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`am PTO—|390 (Modified)
`i
`
`
`,_ TRANSMITTAL LETTER TO THE UNITEI5 STATES
`512-47 PCTIUS
`
`. §
`DESIGFIATEDIELECTED OFFICE (DOIEOIUS)
`
`U.S. APPLICATION NO.‘ (IF KNOWN, SEE 3'.-' CFR
`sh
`CONCERNING A FILING UNDER 35 U.S.C. 371
`1 0/ 474 2 4 O
`
`-- ~
`_
`-
`'ATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`PRIORITY DATE CLAIMED
`-'~'
`-
`PCTfUS02Il0748
`05 A . ril 2002
`05 A - ril 2001
`
`I
`
`ll!
`
`Ill
`
`
`
`
`
`
`
`
`
`
`'.::
`-.'-:'—..
`
`OF INVENTION
`..- rolled Delivery of Tetracycline Compounds and Tetracycline Derivatives
`
`I
`
`FPLICa'NT(s) FOR Doieorus
`Robert A. Ashley
`
`to/an/at
`
`—
`
`A pplicant herewith submits to the United States Designated!Elecled Office (DOIEOJUS) the following items and other information:
`
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`The US has been elected by the expiration of 19 months from the priority date (Article 3 l).
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`A copy of the International Application as filed (35 U.S.C. 371 (c) (2))
`a. CI
`is attached hereto (required only if not communicated by the International Bureau).
`
`b. C]
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`has been communicated by the International Bureau.
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`is not required, as the application was filed in the United States Receiving Office (ROIU S).
`c. E
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`a. D is attached hereto.
`
`_'\
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`b. E]
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`has been previously submitted under 35 U.S.C. l54(d)(4).
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`Amendments to the claims ofthe International Application under PCT Article I9 (35 U.S.C. 371 (c)(3})
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`CFR
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`INTERNATIONAL APPLICATION NO.
`..-
`pcrxusoznona
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`SIGNATURE
`
`Ronald J' B3 mu
`NAME
`
`21281
`REGISTRATION NUMBER
`
`03 October 2003
`
`DATE
`
`Page 2 of 2
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`PCTFUSOZI10748
`urns Hera PCT/PTO 0 3 OCT W5
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`5
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`CONTROLLED DELIVERY OF
`TETRACYCLINE COMCPOUNDS AND TETRACYCLINE DERIVATIVES
`
`10
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`15
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`CROSS-REFERENCE TO RELATED APPLICATION
`
`This application claims the benefit of U.S. Provisional Application No.
`
`60128 1,854, filed April 5, 2001, which is incorporated herein by reference.
`
`BACKGROUND OF INVENTION
`
`The invention relates to delivering a tetracycline compound to a mammal.
`
`More specifically, the invention relates to controlled release of a tetracycline
`
`compound or derivative thereof for treatment of a mammal in the absence of
`
`20
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`antibiotic activity (i.e. antimicrobial activity).
`
`Tetracycline and a number of its chemical relatives form a particularly
`
`successful class of antibiotics. Certain of the tetracycline compounds, including
`
`tetracycline itself, as Well as sporocycline, etc., are broad spectrum antibiotics, having
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`25
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`utility against a wide variety of bacteria.
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`Conventional tetracycline compositions are designed to optimize their ‘
`
`antibiotic properties. The conventional compositions operate by creating a spike i.n
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`serum concentration followed by a rapid diminution in serum concentration.
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`30
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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
`
`compositions to be administered often, e.g every 3-6 hours.
`
`Tetzraeyclines have been described as having a number of other therapeutic
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`35
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`uses in addition to their antibiotic properties. For example, tetracyclines are also
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`PCTIUSOZI 10748
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`known to inhibit the activity of collagen destmctive enzymes such as mammalian
`
`collagenase, gelatinase, macrophage elastase and bacterial collagenase- Golub et al.,
`
`J. Perfodorrt. Res. 20:12-23 (1985); Golub et al. Crit. Revs. Oral Biol. Med. 2:
`
`297-322 (1991);U.S. Pat. Nos. 4,666,897; 4,704,383; 4,935,411; 4,935,412. In
`
`addition, tetracyclines have been known to inhibit wasting and protein degradation in
`
`mammalian skeletal muscle, U.S. Pat. No. 5,045,538.
`
`Furthermore, tetracyclines have been shown to enhance bone protein synthesis
`
`in U.S. Pat. No. Re. 34,656, and to reduce bone resorption in organ culture in U.S.
`
`10
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`Pat. No. 4,704,383.
`
`Similarly, U.S. Pat. No. 5,532,227 to Golub et al, discloses that tetracyclines
`
`can ameliorate the excessive glycosylation of proteins. In particular, tetracyclines
`
`inhibit the excessive collagen cross linking which results from excessive
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`15
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`glycosylation of collagen in diabetes.
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`These properties cause the tetmcyclines to be useful in treatinga number of
`
`diseases. For example, there have been a number of suggestions that tetracyclines,
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`including non—anI:ibiotic tetracyclines, are effective in treating arthritis. See, for
`
`example, Greenwalcl et al., "Tetracyclines Suppress Metalloproteinase Activity in
`
`Adjuvant Arthritis and, in Combination with Flurbiprofen, Ameliorate Bone
`
`Damage," Journal ofRheumatology 19:92‘?-9386992); Greenwald et al., "Treatment
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`of Destructive Arthritic l__)isorders with NEMIP Inhibitors: Potential Role of
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`Tetracyclines in, Inhibition of Matrix Metal1oproteinases:Therapeutic Potential,"
`
`Anrzals ofthe New York Academy ofSc1'ences 732: 181-198 (1994); Kloppenburg et
`
`al., "Minocycline in Active Rheumatoid Arthritis," Art!»-itz's Rheum
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`37:629-636(1 994); Ryan et a1., "Potential of Tetracycline to Modify Cartilage
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`Breakdown in 0steoar1.’on'1:is," Current Opinion in Rheumatalogy 8: 238-2470995);
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`O’DeII et al., "Treatment of Early Rheumatoid Arthritis with Minocycline or
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`Placebo," Arthritis Rheum 40:842-348(l 997).
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`Tetracyclines have also been suggested for use in treating skin diseases- For
`
`example, White et al., Lancet, Apr. 29, p. 966 (1989) report that minocycline is
`
`effective in treating dystmphic epidennolysis bullosa, which is a Iife—threaten.ing skin
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`condition believed to be related to excess collagenase.
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`The efiectiveness of tetracycline in skin disorders has also been studied by
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`Elewski et al., Journal ofthe American Academy ofDermatology 8: 807-812 (1983).
`
`Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory
`
`activity in skin diseases.
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`10
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`Similarly, Plewig et 211., Journal ofInvestigative Dermatology 65: 532 (1975),
`
`disclose experiments designed to test the hypothesis that antibiotics are effective in
`
`treating inflammatory derrnatoses. The experiments of Plewig et al. establish that
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`tetracyclines have anti—in.flammatory properties in treating pustules induced by
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`15
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`potassium iodide patches.
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`The use of tetracyclines in combination with non—steroidal anti-inflammatory
`
`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 ofDermatoiogy 1:
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`10764081 (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 at
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`al., Journal ofthe American Academy ofDermatology 13: 524-525 (1985), disclosed
`similar results by combining antibiotic doses of minocycline with ibuprofen.
`
`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 Iipopolysaccbaride (hereinafter LPS), exerted a protective effect by
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`inhibiting nitrate production by an IL-10 independent mechanism.
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`Therefore, there are numerous uses for tetracycline compounds aside from
`their antibiotic activity. While tetracycline antibiotics are generally effective for
`treating infection, the use of these compounds can lead to undesirable side effects.
`
`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
`
`tetracycline compounds to a mammal that, unlike conventional compositions,
`
`provides a dosage below that which is required for an antibiotic response in the
`
`mammal at a relatively "constant serum level with a longer serum half—life.
`
`SIIMMARY OF INVENTION
`
`The present invention includes a composition for delivering a tetracycline
`
`compound to a mammal. The composition includes an antibiotic tetracycline
`
`compound and at least one controlled-release agent. The tetracycline compound is
`
`associated with the contro11ed—re1ease agent to provide a tetracycline-release profile
`
`characterized by delivery of a dose below that which is required for antibiotic activity
`
`(i.e. antimicrobial activity) such that the mammal is treated with a tetracycline
`
`compound substantially without antibiotic activity.
`
`The amount of the tetracycline compound released by the composition can
`
`vary, as long as it is below the threshold blood serum concentration level required for
`
`antibiotic activity. In general, the blood serum level will be between about 0.1 and
`
`1.0 pg/ml, preferably between about 0.3 and 0.8 pg/ml. This release profile should be
`
`maintained at a substantially constant rate for between about 6-24 hours.
`
`In a preferred embodiment, the tetracycline is doxycycline. The preferred
`
`blood serum level of doxycycline is 0.4-0.8 uglrnl. over a period of 12-24 hours.
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`The composition also can include a controlled-release agent selected from the
`
`group consisting of an instantaneous-release agent, a sustained-release agent, a
`
`delayed—release agent, and combinations thereof. In one embodiment, the
`
`composition can contain all three release agents associated with the tetracycline
`
`compound to provide a substantially constant dosage rate over a designated time
`
`period.
`
`The present invention also includes a method of treating a mammal with a
`
`tetracycline compound. The method includes administering to the mammal a
`
`tetracycline compound which is associated with at least one controlled-release agent
`
`to provide a release profile having nonantibiotic activity over a pre-selected time
`
`period, preferably 6-24 hours.
`
`The method also can include a controlled-release agent selected from the
`
`group consisting of an instantaneous—release agent, a sustained-release agent, a
`
`delayed-release agent, and combinations thereof. In one embodiment, the
`
`composition can contain all three release agents associated with the tetracycline
`
`compound to provide a substantially constant dosage rate over a designated time
`
`period.
`
`A unit dosage is also provided for controlled delivery of a tetracycline
`
`compound. The unit dosage includes a tetracycline compound and at least one
`
`controlled-release agent. The tetracycline compound is associated with the
`
`controlled-release agent-to provide a tetracycline release profile in the mammal
`
`substantially without antibiotic activity. In preferred embodiments, the unit dosage is
`
`either a capsule or a tablet.
`
`The composition for delivering a tetracycline compound to a mammal and the
`
`corresponding method of treating a mammal with a tetracycline compound, as
`
`described herein, provides a number of benefits over conventionally utilized
`
`controlled delivery compositions for administration of a tetracycline compound.
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`PCTIUSO 2! 10748
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`First, by administering the tetracycline compound in a dose below that which
`
`is necessary to provide an antibiotic response, undesirable side effects, such as the
`
`reduction of healthy flora in the body, the production of antibiotic resistant organisms,
`
`or the overgrowth of opportunistic yeast and fungi, are avoided.
`
`Second, the controlled release composition of the invention increases patient
`
`compliance. Instead of administering a low dose of a tetracycline compound many
`
`times during the day, the composition of the invention allows the patient to administer
`
`the tetracycline compound one or two times a day. The controlled release of the
`
`tetracycline compound creates the desired dose profile helowthat which is necessary
`
`for an antibiotic response in the mammal.
`
`The composition of the invention also avoids the reduction in tetracycline
`
`uptake after eating. Very often, with conventional tetracycline compounds, the
`
`percentage of the tetracycline compounds reaching the bloodstream from the GI tract
`
`will decrease once the mammal begins eating. This reduction in tetracycline uptake is
`
`ameliorated with a composition that can be taken once or twice a day, especially with
`
`a controlled release formula that can remain entrapped in the upper portion of the GI
`
`tract as opposed to the small intestine.
`
`Additionally, because the serum concentrations with the composition of the
`
`invention remain substantially lower than peak serum concentrations from an
`
`equivalent dosage administered. as an immediate release formulation, the risk of
`phototoxicity encountered with conventional tetracycline compositions is reduced.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 depicts a tetracycline release profile utilizing a combination of three
`
`different contro1led—release agents which are associated with a tetracycline compound
`
`in a composition according to the present invention.
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`DETAILED DESCRIPTION or INVENTION
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`The composition of the invention is designed to provide a release profile that
`
`is the direct opposite of the conventional profile, described above. More specifically,
`
`the composition of the invention provides for the controlled release of a tetracycline
`
`compound to a mammal whereby there is substantially no antibiotic activity in the
`
`mammal. The composition of the invention provides its therapeutic efiect by
`
`providing a dose of the tetracycline compound below that which is required to
`
`produce an antibiotic effect in the mammal at a substantially constant rate over a
`
`longer period of time, e.g. 12-24 hours.
`
`The composition of the invention is administered to a mammal. Mammals
`
`include, for example, humans, as well as pet animals such as dogs and cats, laboratory
`
`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
`
`tetracycline derivative, as described above, possessing antibiotic activity when
`
`administered above the required serum level threshold, as is known in the art.
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`20
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`The parent compound, tetracycline, has the following generallstructure:
`
`
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`25
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`The numbering system of the multiple ring nucleus is as follows:
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`PC TIU S02! 1 0748
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`Tetracycline, as well as the 5-OH (oxytetracycline, e.g. Terrarnycin) and '?--C1
`(chlorotetracycline, e.g. Aureomycin) derivatives, exist in nature, and are all Well
`known antibiotics. Sernisynthetic derivatives such as 7—dimetl1ylan1ino-tetracycline
`
`(minocycline) and 6o:-deoxy-S-hydroxy-tetracycline (doxycycline) are also known
`
`tetracycline antibiotics- Natural tetracyclines may be modified without losing their
`
`antibiotic properties, although certain elements of the structure must be retained to do
`
`so. Preferred antibiotic tetracyclines include tetracycline, doxycycline,
`
`demeclocycline, minocycline, and lymecycline.
`
`A class of compounds has also been defined which are structurally related to
`
`the antibiotic tetracyclines, but which have had their antibiotic activity substantially or
`
`completely expunged by chemical modification. The modifications that may and may
`
`not be made to the basic tetracycline structure were reviewed by Mitscher, L.A., The
`
`Chemistry of the Tetracycline Antibiotics, Marcel Dekker, New York (1973), Ch. 6.
`
`According to Mitscher, the modification at positions 5-9 of the tetracycline ring
`
`system can be made without causing the complete loss of antibiotic properties.
`
`However, changes to the basic stmcture of the ring system, or replacement of
`
`substituents at positions 1-4 or 10-12, generally lead to synthetic tetracyclines with
`substantially less, or essentially no, antibacterial activity.
`
`The composition of the invention can include, in addition to the tetracycline
`
`compound, one or more other therapeutic agents. The combination of the tetracycline
`
`compound with such other agents can potentiate the therapeutic protocol. The
`
`composition of the invention can also include a combination of the tetracycline
`
`compound in a suitable pharmaceutical carrier (vehicle) or excipient as understood by
`
`practitioners in the art.
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`PCTfUS02l10 748
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`In addition to the tetracycline compound, the composition of the invention
`includes ‘at least one controlled-release agent. Controlled-release agents are known in
`
`theart. See for example, U.S. Patent Nos- 4,837,030; 5,262,164; 5,582,837;
`
`5,681,535; 5,216,631; 5,736,152; 5,840,332; 5,355,915; 6,007,843; 6,020,002;
`6,120,803; and 6,143,353.
`'
`
`The composition of the invention can include various relative amounts of the
`
`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-profile 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 sufiicient 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, andfor secondary chemical bonding,
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`e.g., Vander Waals forces, etc. The tetracycline compoundfcontrolled-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
`tetracycline as a result of normal interaction of the mammal biosystem on the
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`tetracyclinefcontrolled-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, orcombination 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 firorn the
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`group consisting of hydroxypropyl methyl cellulose (I-IPNIC), hydroxyethyl cellulose
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`(1-EEC), hydroxypropyl cellulose (I-IPC), carboxy methyl cellulose (CMC), and
`mixtures thereof. Of these, the most preferred water soluble cellulose polymer is
`I-IPMC.
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`Preferably the HIPMC is a high molecular weight I-IPMC, 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 I-lI’MC having anaverage 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, rnyristyl alcohol,
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`stearyl alcohol, cetyl alcohol and stearic acid. I-Iydrophilic 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, veegum,
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`xanthin gum, carboxymethyl cellulose (CMC), hydroxy propyl cellulose (I-IPC) and
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`hydroxy ethyl cellulose (I-EEC).
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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 embodiment, the tetracycline compoundfcontrolled-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 n1aterial(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—swol1en 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
`time period, andmost 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 pharrnacolcinetics are as follows: 1.0 ,u.g/ml for doxycycline; 0.8 ugiml
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`for minocycline; and 0.5 pg/rnl 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 O.1].Lg/ml, preferably about 0.3 ug/ml; and a maximum of about1.0
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`ttg/ml, more preferably about 0.8 pg/ml. For example, when the tetracycline
`compound utilized is doxycycline, it is preferred‘ that a serum of about 0.4 to about 0.8 _
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`uglml 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; lubricanm, 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 isrnicrocrystallizie cellulose, such as Avicel PH-101 sold by FMC
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`Corporation.
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`Lubricant