. These coating materials can 40
`be employed in coating the surfaces in a range of from about
`1.0% (w/w) to about 50% (w/w) of the pellet composition.
`Preferably these coating materials should be in a range of
`from about 20 to about 40 percent (w/w