.;.
`
`~·
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`-·
`
`U.S. PTO
`12/926932
`12/17/2010
`
`Atty. Dkt. No. 063089-1700
`
`<= en
`=-c Applicant:
`d
`
`Title:
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Rong-Kun Chang et al.
`
`ONCE DAILY FORMULATIONS OF TETRACYCLINES
`
`Prior Appl. No.:
`
`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 37 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, and Abstract (30 pages).
`
`WASH_7573314.1
`
`-1-
`
`1
`
`
`
`~·
`
`-·
`
`U.S. PTO
`12/926932
`12/17/2010
`
`Atty. Dkt. No. 063089-1700
`
`<= en
`=-c Applicant:
`d
`
`Title:
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Rong-Kun Chang et al.
`
`ONCE DAILY FORMULATIONS OF TETRACYCLINES
`
`Prior Appl. No.:
`
`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 37 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, and Abstract (30 pages).
`
`WASH_7573314.1
`
`-1-
`
`1
`
`
`
`·- /'
`
`. '·
`
`Atty. Dkt. No. 063089-1700
`
`[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 (3 7 CFR 1. 76).
`
`The filing fee is calculated below:
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Fee
`Totals
`
`$330.00
`
`$540.00
`$220.00
`
`$0.00
`$0.00
`
`$130.00
`
`1220.00
`0
`$0.00
`$1220.00
`$0.00
`$0.00
`
`1220.00
`
`Basic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`x
`= 0
`3
`Independent:
`+
`If any Multiple Dependent Claim(s) present:
`Surcharge under 3 7 CFR 1.16( e) for late payment of +
`filing fee
`
`36
`
`100
`20
`
`0
`= 0
`
`$330.00
`
`$540.00
`$220.00
`
`$270.00
`$52.00
`
`X
`
`X
`
`[ ]
`
`SUBTOTAL:
`Small Entity Fee·s Apply (subtract Yz of above):
`Basic Filing Fee Reduction for Filing via EFS-Web
`TOTAL FILING FEE:
`+
`$40.00
`Assignment Recordation Fee:
`$130.00 =
`Processing Fee under 37 CFR 1.17(i) for Late Filing +
`of English Translation of Application:
`
`The required filing fees are not enclosed but will be submitted in response to the Notice
`
`to File Missing Parts of Application.
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`WASH_7573314.1
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`-2-
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`2
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`I
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`I
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`- ·
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`Atty. Dkt. No. 063089-1700
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`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Respectfully submitted,
`
`Date ____ -..~.DLJ.iE.I.t...C ..Al-.!.7.....!2~0~10 __ _
`
`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_7573314.1
`
`-3-
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`3
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`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 inflammatory 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
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`molecules involved with such things as inflammation are contributing factors, and
`
`which js a once daily formulation. The compositions are especially useful for treating
`
`such common disease states as periodontal disease, rosacea,· dry eye, acne and
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`rheumatoid arthritis.
`
`Background of the Invention
`
`[02] Conventionally, doxycycline and related tetracyclines are used as
`
`broad spectrum antibiotics to treat various bacterial infections. Tetracyclines
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`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
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`bacteriostatic (preventing growth of bacteria) rather than killing (bactericidal). The
`
`doses commonly used for doxycycline to achieve the antibiotic effect are 1 00 mg
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`and 50 mg.
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`[03] Doxycycline, as well as other tetracyclines, also has other therapeutic
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`uses in addition to its antibiotic properties. For example, doxycycline is known to
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`inhibit the activity of collagen destruction enzymes such as collagenase, gelatinase,
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`and elastase. Its collagenase inhibition activity has been used to treat periodontal
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`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
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`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.
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`[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 6,100,248 teaches
`
`a method of inhibiting cancer growth by administering tetracyclines which have been
`
`chemically modified to attenuate or delete their antibacterial activity. Methods to
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`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
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`of chlorhexidine gluconate in a biodegradable, resorbable matrix. It is recommended
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`that PerioChip® treatment be administered once every three months in pockets that
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`remain at 5 mm or deeper. A second product, Atridox®, is an injectable, resorbable
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`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
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`inhibitor used in patients with adult periodontal disease. Most people would prefer to
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`take a pill to the implant. However, Periostat® requires twice daily dosing and raises
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`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.
`
`Summary 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
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`,,
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`condition, but not as high as to exert an antibacterial effect. Such pharmaceutical
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`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..lg/ml and a maximum of about 1 .0
`
`J..lg/ml.
`
`[010] 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
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`I
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`mg. doxycycline base.
`
`(011 J 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
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`various ratios, although preferred are ratios of about 70:30 to about 80:20, and most
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`preferred 75:25, lA: DR, with the total dosage of doxycycline being less than about
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`50 mg. and preferably about 40 mg. The ratio refers to the dose breakdown
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`between lA and DR, e.g., 80:20 means 80% of 40 mg is from IR portion and 20% of
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`40 mg is from DR portion.
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`(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. 4,66i,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 silico model was first validated and tested using human
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`plasma data from immediate release dosage forms.
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`.
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`[016] Figure 2 shows in silico dissolution profiles for doxycycline
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`monohydrate delayed-release beads.
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`[017] Figure 3 shows in silico dissolution profiles for the composite capsules
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`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
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`DR combinations at 70:30 and 80:20 ratios, and twice-a-day 20 mg doxycycline
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`treatment).
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`(019] Figure 5 represents the pharmacokinetic profiles of 75:25 IR:DR (40
`
`mg.) formulation at day 1 and day 7 (steady state) in humans.
`
`[020] Figure 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
`
`[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
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`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
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`requires that the mammal, preferably human, to take only one dosage a day. The
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`compositions of the present invention are intended to be useful in lieu of multiple
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`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 !Jg/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 !Jg/ml.
`
`[023) The above blood serum levels allow for the desired anti-collagenase
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`and anti-inflammatory activity of doxycycline, without being accompanied by
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`undesirable antibiotic activity. It was surprisingly found that these levels can be
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`accomplished with a single daily dose of an immediate release formulation
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`containing below 50 mg. but more than 25 mg., preferably about 40 mg. doxycycline
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`base.
`
`[024]
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`"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
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`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,
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`pellet (used interchangeably with bead or beadlet herein), particle, capsule or gel.
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`Preferred in the present invention are tablets, or beadlets in a capsule.
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`[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 o'f capsules and, in some markets,
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`powder oral suspensions (to be reconstituted with water). The hyclate is a
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`hydrochloric acid salt solvated with water and ethanol and is typically used in the
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`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 anoth.er therapeutic or nutritional substance in the
`
`dosage forms.
`
`Immediate Release Dosage Forms
`
`[0271 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
`
`phosphate. for example, EMCOMPRESS® (Mendell Inc.); calcium sulfate, for
`
`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®
`
`(FMC Corp.). Antiadherants and glidants employed herein can include talc,
`
`cornstarch, silicon dioxide, sodium lauryl sulfate, colloidal silica dioxide, and metallic
`
`stearates.
`
`[028] Lubricants may be employed, such as magnesium stearate, calcium
`
`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
`
`the like.
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`[029] 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 Sciences, 181
`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 compressed into tablets. Preferably,
`
`the dosage form is prepared by a wet granulation technique or a direct compression
`
`method to form uniform granulates. Alternatively, the active ingredient(s) can be
`
`mixed with the granulate after the granulate is prepared. The moist granulated mass
`
`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]
`
`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 1 0 minutes with an
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`intensifier bar for three minutes. The blend is then compressed into tablets on a
`
`rotary press using appropriate tooling.
`
`[031] As mentioned above, another preferred dosage form for the immediate
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`/
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`release composition is a capsule containing immediate release beadlets or pellets.
`
`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]
`
`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
`
`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
`
`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.
`
`(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-
`
`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 fo~nd
`
`in Gunsel and Dusel, Chapter 5, "Compression-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
`
`[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 lauryl 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.
`
`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
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`selected on the basis of compatibility with the active drug and the physicochemical
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`properties of the pellets. These include, for instance: binders such as cellulose
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`derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
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`hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl
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`acetate copolymer and the like; disintegration agents such as cornstarch,
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`pregelatinized starch, cross-linked carboxymethylcellulose (AC-01-SOL®), sodium
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`starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE®
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`XL), and any disintegration agents used in tablet preparations, which are generally
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`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
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`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
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`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
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`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
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`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
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`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 J 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
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`(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 acrylate 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., EUDAAGIT® L30055, EUDRAGIT® FS30D, EUDRAGIT®
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`L100, KOLLICOAT® EMM30D, ESTACRYL®30D, COATEAIC®, and
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`AQUA TERIC®). The foregoing is a list of possible materials, but one of skill in the
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`art would recognize that it is not comprehensive and that there are other enteric
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`materials that would meet the objectives of the present invention of providing for a
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`delayed release profile. These coating materials can be empl9yed in coating the
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`surfaces in a range of from about 1.0% (w/w) to about 50% (w/w) of the pellet
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`composition. Preferably these coating materials should be in a range of from about
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`20 to about 40 percent (w/w). The pellets may be coated in a fluidized bed
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`apparatus or pan coating, for example.
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`[042] With the enteric coated pellets, there is no substantial release of
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`doxycycline in the acidic stomach environment of approximately below pH 4.5. The
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`doxycycline becomes available when the pH-sensitive layer dissolves at the greater
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`pH of the small intestine; after a certain delayed time; or after the unit passes
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`through the stomach. The preferred delay time is in the range of two to six hours.
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`[043] As a variation of this embodiment, the DR pellet contains layers of the
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`doxycycline, separated by protective layers, and finally an enteric coating, resulting
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`in a "repeat-action" dosage delivery. Such a dosage form may meet the blood level
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`requirements of the release profile of the present invention if the release of the
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`doxycycline, or other tetracycline, in all of the layers is within the absorption window
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`for the drug.
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`[044] An overcoating _layer can further optionally be applied to the lA/DR
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`pellets of the present invention. OPADRY®, OPADRY II® (Colorcon) and
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`corresponding color and colorless grades from Colorcon can be used to protect the
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`pellets from being tacky and provide colors to the product. The suggested levels of
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`protective or color coating are from 1 to 6%, preferably 2·3% (w/w).
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`[045] Many ingredients can be incorporated into the overcoating formula, for
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`example to improve the coating process and product attributes, such as plasticizers:
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`acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin,
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`polyethylene glycols, propylene glycol and others; lubricants: talc, colloidal silica
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`dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate,
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`and the like.
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`[046] The delayed release and immediate release units are combined in the
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`dosage form (in this instance, the different pellets are put into capsules) in a
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`predetermined ratio, preferably about 70:30 to about 80:20, most preferably 75:25
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`(lAlOR), which will achieve the desired steady state blood serum levels with only
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`once-daily dosing.
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`[047] The composition, preferably in beadlet form, can be incorporated into
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`hard gelatin capsules, either with additional excipients, or alone. Typical excipients
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`to be added to a capsule formulation include, but are not limited to: fillers such as
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`microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate,
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`calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there
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`can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate,
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`calcium stearate or any other material imparting flow to powders. A lubricant can
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`further be added if necessary by using polyethylene glycol, leucine, glyceryl
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`behenate, magnesium stearate or calcium stearate.
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`[048] The composition may also be incorporated into a tablet, in particular by
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`incorporation into a tablet matrix, which rapidly disperses the particles after
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`ingestion. In order to incorporate these particles into such a tablet, a filler/binder
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`must be added to a table that can accept the particles, but will not allow their
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`destruction during the tableting process. Materials that are suitable for this purpose
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`include, but are not limited to, microcrystalline cellulose (AVICEL®), soy
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`polysaccharide (EMCOSOY®), pre-gelatinized starches (STARCH® 1500,
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`NATIONAL® 1551), and polyethylene glycols (CARBOWAX®). The materials should
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`be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).
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`[049] In addition, disintegrants are added in order to disperse the beads
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`once the tablet is ingested. Suitable disintegrants include, but are not limited to:
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`cross-linked sodium carboxymethyl cellulose (AC-01-SOL®), sodium starch glycolate
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