THERAPEUTIC COMPOSITIONS COMPRISING IMIDAZOLE AND IMIDAZOLIUM
`
`Patent Application
`1958603.00038
`
`COMPOUNDS
`
`Inventor:
`
`Herriot Tabuteau
`
`FIELD
`
`[1]
`
`Some embodiments relate to therapeutic compositions comprising
`
`substituted irnidazoles and imidazoliums having multiple acidic groups.
`
`[2]
`
`Pharmaceutical compositions comprising:
`
`SUMMARY
`
`OH
`
`A
`
`A
`
`/
`N
`
`0
`
`A
`
`
`
`N
`A~N
`
`HO
`
`+
`
`, and/or
`
`A
`
`OH
`
`A
`
`OH
`
`wherein each A is independently an acidic functional group, may be used for a number
`
`of medical purposes, such as treatment of undesirable conditions or diseases, including
`
`disease or conditions related to bone, cancer, and/or pain. In some embodiments, each
`
`A is CO2H, SO3H, OS02, or PO3H2.
`
`1
`
`ANTECIP EXHIBIT 2027
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`

`

`Patent Application
`1958603.00038
`
`[3]
`
`Some embodiments include a dosage form, such as an oral dosage
`
`form, comprising a composition described herein.
`
`[4]
`
`Some embodiments include a method of treating a disease or
`
`condition related to bone, cancer, or pain, comprising administering a dosage form,
`
`such as an oral dosage form, comprising a composition described herein to a mammal
`
`in need thereof.
`
`DETAILED DESCRIPTION
`
`[5]
`
`Preferably, pharmaceutical compositions comprising zoledronic acid,
`
`Compound 1, and/or Compound 2 (subject compositions), may be used for a number of
`
`medical purposes, such as treatment of undesirable conditions or diseases, including
`
`disease or conditions related to bone, cancer, and/or pain. This may be accomplished
`
`in many instances by administration of dosage forms, such as oral dosage forms,
`
`comprising a subject composition. Generally, an oral dosage form comprising a subject
`
`composition is administered orally to a mammal, such as a human being, at least once,
`
`to treat a disease or condition, such as disease or condition related to bone, cancer, or
`
`pain.
`
`0
`
`HO
`
`PO3H2
`
`OH
`
`PO3H2
`
`-
`
`PO3H2
`
`H203P
`
`
`HO
`
`. _ 3 _H 2
`OH
`
`Compound 1
`
`Compound 2
`
`[6]
`
`The term "treating" or "treatment" broadly includes any kind of
`
`treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in
`
`man or other animals, or any activity that otherwise affects the structure or any function
`
`of the body of man or other animals.
`
`[7]
`
`An oral dosage form comprising a subject composition may be used to
`
`treat, or provide relief of, any type of pain including, but not limited to, inflammatory
`
`pain, arthritis pain, complex regional pain syndrome, lumbosacral pain, musculoskeletal
`
`pain, neuropathic pain, chronic pain, cancer-related pain, acute pain, postoperative
`
`2
`
`

`

`Patent Application
`1958603.00038
`
`pain, etc.
`
`In some instances, pain relief may be palliative, or pain relief may be
`
`provided independent of improvement of the disease or condition or the underlying
`
`cause of the disease or condition. For example, although the underlying disease may
`
`not improve, or may continue to progress, an individual suffering from the disease may
`
`experience pain relief. In some embodiments, enhanced bioavailability of the zoledronic
`
`acid may be achieved in treating one of these conditions by administering a dosage
`
`form comprising a subject composition wherein zoledronic acid is in the form of a
`
`disodium salt. This may allow a reduced molar amount of the disodium salt to be used
`
`as compared to what would be used with the diacid form.
`
`[8]
`
`In some embodiments, the mammal being treated is not suffering from
`
`bone metastasis. In some embodiments, the mammal being treated is not suffering
`
`from cancer. In some embodiments, the mammal being treated is not suffering from
`
`osteoporosis.
`
`[9]
`
`For example, a subject composition may be administered orally to
`
`relieve musculoskeletal pain including low back pain, and pain associated with
`
`rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis,
`
`sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular
`
`disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease,
`
`fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush
`
`fractures, osteoporosis, etc. In some embodiments, enhanced bioavailability of the
`
`zoledronic acid may be achieved in treating one of these conditions by administering a
`
`dosage form comprising a subject composition, wherein the zoledronic acid is in the
`
`form of a disodium salt. This may allow a reduced molar amount of the disodium salt of
`
`zoledronic acid to be used as compared to what would be used with the diacid form.
`
`[10]
`
`In some embodiments, a subject composition may also be
`
`administered orally to relieve neuropathic pain, including diabetic peripheral neuropathy,
`
`post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain,
`
`and central pain. Other causes of neuropathic pain include cancer-related pain, lumbar
`
`nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis
`
`pain, HIV-associated neuropathy, and radio-therapy or chemo-therapy associated
`
`3
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`

`

`Patent Application
`1958603.00038
`
`neuropathy. In some embodiments, enhanced bioavailability of the zoledronic acid may
`
`be achieved in treating one of these conditions by administering a dosage form
`
`comprising a subject composition, wherein the zoledronic acid is in the form of a
`
`disodium salt. This may allow a reduced molar amount of the disodium salt of
`
`zoledronic acid to be used as compared to what would be used with the diacid form.
`
`[11]
`
`In some embodiments, a subject composition may be administered
`
`orally to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and
`
`complex regional pain syndrome. In some embodiments, enhanced bioavailability of
`
`the zoledronic acid may be achieved in treating one of these conditions by administering
`
`a dosage form comprising a subject composition in the form of a disodium salt. This
`
`may allow a reduced molar amount of the disodium salt to be used as compared to what
`
`would be used with the diacid form.
`
`[12]
`
`Examples of musculoskeletal pain include low back pain, pain
`
`associated with vertebral crush fractures, fibrous dysplasia, osteogenesis imperfecta,
`
`Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip.
`
`[13]
`
`Arthritis refers to inflammatory joint diseases that can be associated
`
`with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive
`
`osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-
`
`rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders,
`
`neuropathic arthropaties including Charcot's foot, axial spondyloarthritis including
`
`ankylosing spondylitis, and SAPHO syndrome.
`
`[14]
`
`In some embodiments, a human being that is treated for an
`
`inflammatory condition such as arthritis by a subject composition has an age of about
`
`10 years to about 90 years, about 20 years to about 80 years, about 30 years to about
`
`75 years old, about 40 years to about 70 years, about 1 year to about 16 years, or about
`
`80 years to about 95 years.
`
`[15]
`
`In some embodiments, a human being that is treated for an
`
`inflammatory condition such as arthritis by an oral dosage form of a subject composition
`
`4
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`

`

`Patent Application
`1958603.00038
`
`has suffered from the arthritis for at least 1 month, at least 2 months, at least 6 months,
`
`or at least 1 year.
`
`[16]
`
`In some embodiments, the an inflammatory condition such as arthritis
`
`affects, a knee, an elbow, a wrist, a shoulder, or a hip.
`
`[17]
`
`In some embodiments, a subject composition may be administered
`
`orally to relieve complex regional pain syndrome, such as complex regional pain
`
`syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-
`
`NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also
`
`have a neuropathic component.
`
`[18]
`
`Complex regional pain syndrome is a debilitating pain syndrome. It is
`
`characterized by severe pain in a limb accompanied by edema, and autonomic, motor
`
`and sensory changes.
`
`[19]
`
`With respect to use of a subject composition for relieving pain
`
`associated with an inflammatory condition, relief of pain can be short-term, e.g. for a
`
`period of hours after administration of the dosage form, and/or relief of pain can be long-
`
`term, e.g. lasting for days, weeks, or even months after oral administration of a subject
`
`composition. In some embodiments, a mammal, such as a human being, experiences
`
`significant pain relief at least about 3 hours, at least about 6 hours, at least about 12
`
`hours, at least about 24 hours, at least about 48 hours, at least about one week, at least
`
`about 2 weeks, or at least about 3 weeks after administration of an oral dosage form
`
`comprising a subject composition. In some embodiments, a mammal, such as a human
`
`being, experiences significant pain relief during at least part of the time from about 3
`
`hours to about 2 weeks, about 3 hours to about 3 weeks, about 3 hours to about 24
`
`hours, about 6 hours to about 2 weeks, or about 6 hours to about 24 hours, about 3
`
`days to about 2 weeks, about 6 days to about 2 weeks, after administration of an oral
`
`dosage form comprising a subject composition.
`
`[20]
`
`With respect to the treatment of any condition recited herein, in some
`
`embodiments a first oral dosage form comprising a subject composition is administered
`
`and a second oral dosage form comprising a subject composition is administered. The
`
`5
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`

`Patent Application
`1958603.00038
`
`timing of the administration of the two dosage forms may be such that, with respect to
`
`the first oral dosage form, the second oral dosage with respect to the first oral dosage
`
`form, the second oral dosage form is administered at 5 x Tmax or greater (e.g., if Tmax is
`
`1 hour, at 5 hours or later), at least 10 x Tmax or greater, at least about 15 x Tmax or
`
`greater, at least about 20 x Tmax or greater, at least about 50 x Tmax or greater, or at
`
`least about 200 x Tmax or greater, wherein Tmax is the time of maximum plasma
`
`concentration of zoledronic acid after administration the first oral dosage form.
`
`[21]
`
`Some embodiments include treatment of a condition recited herein,
`
`such as inflammatory pain, arthritis, or complex regional pain syndrome, wherein the
`
`treatment comprises either: administering only one dosage form to a mammal to treat
`
`the condition, or administering a first dosage form to the mammal, followed by
`
`administering a second dosage form to the mammal. If two or more dosage forms are
`
`administered, in some embodiments, the second oral dosage form is administered
`
`before the maximum pain relieving effect of the first oral dosage form is achieved, or
`
`before a peak in the pain relieving effect of the first oral dosage form is experienced, by
`
`a mammal receiving the dosage form. In some embodiments, the second oral dosage
`
`form is administered before an observable pain relieving effect is achieved. In some
`
`embodiments, the second dosage form is administered about 12 hours to about 60
`
`days, about 24 hours to about 28 days, about 24 hours to about 7 days, about 24 hours
`
`to about 14 days, or about 24 hours to about 21 days, after the first dosage form is
`
`administered.
`
`[22]
`
`Some embodiments include treatment of a condition recited herein,
`
`such as inflammatory pain, arthritis, or complex regional pain syndrome, wherein the
`
`treatment comprises administering a first dosage form to the mammal, followed by
`
`administering a second dosage form to the mammal, wherein the second dosage form
`
`is administered after the maximum pain relieving effect of the first oral dosage form is
`
`achieved, and the second oral dosage form is administered while the mammal is still
`
`experiencing pain relief from the first oral dosage form, or while the pain relieving effect
`
`from the first oral dosage form is observable. In some embodiments, the second
`
`dosage form is administered about 12 hours to about 60 days, about 24 hours to about
`
`6
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`

`

`Patent Application
`1958603.00038
`
`28 days, about 24 hours to about 7 days, about 24 hours to about 14 days, or about 24
`
`hours to about 21 days, after the first dosage form is administered.
`
`[23]
`
`A subject composition may also be administered orally to relieve
`
`cancer-related pain, including pain associated with multiple myeloma and bone
`
`metastases from solid tumors. In some embodiments, a subject composition is used to
`
`treat pain that is not cancer-related pain. For example, a subject composition may be
`
`used to treat pain that is not associated with multiple myeloma, bone metastasis from
`
`solid tumors, hypercalcemia of malignancy, giant cell tumor of bone, blood cancers or
`
`leukemias, or solid tumors or cancers. In some embodiments, enhanced bioavailability
`
`of the zoledronic acid may be achieved in treating one of these conditions by
`
`administering a subject composition. This may allow a reduced molar amount of the
`
`disodium salt to be used as compared to what would be used with the diacid form.
`
`[24]
`
`In addition to relieving pain, oral administration of a subject
`
`composition may also be useful to treat diseases or conditions that may or may not
`
`include a pain component. For example, a subject composition may be useful to treat
`
`any of the pain conditions or types of conditions listed above, including treatment that
`
`does not simply relieve the pain of those conditions, and treatment that is carried out in
`
`such a way that the condition is treated without pain relief occurring. In addition to any
`
`pain relief a subject composition may or may not provide, a subject composition may be
`
`used to treat a disease or condition such as a metabolic disease or condition; an
`
`inflammatory disease or condition, including an inflammatory disease or condition that is
`
`not associated with pain; a cancer disease or condition; a neurological disease or
`
`condition; etc. In some embodiments, enhanced bioavailability of the zoledronic acid
`
`may be achieved in treating one of these conditions by administering a dosage form
`
`comprising a subject composition. This may allow a reduced molar amount of the
`
`disodium salt to be used as compared to what would be used with the diacid form.
`
`[25]
`
`In some embodiments, oral administration of a subject composition
`
`may also be useful to treat complex regional pain syndrome, rheumatoid arthritis,
`
`osteoarthritis, erosive osteoarthritis, axial spondyloarthritis including ankylosing
`
`spondylitis, acute vertebral crush fracture, fibrous dysplasia, SAPHO syndrome,
`
`7
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`

`

`Patent Application
`1958603.00038
`
`osteoporosis, transient osteoporosis, or transient osteoporosis of the hip. In some
`
`embodiments, enhanced bioavailability of the zoledronic acid may be achieved in
`
`treating one of these conditions by administering a dosage form comprising a subject
`
`composition, wherein the zoledronic acid is in a disodium salt form. This may allow a
`
`reduced molar amount of the disodium salt to be used as compared to what would be
`
`used with the diacid form.
`
`[26]
`
`In some embodiments, oral administration of a subject composition
`
`may also be useful to treat hypercalcemia of malignancy, multiple myeloma, bone
`
`metastases from solid tumors, Paget's disease of bone, giant cell tumor of bone, blood
`
`cancers or leukemias, or solid tumors or cancers. In some embodiments, enhanced
`
`bioavailability of the zoledronic acid may be achieved in treating one of these conditions
`
`by administering a dosage form comprising a subject composition, wherein the
`
`zoledronic acid is in the form of a disodium salt. This may allow a reduced molar
`
`amount of the disodium salt to be used as compared to what would be used with the
`
`diacid form.
`
`[27]
`
`Zoledronic acid has the structure shown below, and is also referred to
`
`as zoledronate.
`
`Zoledronic acid
`
`[28]
`
`Unless otherwise indicated, any reference to a compound herein, such
`
`as a subject composition, zoledronic acid, Compound 1 or Compound 2, by structure,
`
`name, or any other means, includes pharmaceutically acceptable salts, such as the
`
`disodium salt; alternate solid forms, such as polymorphs, solvates, hydrates, etc.;
`
`8
`
`

`

`Patent Application
`1958603.00038
`
`tautomers; or any other chemical species that may rapidly convert to a compound
`
`described herein under conditions in which the compounds are used as described
`
`herein.
`
`[029]
`
`In some embodiments, zoledronic acid is in a composition or dosage
`
`form comprising a salt form, such as a salt of a dianion of zoledronic acid. In some
`
`embodiments, zoledronic acid is administered in a dosage form comprising a disodium
`
`salt form of zoledronic acid. In some embodiments, zoledronic acid is administered as a
`
`subject composition. In some embodiments, zoledronic acid is administered in a sodium
`
`salt form, such as a monosodium salt, a disodium salt, a trisodium salt, etc. In some
`
`circumstances, use of the disodium salt may be desirable. For example, the disodium
`
`salt is much more soluble in water than the diacid form. As a result, in some processes,
`
`the disodium salt can be easier to work with than the diacid form. Additionally, the
`
`sodium salt may be more bioavailable and/or more rapidly absorbed when taken orally
`
`as compared to the diacid form.
`
`[030] Examples of salts of Compound 1 are shown below:
`
`x-
`
`NA+
`
`0
`
`HO
`
`P03H2
`_\
`N ,.N„ + „N--...../T-P03H2
`OH
`
`0 _ PO3H
`z-!,,,1\1--,_„---TTO3H
`OH
`
`N
`
`HO
`
`—\ PO3H
`0
`if
`,..........,.......„.N,N--......./T-P03H2
`Hcr
`OH
`
`2M+
`
`0 —\ PO3H
`_0 ,,,,„,N ,....k.,,yN.--_,../T-P03H
`OH
`
`wherein X- is any suitable anion, e.g. F, Br, cr, i-, acetate, etc.; and M+ is any suitable
`
`cation, e.g. Na+, K+, NH4+, etc.
`
`[031]
`
`In some embodiments, Compound 1 is administered in a dosage form
`
`comprising a salt form, such as a salt of a dianion of Compound 1. In some
`
`embodiments, Compound 1 is administered in a dosage form comprising a disodium
`
`9
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`

`Patent Application
`1958603.00038
`
`salt form of Compound 1. In some embodiments, Compound 1 is administered in a
`
`sodium salt form, such as a monosodium salt, a disodium salt, a trisodium salt, etc. In
`
`some circumstances, use of the disodium salt may be desirable.
`
`[032]
`
`Compound 1 can be present in any amount, such as less than about
`
`100% w/w, less than about 50% w/w, less than about 20% w/w, less than about 10%
`
`w/w, less than about 1% w/w, less than 0.1% w/w, less than about 0.07% w/w, less than
`
`about 0.05% w/w, less than about 0.04% w/w, less than about 0.03% w/w, less than
`
`about 0.02% w/w; and/or greater than 0% w/w, at least about 0.00000001% w/w, at
`
`least about 0.000001% w/w, or at least about 0.00001% w/w, based upon the total
`
`amount of zoledronic acid, Compound 1, and Compound 2 present in the composition.
`
`[033] Examples of salts of Compound 2 are shown below:
`
`x-
`
`P03H2
`
`PO3H2 /_\
`N,,t ,-N---./\''PO3H2
`...,,, , ,
`OH
`1-'03n2
`
`HO
`
`PO3H2
`
`
`
`N • + -N
`,...,..\ ,
`HO
`P03H2
`
`PO3H-
`
`HO
`
`P03H2
`
`POSH
`
`
`/ \
`N, + ,- N
`PO3H2
`X-7 ---\----
`OH
`
`- m+
`
`2M+
`
`PO3H
`
`POSH /_\
`1\1.,,-Nyt7 N-......../\'PO3H-
`„
`OH
`
`3n2
`
`HO
`
`wherein X- is any suitable anion, e.g. F, Br, cr, i-, acetate, etc.; and M+ is any suitable
`
`cation, e.g. Na+, K+, NH4+, etc.
`
`[034]
`
`In some embodiments, Compound 2 is administered in a dosage form
`
`comprising a salt form, such as a salt of a dianion of Compound 2. In some
`
`embodiments, Compound 2 is administered in a dosage form comprising a disodium
`
`salt form of Compound 2. In some embodiments, Compound 2 is administered in a
`
`sodium salt form, such as a monosodium salt, a disodium salt, a trisodium salt, etc. In
`
`some circumstances, use of the disodium salt may be desirable.
`
`10
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`

`Patent Application
`1958603.00038
`
`[35]
`
`Compound 2 can be present in any amount, such as less than about
`
`100% w/w, less than about 50% w/w, less than about 20% w/w, less than about 10%
`
`w/w, less than about 1% w/w, less than about 0.3%, less than about 0.2%, less than
`
`0.1% w/w, less than about 0.08% w/w, less than about 0.07% w/w, less than about
`
`0.05% w/w, less than about 0.04% w/w, less than about 0.03% w/w, less than about
`
`0.02% w/w; and/or greater than 0% w/w, at least about 0.00000001% w/w, at least
`
`about 0.000001% w/w, or at least about 0.00001`)/0 w/w, based upon the total amount of
`
`zoledronic acid, Compound 1, and Compound 2 present in the composition.
`
`[36]
`
`In some embodiments, Compound 1 and Compound 2 are present in
`
`an amount that is less than 0.1% w/w,
`
`[37]
`
`The oral bioavailability of zoledronic acid in a subject composition may
`
`be enhanced by orally administering the zoledronic acid in the disodium salt form. For
`
`example, the bioavailability of zoledronic acid may be improved by at least about 10%,
`
`at least about 20%, at least about 30%, at least about 50%, and/or up to about 100%, or
`
`up to about 200%, as compared to administration of zoledronic acid in the diacid form.
`
`[38]
`
`Because of the improved bioavailability of the disodium salt a dosage
`
`form may contain, or a mammal, such as a human being, may receive, on a molar
`
`basis, less of the disodium salt form of zoledronic acid than would otherwise be
`
`administered of the diacid form of zoledronic acid. For example, a dosage form may
`
`contain, or a mammal may receive, at least about 10 mole% less, at least about 20
`
`mole% less, at least about 40 mole% less, at least about 50 mole% less, and/or up to
`
`about 90 mole% less or 95 mole% less, of the disodium salt form as compared to the
`
`amount of the diacid form of zoledronic acid that would otherwise be administered, such
`
`as a molar amount that would be administered of zoledronic acid in the diacid form in
`
`order to achieve the same plasma levels of zoledronic acid.
`
`[39]
`
`In some embodiments, a dosage form contains, or a mammal (such as
`
`a human being) is administered, an amount of the disodium salt form of zoledronic acid,
`
`on a molar basis, that has a value of about 0.8nd to about 1.2nd or about 0.9nd to about
`
`1.1nd, wherein:
`
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`

`Patent Application
`1958603.00038
`
`nd = (ba/bd)(na)
`
`wherein ba is the bioavailability of the diacid form, bd is the bioavailability of the disodium
`salt form, and na is the number of moles of the diacid that would be administered in a
`
`dosage form containing the diacid form of zoledronic acid. For example, if the diacid
`
`form has a bioavailability (ba) of 0.01 and the disodium salt form has a bioavailabity (bd)
`
`of 0.015, and a dosage form would normally contain 0.001 moles of the diacid, nd would
`
`be (0.01/0.015)(0.001 moles), or about 0.00067 moles. In some embodiments, the
`
`disodium salt is administered in an amount that has a value of about nd.
`
`[40]
`
`With respect to oral dosage forms comprising a reduced molar amount
`
`of the disodium salt of zoledronic acid as compared to the diacid form of zoledronic
`
`acid, in some embodiments, the bioavailability of the zoledronic acid in the disodium salt
`
`form is sufficiently high that, if the drug is administered to a mammal, at least as much
`
`zoledronic acid is present in the blood of the mammal as would be present if zoledronic
`
`acid were administered in the diacid form.
`
`[41]
`
`With respect to oral dosage forms comprising the disodium salt form of
`
`zoledronic acid, in some embodiments, the disodium salt form is present in a lower
`
`molar amount than would be present if the zoledronic acid were in the diacid form; and
`
`the zoledronic acid in the disodium salt form has an improved bioavailability as
`
`compared to the zoledronic acid in the diacid form to the extent that the lower molar
`
`amount of the disodium salt in the dosage form does not reduce the amount of
`
`zoledronic acid delivered to the plasma of a mammal.
`
`[42]
`
`In some embodiments, the zoledronic acid in the disodium salt form is
`
`present in an amount such that the oral dosage form provides an area under the plasma
`
`concentration curve of zoledronic acid of about 4 ng•h/mL to about 2000 ng•h/mL to the
`
`mammal each time the zoledronic acid in the disodium salt is administered.
`
`[43]
`
`In some embodiments, the zoledronic acid in the disodium salt form is
`
`present in an amount such that the oral dosage form provides an area under the plasma
`
`concentration curve of zoledronic acid of about 100 ng•h/mL to about 2000 ng•h/mL,
`
`about 100 ng•h/mL to about 1000 ng•h/mL, about 500 ng•h/mL to about 1000 ng•h/mL,
`
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`Patent Application
`1958603.00038
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`or about 500 ng•h/mL to about 700 ng•h/mL in the mammal to which the dosage form is
`
`administered. This amount may be suitable for administration of the oral dosage form
`
`about every 3 to 4 weeks.
`
`[44]
`
`In some embodiments, the zoledronic acid in the disodium salt form is
`
`present in an amount such that the oral dosage form provides an area under the plasma
`
`concentration curve of zoledronic acid of about 20 ng•h/mL to about 700 ng•h/mL, about
`
`50 ng•h/mL to about 500 ng•h/mL, or about 100 ng•h/mL to about 200 ng•h/mL, in the
`
`mammal to which the dosage form is administered. This amount may be suitable for
`
`weekly administration of the oral dosage, or for administration of 3 to 5 individual
`
`dosages during a month. The individual dosages could be given at regular intervals,
`
`given during the first week, or at any other schedule that provides 3 to 5 dosages during
`
`the month.
`
`[45]
`
`In some embodiments, the zoledronic acid in the disodium salt form is
`
`present in an amount such that the oral dosage form provides an area under the plasma
`
`concentration curve of zoledronic acid of about 4 ng•h/mL to about 100 ng•h/mL, about
`
`10 ng•h/mL to about 50 ng•h/mL, or about 10 ng•h/mL to about 30 ng•h/mL, in the
`
`mammal to which the dosage form is administered. This amount may be suitable for
`
`daily administration of the oral dosage form.
`
`[46]
`
`Oral administration of a subject composition, particularly oral
`
`administration of a subject composition comprising the disodium salt form of zoledronic
`
`acid, can result in more sustained plasma levels of the drug as compared to parenteral
`
`modes of administration, such intravenous or subcutaneous. For example, the amount
`
`of zoledronic acid in the plasma can be significantly higher for oral administration of the
`
`disodium salt about 12 hours, about 24 hours, about 36 hours, about 48 hours, or about
`
`72 hours, or longer, after administration.
`
`[47]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 12 hour sustained plasma factor of about 5 or higher or about
`
`10 or higher, such as about 10 to about 100, about 20 to about 50, or about 30 to about
`
`40.
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`Patent Application
`1958603.00038
`
`[48]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 24 hour sustained plasma factor of about 3 or higher or about
`
`5 or higher, such as about 5 to about 50, about 10 to about 20, or about 12 to about 15.
`
`[49]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 36 hour sustained plasma factor of about 3 or higher or about
`
`5 or higher, such as about 5 to about 30, about 5 to about 15, or about 9 to about 13.
`
`[50]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 48 hour sustained plasma factor of about 3 or higher or about
`
`5 or higher, such as about 5 to about 30, about 5 to about 15, or about 8 to about 12.
`
`[51]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 72 hour sustained plasma factor of about 3 or higher or about
`
`5 or higher, such as about 5 to about 30, about 5 to about 15, or about 8 to about 12.
`
`[52]
`
`In some embodiments, zoledronic acid in an orally administered
`
`subject composition has a 24 hour sustained plasma level factor of about 1 or higher,
`
`such as about 1 to about 10, about 1 to about 5, about 3 to about 5, or about 3 to about
`
`4.
`
`In some embodiments, a zoledronic acid in an orally administered subject
`
`composition has a 12 hour sustained plasma level factor, a 24 hour sustained plasma
`
`level factor, 36 hour sustained plasma level factor, a 48 hour sustained plasma level
`
`factor, or a 72 hour sustained plasma level factor that is higher, such as at least 1.2
`
`times, at least about 2 times, at least about 5 times, about 1.2 times to about 20 times,
`
`about 2 times to about 15 times, about 5 times to about 10 times, or about 8 to about 15
`
`times that of intravenously administered zoledronic acid. A "sustained plasma level
`
`factor," pf, is determined by the equation:
`
`pf = 1000 (Ct/Cmax)
`
`wherein Cm„ is the maximum plasma concentration of zoledronic acid after it is
`
`administered and Ct is the plasma concentration of zoledronic acid at the time of
`
`interest, such as 24 hours. For parenteral administration, the °max can be about the Co,
`
`or the concentration right after injection of the entire amount of the drug into the body.
`
`Sustained plasma level factors can also be obtained for other times, such as 48 hours,
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`Patent Application
`1958603.00038
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`by using the plasma concentration of zoledronic acid for Ct in the equation above. For
`
`example, if the maximum plasma level of zoledronic acid after administration is 1000
`
`ng/mL and the plasma level of zoledronic acid at 24 hours is 1 ng/mL, the 24 hour
`
`sustained plasma level factor is 1.
`
`[53]
`
`In some embodiments, the disodium salt form of zoledronic acid
`
`provides an enhancement to bioavailability, as compared to the diacid form of
`
`zoledronic acid, which adds to any enhancement to bioavailability provided by any
`
`bioavailability-enhancing agents in the dosage form. In some embodiments, the
`
`disodium salt form of zoledronic acid provides an enhancement to bioavailability, as
`
`compared to the diacid form of zoledronic acid, which is greater than any enhancement
`
`to bioavailability provided by any bioavailability-enhancing agents in the dosage form.
`
`In some embodiments, the disodium salt form of zoledronic acid may be administered in
`
`a dosage form that is substantially free of bioavailability-enhancing agents.
`
`[54]
`
`In some embodiments, a dosage form comprising a subject
`
`composition is a solid.
`
`[55]
`
`In some embodiments, a subject composition is used to treat an
`
`inflammatory condition.
`
`[56]
`
`[57]
`
`In some embodiments, a subject composition is used to treat arthritis.
`
`In some embodiments, a subject composition is used to treat complex
`
`regional pain syndrome.
`
`[58]
`
`In some embodiments, zoledronic acid is in a form that has an
`
`aqueous solubility, meaning the solubility in water, greater than 1% (w/v), about 5%
`
`(w/v) to about 50% (w/v), about 5% (w/v) to about 20% (w/v), about 10% (w/v) to about
`
`15% ( v), or about 12% (wlv) to about 13% (w/v).
`
`[59]
`
`The disodium salt form of zoledronic acid can be more compressible
`
`than the diacid form of zoledronic acid. This can make it easier for a dosage form to
`
`have a desired hardness. It can also make it easier to increase the drug load, so that a
`
`smaller tablet can be given for a given dosage strength. In some embodiments, a solid
`
`dosage form of zoledronic acid, such as the diacid form of zoledronic acid or the
`
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`Patent Application
`1958603.00038
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`disodium salt form of zoledronic acid, can have a hardness of about 5 kPa to about 20
`
`kPa or about 5 kPa to about 14 kPa.
`
`[60]
`
`Zoledronic acid, and Compound 1 and/or Compound 2, may be
`
`combined with a pharmaceutical carrier selected on the basis of the chosen route of
`
`administration and standard pharmaceutical practice as described, for example, in
`
`Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby
`
`incorporated herein by reference, in its entirety. The relative proportions of active
`
`ingredient and carrier may be determined, for example, by the solubility and chemical
`
`nature of the compounds, chosen route of administration and standard pharmaceutical
`
`practice.
`
`[61]
`
`A subject composition may be administered by any means that may
`
`result in the contact of the active agent(s) with the desired site or site(s) of action in the
`
`body of a patient. The compounds may be administered by any conventional means
`
`available for use in conjunction with pharmaceuticals, either as individual therapeutic
`
`agents or in a combination