PTO/SB/08 (09-06)
`Approved for use through 03/31/2007. OMB 0651-0031
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control
`number
`r
`
`Substitute for form 1449/PTO
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`Date Submitted: June 6, 2008
`
`"-Sheet
`
`(use as many sheets as necessary)
`I ot I 2
`I 1
`
`Application Number
`Filing Date
`First Named Inventor
`Art Unit
`Examiner Name
`Attorney Docket Number
`
`U.S. PATENT DOCUMENTS
`
`Complete if Known
`Unassigned
`61612008
`Rong-Kun CHANG
`Unassigned
`Unassigned
`063089-0140
`
`""''Il
`
`.J
`
`I
`
`Examiner
`Initials*
`
`Cite
`No. 1
`
`Document Number
`
`Number-Kind Code2 (if known)
`
`Publication Date
`MM-DD-YYYY
`
`Name of Patentee or Applicant of
`Cited Document
`
`Pages. Columns. Lines,
`Where Relevant
`Passages or Relevant
`Figures Appear
`
`A1
`A2
`A3
`A4
`A5
`A6
`A?
`A8
`A9
`A10
`A11
`A12
`A13
`A14
`A15
`A16
`A17
`A18
`A19
`A20
`A21
`A22
`A23
`A24
`A25
`A26
`A27
`A28
`A29
`A30
`A31
`A32
`A33
`A34
`A35
`A36
`A37
`A38
`A39
`
`2004-0115261 A1
`RE 34,656A
`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
`5,308,839A
`5,321,017 A
`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
`5,834,449A
`5,837,696 A
`5,908,838A
`5,919,775 A
`5,929,055A
`5,977,091 A
`5,998,390 A
`6,015,804 A
`6,043,231 A
`6,100,248 A
`6,114,316A
`6,143,506 A
`6,455,583 B1
`6,506,740 B1
`6,610,274 B1
`6,638,922 B2
`6,730,320 B2
`
`06/17/2004
`07/05/1994
`05/19/1987
`11/03/1987
`06/19/1990
`09/19/1990
`09/03/1991
`06/29/1993
`11/02/1993
`02/01/1994
`05/03/1994
`06/14/1994
`10/17/1995
`06/04/1996
`07/02/1996
`05/19/1998
`06/23/1998
`06/30/1998
`08/04/1998
`08111/1998
`10/27/1998
`10/27/1998
`1111011998
`11117/1998
`06/01/1999
`07/06/1999
`07/27/1999
`11/02/1999
`12/07/1999
`01/18/2000
`03/28/2000
`08/08/2000
`09/05/2000
`11/07/2000
`09/24/2002
`01/14/2003
`08/26/2003
`10/28/2003
`05/04/2004
`
`ASHLEY
`GOLUB et al.
`GOLUB et al.
`McNAMARA et al.
`McNAMARA et al.
`McNAMARA et al.
`SCHNEIDER et al.
`McNAMARA et al.
`GOLUB etal.
`DOYON eal.
`GOLUB et al.
`GOLUB et al.
`GOLUB et al.
`PRUZANSKI et al.
`GOLUB et al.
`SCHWABE et al.
`McNAMARA et al.
`SIMONet al.
`AMIN etal.
`ASHLEY
`SCHWABE
`RAMAMURTHY et al.
`THOMPSON et al.
`GOLUB et al.
`GANS
`AMIN et al.
`RYAN et al.
`NIEMAN et al.
`RAMAMURTHY et al.
`GOLUB et al.
`PRUZANSKI et al.
`GOLUB et al.
`RAMAMURTHY et al.
`GOLUB et al.
`PFLUGFELDER et al.
`ASHLEY et al.
`GARDNER
`ASHLEY et al.
`RUDNIC et al.
`
`Date
`Considered
`
`I Examiner
`
`Signature
`
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not considered.
`Include copy of this form with next communication to applicant. 1 Applicant's unique citation designation number (optional). 2 See Kinds Codes of USPTO Patent
`Documents at www.uspto.gov or MPEP 901.04. 3 Enter Office that issued the document, by the two-letter code (WI PO Standard ST.3). 4 For Japanese patent
`documents. the indication of the year of the reign of the Emperor must precede the serial number of the patent document. 5 Kind of document by the appropriate symbols
`as indicated on the document under WlPO Standard ST.16 if possible. 6 Applicant is to place a check mark here if English language Translation is attached.
`This collection of information is required by 37 CFR 1.97 and 1.98. The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete. including
`gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of
`time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office,
`P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box
`1450, Alexandria, VA 22313-1450.
`
`WASH_ 4185242.1
`
`If you need assistance in completing the form, ca/11-800-PT0-9199 (1-800-786-9199) and select option 2.
`
`1
`
`

`

`PTO/SB/08 (09-06)
`Approved for use through 03/3112007. OMS 0651-0031
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control
`number
`
`,..
`
`Substitute for form 1449/PTO
`
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`Date Submitted: June 6, 2008
`
`\..Sheet
`
`(use as many sheets as necessary)
`I of 1 2
`
`12
`
`Application Number
`Filing Date
`First Named Inventor
`Art Unit
`Examiner Name
`Attorney Docket Number
`
`Complete if Known
`Unassigned
`6/6/2008
`Rong-Kun CHANG
`Unassigned
`Unassigned
`063089-0140
`
`~
`
`..JtJ
`
`Examiner
`Initials*
`
`Cite
`No. 1
`
`UNPUBLISHED U.S. PATENT APPLICATION DOCUMENTS
`U.S. Patent Application
`Document
`Serial Number-Kind Code" (if
`known)
`
`Filing Date of
`Cited Document
`MM-DD-YYYY
`
`Name of Patentee or Applicant of
`Cited Document
`
`Pages, Columns. Lines.
`Where Relevant
`Passages or Relevant
`Figures Appear
`
`FOREIGN PATENT DOCUMENTS
`
`Publication Date
`MM-DD-YYYY
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`Name of Patentee or
`Applicant of Cited Documents
`
`Pages, Columns. lines,
`Where Relevant
`Passages or Relevant
`Figures Appear
`
`r
`
`Examiner
`Initials*
`
`Cite
`No. 1
`
`A40
`
`Foreign Patent Document
`Country Code~ Number Kind
`Code5
`(if known)
`EP 0 464 932 82
`
`01/08/1992
`
`A41
`
`WO 98/05340 A 1
`
`02/12/1998
`
`A42
`
`WO 01/87823 A1
`
`11/22/2001
`
`A43
`
`WO 02/083106 A 1
`
`10/24/2002
`
`The Research Foundation of
`State University of New York
`The Research Foundation of
`State University of New York
`Collagenex Pharmaceuticals,
`Inc.
`Colagenex Pharmaceuticals,
`Inc.
`
`NON PATENT LITERATURE DOCUMENTS
`
`Examiner
`Initials*
`
`Cite
`No. 1
`
`Include name of the author (in CAPITAL LETTERS). title of the article (when appropriate). title of the
`item (book, magazine, journal, serial, symposium, catalog, etc.) date, page(s), volume-issue number(s),
`publisher, city and/or country where published.
`
`r
`
`A44
`
`Gunsel and Dusel, Chapter 5, "Compression-coated and layer tablets," Pharmaceutical Dosage Forms:
`Tablets, Second Edition, Vol. 1, Edited by H.A. Lieberman et al., 1990.
`
`A45
`
`Remington's Pharmaceutical Sciences, 18m Edition, Gennaro, Ed., 1990, Chapters 88-91.
`
`A46
`
`Elewski et al., Journal of the American Academy of Dermatology, 1983, vol. 8, pp. 807-812.
`
`A47
`
`Plewig et al., Journal of Investigative Dermatology, 1975, vol. 65, p. 532.
`
`A48
`
`Ryan et al., "Potential of Tetracycline to Modify Cartilage Breakdown in Osteoarthritis," Current Opinion in
`Rheumatology, 1996, vol. 8, pp. 238-247.
`
`A49
`
`Wong et al., Journal of American Academy of Dermatology, 1984, vol. 1, pp. 1076-1081.
`
`(
`
`~xaminer
`~ignature
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not considered.
`lndude copy of this form with next communication to applicant. 1 Applicant's unique citation designation number {optional). 2 See Kinds Codes of USPTO Patent
`Documents at www.uspto.gov or MPEP 901.04. 3 Enter Office that issued the document, by the two-letter code (WIPO Standard ST.3). 4 For Japanese patent
`documents, the indication of the year of the reign of the Emperor must precede the serial number of the patent document. 5 Kind of document by the appropriate symbols
`as indicated on the document under WIPO Standard ST.16 if possible. 6 Applicant is to place a check mark here if English language Translation is attached.
`This collection of infom1ation is required by 37 CFR 1.97 and 1.98. The infom1ation is required to obtain or retain a benefit by the public which is to file {and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete, induding
`gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount of
`time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer. U.S. Patent and Trademark Office,
`P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box
`1450, Alexandria, VA 22313-1450.
`
`Date
`Considered
`
`1
`
`WASH_ 4185242.1
`
`If you need assistance in completing the form. ca/11-800-PT0-9199 (1-800-786-9199) and select option 2.
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`2
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`

`1§992 U.$. PTO
`1111~111111~~~~~~~1111111111
`
`U.S. PTO
`12/155676
`06/06/2008
`Atty. Dkt. No. 063089-0140
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`Applicant:
`Rong-Ku_n Chang et al.
`
`Title:
`
`ONCE DAILY
`FORMULATIONS OF
`TETRACYCLINES
`
`Prior Appl. No.:
`
`10/819,620
`
`Prior Appl.
`Filing Date:
`
`4/7/2004
`
`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 ofthe 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).
`
`[X] Drawings (6 sheets, Figures 1-6).
`
`WASH_ 4185276.1
`
`-1-
`
`3
`
`

`

`Atty. Dkt. No. 063089-0140
`
`[X] Copy of Declaration and Power of Attorney from prior application (2 pages).
`
`[ X ] Copy of Power of Attorney/Change of Correspondence Address and Statement
`Under 37 CFR 3.73(b) from prior application (2 pages).
`
`[X]
`
`Information Disclosure Statement and Form PTO-SB/08.
`
`[X] Application Data Sheet (37 CFR 1.76).
`
`The filing fee is calculated below:
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Basic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`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
`
`0
`
`$310.00
`
`$510.00
`$210.00
`
`$260.00
`$50.00
`
`$210.00
`$370.00
`$130.00
`
`X
`
`X
`
`X
`+
`+
`
`[ ]
`
`SUBTOTAL:
`Small Entity Fees Apply (subtract 'l'2 of above):
`Basic Filing Fee Reduction for Filing via EFS-Web
`TOTAL FILING FEE:
`+
`$40.00
`+
`$130.00
`
`Assignment Recordation Fee:
`Processing Fee under 37 CFR 1.17(i) for Late Filing
`of English Translation of Application:
`TOTAL FEE
`
`Fee
`Totals
`
`$310.00
`
`$510.00
`$210.00
`
`$0.00
`$0.00
`
`$0.00
`$0.00
`$130.00
`
`$1160.00
`0
`$0.00
`$1160.00
`$0.00
`$0.00
`
`$1160.00
`
`The required filing fees are not enclosed but will be submitted in response to the
`
`Notice to File Missing Parts of Application.
`
`WASH_ 4185276.1
`
`-2-
`
`4
`
`

`

`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Atty. Dkt. No. 063089-0140
`
`Date June 6, 2008
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 672-5569
`Facsimile:
`(202) 672-5399
`
`Respn~·-Y :{:Pe~ A~
`f< f'q. tJo, 3<-f. 7 rJ
`By ____ ~~~---------------------
`Stephen B. Maebius
`Attorney for Applicant
`Registration No. 35,264
`
`WASH_ 4185276.1
`
`-3-
`
`5
`
`

`

`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
`
`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 aminoacyHRNA 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 effect 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
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`1
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`6
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`

`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 coffagenolytic 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.
`
`[05]
`
`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
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`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.
`
`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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`

`'i)_
`• r•
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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
`
`!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 (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 75:25, 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
`
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`

`between IR and OR, e.g., 80:20 means 80% of 40 mg is from IR portion and 20o/o 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. 4,66i,897 of Golub.
`
`[013J 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
`
`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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`'·
`. t•
`
`~ ..
`..•
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`[017] Figure 3 shows in silico dissolution profiles tor 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
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`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:DA (40
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`mg.) formulation at day 1 and day 7 (steady state) in humans.
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`[020] Figure 6 compares the pharmacokinetic curves of 75:25 IR:DA (40
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`mg.) formulation with the Periostat® 20 mg. twice daily dosage form.
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`Detailed Description of the Invention
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`[021] While the following description is directed primarily to doxycycline, it is
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`contemplated that the present invention is applicable to other tetracyclines,
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`particularly other tetracyclines that have similar in vivo absorption profiles as
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`doxycycline, more specifically tetracyclines that have a similar region of absorption
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`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
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`02/083106 and US Patent 6,638,922, each of which are incorporated in their
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`entireties herein by reference.
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`[022] The present invention can be accomplished by providing an orally
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`administered composition of, as an example, doxycycline which is designed to
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`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
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`effects. The preferred blood level of doxycycline, or other tetracyclines of
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`comparable physiological and absorption properties, is between about 0.1 and about
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`1.0 ~g/ml at the steady state. Preferably, the blood levels stay within the preferred
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`blood level, with daily dosing, for the entire course of treatment. More preferably,
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`the blood levels are between about 0.3 ~g/ml and about 0.8 ~g/ml.
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`[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.
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`(024}
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`"About" means within the pharmaceutically acceptable limits found in
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`the United States Pharmacopia (USP-NF 21 ), 2003 Annual Edition, or available at
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`www.usp.org, for amount of active pharmaceutical ingredients. With respect to
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`blood levels, "about'' means within FDA acceptable guidelines.
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`[025} By "immediate release" formulation is meant a dosage form that is
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`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
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`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
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`compound can be used provided it will comply with the required blood serum levels
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`of the present invention. Doxycycline, for instance, is commonly used in
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`pharmaceutical formulations under two chemical forms: the monohydrate form and
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`the hyclate form. The monohydrate is the base molecule hydrated with one
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`molecule of water and is used in the formulation of 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
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`of the present invention refers to doxycycline base. Also, in the compositions of the
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`present invention there may be more than one active ingredient. That is, the
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`doxycycline can be combined with another therapeutic or nutritional substance in the
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`dosage forms.
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`Immediate Release Dosage Forms
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`[0271 There are many ways known in the art to formulate such immediate
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`release dosage forms. For instance, an immediate release tablet can be prepared by
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`mixing doxycycline with a bulking agent such as microcrystalline cellulose, for
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`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, POL YPLASDONE 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 Iaury! 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, 18th
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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 IR
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`pellets). The pellets are filled into capsules, for instance gelatin capsules, by
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`conventional techniques.
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`Combination I A/DR Dosage Forms
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`[032]
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`In another embodiment of the present invention is a composition
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`having a substantially immediate release dose of doxycycline, followed by at least
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`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
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`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
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`to adjust the in vitro drug release profile and in vivo blood concentration profile. By
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`providing such a drug release profile, the compositions eliminate the need for a
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`second dose for the day. Additionally, the total dose of doxycycline is below 50 mg.
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`to avoid the undesirable side effects from its antibiotic properties, but more than 25
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`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
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`these attributes. For example, an immediate-release powder blend can be
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`encapsulated with a delayed-release tablet or delayed-release pellets. A further
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`example is an immediate-release tablet and a delayed-release tablet that are
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`prepared separately and encapsulated into an appropriate sized capsule shell.- Or,
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`for example, a delayed-release tablet can be used as a core and the immediate-
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`release portion can be compressed as an outer layer using a press coater or
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`overcoated using a drug layering technique, both techniques of which can be found
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`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).
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`Multiparticulate Capsules
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`[034] As a preferred embodiment, the IRJDR composition of doxycycline is in
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`the form of a capsule containing beadlets. At present, it is preferred to have two
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`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
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`form. This component can also be a powder if desired or necessary. In either case,
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`the dosage form may have a surface-active agent such as sodium Iaury! sulfate,
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`sodium monoglycerate, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
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`glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, any one of the
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`Pluronic line of surface-active polymers, or any other suitable material with surface
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`active properties or any combination of the above. Preferably, the surface-active
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`agent would be a combination of sodium monoglycerate and sodium Iaury! sulfate.
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`The concentration of these materials in this component can range from about 0.05 to
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`about 10.0% (W//W).
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`[036] Other excipient materials that can be employed in making drug-
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`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 methylceltulose, 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 carboxymethyfcellulose (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 cel