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`Undei th.P.~~ Ad ci19Q5.-.ni:. ~ 11e ~ b ~toii~IIOill'l~~uniellll it~ a'llllld OMS COnlri:ll_nlimiJit,
`POWER o·F ATTORNEY TO PROSECUTE· APPUCAiloNS BEFORE THE USPTO
`
`powers
`
`under
`
`[!] PiadiDCnel'l aaacilted with Ill$ CU&tomor Ntlnbet:
`OR 0 Practlloner(i) na.rrMid beli:iw (11 more ·hnten patent pl'iiCtlllonn n
`
`22428
`
`to bt Mined, U.n·a euitoiTI« lll.ll'l'lber rnu1t ~ uud):
`
`s·
`
`Supe;-nus Pharmaceuticals , :I' I) C ·
`lSso· EaSt Quae Drive
`
`equivalent) Ia requlreci:to bt
`uncler37'1Cfl!U .. 73(b) may 1M! comple11ed by one of.
`on bthaff of tho a55lg~ ...
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`tg proc:ew) 11ft appi~ ~I}At~lly 3CI U.SC 112 a.ncH7 Cf'R 1.11 il1'4 1 14 •. TI'U$ 0011- illftllmallid ta
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`F'.::>IWS TO Tl-il'$ ~ SEND TO: Commlealoner for Patent a, P.O. Box 1~ AIU.wndO... VA 2H1,_i.ui0.
`
`ff)ICIJ fiC!IOd lls:sl:511NCtt lnOCf'tiPiatlrlg tfrtl form. C'ID 1-BOOoPTO.tfl'i Mid 1sl«t optiOf) 2.
`
`TOTAL P.02
`
`1
`
`

`

`...
`
`Application Data Sheet
`
`Application Information
`
`Application number::
`
`Filing Date::
`
`Application Type::
`
`Subject Matter::
`
`Suggested classification::
`
`Suggested Group Art Unit::
`
`Unassigned
`
`12/17/2010
`
`Regular
`
`Utility
`
`CD-ROM or CD-R?::
`
`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`ONCE DAILY FORMULATIONS OF
`
`TETRACYCLINES
`
`Attorney Dock.et Number::
`
`063089-1701
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Suggested Drawing Figure::
`Total Drawing Sheets::
`
`Small Entity?::
`
`Petition included?::
`
`Secrecy Order in Parent Appl. ?: :
`
`No
`
`No
`
`6
`
`No
`
`No
`
`No
`
`Applicant Information
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status::
`
`Given Name::
`Family Name::
`
`City of Residence::
`
`Inventor
`·us
`Full Capacity
`
`Rong-Kun
`
`CHANG
`
`Rockville
`
`WASH_7573280.1
`
`Page# 1
`
`lnitial12/17/2010
`
`2
`
`

`

`..
`
`...........
`
`State or Province of
`
`MD
`
`Residence::
`
`Country of Residence::
`
`Street of mailing address::
`
`City of mailing address::
`
`State or Province of mailing
`address::
`
`us
`13607 Pine View Lane
`
`Rockville
`MD
`
`Zip Code of mailing address::
`
`20850
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
`
`State or Province of
`
`Residence::
`
`Inventor
`us
`Full Capacity
`
`A rash
`
`RAOUFINIA
`
`Springfield
`
`VA
`
`Country of Residence::
`Street of mailing address::
`
`us
`7609 Mulberry Bottom Lane
`
`City of mailing address::
`
`Springfield
`
`State or Province of mailing
`address::
`
`VA
`
`Zip Code of mailing address::
`
`22153
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`Status::
`
`Inventor
`us
`Full Capacity
`
`Given Name::
`
`Family Name::
`City of Residence::
`
`Niraj
`
`SHAH
`
`Owings Mills
`
`WASH_7573280.1
`
`Page# 2
`
`lnitial·12/17/201 0
`
`3
`
`

`

`.. ~.,
`
`.._;,
`
`State or Province of
`
`MD
`
`Residence::
`
`Country of Residence::
`
`Street of mailing address::
`
`City of mailing address::
`
`State or Province of mailing
`
`address::
`
`us
`40 Windbluff Court
`
`Owings Mills
`MD
`
`Zip Code of mailing address::
`
`21117
`
`Correspondence Information
`
`Correspondence Customer Number:: 22428
`E-Mail address::
`
`PTOMaiiWashington@foley.com
`
`Representative Information
`
`Representative Customer
`
`22428
`
`Number::
`
`Domestic Priority Information
`
`Application::
`
`Continuity Type::
`
`Parent
`
`Parent Filing
`
`Application::
`
`This Application
`
`Continuation of
`
`12/155,676
`
`12/155,676
`
`10/819,620
`
`Continuation of
`
`10/819,620
`
`An application
`
`60/460,963
`
`Date::
`
`6/6/2008
`
`4/7/2004
`
`4/7/2003
`
`claiming the benefit
`
`under 35 USC
`
`119(e)
`
`10/819,620
`
`An application
`
`60/547,964
`
`2/26/2004
`
`claiming the benefit
`
`under 35 USC
`
`119(e)
`
`WASH_7573280.1
`
`Page# 3
`
`lnitial12/17/2010
`
`4
`
`

`

`Foreign Priority Information
`
`Country::
`
`Application
`
`number::
`
`Filing Date::
`
`Priority Claimed::
`
`Assignee Information
`
`Assignee Name::
`
`Supernus Pharmaceuticals, Inc.
`
`WASH_7573280.1
`
`Page# 4
`
`Initial 12/17/2010
`
`5
`
`

`

`<:!::)
`
`...;;::,:. a::.
`..... ~
`~ I
`j_ G::
`0 ~
`-
`·
`"'"1:J
`....,:t
`0 Applicant:
`
`U.S. PTO
`12/926934
`12/17/2010
`
`Atty. Dkt. No. 063089-1701
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Rong-Kun Chang et al.
`
`Title:
`
`ONCE DAILY FORMULATIONS OF TETRACYCLINES
`
`Prior Appl. No.:.-r1 12/155,676
`
`Prior Appl.
`Filing Date:
`
`6/6/2008
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`-...,_
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`Transmitted herewith for filing under 3 7 C.F.R. § 1.53(b) is a:
`
`[X] Continuation
`
`[ ] Division
`
`[ ] Continuation-In-Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
`
`termination of proceedings has occurred. Priority to the above-identified prior application is
`
`hereby claimed under 35 U.S.C. § 120 for this continuing application. The entire disclosure of
`
`the above-identified prior application is considered as being part of the disclosure of the
`
`accompanying continuing application and is hereby incorporated by reference therein.
`
`[ ]
`
`Applicant claims small entity status under 37 CFR 1.27.
`
`Enclosed are:
`
`[X] Description, Claims, ~d Abstract (30 pages).
`
`WASH_7573293.1
`
`-1-
`
`6
`
`

`

`..
`
`Atty. Dkt. No. 063089-1701
`
`[ X ] Drawings ( 6 sheets, Figures 1-6) .
`
`. [X] Copy of Declaration and Power of Attorney from prior application (2 pages).
`
`[X] Power of Attorney Form SB80; Statement Under 37 CFR 3.73(b) (2 pages).
`
`[X] Application Data Sheet (37 CFR 1.76).
`
`Fee
`Totals
`
`$330.00
`
`$540.00
`$220.00
`
`$0.00
`$0.00
`
`$0.00
`$0.00
`$130.00
`
`1220.00
`
`The filing fee is calculated below:
`
`Extra
`
`Rate
`
`Included
`in
`asic Fee
`
`-B
`
`Number
`Filed
`
`Cl
`
`r
`
`36
`
`100
`20
`
`Basic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`x
`3
`Independent:
`+
`If any Multiple Dependent Claim(s) present:
`Surcharge under 3 7 CFR 1.16( e) for late payment of +
`filing fee
`
`X
`
`X
`
`0
`0
`
`0
`
`$330.00
`
`$540.00
`$220.00
`
`$270.00
`$52.00
`
`$220.00
`$390.00
`$130.00
`
`[ ]
`
`Small Entity Fees Apply (subtract Yz of above):
`Basic Filing Fee Reduction for Filing via EFS-Web
`TOTAL FILING FEE:
`+
`Assignment Recordation Fee:
`$40.00
`Processing Fee under 37 CFR 1.17(i) for Late Filing +
`$130.00
`of English Translation of Application:
`TOTAL FEE
`
`The required filing fees are not enclosed but will be submitted in response to the Notice
`
`to File Missing Parts of Application.
`
`WASH_7573293.1
`
`-2-
`
`7
`
`

`

`..
`
`Atty. Dkt. No. 063089-1701
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Respectfully submitted,
`
`Date ____ D_E_C _1_7 _2_01_0 __ _
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 672-5569
`Facsimile:
`(202) 672-5399
`
`Stephen B. Maebius
`Attorney for Applicant
`Registration No. 35,264
`
`WASH_7573293.1
`
`-3-
`
`8
`
`

`

`.,
`
`,,
`
`Once Daily Formulations of Tetracyclines
`
`Field of the Invention
`
`[01] The present invention is concerned with once-daily compositions of
`
`tetracyclines, which can be used for the treatment of acute or chronic diseases. for
`
`instance those with infl?lmmatory 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.
`
`Background of the Invention
`
`[02] Conventionally, doxycycline and related tetracyclines are 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 killing (bactericidal). The
`
`doses commonly used for doxycycline to achieve the antibiotic effe.ct are 1 00 mg
`
`and 50 mg.
`
`[03} Doxycycline, as well as other tetracyclines, also has other therapeutic
`
`uses in addition to its antibiotic properties. For example, doxycycline is known to
`
`Express Mail El962944129US
`
`1
`
`9
`
`

`

`inhibit the activity of collagen destruction enzymes such as collagenase, gelatinase,
`
`and elastase. Its collagenase inhibition activity has been used to treat periodontal
`
`disease. For another example, doxycycline can inhibit lipase produced by the
`
`bacterium P. acnes and thus reduces the availability of free fatty acids that are
`
`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.
`
`[04]
`
`Investigators have found that sub-antimicrobial doses of tetracyclines
`
`are useful in the treatment of various ailments, although the mechanisms
`
`responsible for the effects are not entirely clear. For instance, US Patent 6,455,583
`
`discloses treating meibomian gland disease by oral administration of non(cid:173)
`
`antimicrobial amounts of a tetracycline to the patient. US Patent 6,1 00,248 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 lower than the normal amounts used for antimicrobial therapy are
`
`disclosed in US Patent 4,666,897. The patents cited in this paragraph are hereby
`
`incorporated herein by reference.
`
`[OS]
`
`In the market, there are two implantable products for site·specific use
`
`in the treatment of periodontal disease. The 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
`
`Express Ma1l EL962944129US
`
`10
`
`

`

`remain at 5 mm or deeper. A second product, Atridox®, is an injectable, resorbable
`
`gel, which provides the subgingival controlled-release of 42.5 mg doxycycline for
`
`approximately one week. Additionally, there is now available a new oral medication
`
`called Periostat®, which delivers 20 mg doxycycline systemically as a collagenase
`
`inhibitor used in patients with adult periodontal disease. Most people would prefer to
`
`take a 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 formulation for doxycycline.
`
`[06] While doxycycline is generally effective for treating infection, 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 antibiotic resistance
`
`organisms or the overgrowth of yeast and fungi. Because of the undesirable side
`
`effects from its antibiotic 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 effect of tetracyclines, especially doxycycline, is
`
`attained, but antibacterial effects are avoided.
`
`Summarv of the Invention
`
`[07) 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
`
`Express Mail EL962944129US
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`•)
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`

`condition, but not as high as to exert an antibacterial effect. Such pharmaceutical
`
`compositions are formulated into dosage forms that can be taken once a day.
`
`(08] One object of the present invention is to provide a pharmaceutical
`
`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 disease, 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.
`
`[09] One object of the present invention is to provide a once-daily
`
`pharmaceutical composition containing doxycycline that will give steady state blood
`
`levels of doxycycline of a minimum of about 0.1 J,Jg/ml and a maximum of about 1 .0
`
`J,Jg/ml.
`
`[01 0]
`
`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.
`
`(011]
`
`In another aspect, the invention is directed to a pharmaceutical
`
`composition of doxycycline that contains an immediate release (lA) 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 75:25, lA: 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
`
`Express Mail EL962944129US
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`

`between JR and DR, e.g., 80:20 means 80% of 40 mg is from JR portion and 20% of
`
`40 mg is from DR portion.
`
`(012] 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 destruction of tissues, such as periodontal disease, rheumatoid
`
`arthritis, hyperparathyroidism, diabetes and acne, by administering the once-daily
`
`dosage of doxycycline. See, e.g., US Patent No. 4,66€;,897 of Golub.
`
`[013] 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.
`
`[014] Another object of the invention is to provide processes for preparing
`
`the once-daily compositions of the present invention.
`
`Brief Description of the Drawings
`
`[015] Figure 1 shows dissolution profiles for doxycycline monohydrate
`
`immediate-release beads within the scope of the present invention, which were
`
`determined by utilizing a computer 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 si/ico model was first validated and tested using human
`
`plasma data from immediate release dosage forms.
`
`.
`
`[016] Figure 2 shows in silico dissolution profiles for doxycycline
`
`monohydrate delayed-release beads.
`
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`

`

`[017] Figure 3 shows in si/ico dissolution profiles for the composite capsules
`
`with 75% of immediate-release beads and 25% of delayed-release beads.
`
`[018) Figure 4 shows predicted blood levels vs. time profiles at steady state
`
`for various treatments (i.e., 40 mg once-a-day lA formula, 40 mg once-a-day lA and
`
`DR combinations at 70:30 and 80:20 ratios, and twice-a-day 20 mg doxycycline
`
`treatment).
`
`[019] Figure 5 represents the pharmacokinetic profiles of 75:25 IR:DA (40
`
`mg.) formulation at day 1 and day 7 (steady state) in humans.
`
`[020] Figure 6 compares the pharmacokinetic curves of 75:25 IA:DR (40
`
`mg.) formulation with the Periostat® 20 mg. twice daily dosage form.
`
`Detailed Description of the Invention
`
`[021] While the following description is directed primarily to doxycycline, it is
`
`contemplated that the present invention is applicable to other tetracyclines,
`
`particularly other tetracyclines that have similar in vivo absorption profiles as
`
`doxycycline, more specifically tetracyclines that have a similar region of absorption
`
`in the gastrointestinal tract as doxycycline. Different kinds of tetracyclines and the
`
`beneficial effects on various disease states are disclosed in, for example, WO
`
`02/083106 and US Patent 6,638,922, each of which are incorporated in their
`
`entireties herein by reference.
`
`[022) The present invention can be accomplished by providing an orally
`
`administered composition of, as an example, doxycycline which is designed to
`
`provide certain steady state blood levels of the drug, while in a formulation that
`
`E:~press Mail EL962944129US
`
`14
`
`

`

`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-daily dosing, of compositions that achieve the same
`
`effects. The preferred blood level of doxycycline, or other tetracyclines of
`
`comparable physiological and absorption properties, is between about 0.1 and about
`
`1.0 IJg/ml at the steady state. Preferably, the blood levels stay within the preferred
`
`blood level, with daily dosing,. for the entire course of treatment. More preferably,
`
`the blood levels are between about 0.3 !Jg/ml and about 0.8 IJg/ml.
`
`[023] The above blood serum levels allow for the desired anti-collagenase
`
`and anti-inflammatory activity of doxycycline, without being accompanied by
`
`undesirable antibiotic activity. It was surprisingly found that these levels can be
`
`accomplished 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.
`
`[024]
`
`"About" means within the pharmaceutically acceptable limits found in
`
`the United States Pharmacopia (USP-NF 21 ), 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 guidelines.
`
`[025] 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 solid such as a tablet,
`
`t::xpress Mail EL962944129US
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`
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`

`pellet (used interchangeably with bead or beadlet herein), particle, capsule or gel.
`
`Preferred in the present invention are tablets, or beadlets in a capsule.
`
`[026] As pharmaceutically active ingredients, any form of the tetracycline
`
`compound can be used provided it will comply with the required blood serum levels
`
`of the present invention. Doxycycline, for instance, is commonly used in
`
`pharmaceutical formulations under two chemical forms: the monohydrate form and
`
`the hyclate form. The monohydrate is the base molecule hydrated with one
`
`molecule of water and is used in 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 invention refers to doxycycline base. Also, in the compositions 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
`
`dosage forms.
`
`Immediate Release Dosage Forms
`
`[027] 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 bulking agent such as microcrystalline cellulose, for
`
`example, AVICEL® (FMC Corp.) or EMCOCEL® (Mendell Inc.); dicalcium
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`phosphate. for example, EMCOMPRESS® (Mendell Inc.); calcium sulfate, for
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`example, COMPACTROL® (Mendell Inc.); and starches, for example, STARCH
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`1500. Additionally, one can add a disintegrating agent, such as microcrystalline
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`cellulose, starches, crospovidone, for example, POLYPLASDONE XL®
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`(International Specialty Products); sodium starch glycolate, for example,
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`EXPLOTAB® (Mendell Inc.); and croscarmellose sodium, for example, AC-01-SOL®
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`(FMC Corp.). Antiadherants and glidants employed herein can include talc,
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`cornstarch, silicon dioxide, sodium lauryl sulfate, colloidal silica dioxide, and metallic
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`stearates.
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`[028) Lubricants may be employed, such as magnesium stearate, calcium
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`stearate, sodium stearate, stearic acid, sodium stearyl fumarate, sterotex, talc,
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`waxes and the like. Binding agents may be employed, such as polyvinyl pyrollidone,
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`starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and
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`the like.
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`[029] The present invention is preferably formulated into a tablet prepared
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`using methods known in the art, including a wet granulation method and a direct
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`compression method. The oral tablets are prepared using any suitable process
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`known to the art. See, for example, Remington's Pharmaceutical Sciences, 181
`h
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`Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, PA 1990), Chapters 88-91, the
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`entirety of which is hereby incorporated by reference. Typically, the active
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`ingredient, doxycycline, is mixed with pharmaceutically acceptable excipients (e.g.,
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`the binders, lubricants, etc. listed above) and compressed into tablets. Preferably,
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`the dosage form is prepared by a wet granulation technique or a direct compression
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`method to form uniform granulates. Alternatively, the active ingredient(s) can be
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`mixed with the granulate after the granulate is prepared. The moist granulated mass
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`is then dried and sized using a suitable screening device to provide a powder, which
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`can then be filled into capsules or compressed into matrix tablets or caplets, as
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`desired.
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`[030]
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`In a preferred embodiment, the tablets are prepared using the direct
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`compression method. The direct compression method offers a number of potential
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`advantages over a wet granulation method, particularly with respect to the relative
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`ease of manufacture. In the direct compression method, at least one
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`pharmaceutically active agent and the excipients or other ingredients are sieved
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`through a stainless steel screen, such as a 40 mesh steel screen. The sieved
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`materials are then charged to a suitable blender and blended for 1 0 minutes with an
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`intensifier bar for three minutes. The blend is then compressed into tablets on a
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`rotary press using appropriate tooling.
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`[031] As mentioned above, another preferred dosage form for the immediate
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`release composition is a capsule containing immediate release beadlets or pellets.
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`Methods for making such pellets are set forth in the section below (i.e., the lA
`
`pellets). The pellets are filled into capsules, for instance gelatin capsules, by
`
`conventional techniques.
`
`Combination IRIDR Dosage Forms
`
`[032]
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`In another embodiment of the present invention is a composition
`
`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
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`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,
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`coated tablet, or uncoated matrix tablet. The ratio between the immediate-release
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`portion, or component, and the delayed-release portion, or component, can be used
`
`to adjust the in vitro drug release profile and in vivo blood concentration profile. By
`
`providing such a drug release profile, the compositions eliminate the need for a
`
`second dose for the day. Additionally, the total dose of doxycycline is below 50 mg.
`
`to avoid the undesirable side effects from its antibiotic properties, but more than 25
`
`mg. to achieve the anti-collagenase and/or anti-inflammatory effect.
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`[033] Several dosage form variations can be used to achieve a product with
`
`these attributes. For example, an immediate-release powder blend can be
`
`encapsulated with a delayed-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(cid:173)
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`release portion can be compressed as an outer layer using a press coater or
`
`overcoated using a drug layering technique, both techniques of which can be found
`
`in Gunsel and Dusel, Chapter 5, "Compression-coated and layer tablets", in
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`Pharmaceutical Dosage Forms:Tablets, Second Edition, Volume 1, Edited by H.A.
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`Lieberman, L.Lachman, and J.B. Schwartz, Marcel Dekker, Inc. New York and Basel
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`(1990).
`
`Multiparticulate Capsules
`
`[034] As a preferred embodiment, the IRIDR 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.
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`[035] The first unit is an immediate release dosage form, preferably 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 sorbitan monooleate,
`
`glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, any one of the
`
`Pluronic line of surface-active polymers, or any other suitable material with surface
`
`active properties or any combination of the above. Preferably, the surface-active
`
`agent would be a combination of sodium monoglycerate and sodium lauryl sulfate.
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`The concentration of these materials in this component can range from about 0.05 to
`
`about 10.0% (W//W).
`
`[036] Other excipient 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 compatibility with the active drug and the physicochemical
`
`properties of the pellets. These include, for instance: binders such as cellulose
`
`derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
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`hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl
`
`acetate copolymer and the like; disintegration agents such as cornstarch,
`
`pregelatinized starch, cross-linked carboxymethylcellulose (AC-01-SOL®), sodium
`
`starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE®
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`XL), and any disintegration agents used in tablet preparations, which are generally
`
`employed in immediate release dosages such as the one of the present invention;
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`filling agents such as lactose, calcium carbonate, calcium phosphate, calcium
`
`sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol,
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`mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like; surfactants
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`such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan
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`monooleate, bile salts, glyceryl monostearate, the PLURONIC® line (BASF), and the
`
`like; solubilizers such as citric acid, succinic acid, fumaric acid, malic acid, tartaric
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`acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the
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`like; and stabilizers such as any antioxidation agents, buffers, acids, and the like,
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`can also be utilized.
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`[037] The pellet can be made by, for example, simple granulation, followed
`
`by sieving; extrusion and marumerization; rotogranulation; or any agglomeration
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`process that results in a pellet of reasonable size and robustness. For extrusion and
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`marumerization, the drug and other additives are granulated by addition of a binder
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`solution. The wet mass is passed through an extruder equipped with a certain size
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`screen, and the extrudates are spheronized in a marumerizer. The resulting pellets
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`are dried and sieved for further applications. One may also use high-shear
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`granulation, wherein the drug 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
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`granules are kneaded after wetting by the combined actions of mixing and milling.
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`The resulting granules or pellets are dried and sieved for further applications.
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`[038] As stated earlier, it is also possible to have this immediate release
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`component as a powder, although the preferred form is a pellet due to mixing and
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`de-mixing considerations.
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`[039] Alternatively, the immediate release beadlets or pellets of the
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`composition can be prepared by solution or suspension layering, whereby a drug
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`solution or dispersion, with or without a binder, is sprayed onto a core or starting
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`seed (either prepared or a commercially available product) in a fluid bed processor
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`or other suitable equipment. The cores or starting seeds can be, for example, sugar
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`spheres or spheres made from microcrystalline cellulose. The drug thus is coated
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`on the surface of the starting seeds. The drug-loaded pellets are dried for further
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`applications.
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`[040] The second unit should have a delayed release (DR) profile, and
`
`needs to be able to address the changing pH of the Gl tract, and its effect on the
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`absorption of doxycycline or other tetracycline. This pellet should have all of the
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`ingredients as mentioned for the first unit pellet, as well as optionally some organic
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`acid that will be useful to reduce the pH of the microenvironment of the pellet, and
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`thus facilitate dissolution. These materials are., but not limited to, citric acid, lactic
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`acid, tartaric acid, or other suitable organic acids. These materials should be
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`present in concentrations of from about 0 to about 15.0% (w/w); preferably these
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`materials would be present in concentrations of from about 5.0 to about 10.0 percent
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`(w/w). The process for manufacturing these pellets is consistent with the process
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`described above for the first unit pellet.
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`[041] Unlike the first unit pellet, the second unit delayed-release component
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`has a controlling coat applied to the surface of the pellet such that the release of the
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`drug from the pellet is delayed. This is accomplished by applying a coating of
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`enteric materials. "Enteric materials" are polymers that are substantially insoluble in
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`the acidic environment of the stomach, but are predominantly soluble in intestinal
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`fluids at specific pHs. The enteric materials are non-toxic, pharmaceutically
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`acceptable polymers, and include, for example, cellulose acetate phthalate (CAP),
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`hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate
`
`(PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose
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`acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate
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`succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate,
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`copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl
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`acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether
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`and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate(cid:173)
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`chlorotrimethylammonium ethyl acrylat~ copolymer, natural resins such as zein,
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`shellac and copal collophorium, and several commercially available enteric
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`dispersion systems (e.g., EUDRAGIT® L30055, EUDAAGIT® FS30D, EUDRAGIT®
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`L 100,

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