(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property Organization
`International Bureau
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`
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`(43) International Publication Date
`24 October 2002 (24.10.2002)
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`(10) International Publication Number
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`PCT
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`WO 02/083106 A1
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`(51) International Patent Classificati0n7:
`9/26, 9/52
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`A61K 9/22,
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`(21) International Application Number:
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`PCT/US02/10748
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`(22) International Filing Date:
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`5 April 2002 (05.04.2002)
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`(25) Filing Language:
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`(26) Publication Language:
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`(30) Priority Data:
`60/281,854
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`English
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`English
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`5 April 2001 (05.04.2001)
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`US
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`(71) Applicant (for all designated States except US): COL-
`LAGENEX PHARMACEUTICALS, INC. [US/US]; 41
`University Drive, Newtown, PA 18940 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant Ufor US only): ASHLEY, Robert, A.
`[US/US]; 63 Woodhill Road, Newtown, PA 18940 (US).
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`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
`GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
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`Published:
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`with international search report
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`(74) Agent: BARON, Ronald, J,; Hoffmann & Baron, LLP,
`6900 Jericho Turnpike, Syosset, NY 11791 (US).
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`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
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`(54) Title: CONTROLLED DELIVERY OF TETRACYCLINE COMPOUNDS AND TETRACYCLINE DERIVATIVES
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`(57) Abstract: A composition is provided for delivering a tetracycline compound to a mammal. The composition includes an antibi—
`otic tetracycline compound and a controlled—release agent having at least one controlled—release agent. The tetracycline compound
`is associated with the controlled— release matrix to provide a release profile whereby the mammal is treated substantially without
`antibiotic activity. Methods for treating a mammal with a tetracycline compound and a dosage unit are also provided utilizing the
`controlled—release tetracycline composition.
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`CONTROLLED DELIVERY OF
`TETRACYCLINE COMPOUNDS AND TETRACYCLINE DERIVATIVES
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`CROSS—REFERENCE TO RELATED APPLICATION
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`This application claims the benefit of US Provisional Application No.
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`60/281,854, filed April 5, 2001, which is incorporated herein by reference.
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`BACKGROUND OF INVENTION
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`The invention relates to delivering a tetracycline compound to a mammal.
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`More specifically, the invention relates to controlled release of a tetracycline
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`compound or derivative thereof for treatment of a mammal in the absence of
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`antibiotic activity (i.e. antimicrobial activity).
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`Tetracycline and a number of its chemical relatives form a particularly
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`successful class of antibiotics. Certain of the tetracycline compounds, including
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`tetracycline itself, as well as sporocycline, etc., are broad spectrum antibiotics, having
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`utility against a wide variety of bacteria.
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`Conventional tetracycline compositions are designed to optimize their '
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`antibiotic properties. The conventional compositions operate by creating a spike in
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`serum concentration followed by a rapid diminution in serum concentration.
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`Accordingly, relatively high doses are administered which have a short serum
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`concentration half—life. This short serum half—life requires the conventional
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`compositions to be administered often, e.g every 3—6 hours.
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`Tetracyclines have been described as having a number of other therapeutic
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`uses in addition to their antibiotic properties. For example, tetracyclines are also
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`known to inhibit the activity of collagen destructive enzymes such as mammalian
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`collagenase, gelatinase, macrophage elastase and bacterial collagenase. Golub et al.,
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`J. Periodont. Res. 20:12-23 (1985); Golub et al. Crit. Revs. Oral Biol. Med. 2:
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`297—322 (1991);U.S. Pat. Nos. 4,666,897; 4,704,383; 4,935,411; 4,935,412. In
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`addition, tetracyclines have been known to inhibit wasting and protein degradation in
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`mammalian skeletal muscle, US. Pat. No. 5,045,538.
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`Furthermore, tetracyclines have been shown to enhance bone protein synthesis
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`in US. Pat. No. Re. 34,656, and to reduce bone resorption in organ culture in US.
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`Pat. No. 4,704,383.
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`Similarly, US. Pat. No. 5,532,227 to Golub et a1, discloses that tetracyclines
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`can ameliorate the excessive glycosylation of proteins. In particular, tetracyclines
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`inhibit the excessive collagen cross linking which results from excessive
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`glycosylation of collagen in diabetes.
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`These properties cause the tetracyclines to be useful in treating a number of
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`diseases. For example, there have been a number of suggestions that tetracyclines,
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`including non—antibiotic tetracyclines, are effective in treating arthritis. See, for
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`example, Greenwald et al., "Tetracyclines Suppress Metalloproteinase Activity in
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`Adjuvant Arthritis and, in Combination with Flurbiprofen, Ameliorate Bone
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`Damage," Journal ofRheumatology 19:927-93 8(1992); Greenwald et al., "Treatment
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`of Destructive Arthritic Disorders with MMP Inhibitors: Potential Role of
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`Tetracyclines in, Inhibition of Matrix Metalloproteinases:Therapeutic Potential, "
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`Annals ofthe New York Academy ofSciences 732: 181—198 (1994); Kloppenburg et
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`al., "Minocycline in Active Rheumatoid Arthritis," Arthritis Rheum
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`372629-6360 994); Ryan et al., "Potential of Tetracycline to Modify Cartilage
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`Breakdown in Osteoarthritis," Current Opinion in Rheumatology 8: 238—247(1996);
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`O’Dell et al., "Treatment of Early Rheumatoid Arthritis with Minocycline or
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`Placebo," Arthritis Rheum 40:842—848(l997).
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`Tetracyclines have also been suggested for use in treating skin diseases. For
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`example, White et al., Lancet, Apr. 29, p. 966 (1989) report that minocycline is
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`effective in treating dystrophic epiderrnolysis bullosa, Which is a life-threatening skin
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`condition believed to be related to excess collagenase.
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`The effectiveness of tetracycline in skin disorders has also been studied by
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`Elewski et al., Journal oft/1e American Academy ofDermatology 8:807-812 (1983).
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`Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory
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`activity in skin diseases.
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`Similarly, Plewig et al., Journal ofInvestigative Dermatology 65 2532 (1975),
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`disclose experiments designed to test the hypothesis that antibiotics are effective in
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`treating inflammatory dermatoses. The experiments of Plewig et al. establish that
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`tetracyclines have anti—inflammatory properties in treating pustules induced by
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`potassium iodide patches.
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`The use of tetracyclines in combination with non—steroidal anti—inflammatory
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`agents has been studied in the treatment of inflammatory skin disorders caused by
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`acne vulgaris. Wong et al., Journal ofAmerican Academy ofDermatology 1:
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`1076-1081 (1984), studied the combination of tetracycline and ibuprofen and found
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`that tetracycline was an effective agent against acne vulgaris while ibuprofen was
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`useful in reducing the resulting inflammation by inhibition of cycloxygenase. Funt et
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`al., Journal ofthe American Academy ofDermatology 13: 524—525 (1985), disclosed
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`similar results by combining antibiotic doses of minocycline with ibuprofen.
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`An antibiotic tetracycline derivative, doxycycline, has been used to inhibit
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`nitrate production. D’Agostino et al., Journal ofInfectious Diseases: 177:489—92
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`(1998), disclose experiments Where doxycycline, administered to mice injected with ‘
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`bacterial lipopolysaccharide (hereinafter LPS), exerted a protective effect by
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`inhibiting nitrate production by an IL-lO independent mechanism.
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`Therefore, there are numerous uses for tetracycline compounds aside from
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`their antibiotic activity. While tetracycline antibiotics are generally effective for
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`treating infection, the use of these compounds can lead to undesirable side effects.
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`For example, the long term administration of antibiotic tetracyclines can reduce or
`eliminate healthy biotic flora, such as intestinal flora, and can lead to the production
`of antibiotic resistant organisms or the overgrowth of yeast and fungi.
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`Accordingly, there is a need for a composition for improved delivery of
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`tetracycline compounds to a mammal that, unlike conventional compositions,
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`provides a dosage below that which is required for an antibiotic response in the
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`mammal at a relatively constant serum level with a longer serum half—life.
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`SUMMARY OF INVENTION
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`The present invention includes a composition for delivering a tetracycline
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`compound to a mammal. The composition includes an antibiotic tetracycline
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`compOund and at least one controlled~release agent. The tetracycline compound is
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`associated with the controlled—release agent to provide a tetracycline-release profile
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`characterized by delivery of a dose below that which is required for antibiotic activity
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`(i.e. antimicrobial activity) such that the mammal is treated with a tetracycline
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`compound substantially Without antibiotic activity.
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`The amount of the tetracycline compound released by the composition can
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`vary, as long as it is below the threshold blood serum concentration level required for
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`antibiotic activity. In general, the blood serum level will be between about 0.1 and
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`1.0 ug/ml, preferably between about 0.3 and 0.8 ug/ml. This release profile should be
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`maintained at a substantially constant rate for between about 6-24 hours.
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`In a preferred embodiment, the tetracycline is doxycycline. The preferred
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`blood serum level of doxycycline is 0.4-0.8 ug/ml. over a period of 12—24 hours.
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`The composition also can include a controlled—release agent selected from the
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`group consisting of an instantaneous-release agent, a sustained-release agent, a
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`delayed—release agent, and combinations thereof. In one embodiment, the
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`composition can contain all three release agents associated with the tetracycline
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`compound to provide a substantially constant dosage rate over a designated time
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`period.
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`The present invention also includes a method of treating a mammal with a
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`tetracycline compound. The method includes administering to the mammal a
`tetracycline compound which is associated with at least one controlled-release agent
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`to provide a release profile having nonantibiotic activity over a pre-selected time
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`period, preferably 6-24 hours.
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`The method also can include a controlled-release agent selected from the
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`group consisting of an instantaneous—release agent, a sustained-release agent, a
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`delayed—release agent, and combinations thereof. In one embodiment, the
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`composition can contain all three release agents associated with the tetracycline
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`compound to provide a substantially constant dosage rate over a designated time
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`period.
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`A unit dosage is also provided for controlled delivery of a tetracycline
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`compound. The unit dosage includes a tetracycline compound and at least one
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`controlled—release agent. The tetracycline compound is associated With the
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`controlled—release agent'to provide a tetracycline release profile in the mammal
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`substantially without antibiotic activity. In preferred embodiments, the unit dosage is
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`either a capsule or a tablet.
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`The composition for delivering a tetracycline compound to a mammal and the
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`corresponding method of treating a mammal With a tetracycline compound, as
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`described herein, provides a number of benefits over conventionally utilized
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`controlled delivery compositions for administration of a tetracycline compound.
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`First, by administering the tetracycline compound in a dose below that which
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`is necessary to provide an antibiotic response, undesirable side effects, such as the
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`reduction of healthy flora in the body, the production of antibiotic resistant organisms,
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`or the overgrowth of opportunistic yeast and fungi, are avoided.
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`Second, the controlled release composition of the invention increases patient
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`compliance. Instead of administering a low dose of a tetracycline compound many
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`times during the day, the composition of the invention allows the patient to administer
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`the tetracycline compound one or two times a day. The controlled release of the
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`tetracycline compound creates the desired dose profile below that which is necessary
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`for an antibiotic response in the mammal.
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`The composition of the invention also avoids the reduction in tetracycline
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`uptake after eating. Very often, with conventional tetracycline compounds, the
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`percentage of the tetracycline compounds reaching the bloodstream from the GI tract
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`will decrease once the mammal begins eating. This reduction in tetracycline uptake is
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`ameliorated with a composition that can be taken once or twice a day, especially with
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`a controlled release formula that can remain entrapped in the upper portion of the GI
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`tract as opposed to the small intestine.
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`Additionally, because the serum concentrations with the composition of the
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`invention remain substantially lower than peak serum concentrations from an
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`equivalent dosage administered as an immediate release formulation, the risk of
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`phototoxicity encountered with conventional tetracycline compositions is reduced.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`Figure 1 depicts a tetracycline release profile utilizing a combination of three
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`different controlled-release agents which are associated with a tetracycline compound
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`in a composition according to the present invention.
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`DETAILED DESCRIPTION OF INVENTION
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`The composition of the invention is designed to provide a release profile that
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`is the direct opposite of the conventional profile, described above. More specifically,
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`the composition of the invention provides for the controlled release of a tetracycline
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`compound to a mammal whereby there is substantially no antibiotic activity in the
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`mammal. The composition of the invention provides its therapeutic effect by
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`providing a dose of the tetracycline compound below that which is required to
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`produce an antibiotic effect in the mammal at a substantially constant rate over a
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`longer period of time, e.g. 12-24 hours.
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`The composition of the invention is administered to a mammal. Mammals
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`include, for example, humans, as well as pet animals such as dogs and cats, laboratory
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`animals such as rats and mice, and farm animals such as horses and cows.
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`“Tetracycline compound” as defined herein refers to tetracycline or any
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`tetracycline derivative, as described above, possessing antibiotic activity when
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`administered above the required serum level threshold, as is known in the art.
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`The parent compound, tetracycline, has the following general structure:
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`
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`OH O
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`OH O
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`StructureA
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`The numbering system of the multiple ring nucleus is as follows:
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`Tetracycline, as well as the 5-OH (oxytetracycline, e. g. Terramycin) and 7-C1
`(chlorotetracycline, e.g. Aureomycin) derivatives, exist in nature, and are all well
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`known antibiotics. Semisynthetic derivatives such as 7—dimethylamino-tetracyc1ine
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`(minocycline) and 6oz—deoxy-5-hydroxy-tetracycline (doxycycline) are also known
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`tetracycline antibiotics. Natural tetracyclines may be modified without losing their
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`antibiotic properties, although certain elements of the structure must be retained to do
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`so. Preferred antibiotic tetracyclines include tetracycline, doxycycline,
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`demeclocycline, minocycline, and lymecycline.
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`A class of compounds has also been defined which are structurally related to
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`the antibiotic tetracyclines, but which have had their antibiotic activity substantially or
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`completely expunged by chemical modification. The modifications that may and may
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`not be made to the basic tetracycline structure were reviewed by Mitscher, L.A., The
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`Chemistry of the Tetracycline Antibiotics, Marcel Dekker, New York (1978), Ch. 6.
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`According to Mitscher, the modification at positions 5—9 of the tetracycline ring
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`system can be made without causing the complete loss of antibiotic properties.
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`However, changes to the basic structure of the ring system, or replacement of
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`substituents at positions 1-4 or 10-12, generally lead to synthetic tetracyclines with
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`substantially less, or essentially no, antibacterial activity.
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`The composition of the invention can include, in addition to the tetracycline
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`compound, one or more other therapeutic agents. The combination of the tetracycline
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`compound with such other agents can potentiate the therapeutic protocol. The
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`composition of the invention can also include a combination of the tetracycline
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`compound in a suitable pharmaceutical carrier (vehicle) or excipient as understood by
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`practitioners in the art.
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`In addition to the tetracycline compound, the composition of the invention
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`includes at least one controlled-release agent. Controlled-release agents are known in
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`the art. See for example, U.S. Patent Nos. 4,837,030; 5,262,164; 5,582,837;
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`5,681,585; 5,716,631; 5,736,152; 5,840,332; 5,855,915; 6,007,843; 6,020,002;
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`6,120,803; and 6,143,353.
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`The composition of the invention can include various relative amounts of the
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`tetracycline compound and the controlled release agent. For example, the tetracycline
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`can make up 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the
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`composition. The controlled release agent can make up 10%, 20%, 30%, 40%, 50%,
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`60%, 70%, 80% or 90% of the composition.
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`The tetracycline compound is associated with the controlled release matrix to
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`provide a tetracycline-release-prof11e in the mammal whereby the mammal is treated
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`with the tetracycline compound substantially without antibiotic activity. It is
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`preferred that the controlled-release matrix be capable of releasing the tetracycline
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`compound in an amount and at a rate sufficient to maintain an effective tetracycline
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`blood serum level over a designated time period.
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`The tetracycline and controlled-release agent are associated with each other
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`physically (e. g., by mechanical means such as mixing, mulling, compacting, etc.)
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`and/or chemically, such as by chemical reaction, and/0r secondary chemical bonding,
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`e.g., Van‘der Waals forces, etc. The tetracycline compound/controlled-release agent
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`combinations are included in the invention composition in an amount sufficient to
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`provide a highly predictable pre-selected release profile of the therapeutically active
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`tetracycline as a result of normal interaction of the mammal biosystem on the
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`tetracycline/controlled-release matrix system combination.
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`The controlled—release agent can include one or more ingredients for
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`controlling the rate at which the tetracycline component is made available to
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`biological system of the mammal. The controlled-release agent can include an
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`instantaneous release agent, a delayed release agent, a sustained release agent, or any
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`combination thereof.
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`An instantaneous release agent refers to an ingredient which promotes or
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`enhances immediate release to the mammal. The instantaneous release agent can be
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`an additional ingredient that enhances dispersion of the tetracycline compound. An
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`example of an instantaneous release agent is a surfactant.
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`A sustained release agent is an ingredient, or combination of ingredients,
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`which permits release of the tetracycline compound to the mammal at a certain level
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`over a period of time. Examples of sustained release agents include gels, waxes, fats,
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`emulsifiers, combinations of fats and emulsifiers, polymers, starch, cellulose
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`polymers, etc., as well as combinations thereof. The sustained release agent can also
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`include, for example, the above in combination with other polymeric or biodegradable
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`coatings or matrices.
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`A delayed release agent is an ingredient which prevents the tetracycline
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`compound from being made available to the mammal until some time after initial
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`administration. The delayed release agent prevents release of the tetracycline
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`compound until some time in the future. Examples of delayed release agents include,
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`but are not limited to, polymeric or biodegradable coatings or matrices, including
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`cellulose polymers, and combinations thereof.
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`In a preferred embodiment, the composition of the invention comprises more
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`than one controlled—release agent, and can include, all three types of controlled-
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`release agents, i.e., an instantaneous release agent, a sustained release agent, and a
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`delayed release agent. Using all three types of controlled—release agents can produce
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`a profile that administers the tetracycline compound in a specific dose over an
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`extended period of time, e.g., 12-24 hours. Figure 1 depicts a release profile utilizing
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`an instantaneous, delayed, and sustained controlled—release agent.
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`The sustained controlled—release agent preferably consists of a cellulose
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`polymer, preferably a high molecular weight cellulose polymer, selected from the
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`group consisting of hydroxyprOpyl methyl cellulose (HPMC), hydroxyethyl cellulose
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`(HEC), hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), and
`mixtures thereof. Of these, the most preferred water soluble cellulose polymer is
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`HPMC.
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`Preferably the HPMC is a high molecular weight HPMC, with the specific
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`molecular weight selected to provide the desired release profile. For example, a tablet
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`designed to provide a substantially constant release rate over a 12 hour period will
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`preferably contain HPMC having an average molecular weight of at least about
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`65,000, more preferably about 85,000.
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`The controlled~release component can also contain minor amounts of other
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`materials which can affect the release profile. Examples of such materials include
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`conventional waxes and waxy materials used in pharmaceutical formulations, such as
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`canuba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol,
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`beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol,
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`stearyl alcohol, cetyl alcohol and stearic acid. Hydrophilic gums are also
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`contemplated for use, in minor amounts, which can have an effect on the release
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`profile. Examples of hydrophilic gums include acacia, gelatin, tragacanth, veegurn,
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`xanthin gum, carboxymethyl cellulose (CMC), hydroxy propyl cellulose (HPC) and
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`hydroxy ethyl cellulose (HEC).
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`The tetracycline composition of the invention can be administered in the form
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`of a liquid as a suspension or solution, or alternatively in solid form, such as a tablet,
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`pellet, particle, capsule, or soft gel. For example, the form can be polymeric capsules
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`filled with solid particles which can, in turn, be made to release the tetracycline
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`compound according to a known pattern or profile. Such particles can also be made
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`to have more than one release profile so that over an extended time the combined
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`release patterns provide a pre-selected profile.
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`In one embodirnent, the tetracycline compound/controlled—release agent
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`combination is administered in the form of a heterogeneous matrix, such as, for
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`example, a compressed tablet, to control the release of the tetracycline compound
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`either by diffusion, erosion of the matrix or a combination of both.
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`Other combinations of controlled release agent and tetracycline compound
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`contemplated by the invention include a combination of polymeric material(s) and
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`tetracycline compound which is formed into a sandwich, and which relies on, at least
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`the physical disintegration actions of diffusion or erosion to controlledly release the
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`tetracycline. Additionally, heterogeneous dispersions or solutions of tetracycline in
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`water—swellable hydrogel matrices are useful in controlling the release of the
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`tetracycline by slow surface—to-center swelling of the matrix and subsequent release
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`of the tetracycline by a combination of diffusion of the tetracycline from the water-
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`swollen part of the matrix and erosion of the water—swollen matrix containing the
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`tetracycline.
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`The sustained controlled-release agent will preferably provide for a sustained
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`release of tetracycline according to a desired release profile through the use of one or
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`more of the release ingredients described above. More preferably, the controlled—
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`release agent will provide a release profile which releases the tetracycline compound
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`at a substantially constant rate over a designated time period whereby the mammal is
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`treated with the tetracycline substantially without antibiotic activity.
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`As the terminology is used herein, “substantially constant rate” refers to
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`maintaining a release rate of the active ingredient, i.e., tetracycline, within a desired
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`range over at least about 60 % of the designated time period for release, preferably
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`over at least about 70 %, more preferably over at least about 80 % of the designated
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`time period, and most preferably over about 90%.
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`The release profile in the composition of the invention provides substantially
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`no antibiotic activity. In other words, the dosage of the tetracycline compound
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`administered by the release profile is below the amount required for antibiotic
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`activity.
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`For example, an antibiotic tetracycline compound of the invention is
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`advantageously administered in an amount that results in a serum tetracycline
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`concentration which is 10—80% of the minimum antibiotic serum concentration. The
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`minimum antibiotic serum concentration is the lowest concentration known to exert a
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`significant antibiotic effect.
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`Some examples of the plasma antibiotic threshold levels of tetracyclines based
`on steady—state pharmacokinetics are as follows: 1.0 ,LLg/ml for doxycycline; 0.8 ug/ml
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`for minocycline; and 0.5 ug/ml for tetracycline.
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`The amount administered will vary depending on various factors as is known
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`in the art, such as the size of the mammal, the specific tetracycline compound used,
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`etc. The amount can be determined by one skilled in the art.
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`In general, the amount of the tetracycline compound released will provide a
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`blood serum level of tetracycline that has the desired therapeutic activity, but no
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`antibiotic activity. Some examples of blood serum levels of tetracycline include a
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`minimum of about 0.1 ug/ml, preferably about 0.3 ug/ml; and a maximum of aboutl.0
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`ug/ml, more preferably about 0.8 ug/ml. For example, when the tetracycline
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`compound utilized is doxycycline, it is preferred that a serum of about 0.4 to about 0.8
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`ug/ml be maintained.
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`The controlled release agent in the composition is designed to maintain the
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`specified serum concentration levels over an extended period of time, for example 6,
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`8, 12, or 24 hours at a substantially constant rate. It is preferred that the controlled
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`release agent release the tetracycline compound in the mammal to provide the
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`specified sub-antibiotic serum concentration levels for at least 12-24 hours.
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`Other ingredients can be used in accordance with the present invention to
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`improve the tetracycline composition. Such ingredients include binders, which
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`contribute to the ease of formation and general quality of the tablet; lubricants, Which
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`aid in compressing and compacting the tablet; and flow agents or glidants, which
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`adhere to the cohesive material in order to enhance flow properties by reducing
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`interparticle friction.
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`Examples of useful binders include calcium sulfate, calcium carbonate,
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`microcrystalline cellulose, starches, lactose, sucrose, mannitol, sorbitol,
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`polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,
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`ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. A
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`preferred binder is microcrystalline cellulose, such as Avicel PH—lOl sold by FMC
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`Corporation.
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`Lubricants can include, but are not limited to, the following: magnesium
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`stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oils,
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`sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol, sodium benzoate,
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`sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil. Of these, the
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`preferred lubricants are magnesium stearate and stearic acid.
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`Flow agents or glidants which can be used include starch, talc, magnesium and
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`calcium stearate, zinc stearate, dibasic calcium phosphate, magnesium carbonate,
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`magnesium oxide, calcium silicate, silicon dioxide and silica aerogels. A preferred
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`flow agent or glidant is silicon dioxide.
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`A tablet having sufficient mechanical strength and an acceptable release
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`profile can be produced, for example, by mixing a powdered tetracycline compound
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`with HPMC and suitable binders, lubricants and flow agents and compressing the
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`mixture in a tablet press. A typical compression force used in forming the tablets is in
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`the range of about 45 to about 56 KN, preferably about 50 to about 53 KN, to achieve
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`a tablet having a hardness in the range of about 15 kp to about 30 kp, preferably about
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`18 kp to about 25 kp.
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`The invention is also directed to a unit dosage for controlled delivery of a
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`tetracycline compound. The unit dosage utilizes the controlled-release tetracycline
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`composition, as described above, to deliver the tetracycline compound to a mammal
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`substantially Without antibiotic activity in the mammal at a substantially constant rate
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`over a designated time period. The unit dosage being administered can have a release
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`time selected, for example, from about 6, 8, 12 and 24 hours. 12—24 hours is
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`preferred.
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`The unit dosage provides a dosage of antibiotic tetracycline to create a blood
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`serum tetracycline concentration of about 0.1 to about 1.0 ug/ml, more preferably
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`about 0.3 to about 0.8 ug/ml. For example, When the tetracycline utilized is
`doxycycline, it is preferred that a serum of between about 0.4—0.8 ug/ml be
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`maintained.
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`The unit dosage can be administered in the form of a liquid, for example, in a
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`suspension or solution, or alternatively in solid form, such as a tablet, pellet, particle,
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`capsule, or soft gel. A tablet or capsule is preferred.
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`One embodiment of the unit dosage is a capsule which contains beadlets.
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`Within each capsule are beadlets which are coated with various coatings that dissolve
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`at different pH levels.
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`A method is also provided herein for treating a mammal with tetracycline
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`compounds. The method includes administering a tetracycline composition to a
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`mammal as set forth above. The composition includes a tetracycline compound that
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`can be an antibiotic tetracycline compound, non-antibiotic tetracycline compound, or
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`combinations thereof. The composition also includes a controlled-release matrix
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`having at least one controlled—release agent. The tetracycline compound is associated
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`with the controlled—release matrix such that the mammal is treated with the
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`tetracycline substantially Without antibiotic activity.
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`Any suitable form of administration may be utilized. Systemic administration
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`is preferred. Examples of systemic administration are enteral and parenteral.
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`Enteral administration is a preferred route of delivery of the tetracycline
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`composition, and compositions including the tetracycline compound with appropriate
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`diluents, carriers, and the like are readily formulated. Liquid or solid (e.g., tablets,
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`gelatin capsules) formulations can be employed.
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`In a preferred embodiment, the controlled-release composition is entrapped in
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`the upper portion of the gastrointestinal tract, for example, the stomach or duodenum.
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`Such compositions are typically manufactured by utilizing controlled-release agents
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`of a larger particle size, as is known in the art. It is preferred that at least 50%, more
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`preferably greater than 80% of the tetracycline in the composition be released in the
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`upper GI tract.
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`By entrapping the tetracycline composition in the upper portion of the GI tract,
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`the loss of tetracycline uptak