Docket Number: 512-47P
`
`CONTROLLED DELIVERY OF
`TETRACYCLINE AND TETRACYCLINE DERIVATIVES
`
`BACKGROUND OF INVENTION
`
`The invention relates to delivering a tetracycline to a host. More specifically,
`
`the invention relates to controlled release of a tetracycline compound or derivative
`
`thereof for treatment of a host in the absence of antimicrobial activity.
`
`5
`
`10
`
`15
`
`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
`
`utility against a wide variety of bacteria. The parent compound, tetracycline, has the
`
`20
`
`following general structure:
`
`HO
`
`I;I ~(CH3)2
`OH
`=
`:
`
`CONH2
`
`OH
`
`0
`Structure A
`
`25
`
`The numbering system for the multiple ring nucleus is as follows:
`
`30
`
`Structure B
`
`

`

`Tetracycline, as well as the 5-0H (terramycin) and 7-Cl (aureomycin)
`
`derivatives, exist in nature, and are all well known antibiotics. Semisynthetic
`
`derivatives such as 7-dimethylamino-tetracycline (minocycline) and 6a.-deoxy-5-
`
`hydroxy-tetracycline (doxycycline) are also known antibiotics. Natural tetracyclines
`
`5 may be modified without losing their antibiotic properties, although certain elements
`
`of the structure must be retained to do so.
`
`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
`
`1 0
`
`completely expunged by chemical modification. The modifications that may and may
`
`not be made to the basic tetracycline structure have been reviewed by Mitscher
`
`(1978). According to Mitscher, modification at positions 5-9 of the tetracycline ring
`
`system can be made without causing the complete loss of antibiotic properties.
`
`15
`
`Conventional tetracycline compositions are designed to optimize their anti(cid:173)
`
`microbial properties. The conventional compositions operate by creating a spike in
`
`serum concentration followed by a rapid diminution in serum concentration.
`
`Accordingly, relatively high doses are administered which have a short serum
`
`concentration half-life. This short serum half-life requires the conventional
`
`20
`
`compositions to be administered often, e.g every 3-6 hours.
`
`Tetracyclines have been described as having a number of other therapeutic
`
`uses in addition to their anti-microbial properties. For example, tetracyclines are also
`
`known to inhibit the activity of collagen destructive enzymes such as mammalian
`
`25
`
`collagenase, gelatinase, macrophage elastase and bacterial collagenase. Golub et al.,
`
`J Periodont. Res. 20:12-23 (1985); Golub et al. Crit. Revs. Oral Bioi. ivted. 2:
`
`297-322 (199l);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.
`
`30
`
`2
`
`

`

`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.
`
`Pat. No. 4,704,383.
`
`5
`
`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
`
`glycosylation of collagen in diabetes.
`
`10
`
`These properties cause the tetracyclines to be useful in treating a number of
`
`diseases. For example, there have been a number of suggestions that tetracyclines,
`
`including non-antimicrobial tetracyclines, are effective in treating arthritis. See, for
`
`example, Greenwald et al., "Tetracyclines Suppress Metalloproteinase Activity in
`
`Adjuvant Arthritis and, in Combination with Flurbiprofen, Ameliorate Bone
`
`15 Damage," Journal of Rheumatology 19:927-938(1992); Greenwald et al., "Treatment
`
`ofDestructive Arthritic Disorders with MMP Inhibitors: Potential Role of
`
`Tetracyclines in, Inhibition of Matrix Metalloproteinases:Therapeutic Potential,"
`
`Annals ofthe New York Academy ofSciences 732: 181-198 (1994); Kloppenburg et
`
`al., "Minocycline in Active Rheumatoid Arthritis," Arthritis Rheum
`
`20
`
`37:629-636(1994); Ryan et al., "Potential of Tetracycline to Modify Cartilage
`
`Breakdown in Osteoarthritis," Current Opinion in Rheumatology 8: 238-247(1996);
`
`O'Dell et al., ,Treatment of Early Rheumatoid Arthritis with Minocycline or
`
`Placebo," Arthritis Rheum 40:842-848(1997).
`
`25
`
`Tetracyclines have also been suggested for use in treating skin diseases. For
`
`example, White et al., Lancet, Apr. 29, p. 966 (1989) report that the tetracycline
`
`minocycline is effective in treating dystrophic epidermolysis bullosa, which is a
`
`life-threatening skin condition believed to be related to excess collagenase.
`
`30
`
`The effectiveness of tetracycline in skin disorders has also been studied by
`
`Elewski et al., Journal ofthe American Academy of Dermatology 8:807-812 (1983).
`
`3
`
`

`

`Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory
`
`activity in skin diseases.
`
`Similarly, Plewig et al., Journal of Investigative Dermatology 65:532 (1975),
`
`5
`
`disclose experiments designed to test the hypothesis that antimicrobials are effective
`
`in treating inflammatory dermatoses. The experiments ofPlewig et al. establish that
`
`tetracyclines have anti-inflammatory properties in treating pustules induced by
`
`potassium iodide patches.
`
`10
`
`The use of tetracyclines in combination with non-steroidal anti-inflammatory
`
`agents has been studied in the treatment of inflammatory skin disorders caused by
`
`acne vulgaris. Wong et al., Journal of American Academy of Dermatology 1:
`
`1076-1081 (1984), studied the combination oftetracycline and ibuprofen and found
`
`that tetracycline was an effective agent against acne vulgaris while ibuprofen was
`
`15
`
`useful in reducing the resulting inflammation by inhibition of cycloxygenase. Funt et
`
`al., Journal of the American Academy of Dermatology 13: 524-525 (1985), disclosed
`
`similar results by combining antimicrobial doses of minocycline with ibuprofen.
`
`An antimicrobial tetracycline derivative, doxycycline, has been used to inhibit
`
`20
`
`nitrate production. D' Agostino et al., Journal of Jrifectious Diseases: 177:489-92
`
`(1998), disclose experiments where doxycycline, administered to mice injected with
`
`bacterial lipopolysaccharide (hereinafter LPS), exerted a protective effect by
`
`inhibiting nitrate production by an IL-l 0 independent mechanism.
`
`25
`
`Therefore, there are numerous uses for tetracycline compounds aside from
`
`their antimicrobial 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 microbial flora, such as intestinal flora, and can lead to the
`
`30
`
`production of antibiotic resistant organisms or the overgrowth of yeast and fungi.
`
`4
`
`

`

`Accordingly, there is a need for a composition for controlled delivery of
`
`tetracycline to a host that, unlike conventional compositions, provides a dosage below
`
`that which is required for an anti-microbial response in the host at a relatively
`
`constant serum level with a longer serum half-life.
`
`5
`
`SUMMARY OF INVENTION
`
`The present invention includes a composition for delivering tetracycline to a
`
`host. The composition includes an anti-microbial tetracycline compound and at least
`
`10
`
`one controlled-release agent. The tetracycline compound is associated with the
`
`controlled-release agent to provide a tetracycline-release profile delivering a dose
`
`below that which is required for anti-microbial activity, such that the host is treated
`
`with the tetracycline substantially without anti-microbial activity.
`
`15
`
`The amount of tetracycline released by the composition can vary, as long as it
`
`is below the threshold blood serum concentration level required for anti-microbial
`
`activity. In general, the blood serum level will be between about 0.1 and 1.0 Jlg/ml,
`
`preferably between about 0.3 and 0.8 Jlg/ml. This release profile should be
`
`maintained at a substantially constant rate for between about 6-24 hours.
`
`20
`
`In a preferred embodiment, the tetracycline is doxycycline. The preferred
`
`blood serum level of doxycycline is 0.4-0.8 Jlg/ml. over a period of 12-24 hours.
`
`The composition also can include a controlled-release agent selected from the
`
`25
`
`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 to
`
`provide a substantially constant dosage rate over a designated time period.
`
`30
`
`The present invention also includes a method of treating a host with
`
`tetracycline. The method includes administering to the host a tetracycline which is
`
`associated with at least one controlled-release agent to provide a release profile
`
`5
`
`

`

`having a non-anti-microbial activity over a pre-selected time period, preferably 6-24
`
`hours.
`
`The method also can include a controlled-release agent selected from the
`
`5
`
`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 to
`
`provide a substantially constant dosage rate over a designated time period.
`
`10
`
`A unit dosage is also provided for controlled delivery of a tetracycline. 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 host substantially without anti-microbial
`
`activity. In preferred embodiments, the unit dosage is either a capsule or a tablet.
`
`15
`
`20
`
`25
`
`The composition for delivering tetracycline to a host and the corresponding
`
`method of treating a host with tetracycline, as described herein, provides a number of
`
`benefits over conventionally utilized controlled delivery compositions for
`
`administration of tetracycline.
`
`First, by administering the tetracycline in a dose below that which is necessary
`
`to provide an anti-microbial 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 tetracycline many times during
`
`the day, the composition of the invention allows the patient to administer the
`
`tetracycline one or two times a day. The controlled release of the tetracycline creates
`
`30
`
`the desired dose profile below that which is necessary for an anti-microbial response
`
`in the host.
`
`6
`
`

`

`The composition of the invention also avoids the reduction in tetracycline
`
`uptake after eating. Very often, with conventional tetracycline compositions, the
`
`percentage of tetracycline reaching the bloodstream from the GI tract will decrease
`
`once the host begins eating. This reduction in tetracycline uptake is ameliorated with
`
`5
`
`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
`
`10
`
`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
`
`15
`
`20
`
`Figure 1 depicts a tetracycline release profile utilizing a combination of three
`
`different controlled-release agents which are associated with a tetracycline compound
`
`in a composition according to the present invention.
`
`DETAILED DESCRIPTION OF INVENTION
`
`As discussed above, conventional tetracycline compositions are designed to
`
`optimize their anti-microbial properties. The conventional compositions operate by
`
`creating a spike in serum concentration followed by a rapid diminution in serum
`
`25
`
`concentration. Accordingly, relatively high doses are administered which have a
`
`short serum concentration half-life. This short serum half-life requires the
`
`conventional compositions to be administered often, e.g every 3-6 hours.
`
`The composition of the invention is designed to provide a release profile that
`
`30
`
`is the direct opposite of the conventional profile. More specifically, the composition
`
`of the invention provides for the controlled release of tetracycline to a host whereby
`
`there is substantially no anti-microbial activity in the host. The composition of the
`
`7
`
`

`

`invention provides its therapeutic effect by providing a dose of tetracycline below that
`
`which is required to produce an anti-microbial effect in the host at a substantially
`
`constant rate over a longer period of time, e.g. 12-24 hours.
`
`5
`
`The composition of the invention can be used in any biological system defined
`
`herein as a "host." The biological system can be in vitro, ex vivo, or in vivo. In vitro
`
`biological systems typically include cultured cells or tissues, but may involve isolated
`
`or purified organelles or cellular components. Diagnostic tests are typically
`
`performed in vitro. Ex vivo biological systems typically include organ systems
`
`10
`
`removed from a living animal and human. In vivo uses are directed to biological
`
`systems that are living animals, and such uses typically include therapeutic or
`
`pharmaceutical interventions. Thus, embodiments of the invention in which a
`
`tetracycline compound is administered to a mammal are representative of in vivo
`
`methods. Mammals include, for example, humans, as well as pet animals such as
`
`15
`
`dogs and cats, laboratory animals such as rats and mice, and farm animals such as
`
`horses and cows.
`
`"Tetracycline compound" as defined herein refers to any tetracycline or
`
`tetracycline derivative possessing anti-microbial activity when administered above the
`
`20
`
`required serum level threshold, as is known in the art.
`
`Tetracycline exhibits the following general structure:
`
`25
`
`30
`
`CONHQ
`
`OH 0
`Structure A
`
`The numbering system of the multiple ring nucleus is as follows:
`
`8
`
`

`

`Structure B
`
`Tetracycline, as well as the 5-0H (oxytetracycline, e.g. Terramycin) and 7-Cl
`
`5
`
`( chlorotetracycline, e.g. Aureomycin) derivatives, exist in nature, and are all well
`
`known antibiotics. Semisynthetic derivatives such as 7-dimethylamino-tetracycline
`
`(minocycline) and 6a-deoxy-5-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
`
`10
`
`so. Preferred antimicrobial tetracyclines include tetracycline, doxycycline,
`
`demeclocycline, minocycline, and lymecycline.
`
`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
`
`15
`
`Antibiotics, Marcel Dekker, New York (1978), 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
`
`structure 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,
`
`20
`
`antibacterial activity.
`
`The composition of the invention can include with 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
`
`25
`
`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.
`
`In addition to the tetracycline compound, the composition of the invention
`
`includes at least one controlled-release agent. Controlled-release agents are known in
`
`30
`
`the art. The tetracycline compound is associated with the controlled release matrix to
`
`9
`
`

`

`provide a tetracycline-release-profile in the host whereby the host is treated with the
`
`tetracycline compound substantially without antimicrobial activity. It is preferred that
`
`the controlled-release matrix be capable of releasing the tetracycline compound in an
`
`amount and at a rate sufficient to maintain an effective tetracycline blood serum level
`
`5
`
`over a designated time period.
`
`The tetracycline and controlled-release agent are associated with each other
`
`physically (e.g., by mechanical means such as mixing, mulling, compacting, etc.)
`
`and/or chemically, such as by chemical reaction, and/or secondary chemical bonding,
`
`10
`
`e.g., Van der Waals forces, etc. The tetracycline compound/controlled-release agent
`
`combinations are included in the invention composition in an amount sufficient to
`
`provide a highly predictable pre-selected release profile of the therapeutically active
`
`tetracycline as a result of normal interaction of the host biosystem on the
`
`tetracycline/controlled-release matrix system combination.
`
`15
`
`The controlled-release agent can include one or more ingredients for
`
`controlling the rate at which the tetracycline component is made available to
`
`biological system of the host. The controlled-release agent can include an
`
`instantaneous release agent, a delayed release agent, a sustained release agent, or any
`
`20
`
`combination thereof.
`
`An instantaneous release agent is self-explanatory in that it refers to an
`
`ingredient which promotes or enhances immediate release to the host. The
`
`instantaneous release agent can be an additional ingredient that enhances dispersion of
`
`25
`
`the tetracycline throughout the bio-system. An example of an instantaneous release
`
`agent is a surfactant.
`
`A sustained release agent is an ingredient, or combination of ingredients,
`
`which permits release of the tetracycline to the host at a certain level over a period of
`
`30
`
`time. Examples of sustained release agents include gels, waxes, fats, emulsifiers,
`
`combinations of fats and emulsifiers, polymers, starch, cellulose polymers, etc., as
`
`well as combinations thereof. The sustained release agent can also include, for
`
`10
`
`

`

`example, the above in combination with other polymeric or biodegradable coatings or
`
`matrices.
`
`A delayed release agent is an ingredient which prevents the active ingredient,
`
`5
`
`i.e., tetracycline, from being made available to the host until some time after initial
`
`administration. The delayed release agent prevents release of tetracycline until some
`
`time in the future. Examples of delayed release agents include, but are not limited to,
`
`polymeric or biodegradable coatings or matrices, including cellulose polymers, and
`
`combinations thereof.
`
`10
`
`In a preferred embodiment, the composition of the invention comprises more
`
`than one of the controlled-release agents, and can include, all three types of
`
`controlled-release agents, i.e., an instantaneous release agent, a sustained release
`
`agent, and a delayed release agent. Using all three types of controlled-release agents
`
`15
`
`can produce a tetracycline profile that administers the tetracycline in a specific dose
`
`over an extended period of time, e.g., 12-24 hours. Figure 1 depicts a tetracycline
`
`release profile utilizing an instantaneous, delayed, and sustained controlled-release
`
`agent.
`
`20
`
`The sustained controlled-release agent preferably consists of a cellulose
`
`polymer, preferably a high molecular weight cellulose polymer, selected from the
`
`group consisting ofhydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose
`
`(HEC), hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), and
`
`mixtures thereof. Of these, the most preferred water soluble cellulose polymer is
`
`25 HPMC.
`
`Preferably the HPMC is a high molecular weight HPMC, with the specific
`
`molecular weight selected to provide the desired release profile. For example, a tablet
`
`designed to provide a substantially constant release rate over a 12 hour period will
`
`30
`
`preferably contain HPMC having an average molecular weight of at least about
`
`65,000, more preferably about 85,000.
`
`11
`
`

`

`The controlled-release component can also contain minor amounts of other
`
`materials which can affect the release profile. Examples of such materials include
`
`conventional waxes and waxy materials used in pharmaceutical formulations, such as
`
`canuba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol,
`
`5
`
`beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol,
`
`stearyl alcohol, cetyl alcohol and stearic acid. Hydrophilic gums are also
`
`contemplated for use, in minor amounts, which can have an effect on the release
`
`profile. Examples ofhydrophilic gums include acacia, gelatin, tragacanth, veegum,
`
`xanthin gum, carboxymethyl cellulose (CMC), hydroxy propyl cellulose (HPC) and
`
`10
`
`hydroxy ethyl cellulose (HEC).
`
`The tetracycline composition of the invention can be administered in the form
`
`of a liquid as a suspension or solution, or alternatively in solid form, such as a tablet,
`
`pellet, particle, capsule, or soft gel. For example, the form can be polymeric capsules
`
`15
`
`filled with solid particles which can, in turn, be made to release the tetracycline
`
`according to a known pattern or profile. Such particles can also be made to have
`
`more than one release profile so that over an extended time the combined release
`
`patterns provide a pre-selected profile.
`
`20
`
`In one embodiment, the tetracycline/controlled-release agent combination is
`
`administered in the form of a heterogeneous matrix, such as, for example, a
`
`compressed tablet, to control the release of the tetracycline either by diffusion, erosion
`
`of the matrix or a combination ofboth.
`
`25
`
`Other combinations of controlled release agent and tetracycline compound
`
`contemplated by the invention include a combination of polymeric material(s) and
`
`tetracycline which is formed into a sandwich, and which relies on, at least the physical
`
`disintegration actions of diffusion or erosion to controlledly release the tetracycline.
`
`Additionally, heterogeneous dispersions or solutions of tetracycline in water-
`
`30
`
`swellable hydrogel matrices are useful in controlling the release of the tetracycline by
`
`slow surface-to-center swelling of the matrix and subsequent release of the
`
`12
`
`

`

`tetracycline by a combination of diffusion of the tetracycline from the water-swollen
`
`part of the matrix and erosion of the water-swollen matrix containing the tetracycline.
`
`The sustained controlled-release agent will preferably provide for a sustained
`
`5
`
`release of tetracycline according to a desired release profile through the use of one or
`
`more of the release ingredients described above. More preferably, the controlled(cid:173)
`
`release agent will provide a release profile which releases the tetracycline compound
`
`at a substantially constant rate over a designated time period whereby the host is
`
`treated with the tetracycline substantially without anti microbial activity.
`
`10
`
`As the terminology is used herein, "substantially constant rate" refers to
`
`maintaining a release rate of the active ingredient, i.e., tetracycline, within a desired
`
`range over at least about 60 % of the designated time period for release, preferably
`
`over at least about 70 %, more preferably over at least about 80 % of the designated
`
`15
`
`time period, and most preferably over about 90%.
`
`The release profile in the composition of the invention provides substantially
`
`no anti-microbial activity. In other words, the dosage of tetracycline administered by
`
`the release profile is below the amount required for anti-microbial activity. This
`
`20
`
`amount will vary depending on various factors as is known in the art, such as the size
`
`of the host, the specific tetracycline compound used, etc.
`
`In general, the amount of tetracycline released will provide a blood serum
`
`level of tetracycline that has the desired therapeutic activity, but no antimicrobial
`
`25
`
`activity. Some examples ofblood serum levels of tetracycline include a minimum of
`
`about 0.1 f.1.g/ml, preferably about 0.3 llglml; and a maximum of aboutl.O !lg/ml, more
`
`preferably about 0.8 llg/ml. For example, when the tetracycline utilized is
`
`doxycycline, it is preferred that a serum of about 0.4 to about 0.8 llg/ml be
`
`maintained.
`
`30
`
`The controlled release agent in the composition is designed to maintain the
`
`specified serum concentration levels over an extended period of time, for example 6,
`
`13
`
`

`

`8, 12, or 24 hours at a substantially constant rate. It is preferred that the controlled
`
`release agent release the tetracycline in the host to provide the specified sub(cid:173)
`
`antimicrobial serum concentration levels for at least 12-24 hours.
`
`5
`
`Other ingredients can be used in accordance with the present invention to
`
`improve the tetracycline composition. Such ingredients include binders, which
`
`contribute to the ease of formation and general quality of the tablet; lubricants, which
`
`aid in compressing and compacting the tablet; and flow agents or glidants, which
`
`adhere to the cohesive material in order to enhance flow properties by reducing
`
`1 0
`
`interparticle friction.
`
`Examples ofuseful binders include calcium sulfate, calcium carbonate,
`
`microcrystalline cellulose, starches, lactose, sucrose, mannitol, sorbitol,
`
`polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,
`
`15
`
`ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. A
`
`preferred binder is microcrystalline cellulose, such as Avicel PH-101 sold by FMC
`
`Corporation.
`
`Lubricants can include, but are not limited to, the following: magnesium
`
`20
`
`stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oils,
`
`sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol, sodium benzoate,
`
`sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil. Of these, the
`
`preferred lubricants are magnesium stearate and stearic acid.
`
`25
`
`Flow agents or glidants which can be used include starch, talc, magnesium and
`
`calcium stearate, zinc stearate, dibasic calcium phosphate, magnesium carbonate,
`
`magnesium oxide, calcium silicate, silicon dioxide and silica aerogels. A preferred
`
`flow agent or glidant is silicon dioxide.
`
`30
`
`A tablet having sufficient mechanical strength and an acceptable release
`
`profile can be produced by mixing a powdered tetracycline component with HPMC
`
`and suitable binders, lubricants and flow agents and compressing the mixture in a
`
`14
`
`

`

`tablet press. A typical compression force used in forming the tablets is in the range of
`
`about 45 to about 56 KN, preferably about 50 to about 53 KN, to achieve a tablet
`
`having a hardness in the range of about 15 kp to about 30 kp, preferably about 18 kp
`
`to about 25 kp.
`
`5
`
`The invention is also directed to a unit dosage for controlled delivery of
`
`tetracycline. The unit dosage utilizes the controlled-release tetracycline composition,
`
`as described above, to deliver the tetracycline to a host substantially without anti
`
`microbial activity in the host at a substantially constant rate over a designated time
`
`10
`
`period. The unit dosage being administered can have a release time selected, for
`
`example, from about 6, 8, 12 and 24 hours. 12-24 hours is preferred.
`
`The unit dosage provides a dosage of anti microbial tetracycline to create a
`
`blood serum tetracycline concentration of about 0.1 to about 1.0 !lglml, more
`
`15
`
`preferably about 0.3 to about 0.8 !lglml. For example, when the tetracycline utilized
`
`is doxycycline, it is preferred that a serum of between about 0.4-0.8 !lglml be
`
`maintained.
`
`The unit dosage can be administered in the form of a liquid, for example, in a
`
`20
`
`suspension or solution, or alternatively in solid form, such as a tablet, pellet, particle,
`
`capsule, or soft gel. A tablet or capsule is preferred.
`
`A method is also provided herein for treating a host with tetracycline. The
`
`method includes administering a tetracycline composition to a host as set forth above.
`
`25
`
`The composition includes a tetracycline compound that can be an anti microbial
`
`tetracycline, non-anti microbial tetracycline, or combinations thereof. The
`
`composition also includes a controlled-release matrix having at least one controlled(cid:173)
`
`release agent. The tetracycline compound is associated with the controlled-release
`
`matrix such that the host is treated with the tetracycline substantially without anti
`
`30 microbial behavior.
`
`15
`
`

`

`Any suitable form of administration may be utilized. Systemic administration
`
`is preferred. Examples of systemic administration are enteral and parenteral.
`
`Enteral administration is a preferred route of delivery of the tetracycline
`
`5
`
`composition, and compositions including the tetracycline compound with appropriate
`
`diluents, carriers, and the like are readily formulated. Liquid or solid (e.g., tablets,
`
`gelatin capsules) formulations can be employed.
`
`In a preferred embodiment, the controlled-release composition is entrapped in
`
`10
`
`the upper portion of the gastrointestinal tract, for example, the stomach or duodenum.
`
`Such compositions are typically manufactured by utilizing controlled-release agents
`
`of a larger particle size, as is known in the art. It is preferred that at least 50%, more
`
`preferably greater than 80% of the tetracycline in the composition be released in the
`
`upper GI tract.
`
`15
`
`20
`
`By entrapping the tetracycline composition in the upper portion of the GI tract,
`
`the loss of tetracycline uptake encountered after eating is diminished. Also, the loss
`
`ofbeneficial flora in the small and large intestine is reduced, as compared to
`
`conventional tetracycline compositions.
`
`Parenteral use (e.g., intravenous, intramuscular, subcutaneous injection) is also
`
`contemplated, and formulations using conventional diluents, carriers, etc., such as are
`
`known in the art can be employed to deliver the compound.
`
`16
`
`

`

`I
`
`I Claim:
`
`1.
`
`A composition for delivering tetracycline to a host comprising:
`
`a.
`
`b.
`
`an anti-microbial tetracycline, and
`
`at least one controlled-release agent;
`
`said tetracycline compound associated with said at least one controlled-release agent
`
`to provide a tetracycline-release-profile in said host, whereby said host is treated with
`
`said tetracycline substantially without antimicrobial activity.
`
`2.
`
`A composition as described in Claim 1 wherein said release profile
`
`provides a blood serum concentration level of said tetracycline in said host of about
`
`0.1 Jlg/ml to about 1.0 Jlg/ml.
`
`3.
`
`A composition as described in Claim 2 wherein said release profile
`
`provides a blood serum concentration level of said tetracycline in said host of about
`
`0.3 Jlg/ml to about 0.8 J.lg/ml.
`
`4.
`
`A composition as described in Claim 1 wherein said release profile is
`
`maintained at a substantially constant rate for between about 6-24 hours.
`
`5.
`
`A composition as described in Claim 1 wherein said antimicrobial
`
`tetracycline is selected from the group consisting of tetracycline, doxycycline,
`
`demeclocycline, minocycline, and lymecycline.
`
`6.
`
`A composition as described in Claim 5 wherein said tetracycline
`
`compound is doxycycline.
`
`7.
`
`A composition as described in Claim 6 wherein said release profile
`
`provides a blood serum concentration level of said doxycycline in said host of about
`
`0.4 Jlg/ml to about 0.8 Jlg/ml.
`
`17
`
`

`

`8.
`
`A composition as described in Claim 1 wherein said controlled-release
`
`agent is selected from the group consisting of an instantaneous release agent, a
`
`sustained-release agent, a delayed-release agent, and combinations thereof.
`
`9.
`
`A composition according to Claim 8 wherein said instant