JP6457555B2 - Osteoclast inhibitor for pain - Google Patents

Description

  Bisphosphonate compounds are potent inhibitors of osteoclast activity and are used clinically to treat bone related conditions such as osteoporosis and bone permanent disease. It has also been used in cancer-related conditions, including multiple myeloma and bone metastases from solid tumors. They generally have low oral bioavailability.

  Plaque osteoporosis and bone marrow edema can result from hyperfunctioning osteoclasts. Zoledronic acid is a potent inhibitor of bone resorption and osteoclast activity. Nitrogen containing bisphosphonates such as zoledronic acid also inhibits the mevalonate pathway in osteoclasts, thereby preventing normal osteoclast function.

  It has been discovered that oral dosage forms of bisphosphonate compounds such as zoledronic acid can be used to treat or alleviate pain or related conditions.

  Some embodiments include a method of enhancing the oral bioavailability of zoledronic acid comprising orally administering a dosage form containing zoledronic acid in the disodium salt form.

  Some embodiments comprise a dosage form containing a disodium salt form of zoledronic acid, wherein the bioavailability of the disodium salt form of zoledronic acid in a mammal is a diacid form of zoledronic acid in the same dosage form. Greater than the bioavailability.

  Some embodiments include a dosage form containing zoledronic acid, the dosage form comprising about 4 ng · hr / mL to about 2000 ng · hr / mL of zoledronic acid to a human to whom the dosage form is administered. It is characterized by containing an amount of zoledronic acid in the disodium salt form that provides an area under the plasma concentration curve.

  Some embodiments include a dosage form containing the disodium salt form of zoledronic acid, present in a lower molar amount than would exist if the zoledronic acid was assumed to be in the diacid form, and the disodium salt The form of zoledronic acid is improved compared to the diacid form of zoledronic acid to such an extent that even the lower molar amount of disodium salt in the dosage form does not reduce the amount of zoledronic acid delivered to mammalian plasma It is characterized by having bioavailability.

  Oral dosage forms with enhanced bioavailability for bisphosphonate compounds can be used, but bisphosphonate compounds, such as zoledronic acid, that are not enhanced or substantially enhanced bisphosphonate bioavailability Treatment using oral dosage forms containing can also be effective.

  Some embodiments are methods for alleviating inflammatory pain, comprising administering an oral dosage form containing zoledronic acid to a mammal in need thereof, wherein the mammal is after administration of the dosage form. Experience significant pain relief after 3 hours.

  Some embodiments are methods of alleviating pain associated with arthritis, comprising administering an oral dosage form containing zoledronic acid to a human in need thereof.

  Some embodiments are methods of treating complex regional pain syndrome, comprising administering an oral dosage form containing zoledronic acid to a mammal in need thereof.

  Some embodiments include an oral dosage form comprising zoledronic acid, wherein the oral bioavailability of zoledronic acid is not substantially enhanced. For example, in some embodiments, the oral bioavailability in the dosage form is from about 0.01% to about 4%.

  Some embodiments include a medicament comprising a plurality of units of an oral dosage form described herein. In some embodiments, each unit of the oral dosage form contains about 1 mg to about 50 mg of zoledronic acid.

  Some embodiments are methods of alleviating inflammatory pain, comprising administering an oral dosage form containing zoledronic acid to a mammal in need thereof.

In some embodiments, the mammal receives a total monthly dose of zoledronic acid that is about 800 mg / m ² or less.

In some embodiments, the dosage form, based on body surface area of a mammal, comprising from about 10 mg / ^{m 2} to about 20 mg / ^{m 2.}

  Some embodiments are methods of alleviating inflammatory pain comprising orally administering zoledronic acid to a mammal in need thereof.

In some embodiments, about 300 mg / m ² to about 600 mg / m ² of zoledronic acid is administered per month, based on the body surface area of the mammal.

In some embodiments, about 50 mg / m ² to about 600 mg / m ² zoledronic acid is administered per month, based on the body surface area of the mammal.

FIG. 1 is a plot of pain compression thresholds using three different doses of zoledronic acid in a rat model of inflammatory pain. Measurements were made at various time points after administration on the BL (baseline, baseline) and day indicated. FIG. 2A is a graph showing the recovery of arthritic pain for two different doses of zoledronic acid in a rat model of arthritic pain. FIG. 2B is a graph showing the pain threshold for two different doses of zoledronic acid in a rat model of arthritic pain. FIG. 3 is a graph summarizing the results for rats treated with vehicle and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 4 is a diagram showing the hindpaw pain threshold for rats treated with vehicle and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 5 shows the weight bearing for rats treated with vehicle and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 6 shows changes in paw thickness for rats treated with vehicle and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 7 shows the water solubility of zoledronic acid disodium tetrahydrate compared to the diacid form of zoledronic acid. FIG. 8 shows the plasma concentration of zoledronic acid in dogs versus time after administration of 150 mg of the disodium salt form of zoledronic acid and the diacid form of zoledronic acid. FIG. 9 shows the compressibility of a dosage form containing zoledronic acid in the disodium salt form compared to the diacid form. FIG. 10 shows changes in VAS pain scores compared to placebo treated with zoledronic acid treatment for 3 months in patients with osteoarthritic knees, bone marrow lesions, and varying degrees of joint space stenosis. FIG. 11 shows the change in VAS pain score compared to baseline for 3 months of zoledronic acid treatment in patients with osteoarthritic knees, bone marrow lesions, and different degrees of joint space stenosis. FIG. 12 shows changes in VAS pain scores compared to placebo treated with zoledronic acid treatment for 3 months in different subgroups of patients with osteoarthritis with knee and bone marrow lesions. FIG. 13 shows the change in size of BML lesions compared to placebo treated with zoledronic acid treatment for 6 months in patients with osteoarthritic knees, bone marrow lesions, and different degrees of joint space stenosis.

  Inhibitors of osteoclast activity include pamidronate or pamidronate, neridronate or nelidronate, olpadronate or olpadronate, alendronate or alendronate, incadronate or incadronate, ibandronate or ibandronate, risedronate or risedronic acid, Bisphosphonate compounds, such as simadronate or simadronate, zoledronate or zoledronate, etidronate or etidronate, clodronate or clodronate, or tiludronate or tiludronate, etc.

  A RANK / RANKL antagonist can be an inhibitor of osteoclast activity. RANK / RANKL antagonists include, but are not limited to, OPG (osteoprotegerin) or variants thereof, anti-RANKL antibodies such as denosumab, monoclonal anti-RANKL antibodies, small interfering RNAs, microRNAs, precursor molecules, ribozymes, antisense nucleic acids, Or an aptamer targeting RANKL. Antibodies such as AB-25E9, small molecules, small interfering RNAs, microRNAs, precursor molecules, ribozymes, antisense nucleic acids, or aptamers that target the cell surface protein Siglec-15 can be osteoclast inhibitors.

Some Bruton tyrosine kinase (BTK) inhibitors may be inhibitors of osteoclast activity. BTK inhibitors include ONO-4059; ibrutinib; benzo [b] thiophene-2-carboxamide, N- [3- [6-[[4-[(2R) -1,4-dimethyl-3-oxo-2- Piperazinyl] phenyl] amino] -4,5-dihydro-4-methyl-5-oxo-2-pyrazinyl] -2-methylphenyl] -4,5,6,7-tetrahydro- (GDC-0834); RN- 486; benzamide, 4- (1,1-dimethylethyl) -N- [3- [8- (phenylamino) imidazo [1,2-a] pyrazin-6-yl] phenyl]-(CGI-560); Benzamide, N- [3- [4,5-dihydro-4-methyl-6-[[4- (4-morpholinylcarbonyl) phenyl] amino] -5-oxo-2-pyrazinyl] -2-methyl Nil] -4- (1,1-dimethylethyl)-(CGI-1746 CAS Registry Number 910232-84-7); HM-71224; 2-propenamide, N- [3-[[5-fluoro-2- [ [4- (2-methoxyethoxy) phenyl] amino] -4-pyrimidinyl] amino] phenyl]-(CC-292, CAS Registry Number 1202757-89-8); 2-pyridinecarboxamide, 4- [4-[[ 5-Fluoro-4-[[3- (1-oxo-2-propen-1-yl) amino] phenyl] amino] -2-pyrimidinyl] amino] phenoxy] -N-methyl- (CNX-774, CAS registration No. 1202759-32-7), AVL-101 (CAS registration number 1552307-34-2), AVL-291 (CAS registration number 1552307) 35-3), and AVL-292 (CAS Registry Number 1552307-36-4), N- (2-chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) piperazine-1) -Yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide] (dasatinib), alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-bromophenyl) propenamide (LFM- A13), and ONO-WG-307.

  Inhibitors of osteoclast activity can be used for a number of medical purposes, such as the treatment of undesirable conditions or diseases including pain relief. This can be achieved in many cases by administration in an oral dosage form. In general, oral dosage forms comprising bisphosphonates such as zoledronic acid are administered orally at least once to a mammal such as a human to treat a disease or condition or to alleviate pain. .

The following compounds may also be osteoclast inhibitors.

  The term “treat” or “treatment” refers to any kind of therapeutic activity, including diagnosis, cure, alleviation or prevention of disease in a human or other animal, or the structure of a human or other animal body or It broadly includes any activity that has other effects on any function.

  Oral dosage forms of bisphosphonates such as zoledronic acid include, but are not limited to, inflammatory pain, arthritic pain, complex local pain syndrome, lumbosacral pain, musculoskeletal pain, neuropathic pain, chronic pain, cancer-related pain, It can be used to treat or alleviate any type of pain, including acute pain and postoperative pain and the like. In some cases, pain relief may be temporary relief or may be provided independent of amelioration of the disease or condition or the underlying cause of the disease or condition. For example, the underlying disease may not improve or may continue to progress, but can reduce the pain of an individual suffering from the disease. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve treatment of one of these conditions by administering a dosage form comprising zoledronic acid in the disodium salt form. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  In some embodiments, the mammal being treated does not suffer from bone metastases. In some embodiments, the mammal being treated does not suffer from cancer. In some embodiments, the mammal being treated does not suffer from osteoporosis.

  For example, zoledronic acid or another bisphosphonate can cause low back pain and rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthropathy, non-rheumatoid arthritis, periarticular disorder, ankylosis Relieve musculoskeletal pain including pain associated with axial spondyloarthritis including osteomyelitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient lumbar osteoarthritis, spinal fracture and osteoporosis Therefore, it can be administered orally. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve treatment of one of these conditions by administering a dosage form comprising zoledronic acid in the disodium salt form. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  For example, osteoclast inhibitors such as bisphosphonates such as zoledronic acid can be used to treat fractures or enhance fracture healing.

  In some embodiments, zoledronic acid or another bisphosphonate alleviates neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, single radiculopathy, phantom limb pain and central pain Can also be administered orally. Other causes of neuropathic pain are cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation therapy or chemotherapy-related neuropathy Including cancer. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve treatment of one of these conditions by administering a dosage form comprising zoledronic acid in the disodium salt form. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  In some embodiments, zoledronic acid or another bisphosphonate can be administered orally to alleviate inflammatory pain, including musculoskeletal pain, arthritic pain, and complex local pain syndrome. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve treatment of one of these conditions by administering a dosage form comprising zoledronic acid in the disodium salt form. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  Examples of musculoskeletal pain include low back pain and pain associated with spinal fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis and transient osteoporosis of the lumbar region.

  Arthritis refers to an inflammatory joint disease that can be painful. Examples of arthritic pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-rheumatic arthritis, periarticular disorders, Includes neuropathic arthropathy including Charcot's feet, axonal spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

  In some embodiments, a human being treated for a disease or condition such as an inflammatory condition such as arthritis, for example, with an osteoclast inhibitor such as a bisphosphonate such as an oral dosage form of zoledronic acid, for example, about 10 Aged from about 90 years old, from about 20 years old to about 80 years old, from about 30 years old to about 75 years old, from about 40 years old to about 70 years old, from about 1 year old to about 16 years old, or from about 80 years old to about 95 years old.

  In some embodiments, a human being treated for a disease or condition such as an inflammatory condition such as arthritis with an osteoclast inhibitor such as a bisphosphonate, such as an oral dosage form of zoledronic acid, for at least 1 month. Have been suffering from arthritis for at least 2 months, at least 6 months, or at least 1 year.

  In some embodiments, arthritis affects the knee, elbow, finger, wrist, shoulder, ankle, spine or hip joint.

  In some embodiments, for the treatment of arthritis or joint pain, such as knee pain, the human being treated is OARSI grade 0, or Kellgren and Lawrence grade 0 or 1, joints Has stenosis of the cavity.

  In some embodiments, the human has a lesion, such as a bone marrow lesion. In some embodiments, the person undergoing treatment for bone marrow lesions has normal joint knee pain, OARSI grade 0, or Chergren and Lawrence grade 0 or 1, joint space constriction.

  In some embodiments, the human has a baseline pain intensity of 5 or greater measured using a 0-10 numerical rating scale (NRS), or a baseline pain of 50 mm or greater using a 100 mm visual analog scale (VAS). Has strength. In some embodiments, the human being treated for pain has normal joint knee pain, OARSI Grade 0, or Cherglen and Lawrence Grade 0 or 1, joint space constriction.

  Bone marrow lesions (BML) include changes in changes in local bone marrow signal intensity in magnetic resonance imaging (MRI). BML can be present in the knee and can be an important feature of knee osteoarthritis. BML has also been described in other rheumatic conditions such as rheumatoid arthritis, osteonecrosis, ankylosing spondylitis, and transient osteoporosis of the hip joint, often referred to as bone marrow edema (BME).

  In some embodiments, the human being treated for arthritis, such as with zoledronic acid, has knee osteoarthritis associated with a bone marrow lesion.

  In some embodiments, inhibitors of osteoclast activity can be used to treat bone marrow lesions.

  In some embodiments, inhibitors of osteoclast activity can be used to treat bone marrow lesions in the knee, shoulder, ankle, wrist, hand, finger, spine or hip joint.

  Commonly used measures of pain intensity include the visual analog scale (VAS) and the numerical rating scale (NRS). In the VAS approach, patients assess pain severity by scoring a 10 cm (or 100 mm) VAS (0 = no pain, 10 = most likely painful). In the NRS approach, patients assess pain severity by responding verbally to a 10-point NRS (0 = no pain, 10 = most likely painful). The VAS and NRS scores have been shown to be strongly correlated (slope of regression line 1.01), and the 10 cm VAS score has been shown to be equivalent to the 10 point NRS score ( Bijur PE et al., Acad Emerg Med 2003; 10: 390-392). For example, a VAS score of 5 cm (or 50 mm) corresponds to an NRS score of 5. Knee pain in a person with a VAS score of 5 cm or 50 mm or greater or an NRS score of 5 or greater may be referred to herein as moderate to severe knee pain.

  In some embodiments, a patient suffering from pain, inflammation, a similar condition, or any of the conditions described herein has an NRS of 5 or greater, or a VAS of 5 cm or greater. In some embodiments, the patient has an NRS of 4 or greater, or a VAS of 4 cm or greater. In some embodiments, the patient has an NRS of 6 or greater, or a VAS of 6 cm or greater. In some embodiments, the patient has an NRS of 7 or greater, or a VAS of 7 cm or greater. In some embodiments, the patient has an NRS of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10. In some embodiments, the patient has a VAS of about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, or about 10 cm.

  In some embodiments, for pain associated with knee pain or bone marrow lesions, treatment with a nitrogen-containing bisphosphonate such as zoledronic acid has a visual analog (VAS) pain score measured using a 100 mm scale of at least about 5 mm. , At least about 8 mm, at least about 10 mm, at least about 15 mm, an upper limit of about 50 mm, or an upper limit of about 100 mm. In some embodiments, the VAS score may be reduced by at least about 5 mm, at least about 8 mm, at least about 10 mm, at least about 15 mm, by an upper limit of about 50 mm, or by an upper limit of about 100 mm, as compared to a placebo.

  Treatment with a nitrogen-containing bisphosphonate such as zoledronic acid has a numerical rating scale (NRS) pain score measured using a 0-10 scale of at least about 0.1, at least about 0.5, at least about 0.8, at least It can be reduced by about 1, at least about 1.5, by an upper limit of about 5, or by an upper limit of about 10. In some embodiments, the NRS score is at least about 0.1, at least about 0.5, at least about 0.8, at least about 1, at least about 1.5, an upper limit of about 5, as compared to placebo, Alternatively, the upper limit can be reduced by about 10.

  In some embodiments, inhibitors of osteoclast activity can be used to reduce the size of bone marrow lesions. The area of a lesion can be measured as the total area of all lesions or the area of any one lesion. In some embodiments, the entire region includes a medial tibial region, a medial femoral region, a lateral tibial region, and a lateral femoral region. In some embodiments, the bone marrow lesion is located in the patella.

In some embodiments, the use of an inhibitor of osteoclast activity achieves a reduction of at least about 240 mm ² of the total area of the bone marrow lesion. In some embodiments, the total area reduction is at least about 220 mm ² , at least about 200 mm ² , at least about 150 mm ² , at least about 100 mm ² , or at least about 50 mm ² . In some embodiments, the reduction in size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% relative to baseline, Represents a reduction of at least about 70%, at least about 80%, at least about 90%, or about 100%. In some embodiments, the reduction in bone marrow lesion area is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least relative to placebo. About 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300%, at least It represents an improvement of about 350%, at least about 400%, or at least about 450%. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in bone marrow lesion size over time.

  Joint space narrowing (JSN) is typically scored using the Osteoarthritis Research Association (OARSI) Atlas criteria, or the Chergren and Lawrence (K / L) system. The OARSI Atlas criteria are scored using a 0 to 3 scale with Grade 0 indicating no JSN and Grades 1, 2 and 3 indicating mild, moderate, and severe JSN, respectively (Altman and Gold, Osteoarthritis Cartilage 2007; 15 (Suppl A): A1-A56). The K / L system uses 0-4 scales of grade 0 indicating no JSN, grade 1 indicating suspicious JSN, and grades 2, 3 and 4 indicating minimal, moderate and severe JSN, respectively. JSN is scored (Kellgren and Lawrence, Ann Rheum Dis 1957; 16: 494-502). Based on these criteria, OARSI grade 0 (absence of JSN) approximates K / L grade 0-1 (absence or suspicion of JSN). Knee pain in persons with OARSI grade 0 or K / L grade or 1 JSN of the knee where pain occurs may be referred to herein as “normal joint knee pain”.

In some embodiments of patients having OARSI grade 0 or K / L grade 0-1 JSN, the use of an inhibitor of osteoclast activity achieves a reduction of at least about 240 mm ^{2 in} the total area of bone marrow lesions. In some embodiments, the total area reduction is at least about 220 mm ² , at least about 200 mm ² , at least about 150 mm ² , at least about 100 mm ² , or at least about 50 mm ² . In some embodiments, the reduction in bone marrow lesion size is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35% relative to baseline. Represents a decrease of at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100%. In some embodiments, the reduction in bone marrow lesion area is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about placebo. About 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300%, at least An improvement of about 350%, at least about 400%, or at least about 450% is exhibited. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in bone marrow lesion size over time.

In some embodiments of patients with OARSI grade 1-2 or K / L grade 2-4 JSN, the use of an inhibitor of osteoclast activity achieves a reduction of at least about 100 mm ^{2 in} the total area of bone marrow lesions. In some embodiments, reduction of the total area is at least about 50 mm ^2, at least about 60 mm ^2, at least about 80 mm ^2, at least about 85 mm ^2, at least about 90 mm ^2, at least about 100 mm ^2, at least about 105 mm ² of at least about 110mm ² , or at least about 115 mm ² . In some embodiments, the reduction in the size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% relative to baseline, Represents a reduction of at least about 70%, at least about 80%, at least about 90%, or about 100%. In some embodiments, the reduction in bone marrow lesion area is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about placebo. About 70%, at least about 80%, at least about 90%, at least about 100%, at least about 115%, at least about 125%, at least about 135%, at least about 150%, at least about 170%, at least about 200%, at least It represents an improvement of about 250%, at least about 300%, at least about 350%, at least about 400%, or at least about 450%. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in bone marrow lesion size over time.

  In some embodiments, inhibitors of osteoclast activity are used to treat fibromyalgia, such as nitrogen-containing bisphosphonates including zoledronic acid, minodronic acid, and the like.

  According to some embodiments, administration of the inhibitor of osteoclast activity is pain that lasts for at least about 1 month, 2 months, 3 months, 4 months, 6 months, or at least about 12 months To achieve a reduction in According to some embodiments, administration of the inhibitor of osteoclast activity is greater than 3 hours, about 1 day, about 2 to about 5 days, about 1 week, about 2 after administration of the inhibitor of osteoclast activity. About 3 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 6 months, Or achieve the reduction in pain observed at about 12 months.

  According to some embodiments, administration of the inhibitor of osteoclast activity is greater than 3 hours, but prior to 1 week, prior to 2 weeks, prior to 3 weeks, prior to 4 weeks, prior to 5 weeks, prior to 6 weeks, Reducing the pain observed before 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, or 6 months.

  According to some embodiments, administration of the inhibitor of osteoclast activity has a duration of greater than about 3 hours, less than about 3 months, less than about 4 months, less than about 5 months, or less than about 6 months. Achieve reduction in observed pain.

  According to some embodiments, after administration of an inhibitor of osteoclast activity, the area of the bone marrow lesion relative to the size prior to administration is an upper limit of 3 months, an upper limit of 4 months, an upper limit of 5 months, an upper limit of 6 months, Or it remains reduced for more than 12 months. According to some embodiments, after administration of an inhibitor of osteoclast activity, the area of the bone marrow lesion relative to pre-administration size is about 3 months, about 4 months, about 5 months, about 6 months, or about 12 months Is reduced.

  According to some embodiments, after administration of an inhibitor of osteoclast activity, the modic change relative to the size prior to administration or the size of the VESC has an upper limit of 3 months, an upper limit of 4 months, an upper limit of 5 months, and an upper limit of 6 It remains reduced for months or up to 12 months. According to some embodiments, after administration of the inhibitor of osteoclast activity, the modic change relative to the size prior to administration or the size of the VESC is about 3 months, about 4 months, about 5 months, about 6 months, or about Reduced in 12 months.

  In some embodiments, an osteoclast inhibitor such as a nitrogen-containing bisphosphonate such as zoledronic acid, ibandronic acid or minodronic acid is combined local pain syndrome type I (CRPS-1), combined local pain syndrome It can be administered to alleviate complex regional pain syndromes such as type II (CRPS-II), CRPS-NOS, or another type of CRPS.

  In some embodiments, zoledronic acid or another bisphosphonate is complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS or another type of CRPS. To alleviate complex regional pain syndrome, such as CRPS is a type of inflammatory pain. A CRPS can also have a neurogenic component.

  Complex regional pain syndrome is a pain syndrome that leads to weakness. It is characterized by severe limb pain that can be accompanied by edema, as well as changes in autonomic nerves, motor and sensory.

  In some embodiments, the osteoclast inhibitor, such as, for example, a nitrogen-containing bisphosphonate such as zoledronic acid or minodronic acid, suffers from pain, inflammation, a similar condition, or any condition described herein. May be used to reduce the use of non-steroidal anti-inflammatory drugs (NSAIDs), opioids or other analgesics. For example, the use of an NSAID, opioid, or other analgesic is at least about 5%, at least about 10%, at least about at least about the use of an NSAID, opioid, or other analgesic without administration of an osteoclast inhibitor. 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about It can be reduced by 80%, or at least about 90%, with an upper limit of about 100%. The use of opioids, NSAIDS, or other analgesics is at least about 5%, at least about 10%, at least about 15%, at least about at least compared to the use of NSAIDS, opioids, or other analgesics at baseline. 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least It can be reduced by about 90% and an upper limit of about 100%.

  Reduced use of NSAIDs, opioids, or other analgesics is about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months after administration of an osteoclast inhibitor. , About 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year or more.

  With respect to the use of oral zoledronic acid to relieve pain associated with an inflammatory condition, pain relief can be short term, eg, a period of hours after administration of the dosage form, and / or long term, eg After oral administration of zoledronic acid, it can last for days, weeks or even months. In some embodiments, the mammal, such as a human, is 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 after administration of an oral dosage form comprising zoledronic acid. Experience significant pain relief at least about 1 week, at least about 2 weeks, or at least about 3 weeks. In some embodiments, the mammal, such as a human, is at least about 3 hours to about 2 weeks, about 3 hours to about 3 weeks, about 3 hours to about 24 hours after administration of an oral dosage form comprising zoledronic acid. Significant pain relief during at least a portion of time, from about 6 hours to about 2 weeks, from about 6 hours to about 24 hours, from about 3 days to about 2 weeks, or from about 6 days to about 2 weeks To experience. In some embodiments, the human being treated has significant pain relief 3 months, 6 months, 9 months, or 1 year after administration of the most recent dose of an osteoclast inhibitor such as zoledronic acid. Have.

For the treatment of any condition described herein, in some embodiments, a first oral dosage form comprising zoledronic acid is administered and a second oral dosage form comprising oral zoledronic acid is administered. The timing of administration of the two dosage forms is as follows: for the first oral dosage form, for the second oral dosage form for the first oral dosage form, for the second oral dosage form greater than or equal to 5 × T _maximum (eg, if T _maximum is 1 hour, Administered at least 10 × T _max , at least about 15 × T _max , at least about 20 × T _max , at least about 50 × T _max , or at least about 200 × T _max (over 5 hours). The T _max may be such a timing) that is the time of the maximum plasma concentration of the first oral dosage form.

  Some embodiments include treatment of a condition described herein, such as inflammatory pain, arthritis, or complex local pain syndrome, wherein the treatment is 1 for mammals to treat the condition. Characterized in that it comprises either administering only the dosage form or administering the first dosage form to the mammal followed by administering the second dosage form to the mammal. When more than one dosage form is administered, the second oral dosage form is the peak before the maximum pain alleviating effect of the first oral dosage form is achieved, or the peak in the pain relieving effect of the first oral dosage form is Administered before being experienced by the mammal receiving the shape. In some embodiments, the second oral dosage form is administered before the observed pain relief is achieved. In some embodiments, the second dosage form is about 12 hours to about 60 days, about 24 hours to about 28 days, about 24 hours to about 7 days, about 24 hours after the first dosage form is administered. From about 24 hours to about 21 days.

  Some embodiments include treatment of a condition described herein, such as symptomatic pain, arthritis, or complex local pain syndrome, wherein the treatment comprises administering a first dosage form to the mammal followed by feeding Administering a second dosage form to the animal, wherein the second dosage form is administered after the maximum pain relief of the first dosage form has been achieved, and the second oral dosage form is the first oral dosage form by the mammal. Administered while still experiencing pain relief from the form or while the pain relief effect from the first oral dosage form is observed. In some embodiments, the second dosage form is about 12 hours to about 60 days, about 24 hours to about 28 days, about 24 hours to about 7 days, about 24 hours after the first dosage form is administered. From about 24 hours to about 21 days.

  Zoledronic acid or another bisphosphonate can also be administered orally to alleviate cancer-related pain, including pain associated with bone metastases from multiple myeloma and solid tumors. In some embodiments, zoledronic acid is used to treat pain that is not cancer-related pain. For example, zoledronic acid is multiple myeloma, bone metastases from solid tumors, hypercalcemia of malignant tumors, giant cell tumors of bone, blood cancer or leukemia, or pain not associated with solid tumors or cancer Can be used to treat. In some embodiments, the enhanced bioavailability of zoledronic acid can be achieved by treating one of these conditions by administering a dosage form comprising the disodium salt form of zoledronic acid. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  In addition to pain relief, oral administration of zoledronic acid or another bisphosphonate can also be beneficial for treating diseases or conditions that may or may not include a pain component. For example, zoledronic acid or another bisphosphonate includes treatments that do not simply relieve the pain of the condition, and treatments that are performed in a way that the condition is treated without pain relief, including the pain state or the above Can be beneficial for treating any of the types of conditions listed in. In addition to any pain relief that zoledronic acid or another bisphosphonate may or may not provide, zoledronic acid or another bisphosphonate is a metabolic disease or condition, an inflammatory disease or condition that is not painful Can be used to treat diseases or conditions, such as inflammatory diseases or conditions, cancer diseases or conditions, and neurological diseases or conditions. In some embodiments, the enhanced bioavailability of zoledronic acid can be achieved in treating one of these conditions by administering a dosage form comprising the disodium salt form of zoledronic acid. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  In some embodiments, oral administration of zoledronic acid or another bisphosphonate may be combined local pain syndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, axial spondyloarthritis including ankylosing spondylitis, acute spinal crushing It may also be beneficial to treat fractures, fibrous dysplasia, SAPHO syndrome, osteoporosis, transient osteoporosis, or lumbar transient osteoporosis. In some embodiments, the enhanced bioavailability of zoledronic acid can be achieved in treating one of these conditions by administering a dosage form comprising the disodium salt form of zoledronic acid. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

  In some embodiments, oral administration of zoledronic acid or another bisphosphonate comprises hypercalcemia of malignant tumor, multiple myeloma, bone metastasis from solid tumor, Paget's disease of bone, giant cell tumor of bone, blood It may also be beneficial to treat cancer or leukemia, or solid tumors or cancer. In some embodiments, the enhanced bioavailability of zoledronic acid can be achieved in treating one of these conditions by administering a dosage form comprising the disodium salt form of zoledronic acid. This may be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

Some nitrogen-containing bisphosphonates can be represented by Formula A.

With respect to Formula A, R ¹ is F, Cl, Br, H, or OH. In some embodiments, R ¹ is OH.

With respect to Formula A, R ² is, for example, aminoalkyl such as aminoethyl, aminopropyl, aminopentyl, dimethylaminoethyl, methylpentylaminoethyl, or optionally substituted imidazolylmethyl, optionally substituted pyridinylmethyl, etc. Is an optionally substituted heterocyclylalkyl. In some embodiments, R ² is optionally substituted imidazolylalkyl.

Unless otherwise indicated, when a compound or chemical structural feature such as heterocyclylalkyl is referred to as “optionally substituted”, it has no substituents (ie, is not substituted), or Includes substituted features, meaning features having one or more substituents. The term “substituent” has the broadest meaning known to one of ordinary skill in the art and includes moieties that replace one or more hydrogen atoms in the parent compound or structural feature. The term “substitute” is merely used herein for convenience and does not require the formation of a compound by substituting one atom for another. In some embodiments, the substituent may be any conventional organic moiety known in the art, such as 15 g / mol to 50 g / mol, 15 g / mol to 100 g / mol, 15 g / mol to 150 g / mol. It may have a molecular weight (eg, the sum of the atomic masses of the substituent atoms) of mol, 15 g / mol to 200 g / mol, 15 g / mol to 300 g / mol, or 15 g / mol to 500 g / mol. In some embodiments, the substituent comprises or consists of 0-30, 0-20, 0-10, or 0-5 carbon atoms, and 0-30, 0-20, 0. Contain or consist of -10 or 0-5 heteroatoms, wherein each heteroatom is substituted with one C, N, O, P, S, Si, F, Cl, Br or I It may independently be N, O, P, S, Si, F, Cl, Br or I, provided that it contains atoms. In some embodiments, the substituents independently have a molecular weight of about 15 Da to about 600 Da and can consist of 2 to 5 chemical elements, where the chemical elements are independently C, H, O, N, P, S, Si, F, CI, or Br. In some embodiments, the substituent is an optionally substituted alkyl, —O-alkyl (eg, —OCH ₃ , —OC ₂ H ₅ , —OC ₃ H ₇ , —OC ₄ H _9, etc.), — alkyl S- _{(e.g., -SCH 3, -SC 2 H 5} , -SC 3 H 7, etc. _{-SC 4 H 9), - NR'R} '', - OH, -SH, -CN, -CF 3, —NO ₂ , perfluoroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amine or halogen, wherein R ′ and R ″ are independently H or optionally substituted alkyl. Whenever a substituent is described as “optionally substituted,” the substituent can be substituted with the above substituents.

  For convenience, the term “molecular weight” is used in reference to a portion or portion of a molecule to indicate the sum of the atomic weights of the atoms of a portion or portion of a molecule, even if not a complete molecule.

Examples of nitrogen-containing bisphosphonates include, but are not limited to, pamidronic acid, incadronic acid, ibandronic acid, risedronic acid, minodronic acid, simadronic acid, neridronic acid, alendronic acid, olpadronic acid, zoledronic acid and the like.

Zoledronic acid has the following structure and is also called zoledronic acid.

  Unless otherwise stated, any reference to a compound herein, such as zoledronic acid, by structure, name or any other means, is a pharmaceutically acceptable salt, polymorph, such as the disodium salt, Alternative solid forms such as solvates or hydrates, interchangeable isomers, or any that can be rapidly converted to the compounds herein under the conditions in which the compounds are used Other chemical species.

  In some embodiments, zoledronic acid is administered in a dosage form comprising a salt form, such as a dianion salt of zoledronic acid. In some embodiments, zoledronic acid is administered in a dosage form comprising the disodium salt form of zoledronic acid. In some embodiments, zoledronic acid is administered in the sodium salt form, such as the monosodium salt, disodium salt or trisodium salt. Under certain circumstances, it may be desirable to use the disodium salt. For example, the disodium salt has a higher solubility in water than the diacid form. As a result, in some processes, the disodium salt can work together more easily than the diacid form. Additionally, the disodium salt is more bioavailable and / or can be absorbed more rapidly when taken orally compared to the diacid form.

Examples of salts of Compound 1 are shown below.
Here, X ⁻ is any suitable anion, for example, F ⁻ , Br ⁻ , Cl ⁻ , I ⁻ , OH ⁻ , acetate, and the like. M ⁺ is any suitable cation, such as Na ⁺ , K ⁺ , NH ₄ ⁺ and the like. Many other salt forms are possible.

In some embodiments, Compound 1 can be further represented by the following formula:

  In some embodiments, Compound 1 can be in a hydrate form.

  In some embodiments, Compound 1 is administered in a salt form of Compound 1, such as a zwitterionic form, or a dosage form comprising a salt of a cation, monoanion, dianion, trianion, and the like.

  Compound 1 is less than about 100% w / w, less than about 50% w / w, less than about 20% w / w, about 10% based on the total amount of zoledronic acid, Compound 1 and Compound 2 present in the composition. % 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, about 0.04% w / w less than w, 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 It may be present in any amount, such as w, or at least about 0.00001% w / w.

Examples of salts of Compound 2 are shown below.
Here, X ⁻ is any suitable anion, for example, F ⁻ , Br ⁻ , Cl ⁻ , I ⁻ , OH ⁻ , acetate, and the like. M ⁺ is any suitable cation, such as Na ⁺ , K ⁺ , NH ₄ ⁺ and the like. Many other salt forms are possible.

In some embodiments, the salt of Compound 2 can be further represented by the following formula:

  In some embodiments, Compound 2 can be in a hydrate form.

  In some embodiments, Compound 2 is administered in a dosage form comprising a salt form of Compound 2, such as a zwitterionic form, or a salt of a cation, monoanion, dianion, trianion, and the like.

  Compound 2 is less than about 100% w / w, less than about 50% w / w, less than about 20% w / w, based on the total amount of zoledronic acid, Compound 1, and Compound 2 present in the composition Less than 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, about 0 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 it may be present in any amount, such as 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.

  In some embodiments, Compound 1 and Compound 2 are present in an amount less than 0.1% w / w.

  In some embodiments, administering an osteoclast inhibitor such as a nitrogen-containing bisphosphonate such as zoledronic acid, minodronic acid, etc. to a patient or mammal in need thereof is a Modic Change (MC) To affect. For example, associated with Modic changes using any of the above compounds, or bone marrow changes visualized using vertebral endplate signal changes (VESC) and nuclear magnetic resonance imaging (MRI), or cervical pain or Modic changes Can treat back pain.

  Modic changes as used herein include their normal meaning in the art and refer to pathological spinal endplates and bone marrow changes that are visualized using nuclear magnetic resonance imaging (MRI). Modic changes are also called vertebral endplate signal changes (VESC). Modic changes can be classified into various types, including type 1 (M1), type 2 (M2), and type 3 (M3) lesions or changes, all of which include, for example, zoledronic acid, minodronic acid, etc. It can be treated with osteoclast inhibitors such as nitrogen bisphosphonate containing. In the same patient, different types of modic changes may occur, such as type 1 and type 2 modic changes (M1 / 2). In some cases, changes in M1 are associated with lower back pain than other types of Modic changes.

  VESC can be found in various types of low back pain patients including, but not limited to, spondyloarthritis, including spondylitis, trauma, ankylosing spondylitis, Schmall nodules, fractures, tumors, and spinal cord infarction. Ankylosing spondylitis lesions include osteomyelitis and spondylitis, which can be detected using MRI or other medical imaging devices.

  Modic changes can be seen in the cervix, chest, lumbar, and sacral spines. Modic changes are, for example, C1 / 2, C2 / 3, C3 / 4, C4 / 5, C5 / 6, C6 / 7, C7 / T1, T1 / 2, T2 / 3, T3 / 4, T4 / 5, T5 / 6, T6 / 7, T7 / 8, T8 / 9, T9 / 10, T10 / 11, T11 / 12, T12 / L1, L1 / 2, L2 / 3, L3 / 4, L4 / 5, L5 / Any of these can be found at various spinal levels, such as S1, and can be treated with osteoclast inhibitors such as nitrogen bisphosphonates including, for example, zoledronic acid, minodronic acid, and the like.

  In some embodiments, the Modic change being treated is located at L2 / 3. In some embodiments, the Modic change being treated is located at L3 / 4. In some embodiments, the Modic change being treated is located at L4 / 5. In some embodiments, the Modic change being treated is located at L5 / S1.

  In some embodiments, the Modic change being treated is located at C3 / 4. In some embodiments, the modic change being treated is located at C4 / 5. In some embodiments, the Modic change being treated is located at C5 / 6. In some embodiments, the Modic change being treated is located at C6 / 7.

  In some embodiments, the Modic change being treated is located at T5 / 6. In some embodiments, the Modic change being treated is located at T6 / 7. In some embodiments, the Modic change being treated is located at T7 / 8. In some embodiments, the Modic change being treated is located at T8 / 9. In some embodiments, the Modic change being treated is located at T9 / 10.

  In some embodiments, the patient being treated has predominantly M1. In some embodiments, the patient being treated has predominantly M1 / M2. In some embodiments, the patient being treated has predominantly M2. In some embodiments, the patient being treated has predominantly M3.

  In some embodiments, the worst type of lesion that the patient being treated has is M1. In some embodiments, the worst type of lesion that the patient being treated has is M1 / 2. In some embodiments, the worst type of lesion that the patient being treated has is M2.

  In some embodiments, the patient being treated has a Modic change at more than one level. In some embodiments, the patient being treated has a Modic change at three or more levels. In some embodiments, treat patients with modic changes at two levels or more than the pain relief obtained when treating patients with modic changes at a single level or two levels. If so, greater pain relief is obtained.

  In some embodiments, greater pain relief is obtained when treating a patient with a modic change at two levels than the pain relief obtained when treating a patient with a modic change at a single level.

  In some embodiments, greater pain relief is obtained when treating a patient having a Modic change at three or more levels than is obtained when treating a patient having a Modic change at a single level. It is done.

  In some embodiments, greater pain relief is obtained when treating a patient having a modic change at three or more levels than is obtained when treating a patient having a modic change at two levels. .

  In some embodiments, an inhibitor of osteoclast activity is used to reduce the level of pro-inflammatory cytokines in patients with low back pain or in patients with any other type of pain or condition listed herein. Can be reduced. In some embodiments, greater pain in patients with higher baseline levels of inflammatory cytokines when treated with inhibitors of osteoclast activity such as, for example, nitrogen-containing bisphosphonates including zoledronic acid, minodronic acid, etc. Relaxation can be obtained. In some embodiments, for example, in patients who experience a decreased or greater decrease in levels of inflammatory cytokines when treated with inhibitors of osteoclast activity such as nitrogen-containing bisphosphonates such as zoledronic acid, minodronic acid, etc. , Greater pain relief can be obtained. Inflammatory cytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis alpha (TNF-alpha), interferon gamma, etc. Etc.

  In some embodiments, an inhibitor of osteoclast activity is used in a patient or mammal in need thereof, for example, an inhibitor of osteoclast activity such as nitrogen-containing bisphosphonates including zoledronic acid, minodronic acid, and the like. To at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40% relative to a baseline of Modic change or VESC size A reduction of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%. In some embodiments, the Modic change or the decrease in the size of the VESC is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 40% relative to the placebo. At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200% An improvement of at least about 250%, at least about 300%, at least about 350%, at least about 400%, or at least about 450%. In some embodiments, the use of an inhibitor of osteoclast activity inhibits Modic changes over time or an increase in the size of VESC.

  The oral bioavailability of zoledronic acid can be enhanced by oral administration of the disodium salt form of zoledronic acid. For example, the bioavailability of zoledronic acid is at least about 10%, at least about 20%, at least about 30%, at least about 50%, and / or an upper limit of about 100% compared to administration of the diacid form of zoledronic acid Only, or by an upper limit of about 200.

  Due to the improved bioavailability of the disodium salt, the dosage form may include a disodium salt form of zoledronic acid on a molar basis, compared to when the diacid form of zoledronic acid is administered, or a mammal such as a human Can receive. For example, to achieve the same plasma concentration of zoledronic acid, at least about 10 mole% compared to the amount of zoledronic acid in the diacid form, such as the molar amount when the diacid form of zoledronic acid is administered. The dosage form may include a disodium salt form of less than, at least less than about 20 mole%, at least less than about 40 mole%, at least less than about 50 mole%, and / or an upper limit of less than 90 mole%, or an upper limit of less than 95 mole%. Or a mammal can receive.

In some embodiments, on a molar basis the amount of disodium salt form having a value of from about 0.8n _d about 1.2 N _d or about 0.9n _d about 1.1 N _d, dosage form comprises, or Mammals (eg, humans) are administered. Where n _d = (b _a / b _d ) (n _a ), b _a is the bioavailability of the diacid form, b _d is the bioavailability of the disodium salt form, n _a is the number of moles of diacid when administered in a dosage form comprising the diacid form of zoledronic acid. For example, the diacid form has a bioavailability (b _a ) of 0.01, the disodium form has a bioavailability (b _d ) of 0.015, and the dosage form is 0.001 mol diacid If usually contain, _{n d} is (0.01 / 0.015) (0.001 mol), i.e. about 0.00067 mol. In some embodiments, the disodium salt, is administered in an amount having a value of approximately n _d.

  In some embodiments, for an oral dosage form that includes a reduced molar amount of the disodium salt of zoledronic acid as compared to the diacid form of zoledronic acid, the bioavailability of the disodium salt form of zoledronic acid is: When the drug is administered to a mammal, it is sufficiently high that at least as much zoledronic acid is present in the blood of the mammal as is present when zoledronic acid is administered in the diacid form.

  In some embodiments, with respect to oral dosage forms comprising the disodium salt form of zoledronic acid, the disodium salt form is present in a lower molar amount than would exist if the zoledronic acid was assumed to be the diacid form. However, the disodium salt form of zoledronic acid does not reduce the amount of zoledronic acid delivered to the plasma of mammals to a degree that does not reduce the molar amount of disodium salt in the dosage form. Has improved bioavailability.

  Some oral dosage forms containing zoledronic acid have dosages and forms of zoledronic acid that are suitable for a particular species of mammal, such as a dog, rat, human, and the like. Such dosage forms may have zoledronic acid present in an amount that provides the desired range for the area under the plasma concentration curve (AUC) of zoledronic acid in that particular species of mammal. For example, the dosage and oral dosage form of zoledronic acid can be about 1 ng · hour / mL to about 700 ng · hour / mL, about 3 ng · hour / mL to about 30 ng · hour for administration of an oral dosage form to a mammal. / ML, about 3 ng · hour / mL to about 10 ng · hour / mL, about 50 ng · hour / mL to about 700 ng · hour / mL, about 130 ng · hour / mL to about 180 ng · hour / mL, about 300 ng · hour / mL mL to about 450 ng / hr / mL, about 300 ng / hr / mL to about 350 ng / hr / mL, about 300 ng / hr / mL to about 310 ng / hr / mL, about 340 ng / hr / mL to about 350 ng / hr / mL About 370 ng · hour / mL to about 420 ng · hour / mL, about 380 ng · hour / mL to about 390 ng · hour / mL, about 405 ng · hour / mL 415 ng · hr / mL, about 140 ng · hr / mL to about 160 ng · hr / mL, about 140 ng · hr / mL to about 150 ng · hr / mL, about 150 ng · hr / mL to about 160 ng · hr / mL, about 140 ng Time / mL, 142 ng / hour / mL, about 155 ng / hour / mL, about 305 ng / hour / mL, 304 ng / hour / mL, about 345 ng / hour / mL, 343 ng / hour / mL, about 385 ng / hour / mL 384 ng · hr / mL, about 410 ng · hr / mL AUC of zoledronic acid, or any AUC in the range bounded by any of these values, or any AUC between any of these values .

Unless otherwise indicated, AUC refers to the AUC calculated for the last measured concentration (AUC _(0-t) ) and extrapolated to infinity (AUC _(0-inf) ).

An oral dosage form comprising zoledronic acid having a dosage and form of zoledronic acid suitable for a particular mammalian species is from about 0.2 ng / mL to about 300 ng / mL, about 0.00 for oral dosage form administration to a mammal. 5 ng / mL to about 5 ng / mL, about 5 ng / mL to about 300 ng / mL, about 5 ng / mL to about 50 ng / mL, about 20 ng / mL to about 50 ng / mL, about 30 ng / mL to about 50 ng / mL, about 50 ng / mL to about 200 ng / mL, about 50 ng / mL to about 150 ng / mL, about 80 ng / mL to about 120 ng / mL, about 90 ng / mL to about 100 ng / mL, about 50 ng / mL to about 200 ng / mL, about 40 ng / mL, about 95 ng / mL, C _maximum zoledronic acid of approximately 97 ng / mL or bounded by any of these values, Any C _maximum extent eclipsed or have zoledronic acid present in an amount to provide any C _up between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and form of zoledronic acid suitable for a particular mammalian species is such that administration of the oral dosage form to a particular mammal is about 0 to about 0 hours to about 1 hour. .5 hours, or T _up to about 0.75 hours zoledronic acid, or to provide _maximum any T between any T _up or any value of the range bounded by any of these values Can be configured.

  In some embodiments, the disodium salt form of zoledronic acid is administered to the mammal in an oral dosage form from about 4 ng · hr / mL to about 2000 ng · hr / hr each time zoledronic acid is administered in the disodium salt. It is present in an amount to provide an area under the plasma concentration curve of mL zoledronic acid.

  In some embodiments, the zoledronic acid is administered in an oral dosage form from about 100 ng · hour / mL to about 2000 ng · hour / mL, from about 100 ng · hour / mL to about 1000 ng · hour in the mammal to which the dosage form is administered. Present in an amount to provide an area under the plasma concentration curve of zoledronic acid from about 500 ng · hr / mL to about 1000 ng · hr / mL, or from about 500 ng · hr / mL to about 700 ng · hr / mL. This amount may be suitable for administration of an oral dosage form about every 3 to 4 weeks.

  In some embodiments, the zoledronic acid is administered in an oral dosage form from about 20 ng · hour / mL to about 700 ng · hour / mL, from about 50 ng · hour / mL to about 500 ng · hour in the mammal to which the dosage form is administered. / ML, about 50 ng · hour / mL to about 400 ng · hour / mL, about 50 ng · hour / mL to about 300 ng · hour / mL, about 50 ng · hour / mL to about 200 ng · hour / mL, about 100 ng · hour / mL mL to about 500 ng / hour / mL, about 100 ng / hour / mL to about 400 ng / hour / mL, about 100 ng / hour / mL to about 300 ng / hour / mL, about 100 ng / hour / mL to about 200 ng / hour / mL About 125 ng · hr / mL to about 500 ng · hr / mL, about 125 ng · hr / mL to about 400 ng · hr / mL L, plasma concentration of zoledronic acid from about 125 ng · hour / mL to about 300 ng · hour / mL, from about 125 ng · hour / mL to about 200 ng · hour / mL, or from about 200 ng · hour / mL to about 300 ng · hour / mL It is present in an amount that provides the area under the curve. This amount is suitable for weekly administration of an oral dosage form or for administration at 3 to 5 individual doses for a month. Individual doses can be given at regular intervals, can be given during the first week, or can be given on any other schedule that provides 3 to 5 doses for one month.

  In some embodiments, the zoledronic acid is administered in an oral dosage form from about 4 ng · hr / mL to about 100 ng · hr / mL, from about 10 ng · hr / mL to about 50 ng · hr in the mammal to which the dosage form is administered. / ML, about 10 ng · hour / mL to about 30 ng · hour / mL, 20 ng · hour / mL to about 700 ng · hour / mL, about 50 ng · hour / mL to about 500 ng · hour / mL, about 50 ng · hour / mL To about 400 ng / hour / mL, about 50 ng / hour / mL to about 300 ng / hour / mL, about 50 ng / hour / mL to about 200 ng / hour / mL, about 100 ng / hour / mL to about 500 ng / hour / mL, About 100 ng · hour / mL to about 400 ng · hour / mL, about 100 ng · hour / mL to about 300 ng · hour / mL, about 10 ng-hour / mL to about 200 ng-hour / mL, about 125 ng-hour / mL to about 500 ng-hour / mL, about 125 ng-hour / mL to about 400 ng-hour / mL, about 125 ng-hour / mL to about 300 ng Providing an area under the plasma concentration curve of zoledronic acid from hours / mL, from about 125 ng · hour / mL to about 200 ng · hour / mL, or from about 200 ng · hour / mL to about 300 ng · hour / mL; This amount may be suitable for daily administration of oral dosage forms. In some embodiments, the dosage form can be administered continuously for 2, 3, 4, 5, 6, 7, 8, 9 or 10, 5-10, or 6-10 days.

Oral administration of zoledronic acid, especially the disodium salt form of zoledronic acid, can result in a more sustained plasma concentration of the drug compared to parenteral modes of administration such as intravenous or subcutaneous. For example, the amount of plasma zoledronic acid can be much higher for oral administration of the disodium salt for about 24 hours, or 48 hours, or longer after administration. In some embodiments, oral zoledronic acid has about one or more 24-hour sustained plasma concentration factors, such as about 1 to about 10, about 1 to about 5, about 3 to about 5, or about 3 to about 4. Have. In some embodiments, the orally administered dosage form of zoledronic acid is, for example, at least 1.2 times, at least 1.2 times greater than the 24-hour or 48-hour sustained plasma concentration factor of parenterally administered zoledronic acid. 24-hour sustained plasma concentration factor that is 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 higher Or have a 48-hour sustained plasma concentration factor. “Sustained plasma concentration factor”, p _f is defined by the formula p _f = 1000 (C _t / C _max ), where C _max is the maximum plasma concentration of zoledronic acid after administration, and C _t is 24 The plasma concentration of zoledronic acid at a subject time such as time. For parenteral administration, the C _max may be about C ₀ , or may be the concentration immediately after infusion of the full amount of drug into the body. The sustained plasma concentration factor can be obtained for other times, such as 48 hours, using the plasma concentration of zoledronic acid at C _t in the above formula. For example, if the maximum plasma concentration of zoledronic acid after administration is 1000 ng / mL and the plasma concentration of zoledronic acid at 24 hours is 1 ng / mL, the 24-hour sustained plasma concentration factor is 1.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is such that the zoledronic acid is about 12 to about 50, about 20 to about 20 for a particular species of mammal. 40, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 33, about 30, about 35, or any 12 hour sustained plasma concentration factor in the range bounded by any of these values Or any 12 hour sustained plasma concentration factor between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is such that the zoledronic acid is about 10 to about 30, about 10 to about 10 for a particular species of mammal. 20, about 10 to about 15, about 12 to about 15 or 16, about 15 to about 20, about 14, about 12, about 15, or any 24-hour plasma in a range bounded by any of these values It may be configured to have a concentration factor, or any 24-hour sustained plasma concentration factor between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is such that the zoledronic acid is about 6 to about 20, about 8 to about 8 for a particular species of mammal. 15, about 9 to about 12 or 13, about 8 to about 10, about 11 to about 13, about 9, about 13, or any 36 hour sustained plasma concentration factor in the range bounded by any of these values; Or it can be configured to have any 36 hour sustained plasma concentration factor between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is such that the zoledronic acid is about 5 to about 20, about 6 to about 6 for a particular species of mammal. 15, about 7 or 8 to about 12 or 13, about 8 to about 10, about 11 to about 13, about 8, about 12, or any 48 hour sustained plasma concentration in the range bounded by any of these values It may be configured to have a factor, or any 48 hour sustained plasma concentration factor between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is such that the zoledronic acid is about 4 to about 20, about 5 to about 5 for a particular species of mammal. 10, about 5 or 6 to about 10 or 11, about 5 to about 6, about 9 to about 10, about 6, about 10, or any 72-hour sustained plasma concentration in the range bounded by any of these values It may be configured to have a factor, or any 72 hour sustained plasma concentration factor between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for the particular species of mammal is from about 0.5 ng / mL to about 5 ng / mL, about 1 ng / mL of the particular species of mammal. To about 3 ng / mL, about 1 ng / mL to about 2 ng / mL, about 2 ng / mL to about 3 ng / mL, about 3 ng / mL to about 4 ng / mL, about 1.2 ng / mL, about 2.6 ng / mL, It can be configured to have a plasma concentration of zoledronic acid at about 3.2 ng / mL, or any plasma concentration in the range bounded by any of these values, or any 12 hours between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for the particular species of mammal is from about 0.2 ng / mL to about 2 ng / mL, about 0.5 ng of the particular species of mammal. / ML to about 1.5 ng / mL, about 0.5 ng / mL to about 1 ng / mL, about 1 ng / mL to about 1.5 ng / mL, about 0.5 ng / mL, about 1.0 ng / mL, about 1 It can be configured to have a plasma concentration of zoledronic acid at any plasma concentration in the range bounded by .4 ng / mL, or any of these values, or any 24 hours between any of these.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is from about 0.1 ng / mL to about 2 ng / mL, about 0.2 ng for a particular species of mammal. / ML to about 1.5 ng / mL, about 0.2 ng / mL to about 0.5 ng / mL, about 0.5 ng / mL to about 1 ng / mL, about 1 ng / mL to about 1.3 ng / mL, about 0 Zoledronic acid at 3 ng / mL, about 0.8 ng / mL, about 1.1 ng / mL, or any plasma concentration in the range bounded by any of these values, or any 36 hours between them Can be configured to have a plasma concentration of

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal is from about 0.1 ng / mL to about 2 ng / mL, about 0.2 ng for a particular species of mammal. / ML to about 1.5 ng / mL, about 0.2 ng / mL to about 0.5 ng / mL, about 0.5 ng / mL to about 0.9 ng / mL, about 0.9 ng / mL to about 1.3 ng / mL mL, about 0.3 ng / mL, about 0.7 ng / mL, about 1.1 ng / mL, or any plasma concentration in the range bounded by any of these values, or any 48 between these It can be configured to have a plasma concentration of zoledronic acid over time.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for the particular species of mammal is from about 0.2 ng / ml to about 1 ng / ml, about 0.2 ng of the particular species of mammal. / ML to about 1.5 ng / mL, about 0.1 ng / mL to about 0.3 ng / mL, about 0.3 ng / mL to about 0.6 ng / mL, about 0.6 ng / mL to about 1 ng / mL, About 0.2 ng / mL, about 0.5 ng / mL, about 0.9 ng / mL, or any plasma concentration in the range bounded by any of these values, or any 72 hours between these It can be configured to have a plasma concentration of zoledronic acid.

  An oral dosage form comprising zoledronic acid having an amount and form of zoledronic acid appropriate for a particular species of mammal has an elimination half-life of zoledronic acid in a particular species of mammal of about 30 hours to about 100 hours, about 40 hours to about 60 hours, about 40 hours to about 50 hours, about 50 hours to about 60 hours, about 42 hours, about 51 hours, about 59 hours, or any range bounded by any of these values Can be configured to be any half-life of, or any value between these.

  As used herein, “excretion half-life” refers to the apparent primary terminal phase plasma elimination half-life obtained by non-compartmental analysis using Win-Nonlin. Terminal phase plasma elimination half-life is the time required to reduce plasma concentration by half after reaching pseudo-equilibrium, not the time required to excrete half of the dose administered. For drugs that are administered orally, end-phase plasma elimination half-life can be affected by the absorption of the drug and the degree of plasma clearance and distribution.

  In some embodiments, the disodium salt form of zoledronic acid is compared to the diacid form of zoledronic acid that facilitates any enhancement to the bioavailability provided by any bioavailability enhancer in the dosage form. Provide enhancements to bioavailability. In some embodiments, the disodium salt form of zoledronic acid may be compared to the diacid form of zoledronic acid that is greater than any enhancement to bioavailability provided by any bioavailability enhancer in the dosage form. Provide an enhancement to bioavailability. In some embodiments, the disodium salt form of zoledronic acid can be administered in a dosage form that is substantially free of bioavailability enhancers.

  In some embodiments, the dosage form comprising the disodium salt of zoledronic acid is a solid.

  In some embodiments, dosage forms comprising the disodium salt of zoledronic acid are used to treat inflammatory conditions.

  In some embodiments, dosage forms comprising the disodium salt of zoledronic acid are used to treat arthritis.

  In some embodiments, dosage forms comprising the disodium salt of zoledronic acid are used to treat complex regional pain syndrome.

  In some embodiments, the zoledronic acid is greater than 1% (w / v), from about 5% (w / v) to about 50% (w / v), from about 5% (w / v) to about Solubility in water of 20% (w / v), about 10% (w / v) to about 15% (w / v), or about 12% (w / v) to about 13% (w / v) It is present in a form having water solubility.

  The disodium salt form of zoledronic acid can be compressed higher than the diacid form of zoledronic acid. This can facilitate the dosage form to the desired hardness. It can also facilitate to increase the drug load of the dosage form so that smaller tablets can obtain a given dose strength. In some embodiments, a solid dosage form of zoledronic acid, such as the diacid form of zoledronic acid or the 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. .

  Zoledronic acid or another bisphosphonate may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Such standard pharmaceutical practices are described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is incorporated herein by reference in its entirety. The relative proportions of active ingredient and carrier can be determined, for example, by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice.

  Zoledronic acid or another bisphosphonate can be administered by any means that can result in contact of the active agent (s) with the desired site (s) of action in the patient's body. The compounds can be administered by any conventional means that can be used with pharmaceuticals, either as individual therapeutic agents or combinations of therapeutic agents. For example, they can be administered as the sole active agent in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

  In some embodiments, the osteoclast inhibitor is co-administered with a steroid. Suitable steroids include, for example, hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amsinonide, budesonide, desonide, fluocinonide, fluocinolone, Halocinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortron, hydrocortisone-17-valerate, acreomethasone dipropionate, betamethasone valerate, dipropionate betamethasone, prednicarbate, clobetasone-17 -Butyrate, clobetasol-17-propionate, fluo Ruchi Ronka caproate, including fluocortolone pivalate and full pre-Denis Den acetate, hydrocortisone 17-butyrate, 17-Aseponeto, 17 Butepureto, and prednicarbate.

  An effective amount of steroid can be administered to a person. In some embodiments, the dose of steroid can be from about 1 to about 500 mg of steroid. In some embodiments, the dose of steroid is 5 mg to 25 mg of steroid.

  Steroids can be given orally (eg, 7.5 mg prednisone) by separate infusion (eg, 7.5 mg methylprednisolone), mixed with zoledronic acid at the same infusion, or by rectal suppository Can be administered intramuscularly, subcutaneously, or injected directly into the joint.

  Zoledronic acid or another bisphosphonate can be administered to a human patient in a variety of forms compatible with the chosen route of administration, eg, oral, rectal or parenteral. Parenteral administration here includes, but is not limited to, administration by the following route. Lung, intrathecal, intravenous, intramuscular, subcutaneous, intraocular, intraarticular synovial sac, percutaneous, transepithelial including sublingual and buccal, local, nasal inhalation via insufflation, and systemic rectum.

  The effective amount of zoledronic acid or another bisphosphonate depends on the severity of the condition being treated, the route of administration, the formulation and dosage form, the physical properties of the bisphosphonate compound used, and the age, weight and counter-stimulus response of the individual patient Will vary depending on various factors known to the treating physician.

  The amount of zoledronic acid or another bisphosphonate in the therapeutic composition can vary. For example, some liquid compositions can have about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0 .01% (w / v) to about 10% (w / v), about 0.001% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% ( w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), About 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / V), or about 40% (w / v) to about 50% (w / v) zoledronic acid.

  Some solid compositions have at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80% (w / w), about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / W), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) w) to about 60% (w / w), about 70% (w / w) to about 75% (w / w), about 70% (w / w) to about 80% (w / w), or About 80% (w / w) to about 90% (w / w) It may include zoledronic acid).

  For example, an appropriate amount of osteoclast inhibitor including bisphosphonates such as nitrogen-containing bisphosphonates such as zoledronic acid, minodronic acid or ibandronic acid can be used. Some solid or liquid oral dosage forms, or units of oral dosage forms (collectively referred to herein as “oral dosage forms”) can have about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, About 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about 50 mg, about 40 mg to about 60 mg, about 50 mg to about 60 mg, about 55 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to about 600 m About 40 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 25 mg to about 800 mg, about 30 mg to about 800 mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about 50 mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about 2000 mg, about 300 mg to about 1500 mg, about 200 mg to about 1000 mg, about 100 mg to about 500 mg, or about 150 mg of zoledronic acid, or within a range bounded by any of these numbers Or any amount between these numbers can contain any amount of osteoclast inhibitor. In some embodiments, the oral osteoclast inhibitor is administered daily, weekly, monthly, every 2 or 3 months, once a year, or twice a year.

  Some oral dosage forms have from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg, from about 1 mg to about 500 mg, from about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about 50 mg, about 40 mg to about 60 mg, about 50 mg to about 60 mg, about 55 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 40 mg to About 2000 mg, about 40 mg to about 80 mg, about 25 mg to about 800 mg, about 30 mg to about 800 mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about 50 mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about 2000 mg, about 300 mg to about 1500 mg, About 200 mg to about 1000 mg, about 100 mg to about 500 mg or about 150 mg of osteoclast inhibitor, or any amount of breakage within or between any of these numbers Bone cell inhibitors can be included. In some embodiments, the osteoclast inhibitor is administered daily, weekly, monthly, every 2 or 3 months, once a year, or twice a year.

In some embodiments, the oral dosage form has a dosage of about 10 mg / m ² to about 20 mg / m ² , about 15 mg / m ² to about 20 mg / m ² , about 18 mg / m ² , about 80 mg / m ² to about 150 mg. / M ² , about 90 mg / m ² to about 150 mg / m ^2, or about 100 mg / m ² to about 150 mg / m ² zoledronic acid, or a range bounded by any of these numbers, or any of these Any amount of zoledronic acid between these numbers can be included. All dose ranges or amounts expressed in mg / m ² are based on the body surface area of the mammal.

In some embodiments, the daily oral dose of osteoclast inhibitor comprising a bisphosphonate such as, for example, a nitrogen-containing bisphosphonate such as zoledronic acid, minodronic acid, or ibandronic acid is about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, or any range within or between any of these numbers Of quantity. In some embodiments, the daily oral dose of osteoclast inhibitor is less than about 35 mg / ^{m 2,} less than about 30 mg / ^{m 2,} less than about 25 mg / ^{m 2,} from about 1 mg / ^{m 2} to about 35 mg / ^{m 2} About 1 mg / m ² to about 30 mg / m ² , about 1.5 mg / m ² to about 25 mg / m ² , about 1.8 mg / m ² to about 20 mg / m ² , about 10 mg / m ² to about 20 mg / m ² m ² , about 10 mg / m ² to about 30 mg / m ² , about 15 mg / m ² to about 20 mg / m ² , about 18 mg / m ² , or a range of zoledronic acid within a range bounded by any of these numbers Any amount, or any amount of zoledronic acid between any of these numbers.

In some embodiments, the daily oral dose of osteoclast inhibitor comprising a bisphosphonate such as, for example, a nitrogen-containing bisphosphonate such as zoledronic acid, minodronic acid, or ibandronic acid is about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, or any range within or between any of these numbers Amount of osteoclast inhibitor. In some embodiments, the daily oral dose of osteoclast inhibitor is less than about 35 mg / ^{m 2,} less than about 30 mg / ^{m 2,} less than about 25 mg / ^{m 2,} from about 1 mg / ^{m 2} to about 35 mg / ^{m 2} About 1 mg / m ² to about 30 mg / m ² , about 1.5 mg / m ² to about 25 mg / m ² , about 1.8 mg / m ² to about 20 mg / m ² , about 10 mg / m ² to about 20 mg / m ² osteoclasts within a range bound by m ² , from about 10 mg / m ² to about 30 mg / m ² , from about 15 mg / m ² to about 20 mg / m ² , about 18 mg / m ² , or any numerical value thereof Any amount of inhibitor, or any amount of osteoclast inhibitor between any of these numbers.

In some embodiments, the daily oral dosage of zoledronic acid is about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, or Any amount of zoledronic acid within the range bounded by or between any of these numbers. In some embodiments, the daily oral doses of zoledronic acid is less than about 35 mg / ^{m 2,} less than about 30 mg / ^{m 2,} less than about 25 mg / ^{m 2,} from about 1 mg / ^{m 2} to about 35 mg ^{/ m} 2, About 1 mg / m ² to about 30 mg / m ² , about 1.5 mg / m ² to about 25 mg / m ² , about 1.8 mg / m ² to about 20 mg / m ² , about 10 mg / m ² to about 20 mg / m ² , about 10 mg / m ² to about 30 mg / m ² , about 15 mg / m ² to about 20 mg / m ² , about 18 mg / m ² , or any of the zoledronic acid within the range bounded by any of these numbers Or any amount of zoledronic acid between any of these numbers.

In some embodiments, the weekly oral dose of an osteoclast inhibitor comprising a bisphosphonate such as, for example, a nitrogen-containing bisphosphonate such as zoledronic acid, minodronic acid, or ibandronic acid is about 1 mg to about 1000 mg, about 1 mg About 500 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg, about 20 mg to about 150 mg, about 20 mg to about 60 mg About 30 mg to about 70 mg, about 40 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg, about 55 mg, about 100 mg to about 150 mg, or about 30 mg to about 100 mg. In some embodiments, weekly oral doses of osteoclast inhibitor is about 250 mg / ^m less than ^2, less than about 200 mg / ^{m 2,} about 175 mg / ^m less than ^2, from about 6 mg / ^{m 2} to about 250 mg / ^{m 2} About 10 mg / m ² to about 210 mg / m ² , about 10 mg / m ² to about 170 mg / m ² , about 4 mg / m ² to about 140 mg / m ² , about 100 mg / m ² to about 140 mg / m ² , about 126 mg / m ² , or any amount within the range bounded by any of these numbers, or any amount between these numbers. Weekly oral doses may be given as a single dose once a week, or may be given in unit doses of 2, 3, 4, 5, 6 or 7 during a week .

In some embodiments, the weekly oral dosage of zoledronic acid is from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 10 mg to about 250 mg, from about 100 mg to about 300 mg, from about 10 mg to about 100 mg, from about 10 mg. About 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg, about 20 mg to about 150 mg, about 20 mg to about 60 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg, about 55 mg About 100 mg to about 150 mg, or about 30 mg to about 100 mg. In some embodiments, the oral dosage of weekly zoledronic acid is less than about 250 mg / ^{m 2,} less than about 200 mg / ^{m 2,} less than about 175 mg / ^{m 2,} from about 6 mg / ^{m 2} to about 250 mg ^{/ m} 2, About 10 mg / m ² to about 210 mg / m ² , about 10 mg / m ² to about 170 mg / m ² , about 4 mg / m ² to about 140 mg / m ² , about 100 mg / m ² to about 140 mg / m ² , about 126 mg / M ² , or any amount of zoledronic acid within the range bounded by or between any of these numbers. The weekly oral dose may be given as a single dose given once a week or in units of 2, 3, 4, 5, 6 or 7 during the week. May be.

In some embodiments, for example, a monthly dose of osteoclast inhibitor comprising a bisphosphonate, such as a nitrogen-containing bisphosphonate such as zoledronic acid, minodronic acid, or ibandronic acid, or administered over a one month period The amount of osteoclast inhibitor is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1 mg to about 4000 mg, about 1 mg to about 1000 mg, about 10 mg. To about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg to about 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200 mg, about 200 mg to about 300 g, about 250 mg to about 350 mg, or about 100 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 50 mg to about 800 mg, or about 100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, or about 100 mg to about 1000 mg, or any amount within the range bounded by any of these numbers, or any amount between these numbers. In some embodiments, the monthly oral dose of osteoclast inhibitor is less than about 1000 mg / m ^2, less than about 800 mg / m ^2, less than about 600 mg / m ² , about 10 mg / m ² to about 1000 mg / m ^{2. 2} , about 50 mg / m ² to about 800 mg / m ² , about 70 mg / m ² to about 700 mg / m ² , about 100 mg / m ² to about 700 mg / m ² , about 100 mg / m ² to about 600 mg / m ² , About 50 mg / m ² to about 200 mg / m ² , about 300 mg / m ² to about 600 mg / m ² , about 450 mg / m ² to about 600 mg / m ² , about 300 mg / m ² to about 1000 mg / m ² , about 400 mg / M ² to about 1000 mg / m ² , about 500 mg / m ² to about 1000 mg / m ² , about 400 mg / m ² to about 700 mg / any of zoledronic acid within or between m ² , about 500 mg / m ² to about 600 mg / m ² , about 540 mg / m ² , or bounded by any of these numbers Is the amount. The monthly dose may be given as a single dose, or may be given as two or more individual doses administered during a month. In some embodiments, the monthly dose is administered in 2 or 3 weekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28 to 31 daily doses. In some embodiments, the monthly dose is administered in 5 to 10 unit doses during a month. The monthly dose may be administered for only one month, or may be administered repeatedly for two months or more.

In some embodiments, the monthly dose of zoledronic acid or the amount of zoledronic acid administered over a period of one month is about 5000 mg or less, about 4000 or less, about 3000 or less, about 2000 or less, about 1000 or less, About 700 or less, about 600 or less, about 1 mg to about 4,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg To about 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200 mg, about 200 mg to about 300 mg, about 250 mg to about 350 mg, or about 100 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 50 mg About 800m Or about 100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, or about 100 mg to about 1000 mg, or any amount of zoledronic acid within a range bounded by any of these numbers, or these Any amount of zoledronic acid between any of the numbers. In some embodiments, the monthly oral dose of zoledronic acid is less than about 1000 mg / m ^2, less than about 800 mg / m ^2, less than about 600 mg / m ² , about 10 mg / m ² to about 1000 mg / m ² , about 50 mg / m ² to about 800 mg / m ² , about 70 mg / m ² to about 700 mg / m ² , about 100 mg / m ² to about 700 mg / m ² , about 100 mg / m ² to about 600 mg / m ² , about 50 mg / m ² m ² to about 200 mg / m ² , about 300 mg / m ² to about 600 mg / m ² , about 450 mg / m ² to about 600 mg / m ² , about 300 mg / m ² to about 1000 mg / m ² , about 400 mg / m ² about 1000 mg / ^{m 2} of from about 500 mg / ^{m 2} to about 1000 mg / ^{m 2,} about 400 mg / ^{m 2} to about 700 mg / ^{m 2,} about 200 mg / ^{m 2} to about 600 mg / ^{m 2,} about 540 mg / ^{m 2,} or, in a range bounded by any of these numbers, or between any of these numbers, is any amount of zoledronic acid . The monthly dose may be given as a single dose or may be given as two or more unit doses administered during a month. In some embodiments, the monthly dose is administered at a dose of 2 or 3 weeks. In some embodiments, the monthly dose is administered at a dose of 4 or 5 weeks. In some embodiments, the monthly dose is administered as a daily dose of 28-31 days. In some embodiments, the monthly dose is administered at a dose of 5-10 units during a month. The monthly dose may be administered for only one month, or may be administered repeatedly for 2 months or more.

  For oral administration of zoledronic acid to mammals such as dogs, rats, rabbits, monkeys, apes, or humans, from about 0.4 mg / kg to about 3 mg / kg, from about 0.4 mg / kg to about 1.5 mg / Kg, about 0.4 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 0.6 mg / kg, about 0.6 mg / kg to about 0.7 mg / kg, about 0.7 mg / kg kg to about 0.8 mg / kg, about 0.8 mg / kg to about 0.9 mg / kg, about 0.9 mg / kg to about 1 mg / kg, about 1 mg / kg to about 1.1 mg / kg, about 1. 1 mg / kg to about 1.2 mg / kg, about 1.2 mg / kg to about 1.3 mg / kg, about 1.3 mg / kg to about 1.4 mg / kg, about 1.4 mg / kg to about 1.5 mg / Kg, about 1.5 mg / kg to about 1. mg / kg, about 1.6 mg / kg to about 1.7 mg / kg, about 1.7 mg / kg to about 1.8 mg / kg, about 1.8 mg / kg to about 1.9 mg / kg, about 1.9 mg / Kg to about 2 mg / kg, about 2 mg / kg to about 2.1 mg / kg, about 2.1 mg / kg to about 2.2 mg / kg, about 2.2 mg / kg to about 2.3 mg / kg, about 2 .3 mg / kg to about 2.4 mg / kg, about 2.4 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 2.6 mg / kg, about 2.6 mg / kg to about 2. 7 mg / kg, about 2.7 mg / kg to about 2.8 mg / kg, about 2.8 mg / kg to about 2.9 mg / kg, about 2.9 mg / kg to about 3 mg / kg, about 3 mg / kg to about 3.1 mg / kg, about 3.1 mg / kg to about 3.2 mg / k From about 3.2 mg / kg to about 3.3 mg / kg, from about 3.3 mg / kg to about 3.4 mg / kg, from about 3.4 mg / kg to about 3.5 mg / kg, from about 3.5 mg / kg About 3.6 mg / kg, about 3.6 mg / kg to about 3.7 mg / kg, about 3.7 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 3.9 mg / kg, about 3.9 mg / kg to about 4 mg / kg, about 0.4 mg / kg to about 0.6 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, about 0.8 mg / kg to about 1 mg / kg About 1 mg / kg to about 1.2 mg / kg, about 1.2 mg / kg to about 1.4 mg / kg, about 1.4 mg / kg to about 1.6 mg / kg, about 1.6 mg / kg to about 1 .8 mg / kg, about 1.8 mg / kg to about 2 mg / kg, about 2 mg / Kg to about 2.2 mg / kg, about 2.2 mg / kg to about 2.4 mg / kg, about 2.4 mg / kg to about 2.6 mg / kg, about 2.6 mg / kg to about 2.8 mg / kg kg, about 2.8 mg / kg to about 3 mg / kg, about 3 mg / kg to about 3.2 mg / kg, about 3.2 mg / kg to about 3.4 mg / kg, about 3.4 mg / kg to about 3. 6 mg / kg, about 3.6 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 4 mg / kg, about 0.4 mg / kg to about 0.7 mg / kg, about 0.7 mg / kg To about 1 mg / kg, about 1 mg / kg to about 1.3 mg / kg, about 1.3 mg / kg to about 1.6 mg / kg, about 1.6 mg / kg to about 1.9 mg / kg, about 1.9 mg / Kg to about 2.2 mg / kg, about 2.2 mg / kg to about 2 5 mg / kg, about 2.5 mg / kg to about 2.8 mg / kg, about 2.8 mg / kg to about 3 mg / kg, about 3.3 mg / kg to about 3.6 mg / kg, about 3.6 mg / kg From about 0.03 mg / kg to about 10 mg / kg, such as from about 0.4 mg / kg to about 4 mg / kg, from about 0.4 mg / kg to about 1 mg / kg, or from about 0.5 mg / kg to about 1 mg / kg, or within this range Any smaller range of doses may be administered once a day to once a year, once a day to twice a year, once a day to 3 times a year. Dosing, once daily to every 3 months, once daily to every 2 months, once daily to every 2 months, once daily to every month Administration, once a day to every 2-4 weeks, once a day to once a week, etc. It may be a safe dose for repeated oral administration such as.

  The dose referred to the above paragraph of administration of zoledronic acid to a mammal is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times, once a day, or less frequently, such as once a week, once every two weeks, once a month, etc.

  In some embodiments, for oral administration of zoledronic acid once daily to weekly to a mammal such as a mouse, rat, dog, primate, or human, a safe repeat dose is about 0.01 mg / kg to about 0.02 mg / kg, about 0.02 mg / kg to about 0.03 mg / kg, about 0.03 mg / kg to about 0.04 mg / kg, about 0.04 mg / kg to about 0 .05 mg / kg, about 0.05 mg / kg to about 0.06 mg / kg, about 0.06 mg / kg to about 0.07 mg / kg, about 0.07 mg / kg to about 0.08 mg / kg, about 0.0. 08 mg / kg to about 0.09 mg / kg, about 0.09 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.11 mg / kg, about 0.11 mg / kg to about 0.12 mg / Kg, about 0 12 mg / kg to about 0.13 mg / kg, about 0.13 mg / kg to about 0.14 mg / kg, about 0.14 mg / kg to about 0.15 mg / kg, about 0.15 mg / kg to about 0.16 mg / Kg, about 0.16 mg / kg to about 0.17 mg / kg, about 0.17 mg / kg to about 0.18 mg / kg, about 0.18 mg / kg to about 0.19 mg / kg, about 0.19 mg / kg kg to about 0.2 mg / kg, about 0.2 mg / kg to about 0.21 mg / kg, about 0.21 mg / kg to about 0.22 mg / kg, about 0.22 mg / kg to about 0.23 mg / kg From about 0.23 mg / kg to about 0.24 mg / kg, from about 0.24 mg / kg to about 0.25 mg / kg, from about 0.25 mg / kg to about 0.26 mg / kg, from about 0.26 mg / kg About 0. 7 mg / kg, about 0.27 mg / kg to about 0.28 mg / kg, about 0.28 mg / kg to about 0.29 mg / kg, about 0.29 mg / kg to about 0.3 mg / kg, about 0.3 mg / Kg to about 0.31 mg / kg, about 0.31 mg / kg to about 0.32 mg / kg, about 0.32 mg / kg to about 0.33 mg / kg, about 0.33 mg / kg to about 0.34 mg / kg kg, about 0.34 mg / kg to about 0.35 mg / kg, about 0.35 mg / kg to about 0.36 mg / kg, about 0.36 mg / kg to about 0.37 mg / kg, about 0.37 mg / kg From about 0.38 mg / kg, from about 0.38 mg / kg to about 0.39 mg / kg, from about 0.39 mg / kg to about 0.4 mg / kg, from about 0.05 mg / kg to about 0.2 mg / kg, About 0.05mg / kg to about 0.15 mg / kg, about 0.06 mg / kg to about 0.15 mg / kg, about 0.07 mg / kg to about 0.15 mg / kg, about 0.08 mg / kg to about 0.15 mg / kg From about 0.09 mg / kg to about 0.15 mg / kg, from about 0.1 mg / kg to about 0.15 mg / kg, from about 0.03 mg / kg to about 0.5 mg / kg, from about 0.06 mg / kg About 0.2 mg / kg, about 0.07 mg / kg to about 0.2 mg / kg, about 0.08 mg / kg to about 0.2 mg / kg, about 0.09 mg / kg to about 0.2 mg / kg, about 0.1 mg / kg to about 0.2 mg / kg, about 0.4 mg to about 4 mg, about 0.4 mg / kg to about 0.6 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, about 0.8mg / kg to about 1mg / kg About 1 mg / kg to about 1.2 mg / kg, about 1.2 mg / kg to about 1.4 mg / kg, about 1.4 mg / kg to about 1.6 mg / kg, about 1.6 mg / kg to about 1. 8 mg / kg, about 1.8 mg / kg to about 2 mg / kg, about 2 mg / kg to about 2.2 mg / kg, about 2.2 mg / kg to about 2.4 mg / kg, about 2.4 mg / kg to about 2.6 mg / kg, about 2.6 mg / kg to about 2.8 mg / kg, about 2.8 mg / kg to about 3 mg / kg, about 3 mg / kg to about 3.2 mg / kg, about 3.2 mg / kg To about 3.4 mg / kg, about 3.4 mg / kg to about 3.6 mg / kg, about 3.6 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 4 mg / kg, about 0 .5 mg / kg to about 2 mg / kg, about 0.6 mg / kg From about 2 mg / kg, from about 0.7 mg / kg to about 2 mg / kg, from about 0.8 mg / kg to about 2 mg / kg, from about 0.5 mg / kg to about 1.5 mg / kg, from about 0.6 mg / kg About 1.5 mg / kg, about 0.7 mg / kg to about 1.5 mg / kg, about 0.8 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about 0.9 mg / kg, about 0.6 mg / kg to about 0.9 mg / kg, about 0.7 mg / kg to about 0.9 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 0.6 mg / kg to about 1 mg / kg From about 0.03 mg / kg, such as from about 0.7 mg / kg to about 1 mg / kg, from about 0.8 mg / kg to about 1 mg / kg, or from about 0.8 mg / kg to about 0.9 mg / kg About 4 mg / kg or any small range within this range It can be.

  In some embodiments, for oral administration of zoledronic acid once or less weekly to a mammal such as a mouse, rat, dog, primate or human, a safe repeated dose is about 0 .4 mg / kg to about 0.6 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, about 0.8 mg / kg to about 1 mg / kg, about 1 mg / kg to about 1.2 mg / kg, About 1.2 mg / kg to about 1.4 mg / kg, about 1.4 mg / kg to about 1.6 mg / kg, about 1.6 mg / kg to about 1.8 mg / kg, about 1.8 mg / kg to about 2 mg / kg, about 2 mg / kg to about 2.2 mg / kg, about 2.2 mg / kg to about 2.4 mg / kg, about 2.4 mg / kg to about 2.6 mg / kg, about 2.6 mg / kg To about 2.8 mg / kg, about 2.8 g / kg to about 3 mg / kg, about 3 mg / kg to about 3.2 mg / kg, about 3.2 mg / kg to about 3.4 mg / kg, about 3.4 mg / kg to about 3.6 mg / kg, about 3.6 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 4 mg / kg, about 4 mg / kg to about 4.2 mg / kg, about 4.2 mg / kg to about 4.4 mg / kg About 4.4 mg / kg to about 4.6 mg / kg; about 4.6 mg / kg to about 4.8 mg / kg; about 4.8 mg / kg to about 5 mg / kg; about 5 mg / kg to about 5.2 mg. / Kg, about 5.2 mg / kg to about 5.4 mg / kg, about 5.4 mg / kg to about 5.6 mg / kg, about 5.6 mg / kg to about 5.8 mg / kg, about 5.8 mg / kg kg to about 6 mg / kg, about 6 mg / kg to about 6.2 mg kg, about 6.2 mg / kg to about 6.4 mg / kg, about 6.4 mg / kg to about 6.6 mg / kg, about 6.6 mg / kg to about 6.8 mg / kg, about 6.8 mg / kg To about 7 mg / kg, about 7 mg / kg to about 7.2 mg / kg, about 7.2 mg / kg to about 7.4 mg / kg, about 7.4 mg / kg to about 7.6 mg / kg, about 7.6 mg / Kg to about 7.8 mg / kg, about 7.8 mg / kg to about 8 mg / kg, about 8 mg / kg to about 8.2 mg / kg, about 8.2 mg / kg to about 8.4 mg / kg, about 8 .4 mg / kg to about 8.6 mg / kg, about 8.6 mg / kg to about 8.8 mg / kg, about 8.8 mg / kg to about 9 mg / kg, about 9 mg / kg to about 9.2 mg / kg, About 9.2 mg / kg to about 9.4 mg / kg, about 9.4 mg / Kg to about 9.6 mg / kg, about 9.6 mg / kg to about 9.8 mg / kg, about 9.8 mg / kg to about 10 mg / kg, about 0.5 mg / kg to about 2 mg / kg, about 0 .6 mg / kg to about 2 mg / kg, about 0.7 mg / kg to about 2 mg / kg, about 0.8 mg / kg to about 2 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 0 .6 mg / kg to about 1.5 mg / kg, about 0.7 mg / kg to about 1.5 mg / kg, about 0.8 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about 1 mg / kg kg, about 0.6 mg / kg to about 1 mg / kg, about 0.7 mg / kg to about 1 mg / kg, about 0.8 mg / kg to about 1 mg / kg, or about 0.8 mg / kg to about 0.9 mg About 0.4 mg to about 10 mg, such as / kg Others can be any small ranges within this range.

  In some embodiments, the osteoclast inhibitor comprises zoledronic acid and the oral zoledronic acid or its disodium salt is about 0.1 mg to about 10 mg zoledronic acid administered parenterally, such as intravenously. Or it may be administered in combination with a salt thereof. In some embodiments, about 50 mg, about 100 mg or about 150 mg of zoledronic acid disodium salt is administered orally in combination with parenteral 1 mg zoledronic acid, such as intravenously. In some embodiments, the parenteral dose of zoledronic acid is about 0.25 mg to about 25 mg, about 0.25 mg to about 10 mg, or about 0.5 mg to about 7.5 mg.

  For example, for oral administration of osteoclast inhibitors, such as zoledronic acid, ibandronic acid or minodronic acid, or other bisphosphonates, for pain associated with inflammation, arthritis, CRPS, or any other condition described herein For treatment, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, or at least about 12 hours before the osteoclast inhibitor is administered. It can be helpful if the mammal or human being administered the osteoclast inhibitor does not eat or drink (other than any water needed to swallow the oral dosage form). Also, the mammal or human being administered the osteoclast inhibitor for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 4 hours before the osteoclast inhibitor is administered. It can be helpful if you don't eat food or drink. In some embodiments, the human to whom zoledronic acid is administered avoids lying down for at least about 30 minutes or about 1 hour after receiving a dosage form comprising an osteoclast inhibitor, or remains upright or upright. sit. Avoiding food or drink before or after oral administration of the osteoclast inhibitor may improve the bioavailability of the osteoclast inhibitor.

  The oral bioavailability of osteoclast inhibitors in the dosage form can vary. Certain dosage forms may have ingredients added to enhance bioavailability. However, enhanced bioavailability is not always necessary for an effective oral dosage form. In some embodiments, the dosage form is substantially free of bioavailability enhancers. In some embodiments, the oral dosage form is from about 0.01% to about 10%, from about 0.1% to about 7%, or from about 0.1% to about 5%, such as zoledronic acid, ibandronic acid or It may have the oral bioavailability of osteoclast inhibitors such as minodronate. Even in the absence of ingredients or other methods to enhance bioavailability, bisphosphonates such as zoledronic acid typically have low bioavailability in oral dosage forms. In some embodiments, the oral bioavailability of zoledronic acid is not enhanced or not substantially enhanced. For example, the oral bioavailability of zoledronic acid is about 0.01% to about 5%, about 0.01% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%. About 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5%, about 0.3% to about 1%, about 1% to about 3%, about 1.2% to about 3.5%, about 1.2% to about 3%, about 1% to about 4%, about 1.5% to about 4.5%, about 0.1% From about 0.5%, from about 0.3% to about 0.5%, from about 0.5% to about 1%, from about 0.6% to about 0.7%, from about 0.7% to about 0. 8%, about 0.8% to about 0.9%, about 0.9%, about 1% to about 1.1%, about 1.1% to about 1.2%, about 1.2% to about 1.3%, 1.3% to 1.4%, 1.4% to 1.5%, 1.5% to 1.6% From about 1.6% to about 1.8%, it can be from about 1.8% to about 2%, or about 2% to 2.5%.

  One embodiment is a pharmaceutical composition comprising an osteoclast inhibitor such as, for example, zoledronic acid, ibandronic acid or minodronic acid, wherein the oral bioavailability of zoledronic acid in the dosage form is from about 0.01% to about 10%.

  In some embodiments, the oral bioavailability of the osteoclast inhibitor is about 0.01% to about 5%, about 0.1% to about 7%, about 0.1% to about 5%, about 0%. .1% to about 3%, about 0.1% to about 2%, about 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5 %, Or about 0.3% to about 1.0%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.01% to about 5%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.1% to about 7%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.1% to about 5%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.1% to about 3%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.1% to about 2%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.2% to about 2%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is about 0.2% to about 1.5%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.3% to about 1.5%.

  In some embodiments, the oral bioavailability of zoledronic acid in the dosage form is from about 0.3% to about 1.0%.

  In some embodiments, the oral dosage form contains about 10 mg to about 300 mg of zoledronic acid, ibandronic acid or minodronic acid and is administered daily for about 2 to about 15 consecutive days. This dosage regimen is once a month, once every two months, once every three months, once every four months, once every five months, once every six months, It can be repeated once every year or once every two years.

  In some embodiments, the oral dosage form comprises about 10 mg to about 150 mg or about 10 mg to about 100 mg of zoledronic acid, ibandronic acid or minodronic acid and is administered daily for about 2 to about 15 days in a row. This dosage regimen is once a month, once every two months, once every three months, once every four months, once every five months, once every six months, It can be repeated once every year or once every two years.

  In some embodiments, the oral dosage form comprises about 10 mg to about 150 mg or about 10 mg to about 100 mg of zoledronic acid, ibandronic acid or minodronic acid and is administered daily for about 5 to about 10 days in a row. This dosage regimen is once a month, once every two months, once every three months, once every four months, once every five months, once every six months, It can be repeated once every year or once every two years.

  In some embodiments, the oral dosage form contains about 40 mg to about 150 mg of zoledronic acid, ibandronic acid or minodronic acid and is administered daily for about 5 to about 10 days in a row. This dosage regimen is once a month, once every two months, once every three months, once every four months, once every five months, once every six months, It can be repeated once every year or once every two years.

  In some embodiments, oral zoledronic acid, ibandronic acid or minodronic acid can be administered from about 100 mg to about 2000 mg as a single dose. In some embodiments, oral zoledronic acid, ibandronic acid or minodronic acid can be administered from about 300 mg to about 1500 mg as a single dose. In some embodiments, oral zoledronic acid, ibandronic acid or minodronic acid can be administered from about 200 mg to about 1000 mg as a single dose. The dose of zoledronic acid, ibandronic acid or minodronic acid can be administered in a single or divided dose.

  Osteoclast inhibitors such as zoledronic acid, ibandronic acid or minodronic acid can be formulated for oral administration, eg, with an inert diluent or an edible carrier. Alternatively, they may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the dietary food. For oral therapeutic administration, the active compound may be incorporated with excipients and taken orally, such as buccal tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches Etc. can be used.

  Tablets, troches, pills, capsules and the like may also contain one or more of the following. Binders such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, sucrose, lactose or Sweetening agents such as saccharin or flavoring agents such as peppermint, wintergreen oil or cherry flavors. When the unit dosage form is a capsule, it may contain, in addition to the above types of materials, a liquid carrier. A variety of other materials may be present as coatings, for example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. It may be desirable for the material in the dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts used.

  Certain compositions or dosage forms may be liquid or may comprise a solid phase dispersed in the liquid.

  Osteoclast inhibitors such as zoledronic acid, ibandronic acid or minodronic acid can be formulated for parenteral or intraperitoneal administration. Solutions of the active compounds, such as free acids or pharmaceutically acceptable salts, can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersion may also have oil dispersed in or within glycerol, liquid polyethylene glycol and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

  In some embodiments, the oral dosage form may comprise a silicified microcrystalline cellulose such as prosolv. For example, about 20% (wt / wt) to about 70% (wt / wt), about 10% (wt / wt) to about 20% (wt / wt), about 20% (wt / wt) to about 40% (Wt / wt), about 25% (wt / wt) to about 30% (wt / wt), about 40% (wt / wt) to about 50% (wt / wt), or about 45% (wt / wt) wt) to about 50% (wt / wt) of silicified microcrystalline cellulose may be present in the oral dosage form or unit of the oral dosage form.

  In some embodiments, the oral dosage form can include a cross-linked polyvinyl pyrrolidone such as crospovidone. For example, from about 1% (wt / wt) to about 10% (wt / wt), from about 1% (wt / wt) to about 5% (wt / wt), or from about 1% (wt / wt) to about 3% (wt / wt) of cross-linked polyvinyl pyrrolidone may be present in the oral dosage form or unit of the oral dosage form.

  In some embodiments, the oral dosage form can include fumed silica such as Aerosil. For example, about 0.1% (wt / wt) to about 10% (wt / wt), about 0.1% (wt / wt) to about 1% (wt / wt), or about 0.4% ( wt / wt) to about 0.6% (wt / wt) fumed silica may be present in the oral dosage form or unit of the oral dosage form.

  In some embodiments, the oral dosage form can include magnesium stearate. For example, about 0.1% (wt / wt) to about 10% (wt / wt), about 0.1% (wt / wt) to about 1% (wt / wt), or about 0.4% ( wt / wt) to about 0.6% (wt / wt) magnesium stearate may be present in the oral dosage form or unit of the oral dosage form.

  An oral dosage form comprising zoledronic acid or another bisphosphonate or osteoclast inhibitor may be included in a pharmaceutical product comprising multiple units of the oral dosage form.

  A pharmaceutical product containing an oral dosage form for daily use may contain 28, 29, 30 or 31 units of the oral dosage form for monthly supply. A daily use supply of about 6 weeks can contain 40 to 45 units of the oral dosage form. A daily use supply of about 3 months can contain 85 to 95 units of the oral dosage form. A daily use supply of about 6 months can contain 170 to 200 units of the oral dosage form. A daily use supply of about one year can contain 350 to 380 units of the oral dosage form.

  A pharmaceutical product containing an oral dosage form for weekly use can contain 4 or 5 units of the oral dosage form for monthly supply. A supply for about two months of weekly use can contain 8 to 9 units of the oral dosage form. A supply of about 6 weeks with weekly use can contain 6 units of the oral dosage form. A supply for about 3 months with weekly use can contain 12, 13 or 14 units of the oral dosage form. A supply for about 6 months of weekly use can contain 22 to 30 units of the oral dosage form. A supply of about one year with weekly use can contain 45 to 60 units of the oral dosage form.

  The pharmaceutical product may be adapted to other dosage regimens. For example, the pharmaceutical product may comprise 5 to 10 units of the oral dosage form, each unit of the oral dosage form containing from about 40 mg to about 150 mg of zoledronic acid, ibandronic acid or minodronic acid. A pharmaceutical product may contain 1 to 10 units of the oral dosage form, and the product contains about 200 mg to about 2000 mg of zoledronic acid, ibandronic acid or minodronic acid. With such a product, each unit of the oral dosage form may be taken daily at the beginning of the month, for example, 1 to 10 days or 5 to 10 days during the month.

  Some oral dosage forms including osteoclast inhibitors such as zoledronic acid, minodronic acid, or a suitable bisphosphonate such as ibandronic acid or salts thereof may have an enteric coating or a film coating. In some embodiments, the oral dosage form of the osteoclast inhibitor comprises a tablet having an enteric coating. In some embodiments, the oral dosage form of the osteoclast inhibitor comprises a capsule having an enteric coating. In some embodiments, the oral dosage form of the osteoclast inhibitor comprises a tablet having a film coating. In some embodiments, the oral dosage form of the osteoclast inhibitor comprises a capsule having a film coating.

  Useful dosages of antibodies against RANK or RANKL, such as denosumab, are about 0.1 mg / kg to about 20 mg / kg, about 0.75 mg / kg to about 7.5 mg / kg, about 0.1 mg / kg to about 5 mg / Kg, about 1 mg / kg to about 2 mg / kg, about 10 mg / kg to about 20 mg / kg, about 12 to about 17 mg / kg, about 15 mg / kg to about 20 mg / kg, about 1 mg / kg, about 1 mg / kg To about 10 mg / kg, or any value bounded by these ranges based on the weight of the mammal, or any value between these ranges based on the weight of the mammal. The selected dose may be administered repeatedly, especially for chronic conditions, or the amount per dose may increase or decrease as treatment progresses. The selected dose can be administered at least once a week, once a month, once every two months, once every three months, once every six months, or yearly.

  In some embodiments, 60 mg of denosumab is administered subcutaneously to a patient in need of treatment. In some embodiments, administration is repeated every 6 months.

  There are many ways in which a portion of Compound 1 and / or Compound 2 can be removed from the zoledronic acid product. For example, HPLC, preparative TLC, crystallization, sublimation, or zone purification can be used. Solvents that may be useful in HPLC, TLC or crystallization include but are not limited to water or hexane, diethyl ether, ethyl acetate, methyl acetate, acetone, acetic acid, acetonitrile, tetrahydrofuran, ethanol, methanol, isopropyl alcohol, chloroform, diethyl Organic solvents such as ether, toluene, dimethylformamide, and benzene may be included. A gradient, or two solvent systems can be used as well. For example, HPLC separation may begin by eluting with water, and some time after elution with water, organic solvents such as acetonitrile, methanol, ethanol, ethyl acetate, acetone, acetic acid, methyl acetate or other solvents Can be gradually added to the water or completely replaced with water. Similarly, crystallization or recrystallization can use a single solvent or a combination of solvents. For example, zoledronic acid or a salt thereof, such as a disodium salt, can be recrystallized from water, ethanol, methanol, diethyl ether, methyl acetate, acetic acid, or the like, or from these solvents or combinations of other solvents. In some embodiments, zoledronic acid or a salt thereof, such as the disodium salt, can be dissolved in one solvent such as water or acetic acid and hexane, diethyl ether, chloroform, dichloromethane, ethyl acetate, methyl acetate, acetic acid Can be crystallized with a second solvent or solvent system, such as ethanol, methanol, or combinations thereof. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding hexane. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding diethyl ether. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding chloroform. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding dichloromethane. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding ethyl acetate. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and crystallized by adding methyl acetate. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by adding acetic acid. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding ethanol. In some embodiments, the disodium salt of zoledronic acid is crystallized by dissolving in water and then adding methanol. In embodiments using water and a second solvent, the ratio of water to second solvent (second solvent) is about 1: 100 to about 100: 1, about 1:10 to about 1: 5, about 1: 5 to about 1: 4, about 1: 4 to about 1: 3, about 1: 3 to about 1: 2, about 1: 2 to about 1: 1, about 1: 1 to about 2: 1, about It can be from 2: 1 to about 3: 1, from about 3: 1 to about 4: 1, from about 4: 1 to about 5: 1, or from about 1: 1 to about 10: 1.

  In some embodiments, a combination of the two methods listed in the previous paragraph, such as HPLC or TLC and crystallization, can be used. In some embodiments, methods such as HPLC, preparative TLC, crystallization, sublimation, or zone purification may be repeated. In some embodiments, the purification methods listed in the paragraph above can be performed twice. In some embodiments, the purification methods listed in the paragraph above can be performed three or four times.

  In the following examples, zoledronic acid was administered in the disodium salt form as disodium zoledronic acid tetrahydrate. A bioavailability enhancer was not used in the test composition.

Example 1
Effects of Oral Administration of Zoledronic Acid in a Rat Model of Inflammatory Pain Methods The effects of oral administration of zoledronic acid on inflammatory pain were investigated using a rat complete Freund's adjuvant (CFA) model. On day 0, inflammatory pain was induced by injecting 75 μL volume of 100% CFA into the left hind paw of Sprague-Dawley rats, followed by evaluation on days 1-3. . From day 1 to day 3, the animals received daily solvent (control), zoledronic acid 18 mg / m ² (or 3 mg / kg), zoledronic acid 120 mg / m ² (or 20 mg / kg), or zoledronic acid 900 mg / kg. m ² (or 150 mg / kg) was orally administered. The drug was dissolved in distilled water and prepared fresh daily. The animals were fasted before dosing. Under current FDA guidelines for extrapolating starting doses from animals to humans, doses expressed in mg / m ² are considered equally among mammalian species. Thus, for example, 18 mg / m ^{2 in} rats is considered equivalent to 18 mg / m ^{2 in} humans, whereas 3 mg / kg in rats cannot be equivalent to 3 mg / kg in humans.

  Obtain values of inflammatory pain (mechanical hyperalgesia) in vehicle and drug treated animals on day 0 before CFA infusion and on baseline (baseline) and post-treatment on days 1 to 3 It was. Pain was assessed using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, Calif.). The animals were placed in a restraining sling, leaving the hind limb used for the study. The foot compression threshold was measured by applying a pressure increase to the bottom surface of the hind paw using a domed tip placed between the third and fourth metatarsals. The pressure was gradually applied over about 10 seconds. Measurements were taken from the first observed defensive behavior of speech, struggle or withdrawal. A cut-off value of 300 g was used to prevent damage to the animals.

The recovery of inflammatory pain was calculated according to the following formula:
% Recovery = (post-treatment-baseline after CFA treatment) / (baseline before CFA treatment-baseline after CFA treatment) x 100

  Experiments were performed using 9 to 10 animals per group.

Results Oral administration of zoledronic acid significantly improved the threshold of inflammatory pain compared to vehicle. The pain threshold measured at various times is shown in FIG. The threshold for paw compression in the 18 mg / m ² group was higher than the solvent during the entire measurement period, starting 30 minutes after the start of treatment. On day 3, the threshold for paw compression in both the 18 mg / m ² and 900 mg / m ² groups was greater than the solvent. Improvements in pain thresholds of 49% and 83% from baseline were observed in the 18 mg / m ² and 900 mg / m ² groups, respectively.

Orally administered zoledronic acid resulted in 29% recovery of inflammatory pain at 18 mg / m ² dose and 48% recovery at 900 mg / m ² dose. The magnitude of this effect is comparable to that obtained with clinical doses of commercially available NSAIDs when tested in similar inflammatory pain models. Under current FDA guidelines, the standard body surface area of a human adult is 1.62 m ² . Therefore, 18 mg / ^{m 2} doses of daily corresponds to 560 mg / ^{m 2} doses of about 500 to monthly, or corresponding to about 800 to human dose of 900 mg.

Surprisingly, the two higher doses resulted in a lower threshold than the solvent during the first two days of administration. The 120 mg / m ² group was approximately equal or inferior to the solvent at all time points during the evaluation period. The 900 mg / m ² group showed efficacy on day 3, but this result was accompanied by significant toxicity that forced euthanasia of all animals in this group 2 days after discontinuation of treatment. .

Example 2
Effect of Oral Administration of Zoledronic Acid in a Rat Model of Arthritic Pain Methods The effect of oral administration of zoledronic acid on arthritic pain was investigated in a rat complete Freund's adjuvant (CFA) model of arthritic pain. In this model, 75 μL volume of 100% complete Freund's adjuvant (CFA) was injected into the left hind paw to develop arthritic pain and continued for a period of 10 to 14 days. Animals received 3 vehicles (control), zoledronic acid 54 mg / m ² (or 9 mg / kg), or zoledronic acid 360 mg / m ² (or 60 mg / kg) during the first 3 days of CFA infusion treatment. Oral administration was divided into daily doses equally divided into two. The drug was dissolved in distilled water and prepared fresh daily. The animals were fasted before dosing.

  Arthritic pain (mechanical hyperalgesia) in vehicle- and drug-treated animals was measured using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodhill Hills, Calif.) 14 after CFA infusion treatment. Evaluated on day. The animals were placed in a restraining sling, leaving the hind limb used for the study. The foot compression threshold was measured by applying a pressure increase to the bottom surface of the hind paw using a domed tip placed between the third and fourth metatarsals. The pressure was gradually applied over about 10 seconds. Measurements were taken from the first observed infringement defensive behavior of speech, struggle or withdrawal. A cut-off value of 300 g was used to prevent damage to the animals.

The recovery of arthritic pain in the ipsilateral (CFA-injected) foot was calculated according to the following formula:
% Recovery = (Isolateral drug threshold-Ipsilateral solvent threshold) / (Opposite solvent threshold-Ipsilateral solvent threshold) x 100

  Experiments were performed using 7 to 10 animals per group.

Results Oral administration of zoledronic acid significantly improved the threshold for arthritic pain compared to vehicle. As shown in FIGS. 2A and 2B, oral administration of zoledronic acid resulted in recovery of arthritic pain as a function of dose. 54 mg / in the group of ^{m 2} 33% recovery was observed in the group of 360 mg / ^{m 2} of 54% recovery was observed. Under current FDA guidelines, the standard body surface area of a human adult is 1.62 m ² . Thus, 54 mg / m ² in rats is equivalent to a suggested human dose of about 87 mg, and 360 mg / m ^{2 in} rats is equivalent to a suggested human dose of about 583 mg.

Example 3
Treatment of Complex Local Pain Syndrome Using Oral Administration of Zoledronic Acid The effect of oral administration of zoledronic acid was investigated in a rat model of tibial fracture with complex regional pain syndrome (CRPS). CRPS is performed by casting the hind paw in 4 weeks after crushing and breaking the rat right distal tibia as disclosed by Guo TZ et al. (Pain. 2004; 108: 95-107). Induced in rats. This animal model has been shown to reproduce the phantom trauma, natural history, signs, symptoms and pathological changes observed in human CRPS patients (Kingery WS et al., Pain. 2003; 104: 75). -84).

Beginning on the day of fracture and mold placement, animals were orally dosed with either vehicle (control) or zoledronic acid at a dose of 18 mg / m ² / day (3 mg / kg / day) over 28 days. The drug was dissolved in distilled water and administered by gavage. The animals were fasted 4 hours before dosing and 2 hours after dosing. At the end of the 28 day period, the mold was removed and on the following day the rats were tested for hind paw pain, edema and warmth.

Pain assessment Pain was assessed by measuring hyperalgesia and weight bearing.

  An up-down von Freytest paradigm was used to assess hyperalgesia. Rats were placed in a clear plastic cylinder (20 cm diameter) with a wire mesh bottom and allowed to acclimate for 15 minutes. The foot was tested with one of eight series of von Frey hairs ranging in stiffness from 0.41 g to 15.14 g. The von Frey hair was applied to the hind plantar skin approximately in the midsole, taking care to avoid an annular pad. The fiber was pressed until it bends slightly and then rocked in that position for 6 seconds. Stimulation was applied at intervals of a few seconds. The withdrawal of the hind legs from the fiber was considered a positive response. The initial fiber presentation pressure was 2.1 g and the fiber was applied according to Dixon's up-down method to produce 6 responses in the immediate vicinity of the 50% threshold. Stimulation was applied at intervals of a few seconds.

  Incapacitance devices (IITC Inc. Life Sciences Woodland, CA, USA) were used to measure hind paw weight load, postural effects of pain. The rat was manually held in a vertical position across the device with the hind paw resting on a separate metal scale plate, and the entire weight of the rat was supported on the hind paw. The duration of each measurement was 6 seconds, and 10 consecutive measurements were taken at 60 second intervals. Eight measurements (except the highest and lowest) were averaged to calculate bilateral hind paw weight load values. The weight bearing data were analyzed as the ratio of the hind paw weight loading value between the right (fracture) and the left ((2R / (R + L)) × 100%).

Edema assessment Laser sensor technology was used to determine dorsal-ventral hind paw thickness. Prior to baseline testing, a 2 to 3 mm spot tattoo was placed on the bilateral hind paws on the dorsal skin beyond the midpoint of the third metatarsal. For laser measurements, each rat was briefly anesthetized with isoflurane and then held vertically so that the hind paws were resting on the table top under the laser. A small metal rod applied to the top of the ankle joint was used to hold the foot flat and gently on top of the table. Using optical triangulation, using a laser equipped with a distance measuring sensor, measure the distance to the top of the table and the distance to the top of the back foot at the tattoo site, and measure that distance on the dorsal-ventral foot. Used to calculate thickness. The measurement sensor device used in this experiment (4381 Precicura, Limab, Gotenburg, Sweden) has a measurement range of 200 mm with a resolution of 0.01 mm.

Measurement of hind paw temperature The hind paw temperature was measured using a thin wire thermocouple (Omega, Stanford, CT, USA) applied to the skin of the paw. Six locations per hind leg were tested. Six measurements on each hind paw were averaged as the average temperature.

Results As shown in FIG. 3, treatment with oral administration of zoledronic acid reversed pain, restored weight bearing, and prevented edema when compared to animals treated with solvent.

  As shown in FIG. 4, von Frey's pain threshold in the right (fracture) hind paw was reduced by 72% relative to the contralateral (normal) hind paw in animals treated with solvent. Zoledronic acid treatment reversed the fracture-induced pain by 77% compared to solvent treatment.

  As shown in FIG. 5, the decrease in the body weight effect of the weight load and pain was significantly larger in the solvent treatment group than in the zoledronic acid treatment group. Body weight burden in the fractured hindlimb was reduced to the normal 55% in the solvent-treated group. Zoledronic acid treatment significantly recovered hind limb weight load compared to solvent treatment (86% of normal).

  As shown in FIG. 6, the expected increase in hind paw thickness, reflecting edema development, was greater in the solvent treated group compared to the zoledronic acid treated group. Zoledronic acid treatment reduced 60% hind paw edema over solvent treatment.

  Zoledronic acid reduced hind paw warming by 5% relative to solvent treatment.

The daily dose in the above experiment was 18 mg / m ² / day. Under current FDA guidelines, the standard body surface area of a human adult is 1.62 m ² . Thus, the daily dose of 18 mg / ^{m 2} corresponds to about 500 to monthly dose of 560 mg / ^{m 2,} or corresponding to about 800 to human dose of 900 mg.

Example 6
Solubility of zoledronic acid disodium salt The water solubility of zoledronic acid and zoledronic acid disodium tetrahydrate was measured. One gram of test compound was measured in a beaker. Thereafter, demineralized water (pH 5.5) was added in small portions to the test compound, and sonication was applied to the mixture. The procedure was continued until completely dissolved. It was determined that complete dissolution was reached when there was no visible material and a clear solution was present. The volume of water required to reach the complete dissolution was used to calculate the solubility value expressed in grams per 100 mL. The procedure was performed on each compound.

Results As shown in FIG. 7, the water solubility of zoledronic acid disodium tetrahydrate is about 50 times that of zoledronic acid. Zoledronic acid disodium tetrahydrate has a solubility of 12.5 g / 100 mL compared to a solubility of only 0.25 g / 100 mL in zoledronic acid.

Example 7
Bioavailability of oral administration of zoledronic acid and disodium zoledronic acid Tablets containing either pure zoledronic acid or the disodium salt of zoledronic acid (zoledronate disodium tetrahydrate) were produced. Both types of tablets had a 50 mg zoledronic acid equivalent per tablet. The same excipients were used in both types of tablets in amounts prepared taking into account the molecular weight difference between the acid and disodium salt.

  Tablets with 150 mg of zoledronic acid equivalent in either the zoledronic acid disodium form (group 1) or the pure zoledronic acid form (group 2) were orally administered to beagle dogs. Each animal was given three 50 mg equivalent tablets (total 150 mg) that were administered together. The animal's mouth was moistened with water before placing the tablet on the underside of the animal. Animals were fasted before and after dosing. The animals weighed 6 to 10 kg between 6 and 9 months of age on the day of dosing. There were 3 dogs per group.

Following administration for measurement of zoledronic acid plasma concentration, serial blood samples were taken from each animal by venipuncture of the jugular vein at various points. Blood samples were collected in chilled tubes containing K ₂ EDTA as an anticoagulant. The sample was then centrifuged at approximately 3000 rpm at + 4 ° C. for 10 minutes for plasma derivation. The plasma concentration of zoledronic acid was measured using the LC / MS / MS method.

Results The average plasma concentration of zoledronic acid in each group of dogs is summarized in Table 1 and shown in FIG. A detectable plasma concentration of zoledronic acid was observed and measured for a total of 48 hours.

Zoledronic acid disodium produced plasma concentrations of zoledronic acid that were much higher than pure zoledronic acid and showed improved oral absorption in salt form. Disodium salt resulted in an increase of 119% in bioavailability and 74% weight adjustment as compared to pure zoledronic acid as measured using peak plasma concentration (C _max ). Bioavailability, as measured using the area under the plasma concentration curve (AUC _0-∞ ), was 84% and 46% greater for disodium salt than pure zoledronic acid, respectively, on a weight-adjusted basis. The average AUC _0-∞ of the ninatrim salt was 4073 ng · hour / mL, and the average AUC _0-∞ of the diacid was 2217 ng · hour / mL. AUC _0-∞ was found to be proportional to dose. Thus, for beagle dogs similar to those tested, about 3 mg to about 4 mg of disodium salt is expected to yield about 100 ng · hr / mL of AUC _0-∞ and about 7 mg to about 8 mg of disodium. The salt would be expected to yield about 200 ng · hr / mL of AUC _0-∞ .

Example 8
Tablets were prepared by combining zoledronic acid in the form of the free acid or disodium salt with the same excipients. For dosage forms containing higher amounts of active agent, the amount of excipient is reduced proportionately to maintain the tablet weight at about 100 mg. After compounding, the material is compressed at various pressures and then film coated. The obtained tablets were obtained from Dr. The hardness was tested using a Schleuniger Pharmatron 8M tablet hardness tester. The results are shown in Table 2 and FIG.

  Several embodiments related to joint pain, bone marrow lesions, and osteoarthritis were considered as a result of analyzing data from clinical studies. Some of the results of this study were reported by Laslett et al., Described in Ann Rheum Dis 2012; 71: 1322-1328. Some of the descriptions and data reported below were not published prior to filing this application. 52 patients with clinical knee arthropathy and knee bone lesions (BML) were randomized to receive intravenous zoledronic acid (5 mg) or placebo in a double-blind manner. All patients had to have at least one bone marrow lesion (BML) in the knee affected by magnetic resonance imaging (MRI). Knee radiographs were taken for all patients for determination of joint stenosis (JSN) scored according to the Osteoarthritis Research Association (OARSI) Atlas. Patients did not have either joint space constriction (OARSI grade 0) or a greater degree of joint space constriction (OARSI grade 1 and grade 2). Twenty-six patients were treated with zoledronic acid (8, 6, and 12 with OARSI grades 0, 1, and 2, respectively). Twenty-six patients received placebo (8, 8 and 10 for OARSI grades 0, 1 and 2 respectively).

  Pain intensity was assessed at baseline and 3 months using a 100 mm visual analog scale (VAS) at 0 representing no pain and 100 representing extreme pain. The change in pain intensity from baseline to 3 months was calculated.

  Zoledronic acid treatment significantly reduced pain in patients without joint space stenosis (OARSI grade 0) compared to placebo, but not in patients with joint space stenosis (OARSI grades 1-2). As shown in Table 3 and FIG. 10, the average VAS score was reduced by 15 mm compared to placebo in the OARSI Grade 0 group, but only 0.28 compared to placebo in OARSI Grade 1-2 patients Met.

In the zoledronic acid group, the mean VAS score at 3 months decreased from baseline in OARSI grade 0 and 1 patients by approximately 25 mm and 21 mm, respectively, but decreased by only 9 mm in OARSI grade 2 patients (Fig. 11).

Zoledronic acid treatment significantly reduced pain compared to placebo in patients with a baseline VAS pain intensity score of 50 mm or greater, but not in patients with a baseline VAS score of less than 50 mm. As shown in Table 4, the average VAS score was reduced by 9 mm compared to placebo in patients with baseline VAS ≧ 50 mm, but decreased by 0.6 compared to placebo in patients with baseline VAS <50 mm did.

As summarized in Table 5 and shown in FIG. 12, patients with baseline VAS ≧ 50 mm have greater pain reduction, patients with OARSI grade 0 joint space constriction have even greater pain reduction, and baseline VAS ≧ 50 mm and Pain reduction was greatest in patients with OARSI grade 0 joint stenosis.

BML was evaluated using proton density weighted fat saturation MR images. BML was evaluated using Osiris software (University of Geneva, Geneva, Switzerland). Maximum size was measured in mm ² using a software cursor applied to the maximum area of each lesion. If there were multiple lesions at the same site, the lesion with the highest score was used. Each patient had a BML score (mm ² ) at each of the four sites (medial tibia, medial thigh, lateral tibia and lateral thigh sites), which were summed to produce a total BML score (mm ² ). . The change in the total area of BML from baseline to 6 months was calculated.

Zoledronic acid treatment reduced the size of BML. As shown in FIG. 13 and Table 6, the average BML area was reduced by about 190 mm ² compared to placebo in the OARSI Grade 0 group, but only about 33 mm ² compared to placebo in OARSI Grade 1-2 patients. Diminished.

Example 10
Methods A study was conducted to evaluate the efficacy of a single intravenous infusion of 5 mg ZA compared to intravenous placebo infusion and MRI Modic changes in patients with chronic low back pain (LBP). This study was a double-blind randomized placebo-controlled clinical trial of patients with low back pain (LBP). Patients must have at least 3 (6) LBP on the 10 cm visual analog scale (VAS), Oswestry disability index (ODI) of at least 30%, and up to 6 months prior to hospitalization for at least 3 months Patients were included in this study if there was an MRI M1, mixed M1 / 2 or M2 type change performed.

  Patients have known hypersensitivity to components of nephropathy, hypocalcemia, zoledronic acid or other bisphosphonates or infusion products with reduced creatinine clearance, defined as an estimated glomerular filtration rate (eGFR) of less than 40 ml / min Patients were excluded from the study if they had warnings, nerve root strangulation, or early retirement motivation. We also excluded premenopausal women who could become pregnant. To assess serum concentrations of calcium and creatinine, blood samples were taken before infusion. Laboratory tests included a history and clinical evaluation of waist flexibility, tendon signs, and motor and sensory tests.

  After confirmation of eligibility, patients were randomized and infused once intravenously over 15 minutes with 5 ml of zoledronic acid (n = 20) or placebo (n = 20) for 15 minutes. Information on concomitant medications and hospital use was recorded. Blood samples were taken for assessment of safety, inflammatory mediators and bone turnover markers at baseline, 1 month and 1 year.

  Clinical evaluations were performed for 14 days prior to hospitalization (screening visit) and follow-up visits at 1 month and 1 year after infusion. The main result was a change in the strength of the LBP on the VAS. Side effects included leg pain intensity, ODI, health-related QOL as assessed by RAND-36, patient-reported sick leave and lumbar flexibility. These outcome measures were evaluated at baseline and at each follow-up. Lumbar flexibility was assessed using finger-to-floor and trunk-side bend scales (in cm). The percentage of patients who received a 20% relative improvement, the percentage of patients with a VAS score of 40 or less in the primary outcome, and the patient's acceptable symptom status (PASS) were also assessed. During the follow-up visit, he was asked about the use of painkillers.

Results Zoledronic acid treatment resulted in a greater improvement in LBP intensity at 1 month compared to placebo treatment. In addition, patients receiving zoledronic acid were reported to be significantly less frequently used for NSAIDs at 1 year than for the placebo group. Overall, the improvement in most of the evaluated parameters was greater in the zoledronic acid group over the entire follow-up period.

  The clinical characteristics of the study participants at baseline are shown in Table 6. Average LBP duration was 293 days, initial LBP intensity was VAS 6.7, leg pain was VAS 2.9, and ODI score was 32%. Nineteen patients in the ZA group and 18 patients in the placebo group had M1 / 2 lesions. Modic changes were most common with L4 / 5 or L5 / S1 (70%). The zoledronic acid group and placebo group were similar in terms of demographic and background characteristics of all patients at baseline (Table 6).

  The mean difference (MD) between treatment groups in the main outcome, the mean difference between treatment groups in the intensity of LBP (MD) was significantly superior to zoledronic acid at 1 month (MD1.4; 95% CI 0.01-2.9) was not significantly different at 1 year (MD 0.7; 95% CI -1.0-2.4; Table 7). The percentage of patients showing at least a 20% improvement in the intensity of LBP and PASS was superior to zoledronic acid treatment at 1 month: zoledronic acid 55% vs placebo 25% (p = 0.105) and zoledronic 50% acid vs. 20% placebo (p = 0.096).

  For patients treated with zoledronic acid, the decrease in pain intensity was greater in patients with higher baseline pain intensity as shown in Table 9. The average decrease in pain from baseline was 3.4 for patients with baseline pain intensity ≧ 7 compared to a decrease of only 0.1 for patients with baseline pain intensity <6.

  Of the secondary results, the improvement in ODI was superior to zoledronic acid at 1 month, with a 6.0% (95% CI -0.6 to 13) difference between groups. That was not the case at year (Table 7). Similarly, scoliosis (right and left) was superior to zoledronic acid treatment at 1 month but not at 1 year (Table 7). The total RAND-36 and changes in physical and mental elements of RAND-36 are shown in Table 8.

At baseline, there were no differences between treatment groups with self-administration of nonsteroidal anti-inflammatory drugs (NSAIDs), but at year 1 only 20% of patients in the ZA group using NSAIDs On the other hand, it was 60% in the placebo group.

Example 11

1,3-bis (2-methoxy-2-oxoethyl) -1H-imidazole-3-ium chloride (9)
Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added dropwise to 1- (trimethylsilyl) -1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated at 60 ° C. for 24 hours. The mixture was cooled to room temperature, washed with Et ₂ O (3 × 500 mL) and dried in vacuo to give 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.

1,3-bis (carboxymethyl) 1H-imidazole-3-ium chloride (10)
1,3-bis (2-methoxy-2-oxoethyl) -1H-imidazole-3-ium chloride (9; 41.00 g, 164.88 mmol, 1 eq) with 37% aq. HCl (30.03 mL, 362.74 mmol, 2.2 eq) was added. The mixture was stirred at reflux for 0.5 hours. The mixture was concentrated and the remaining solid was washed with acetone (2 × 200 mL) and Et ₂ O (3 × 200 mL). Drying in vacuo gave 10 (31.89 g, 144.55 mmol, 87.7%) as a white solid.

  Compound 1: Compound 10 is reacted with an equimolar amount of phosphorous acid followed by an equimolar amount of phosphorous trichloride and excess water to form Compound 1, which is precipitated from ethanol.

Compound 2: 1,3-bis (carboxymethyl) -1H-imidazol-3-ium chloride (10, 2.00 g, 9 mmol, 1.0 eq) and H ₃ PO ₃ (7.37 g, 90 mmol, 10 eq) ) Was dissolved in toluene (10 mL) and heated to 70 ° C. After the reaction mixture was stirred at this temperature for 20 minutes, PCI ₃ (16 mL, 180 mmol, 20 eq) was added within 30 minutes. The reaction mixture was then heated to 95 ° C. and stirred at this temperature for 2 hours. Next, aq. HCl (30 mL, 37% HCl and 5 mL H ₂ O) was added. The reaction mixture was heated to 100 ° C., stirred at this temperature for 7 hours, at room temperature for 2 days and then filtered. The filtrate was cooled in an ice bath and added to absolute EtOH (90 mL) within 45 minutes. The resulting suspension was stirred at room temperature for 1 hour, and the solid was filtered off. The filter cake (46-1) was isolated and analyzed by 2D-NMR spectroscopy and mass spectrometry (m / z = 477). The filtrate was concentrated in vacuo to give residue 46-2. 500 mg of this residue was added to aq. Treated with NaOH (150 mg in 3.5 mL H ₂ O), to which EtOH (7 mL) was added. After standing overnight, the liquid was decanted and the resulting solid (46-M4) was analyzed by NMR and mass spectrometry (m / z = 477).

The following embodiments are specifically contemplated.
(Embodiment 1)
A method for alleviating inflammatory pain,
Administering an oral dosage form containing zoledronic acid to a mammal in need thereof,
The mammal is about 800 mg / m 2 based on the body surface area of the mammal. ² Receiving a total monthly dose of zoledronic acid that is:
(Embodiment 2)
The mammal is about 30 mg / m ² To about 700mg / m ² The method of embodiment 1, wherein the human is receiving a total monthly dose of zoledronic acid.
(Embodiment 3)
The method of embodiment 2, wherein the total monthly dose is administered in 4 or 5 weekly doses.
(Embodiment 4)
The method of embodiment 2, wherein the total monthly dose is administered in 28 to 31 daily doses.
(Embodiment 5)
The method of embodiment 2, wherein the total monthly dose is administered in 5 to 10 unit doses during the month.
(Embodiment 6)
The method of embodiment 1, wherein the mammal is a human receiving a total weekly dose of zoledronic acid that is about 10 mg to about 300 mg.
(Embodiment 7)
The method of embodiment 6, wherein the total weekly dose is a single dose and is administered once a week.
(Embodiment 8)
The method of embodiment 6, wherein the total weekly dose is administered in 2 to 7 unit doses during the week.
(Embodiment 9)
The method of embodiment 1, wherein the mammal is a human receiving a total weekly dose of zoledronic acid that is about 10 mg to about 150 mg.
(Embodiment 10)
The method of any one of embodiments 1-9, wherein the mammal experiences significant pain relief after 3 hours after administration of the dosage form.
(Embodiment 11)
The method of embodiment 10, wherein the mammal experiences significant pain relief during at least a portion of about 3 hours to about 24 hours after administration of the dosage form.
Embodiment 12
The method of embodiment 10, wherein the mammal experiences significant pain relief during at least a portion of a period of about 3 hours to about 3 weeks after administration of the dosage form.
(Embodiment 13)
A method for alleviating inflammatory pain,
Administering an oral dosage form containing zoledronic acid to a mammal in need thereof,
The oral dosage form is about 10 mg / m 2 based on the body surface area of the mammal. ² To about 20 mg / m ² Containing zoledronic acid.
(Embodiment 14)
The oral dosage form is about 15 mg / m 2 based on the body surface area of the mammal. ² To about 20 mg / m ² Embodiment 14. The method of embodiment 13 comprising the zoledronic acid of
(Embodiment 15)
A method for alleviating inflammatory pain,
Based on the body surface area of the mammal, about 300 mg / m per month ² To about 600mg / m ² Comprising orally administering the zoledronic acid of:
(Embodiment 16)
Based on the body surface area of the mammal, the mammal is about 450 mg / m 2 per month. ² To about 600mg / m ² 16. The method of embodiment 15, comprising orally administering the zoledronic acid of:
(Embodiment 17)
Embodiment 17. The method of any one of embodiments 1-16, wherein the mammal does not suffer from bone metastasis.
(Embodiment 18)
Embodiment 18. The method of any one of embodiments 1 through 17, wherein the mammal does not suffer from cancer.
(Embodiment 19)
Embodiment 19. The method of any one of embodiments 1-18, wherein the zoledronic acid is administered as a dianion salt of zoledronic acid.
(Embodiment 20)
A method for alleviating pain associated with arthritis,
Administering an oral dosage form containing zoledronic acid to a human in need thereof.
(Embodiment 21)
21. The method of embodiment 20, wherein the human receives a total monthly dose of zoledronic acid that is about 40 mg to about 2000 mg.
(Embodiment 22)
Embodiment 22. The method of embodiment 21, wherein the total monthly dose is administered in 4 or 5 weekly doses.
(Embodiment 23)
Embodiment 22. The method of embodiment 21, wherein the total monthly dose is administered in 28 to 31 daily doses.
(Embodiment 24)
Embodiment 22. The method of embodiment 21, wherein the total monthly dose is administered in 5 to 10 unit doses during the month.
(Embodiment 25)
The method of embodiment 20, wherein the human receives a total weekly dose of zoledronic acid that is about 100 mg to about 300 mg.
(Embodiment 26)
26. The method of embodiment 25, wherein the total weekly dose is a single dose and is administered once a week.
(Embodiment 27)
26. The method of embodiment 25, wherein the total weekly dose is administered in 2 to 7 unit doses during the week.
(Embodiment 28)
The method of embodiment 20, wherein the human receives a total weekly dose of zoledronic acid that is about 10 mg to about 100 mg.
(Embodiment 29)
The method according to any one of embodiments 20-28, wherein said human experiences significant pain relief after 3 hours after administration of said dosage form.
Embodiment 30
30. The method of embodiment 29, wherein the human experiences significant pain relief during at least a portion of the time from about 3 hours to about 24 hours after administration of the dosage form.
Embodiment 31
30. The method of embodiment 29, wherein the human experiences significant pain relief during at least a portion of about 3 hours to about 3 weeks after administration of the dosage form.
(Embodiment 32)
The dosage form is about 10 mg / m 2 based on the human body surface area. ² To about 20 mg / m ² 32. The method of any one of embodiments 20-31, comprising the zoledronic acid of
Embodiment 33
The dosage form is about 15 mg / m2 based on the human body surface area. ² To about 20 mg / m ² 35. The method of embodiment 32, comprising the zoledronic acid of
(Embodiment 34)
Based on the human body surface area, about 50 mg / m per month ² To about 200 mg / m ² Embodiment 34. The method of any one of embodiments 20-33, wherein the zoledronic acid of is administered orally.
(Embodiment 35)
The dosage form is about 80 mg / m2 based on the human body surface area. ² To about 150 mg / m ² 32. The method of any one of embodiments 20-31, comprising the zoledronic acid of
Embodiment 36
Based on the human body surface area, about 300 mg / m per month ² To about 1000 mg / m ² 36. The method of embodiment 35, wherein said zoledronic acid is administered orally.
(Embodiment 37)
The method according to any one of embodiments 20-36, wherein said human does not suffer from bone metastasis.
(Embodiment 38)
38. The method of any one of embodiments 20-37, wherein the human is not suffering from cancer.
(Embodiment 39)
39. The method of any one of embodiments 1-38, wherein the zoledronic acid is in the disodium salt form.
(Embodiment 40)
Contains zoledronic acid,
An oral dosage form wherein the oral bioavailability of zoledronic acid in the dosage form is from about 0.01% to about 4%.
Embodiment 41
41. The oral dosage form of embodiment 40, comprising about 10 mg to about 300 mg zoledronic acid.
(Embodiment 42)
41. The oral dosage form of embodiment 40, containing about 10 mg to about 50 mg zoledronic acid.
(Embodiment 43)
43. The oral dosage form according to any one of embodiments 40-42, wherein the oral bioavailability of zoledronic acid in the dosage form is from about 0.1% to about 2%.
(Embodiment 44)
41. A pharmaceutical product comprising a plurality of units of an oral dosage form according to embodiment 40.
(Embodiment 45)
45. The pharmaceutical product of embodiment 44, wherein each unit of the oral dosage form contains about 1 mg to about 50 mg of zoledronic acid.
(Embodiment 46)
The pharmaceutical product according to embodiment 45, comprising 28, 29, 30 or 31 units of said oral dosage form for zoledronic acid administered in a total of about 28 mg to about 1600 mg over a period of about 1 month.
(Embodiment 47)
The pharmaceutical product according to embodiment 45, comprising 85 to 95 units of said oral dosage form for zoledronic acid administered in a total of about 85 mg to about 4800 mg over a period of about 3 months.
Embodiment 48
The pharmaceutical product according to embodiment 45, comprising 170 to 200 units of said oral dosage form for zoledronic acid administered in a total of about 170 mg to about 10,000 mg over a period of about 6 months.
(Embodiment 49)
46. The pharmaceutical product according to embodiment 45, comprising 350 to 380 units of said oral dosage form for zoledronic acid administered in a total of about 350 mg to about 19000 mg in about 1 year.
(Embodiment 50)
The pharmaceutical product according to embodiment 44, wherein each unit of the oral dosage form contains from about 10 mg to about 300 mg.
(Embodiment 51)
The pharmaceutical product according to embodiment 50, comprising 4 or 5 units of said oral dosage form for zoledronic acid administered in a total of about 40 mg to about 1500 mg within a period of about 1 month.
(Embodiment 52)
The pharmaceutical product according to embodiment 50, comprising 8 or 9 units of said oral dosage form for zoledronic acid administered in a total of about 80 mg to about 2700 mg in about 2 months.
(Embodiment 53)
The pharmaceutical product according to embodiment 50, comprising 12, 13 or 14 units of said oral dosage form for zoledronic acid administered in a total of about 120 mg to about 4200 mg in about 3 months.
(Embodiment 54)
The pharmaceutical product according to embodiment 50, comprising 22 to 30 units of said oral dosage form for zoledronic acid administered in a total of about 220 mg to about 9000 mg over a period of about 6 months.
(Embodiment 55)
The pharmaceutical product according to embodiment 50, comprising 45 to 60 units of said oral dosage form for zoledronic acid administered in a total of about 450 mg to about 18000 mg over a period of about one year.
(Embodiment 56)
Comprising 1 to 10 units of the oral dosage form,
The pharmaceutical product according to embodiment 44, wherein said product contains from about 200 mg to about 2000 mg of zoledronic acid.
(Embodiment 57)
The oral dosage form according to any one of embodiments 40-43, wherein the zoledronic acid is in the form of a sodium salt.
(Embodiment 58)
57. The oral dosage form according to any one of embodiments 40-43 or 57, wherein the zoledronic acid is in a form having a water solubility greater than 1% (w / v).
(Embodiment 59)
The oral preparation according to any one of embodiments 40-43, 57 or 58, wherein the zoledronic acid is in a form having a water solubility of about 5% (w / v) to about 50% (w / v). form.
(Embodiment 60)
Including zoledronic acid and excipients,
The oral dosage form, wherein the zoledronic acid is in a form having a water solubility greater than 1% (w / v).
Embodiment 61
61. The oral dosage form of embodiment 60, wherein the zoledronic acid is in a form having a water solubility of about 5% (w / v) to about 50% (w / v).
(Embodiment 62)
A method of treating complex regional pain syndrome, comprising:
Administering an oral dosage form containing zoledronic acid to a mammal in need thereof.
(Embodiment 63)
The mammal is about 30 mg / m for a period of less than one month. ² To about 700mg / m ² 63. The method of embodiment 62, wherein the human is receiving an amount of zoledronic acid.
(Embodiment 64)
64. The method of embodiment 63, wherein 4 or 5 weekly doses are administered in a period of up to 1 month.
(Embodiment 65)
64. The method of embodiment 63, wherein 28 to 31 daily doses are administered over a period of one month or less.
Embodiment 66
64. The method of embodiment 63, wherein a dosage of 5 to 10 units is administered over a period of one month.
Embodiment 67
About 30mg / m ² To about 700mg / m ² 64. The method of embodiment 63, wherein said zoledronic acid is administered during only one month.
Embodiment 68
About 30mg / m ² To about 700mg / m ² 64. The method of embodiment 63, wherein said zoledronic acid is administered in a period of up to 1 month continuously for 2 months or more.
(Embodiment 69)
The mammal is about 10 mg / m daily. ² To about 30 mg / m ² 63. The method of embodiment 62, wherein the method receives zoledronic acid.
(Embodiment 70)
63. The method of embodiment 62, wherein the mammal is a human receiving a total weekly dose of zoledronic acid that is about 10 mg to about 300 mg.
Embodiment 71
The method of embodiment 70, wherein the total weekly dose is a single dose and is administered once a week.
(Embodiment 72)
71. The method of embodiment 70, wherein the total weekly dose is administered in 2 to 7 unit doses during the week.
(Embodiment 73)
The method according to any one of embodiments 62-72, wherein the complex regional pain syndrome is complex regional pain syndrome type I.
Embodiment 74
The method according to any one of embodiments 62-72, wherein the complex regional pain syndrome is complex regional pain syndrome type II.
(Embodiment 75)
The method according to any one of embodiments 62-74, wherein said zoledronic acid is in a salt form.
Embodiment 76
The dosage form is about 10 mg / m 2 based on the body surface area of the mammal. ² To about 20 mg / m ² The method according to any one of embodiments 62-75, comprising the zoledronic acid of
Embodiment 77
The dosage form is about 15 mg / m 2 based on the body surface area of the mammal. ² To about 20 mg / m ² 77. The method of embodiment 76, comprising zoledronic acid.
(Embodiment 78)
A method of treating complex regional pain syndrome, comprising:
Administering pamidronic acid to a human in need thereof.
Embodiment 79
A method of treating complex regional pain syndrome, comprising:
Administering nelidronic acid to a human in need thereof.
(Embodiment 80)
A method of treating complex regional pain syndrome, comprising:
Administering olpadronic acid to a human in need thereof.
Embodiment 81
A method of treating complex regional pain syndrome, comprising:
Administering alendronate to a human in need thereof.
(Embodiment 82)
A method of treating complex regional pain syndrome, comprising:
Administering an incadronic acid to a human in need thereof.
(Embodiment 83)
A method of treating complex regional pain syndrome, comprising:
Administering ibandronic acid to a human in need thereof.
(Embodiment 84)
A method of treating complex regional pain syndrome, comprising:
Administering a risedronate to a human in need thereof.
(Embodiment 85)
A method of treating pain,
Administering pamidronic acid to a human in need thereof.
(Embodiment 86)
A method of treating pain,
Administering nelidronic acid to a human in need thereof.
(Embodiment 87)
A method of treating pain,
Administering olpadronic acid to a human in need thereof.
(Embodiment 88)
A method of treating pain,
Administering alendronate to a human in need thereof.
(Embodiment 89)
A method of treating pain,
Administering an incadronic acid to a human in need thereof.
(Embodiment 90)
A method of treating pain,
Administering ibandronic acid to a human in need thereof.
(Embodiment 91)
A method of treating pain,
Administering a risedronate to a human in need thereof.
(Embodiment 92)
A method of treating arthritic pain,
Administering pamidronic acid to a human in need thereof.
(Embodiment 93)
A method of treating arthritic pain,
Administering nelidronic acid to a human in need thereof.
(Embodiment 94)
A method of treating arthritic pain,
Administering olpadronic acid to a human in need thereof.
(Embodiment 95)
A method of treating arthritic pain,
Administering alendronate to a human in need thereof.
(Embodiment 96)
A method of treating arthritic pain,
Administering an incadronic acid to a human in need thereof.
(Embodiment 97)
A method of treating arthritic pain,
Administering ibandronic acid to a human in need thereof.
Embodiment 98
A method of treating arthritic pain,
Administering a risedronate to a human in need thereof.
Embodiment 99
A method of treating inflammatory pain, comprising:
Administering pamidronic acid to a human in need thereof.
(Embodiment 100)
A method of treating inflammatory pain, comprising:
Administering nelidronic acid to a human in need thereof.
(Embodiment 101)
A method of treating inflammatory pain, comprising:
Administering olpadronic acid to a human in need thereof.
(Embodiment 102)
A method of treating inflammatory pain, comprising:
Administering alendronate to a human in need thereof.
(Embodiment 103)
A method of treating inflammatory pain, comprising:
Administering an incadronic acid to a human in need thereof.
(Embodiment 104)
A method of treating inflammatory pain, comprising:
Administering ibandronic acid to a human in need thereof.
(Embodiment 105)
A method of treating inflammatory pain, comprising:
Administering a risedronate to a human in need thereof.
(Embodiment 106)
A method of treating complex regional pain syndrome, comprising:
Administering etidronic acid to a human in need thereof.
Embodiment 107
A method of treating pain,
Administering etidronic acid to a human in need thereof.
Embodiment 108
A method of treating arthritic pain,
Administering etidronic acid to a human in need thereof.
Embodiment 109
A method of treating inflammatory pain, comprising:
Administering etidronic acid to a human in need thereof.
(Embodiment 110)
A method of treating complex regional pain syndrome, comprising:
Administering clodronic acid to a human in need thereof.
(Embodiment 111)
A method of treating pain,
Administering clodronic acid to a human in need thereof.
(Embodiment 112)
A method of treating arthritic pain,
Administering clodronic acid to a human in need thereof.
(Embodiment 113)
A method of treating inflammatory pain, comprising:
Administering clodronic acid to a human in need thereof.
(Embodiment 114)
A method of treating complex regional pain syndrome, comprising:
Administering a tiludronic acid to a human in need thereof.
Embodiment 115
A method of treating pain,
Administering a tiludronic acid to a human in need thereof.
Embodiment 116
A method of treating arthritic pain,
Administering a tiludronic acid to a human in need thereof.
(Embodiment 117)
A method of treating inflammatory pain, comprising:
Administering a tiludronic acid to a human in need thereof.
(Embodiment 118)
118. The method according to any one of embodiments 78-117, wherein the active compound is administered orally.
Embodiment 119
118. The method of any one of embodiments 78 to 117, wherein the active compound is administered parenterally.
(Embodiment 120)
A method for enhancing the oral bioavailability of zoledronic acid comprising orally administering a dosage form comprising zoledronic acid in disodium salt form.
(Embodiment 121)
The zoledronic acid in the disodium salt form enhances any bioavailability provided by any bioavailability enhancer in the dosage form compared to the diacid form of zoledronic acid. The method of embodiment 120, wherein the method provides an enhancement to.
(Embodiment 122)
121. The method of embodiment 120, wherein the dosage form is substantially free of bioavailability enhancers.
(Embodiment 123)
The zoledronic acid form of the disodium salt is a plasma concentration curve of zoledronic acid from about 4 ng · hr / mL to about 2000 ng · hr / mL to a mammal each time the zoledronic acid in the disodium salt form is administered. 121. The method of embodiment 120, wherein the method is administered to the mammal in an amount that provides a subarea.
(Embodiment 124)
The zoledronic acid in the disodium salt form is a plasma concentration curve of zoledronic acid from about 100 ng · hr / mL to about 2000 ng · hr / mL to a mammal each time the zoledronic acid in the disodium salt form is administered. 124. The method of embodiment 123, wherein the method is administered at an interval of about 3 to about 4 weeks in an amount to provide a sub-area.
(Embodiment 125)
The zoledronic acid in the disodium salt form is present under the zoledronic acid plasma concentration curve from about 20 ng · hr / mL to about 700 ng · hr / mL to the mammal each time the disodium form of zoledronic acid is administered. 124. The method of embodiment 123, wherein the method is administered 3-5 times weekly or monthly in an amount that provides an area.
(Embodiment 126)
The zoledronic acid in the disodium salt form is a plasma concentration curve of zoledronic acid from about 4 ng · hr / mL to about 100 ng · hr / mL to a mammal each time the zoledronic acid in the disodium salt form is administered. 124. The method of embodiment 123, wherein the method is administered daily in an amount that provides a subarea.
(Embodiment 127)
121. The method of embodiment 120, wherein the dosage form is a solid.
(Embodiment 128)
128. The method of embodiment 120, 121, 122, 123, 124, 125, 126 or 127, wherein the bioavailability of zoledronic acid is improved by at least about 20% compared to administration of the diacid form of zoledronic acid. .
Embodiment 129
Embodiments further comprising administering, on a molar basis, an amount of said disodium salt form of zoledronic acid, on a molar basis, to achieve the same plasma concentration of zoledronic acid than the amount to which said diacid form of zoledronic acid is administered. 120. A method according to 120, 121, 122, 123, 124, 125, 126, 127 or 128.
(Embodiment 130)
Embodiment 129. The disodium salt form is administered in an amount that is at least about 10 mol% less than the amount of zoledronic acid administered to achieve the same plasma concentration of zoledronic acid. the method of.
(Embodiment 131)
The disodium salt form is about 0.8 n on a molar basis. _d About 1.2n _d Administered in an amount having a value of
n _d = (B _a / B _d ) (N _a )The filling,
b _a Is the bioavailability of the diacid form, b _d Is the bioavailability of the disodium salt form, n _a 130. The method of embodiment 129, wherein is the number of moles of the diacid form of zoledronic acid administered to achieve the same plasma concentration of zoledronic acid.
(Embodiment 132)
The disodium salt is about n _d 132. The method of embodiment 131, wherein the method is administered in an amount having a value of:
(Embodiment 133)
The method according to any one of embodiments 120-132, wherein said zoledronic acid is used to treat an inflammatory condition.
(Embodiment 134)
140. The method of embodiment 133, wherein the zoledronic acid is used to treat arthritis.
(Embodiment 135)
134. The method of embodiment 133, wherein the zoledronic acid is used to treat complex regional pain syndrome.
(Embodiment 136)
A first oral dosage form is administered;
A second oral dosage form is administered;
For the first oral dosage form, the second oral dosage form is 10 × T _maximum The above is administered and T _maximum The method of any one of embodiments 1-39, 62-77, and 120-135, wherein is the time that the first oral dosage form is at the maximum plasma concentration.
(Embodiment 137)
A dosage form comprising a disodium salt form of zoledronic acid in which the bioavailability of the disodium salt form of zoledronic acid in a mammal is greater than the bioavailability of the diacid form of zoledronic acid.
(Embodiment 138)
A dosage form comprising zoledronic acid in the disodium salt form,
The dosage form comprises zoledronic acid in the form of the disodium salt that provides an area under the plasma concentration curve of zoledronic acid from about 4 ng · hr / mL to about 2000 ng · hr / mL to a human to whom the dosage form is administered. Dosage form, including quantity.
(Embodiment 139)
The dosage form comprises an amount of zoledronic acid in the disodium salt form that provides an area under the plasma concentration curve of zoledronic acid from about 100 ng · hr / mL to about 2000 ng · hr / mL to a human to whom the dosage form is administered. The dosage form of embodiment 138.
(Embodiment 140)
The dosage form comprises an amount of zoledronic acid in the disodium salt form that provides an area under the plasma concentration curve of zoledronic acid from about 20 ng · hr / mL to about 700 ng · hr / mL to a human to whom the dosage form is administered. The dosage form of embodiment 138.
(Embodiment 141)
The dosage form comprises an amount of zoledronic acid in the disodium salt form that provides an area under the plasma concentration curve of zoledronic acid from about 4 ng · hr / mL to about 100 ng · hr / mL to a human to whom the dosage form is administered. The dosage form of embodiment 138.
(Embodiment 142)
A dosage form comprising zoledronic acid in the diacid salt form,
The disodium salt form is present in a lower molar amount than is present when the zoledronic acid is assumed to be the diacid form, and the disodium salt form of zoledronic acid is more of the dosage form. An agent having improved bioavailability compared to the diacid form of the zoledronic acid to such an extent that a small molar amount of the disodium salt does not reduce the amount of zoledronic acid delivered to the plasma of a mammal form.
(Embodiment 143)
142. The dosage form of embodiment 137, 138, 139, 140, 141 or 142, wherein the dosage form is a solid.
(Embodiment 144)
145. The embodiment 142 or 143 wherein the bioavailability of the diacid sodium salt form of zoledronic acid is improved by at least about 10% compared to an otherwise identical dosage form comprising the diacid form of zoledronic acid. Dosage form.
(Embodiment 145)
Embodiments 142, 143 or 143 comprising the disodium salt form at least about 20 mol% lower than the amount of zoledronic acid in the diacid form present assuming the zoledronic acid is in the diacid form 144. The dosage form according to 144.
(Embodiment 146)
The disodium salt form is about 0.9 n on a molar basis. _d About 1.1n _d Present in an amount having a value of
n _d = (B _a / B _d ) (N _a )The filling,
b _a Is the bioavailability of the diacid form, b _d Is the bioavailability of the disodium salt form, n _a 142. The dosage form of embodiment 142, wherein is the number of moles of the diacid form present assuming the zoledronic acid is the diacid form.
(Embodiment 147)
The disodium salt form is about n _d 147. The dosage form of embodiment 146, administered in an amount having a value of:
Embodiment 148
The oral dosage form is administered only once, or
A first oral dosage form is administered, and a second oral dosage form is administered after said first oral dosage form;
The second oral dosage form is administered before the maximum pain relief effect of the first oral dosage form is achieved, or the second oral dosage form is administered before an observable pain relief effect is achieved. The method of any one of embodiments 1-39, 62-77 and 120-136.
(Embodiment 149)
148. The method of embodiment 148, wherein the second oral dosage form is administered before an observable pain relief effect is achieved.
(Embodiment 150)
A first oral dosage form is administered followed by a second oral dosage form;
The second oral dosage form is administered after the maximum pain relief of the first oral dosage form is achieved; and
134. The method of any one of 1 to 39, 62 to 77, and 120 to 132, wherein the second oral dosage form is administered while the pain relief effect from the first oral dosage form is observable.
(Embodiment 151)
156. The method of embodiment 148, 149 or 150, wherein the second oral dosage form is administered from about 24 hours to about 28 days after the first oral dosage form is administered.
(Embodiment 152)
40. The method of any one of embodiments 20 to 39, wherein the human is about 30 to about 75 years old.
(Embodiment 153)
40. The method of any one of embodiments 20 to 39, wherein the human is about 1 to about 16 years old.
(Embodiment 154)
40. The method of any one of embodiments 20 to 39, wherein the human is about 80 to about 95 years old.
(Embodiment 155)
40. The method of any one of embodiments 20 to 39, wherein the human has been suffering from arthritis for at least 2 months.
(Embodiment 156)
40. The method of any one of embodiments 20 to 39, wherein the arthritis affects the knee, elbow, wrist, shoulder, or waist.
(Embodiment 157)
From Embodiments 1-44, 62-133, and 144, wherein the mammal or human being administered zoledronic acid has not eaten or drank any food for at least 1 hour prior to the administration of zoledronic acid 156. The method according to any one of 156.
(Embodiment 158)
158. The method of embodiment 157, wherein the mammal or human being administered zoledronic acid has not eaten or drank a drink for at least 2 hours prior to the administration of zoledronic acid.
(Embodiment 159)
158. The method of embodiment 157, wherein the mammal or human to whom zoledronic acid is administered has not eaten or consumed a drink for at least 4 hours before the zoledronic acid is administered.
(Embodiment 160)
158. The method of embodiment 157, wherein the mammal or human to which zoledronic acid is administered has not eaten or drinked food for at least 6 hours before the zoledronic acid is administered.
(Embodiment 161)
165. Embodiment according to any one of embodiments 157 to 160, wherein the mammal or human being administered zoledronic acid has not eaten or drank a drink for at least 30 minutes after the administration of zoledronic acid. Method.
(Embodiment 162)
166. The method of embodiment 161, wherein the mammal or human to which zoledronic acid is administered has not eaten or drinked for at least 1 hour after the administration of zoledronic acid.
(Embodiment 163)
166. The method of embodiment 161, wherein the mammal or human to which zoledronic acid is administered has not eaten or drinked food for at least 2 hours after the administration of zoledronic acid.
(Embodiment 164)
164. The method, dosage form, or product of any one of embodiments 1-163, wherein the zoledronic acid in the oral dosage form has a 24-hour plasma concentration factor of about 1 or greater.
(Embodiment 165)
165. The embodiment of any one of embodiments 1-164, wherein the oral dosage form of the zoledronic acid has a 24-hour sustained plasma concentration factor that is higher than the 24-hour sustained plasma concentration factor of intravenously administered zoledronic acid. Method, dosage form or product.
(Embodiment 166)
The method, dosage form, or product of any one of embodiments 1 to 165, wherein the oral dosage form is a solid having a hardness of about 5 k to about 20 kPa.
(Embodiment 167)
A method of treating a bone marrow lesion comprising selecting a patient having a bone marrow lesion and OARSI grade 0 joint space stenosis, and administering an inhibitor of osteoclast activity to the patient for the treatment of the bone marrow lesion.
(Embodiment 168)
The method of embodiment 167, wherein said inhibitor of osteoclast activity is administered at least twice.
(Embodiment 169)
166. The method of embodiment 167, wherein the inhibitor of osteoclast activity is administered about every 3 months or more often.
(Embodiment 170)
168. The method of embodiment 167, wherein the inhibitor of osteoclast activity comprises a nitrogen-containing bisphosphonate.
(Embodiment 171)
170. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is zoledronic acid or comprises zoledronic acid.
(Embodiment 172)
170. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is pamidronic acid or comprises pamidronic acid.
(Embodiment 173)
171. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is neridronate or comprises neridronate.
(Embodiment 174)
171. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is or comprises olpadronate.
(Embodiment 175)
171. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is or comprises alendronate.
(Embodiment 176)
Embodiment 171. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is or comprises incadronic acid.
(Embodiment 177)
170. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is ibandronic acid or comprises ibandronic acid.
(Embodiment 178)
171. The method of any one of embodiments 167 to 170, wherein the inhibitor of osteoclast activity is risedronate or comprises risedronate.
(Embodiment 179)
The method of any one of embodiments 167 to 178, wherein said inhibitor of osteoclast activity is administered orally.
(Embodiment 180)
The method of any one of embodiments 167 to 178, wherein the inhibitor of osteoclast activity is administered intravenously.
(Embodiment 181)
181. The method of any one of embodiments 167-180, wherein the patient experiences a bone marrow lesion size reduction that is at least about 100% greater than the bone marrow lesion size reduction achieved with a placebo.
(Embodiment 182)
181. The method of any one of embodiments 167-180, wherein the patient experiences a bone marrow lesion size reduction that is at least about 150% greater than the bone marrow lesion size reduction achieved with a placebo.
(Embodiment 183)
184. The method of any one of embodiments 167 to 182 wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.
(Embodiment 184)
184. The method of any one of embodiments 167 to 183, wherein the inhibitor of osteoclast activity is administered once a week for a period of 6 weeks.
(Embodiment 185)
185. The method of any one of embodiments 167 to 184, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is between about 25 mg and about 75 mg,
(Embodiment 186)
A method of treating knee pain, comprising selecting a patient having an OARSI grade 0 of knee pain and joint space narrowing, and administering an inhibitor of osteoclast activity to the patient for the treatment of knee pain Including a method.
(Embodiment 187)
184. The method of embodiment 186, wherein the inhibitor of osteoclast activity is administered at least twice.
(Embodiment 188)
188. The method of embodiment 186 or 187, wherein the inhibitor of osteoclast activity is administered about every 3 months or more often.
(Embodiment 189)
189. The method of any one of embodiments 186 to 188, wherein the inhibitor of osteoclast activity comprises a nitrogen-containing bisphosphonate.
(Embodiment 190)
188. The method of any one of embodiments 186 to 189, wherein the patient experiences pain relief 3 months after administration of the inhibitor of bone cell activity.
(Embodiment 191)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or comprises zoledronic acid.
(Embodiment 192)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or comprises pamidronic acid.
(Embodiment 193)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or includes neridronate.
(Embodiment 194)
191. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is orpadronic acid.
(Embodiment 195)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or comprises alendronate.
(Embodiment 196)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or includes incadronic acid.
(Embodiment 197)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is or includes ibandronic acid.
(Embodiment 198)
190. The method of any one of embodiments 186 to 190, wherein the inhibitor of osteoclast activity is risedronate or comprises risedronate.
Embodiment 199
199. The method of any one of embodiments 186 to 198, wherein the patient experiences a pain intensity reduction of at least about 20 when using a 100 mm visual analog scale.
(Embodiment 200)
A method for treating bone marrow lesions of the knee, comprising selecting patients with knee bone marrow lesions and OARSI grade 0 or narrow joint chelgrains and Lawrence grade 0 or grade 1, and treating bone marrow lesions Administering to the patient an inhibitor of osteoclast activity.
Embodiment 201
200. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered at least twice.
(Embodiment 202)
202. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered about every 3 months or more often.
Embodiment 203
200. The method of embodiment 200, wherein the inhibitor of osteoclast activity comprises a nitrogen-containing bisphosphonate.
(Embodiment 204)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is zoledronic acid.
Embodiment 205
The method of embodiment 203, wherein the inhibitor of osteoclast activity is pamidronic acid.
(Embodiment 206)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is neridronate.
(Embodiment 207)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is olpadronate.
(Embodiment 208)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is minodronic acid.
(Embodiment 209)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is incadronic acid.
(Embodiment 210)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is ibandronic acid.
(Embodiment 211)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is risedronate.
(Embodiment 212)
The method of embodiment 203, wherein the inhibitor of osteoclast activity is alendronate.
(Embodiment 213)
200. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered orally.
(Embodiment 214)
200. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered intravenously.
(Embodiment 215)
200. The method of embodiment 200, wherein the patient experiences a reduction in bone marrow lesion size that is at least about 15% within about 6 months after administering the inhibitor of osteoclast activity to the patient.
(Embodiment 216)
The method of embodiment 200, wherein the patient experiences a reduction in bone marrow lesion size that is at least about 25% within about 6 months after administration of the inhibitor of osteoclast activity to the patient.
(Embodiment 217)
202. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.
(Embodiment 218)
202. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered once a week for a period of 6 weeks.
(Embodiment 219)
219. The method of embodiment 218, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is between about 25 mg and about 75 mg.
(Embodiment 220)
A method of treating knee pain,
a. Knee pain,
i. OARSI Grade 0 or Narrow Cleft Churgren and Lawrence Grade 0 or 1 or
ii. Pain intensity of 5 or more measured using 0-10 NRS or pain intensity of 5 cm or more measured using VAS of 10 cm;
Selecting patients with
b. Administering to the patient an inhibitor of osteoclast activity.
(Embodiment 221)
220. The method of embodiment 220 comprising selecting a patient with narrow joint space OARSI grade 0 or Czergren and Lawrence grade 0 or grade 1.
(Embodiment 222)
222. The method of embodiment 220 or 221 comprising selecting a patient having a pain intensity of 5 or more measured using 0-10 NRS or a pain intensity of 5 cm or more measured using 10 cm VAS.
(Embodiment 223)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered at least twice.
(Embodiment 224)
222. The method of embodiment 223, wherein the inhibitor of osteoclast activity is administered about every 3 months or more frequently.
(Embodiment 225)
The method of embodiment 220, wherein the inhibitor of osteoclast activity comprises a nitrogen-containing bisphosphonate.
(Embodiment 226)
The method of embodiment 220, wherein the patient experiences pain relief within about 3 months after administration of the inhibitor of osteoclast activity to the patient.
(Embodiment 227)
226. The method of embodiment 226, wherein the patient experiences pain relief at least 24 hours after administering the inhibitor of osteoclast activity to the patient.
(Embodiment 228)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is zoledronic acid.
(Embodiment 229)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is minodronic acid.
(Embodiment 230)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is neridronate.
(Embodiment 231)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is olpadronate.
(Embodiment 232)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is alendronate.
(Embodiment 233)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is incadronic acid.
(Embodiment 234)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is ibandronic acid.
(Embodiment 235)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is risedronate.
(Embodiment 236)
The method of embodiment 220, wherein the patient experiences a reduction in pain intensity of at least about 5 when using a 100 mm visual analog scale.
(Embodiment 237)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.
(Embodiment 238)
The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered once a week for a period of 6 weeks.
(Embodiment 239)
238. The method of embodiment 238, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is between about 25 mg and about 75 mg.
(Embodiment 240)
A method for moderately treating severe knee pain, comprising administering an inhibitor of osteoclast activity to a person suffering from moderate to severe knee pain.
(Embodiment 241)
The method of embodiment 240, wherein the person suffering from said moderate to severe knee pain has a normal joint space in the knee.
(Embodiment 242)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered at least twice.
(Embodiment 243)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered about every 3 months or more often.
(Embodiment 244)
The method of embodiment 240, wherein the inhibitor of osteoclast activity comprises a nitrogen-containing bisphosphonate.
(Embodiment 245)
The method of embodiment 240, wherein the patient experiences pain relief within about 3 months after administering the inhibitor of osteoclast activity to the patient.
(Embodiment 246)
254. The method of embodiment 245, wherein the patient experiences pain relief at least 24 hours after the inhibitor of osteoclast activity is administered to the patient.
(Embodiment 247)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is zoledronic acid.
(Embodiment 248)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is minodronic acid.
(Embodiment 249)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is neridronate.
(Embodiment 250)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is olpadronate.
(Embodiment 251)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is alendronate.
(Embodiment 252)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is incadronic acid.
(Embodiment 253)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is ibandronic acid.
(Embodiment 254)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is risedronate.
(Embodiment 255)
241. The method of embodiment 240, wherein the patient experiences a pain intensity reduction of at least about 5 when the patient uses a 100 mm visual analog scale.
(Embodiment 256)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.
(Embodiment 257)
The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered once a week for a period of 6 weeks.
(Embodiment 258)
The method of embodiment 257, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is between about 25 mg and about 75 mg.
(Embodiment 259)
Orally administering about 0.4 mg / kg to about 4 mg / kg of zoledronic acid to the mammal at a frequency of no more than once a day and more than once a week, or
Orally administering about 0.4 mg / kg to about 10 mg / kg once a week or less,
A method of safely delivering zoledronic acid to mammalian blood by repeated oral administration comprising:
(Embodiment 260)
The method of any one of embodiments 1 to 259, such as embodiment 259, wherein about 0.5 mg / kg to about 2 mg / kg is orally administered to the mammal daily.
(Embodiment 261)
260. The method of any one of embodiments 1-260, such as embodiment 260, wherein about 0.6 mg / kg to about 0.9 mg / kg is orally administered to the mammal daily.
(Embodiment 262)
264. The method of any one of embodiments 1-261, such as embodiment 259, wherein about 0.5 mg / kg to about 2 mg / kg is orally administered to the mammal weekly.
(Embodiment 263)
264. The method of any one of embodiments 1 to 262, such as embodiment 263, wherein about 0.6 mg / kg to about 0.9 mg / kg is orally administered to the mammal weekly.
(Embodiment 264)
The method of any one of embodiments 1 to 263, such as embodiments 259, 260, 261, 262, or 263, wherein zoledronic acid is orally administered from about 3 to about 10 times.
(Embodiment 265)
Zoledronic acid is administered in any one of Embodiments 1 to 264, such as Embodiments 259, 260, 261, 262, 263, or 264, administered orally in a dosage form comprising greater than about 10% by weight of zoledronic acid. The method described.
(Embodiment 266)
Zoledronic acid is an AUC of zoledronic acid that is about 50 ng · hr / mL to about 500 ng · hr / mL with each administration of zoledronic acid. _0-24 The method of any one of embodiments 1 to 265, such as embodiments 259, 260, 261, 262, 263, 264, or 265, administered in a method and amount resulting in a mammal having:
(Embodiment 267)
Zoledronic acid is an AUC of zoledronic acid that is about 100 ng · hour / mL to about 500 ng · hour / mL for each administration of zoledronic acid. _0-24 The method of any one of embodiments 1 to 266, such as embodiment 266, administered in a method and amount resulting in said mammal having:
(Embodiment 268)
A method of preparing an oral dosage form that is safe for repeated administration to a mammal comprising combining zoledronic acid and a pharmaceutically acceptable excipient to a mammal, comprising: The amount of zoledronic acid combined is present in the oral dosage form in an amount such that zoledronic acid is from 0.4 mg / kg to about 10 mg / kg based on the weight of the mammal.
(Embodiment 269)
The amount of zoledronic acid combined with the excipients is any one of embodiments 1 to 268, such as embodiment 268, wherein the oral dosage form is such that the oral dosage form contains greater than about 10% by weight zoledronic acid. The method described in one.
(Embodiment 270)
The amount of zoledronic acid combined with the excipient is present in the oral dosage form in an amount that the zoledronic acid is 0.4 mg / kg to about 3 mg / kg based on the weight of the mammal, or the embodiment 268 or 269. A method according to any one of embodiments 1-269, such as 269.
(Embodiment 271)
The amount of zoledronic acid combined with the excipient is present in the oral dosage form in an amount such that zoledronic acid is from 0.4 mg / kg to about 1.5 mg / kg based on the weight of the mammal. 270. A method according to any one of embodiments 1 to 270, such as 270.
(Embodiment 272)
The amount of zoledronic acid combined with the excipient is present in the oral dosage form in an amount such that zoledronic acid is from 0.6 mg / kg to about 0.9 mg / kg based on the weight of the mammal. 270. A method according to any one of embodiments 1 to 271 such as 270.
(Embodiment 273)
The oral dosage form is from embodiment 1 such as embodiment 268, 269, 270, 271, or 272, which is safe for once daily administration of the oral dosage form for about 3 to about 10 days. 272. The method according to any one of 272.
(Embodiment 274)
Embodiment 1 such as Embodiment 268, 269, 270, 271, or 272, wherein said oral dosage form is safe for once weekly administration of said oral dosage form for about 3 to about 10 weeks 273. The method according to any one of 273 to 273.
(Embodiment 275)
Orally administering about 0.05 mg / kg to about 4 mg / kg of zoledronic acid to the mammal at a frequency of no more than once a day and more than once a week, or
Orally administering about 0.1 mg / kg to about 10 mg / kg to said mammal at a frequency of no more than once a week;
Zoledronic acid is orally administered at least 5 times,
A method of safely delivering zoledronic acid to mammalian blood by repeated oral administration.
(Embodiment 276)
The method of any one of embodiments 1 to 275, such as embodiment 275, wherein zoledronic acid is orally administered about 5 to about 10 times.
(Embodiment 277)
The method of any one of embodiments 1 to 276, such as embodiment 275 or 276, wherein zoledronic acid is orally administered in a dosage form comprising greater than about 10% by weight zoledronic acid.
(Embodiment 278)
The mammal is a human, as in embodiments 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, or 277. The method of any one of embodiments 1 to 277.
(Embodiment 279)
Embodiments 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271 wherein about 50 mg to about 350 mg of oral zoledronic acid is administered to the mammal every month 272. A method according to any one of embodiments 1 to 278, such as 272, 273, 274, 275, 276, 277, 278 or 279.
(Embodiment 280)
Embodiments 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279 To 279. An oral dosage form prepared by the method of any one of.

  Unless otherwise stated, properties such as component amounts, molecular weight, reaction conditions, and all numbers representing such as used in the specification and claims are to be expressed exactly as indicated. It should be understood in all cases as indicating both the value and the value as modified by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that can vary depending on the conditions under which the desired property can be obtained. . At a minimum, it does not limit the application of the doctrine of equivalents to the claims aspect, and each numeric parameter shall apply at least in light of the number of significant figures reported and apply normal rounding techniques. Should be interpreted.

  As used herein in the context of describing the present invention (especially in the context of the following claims), the terms “one”, “the” and like reference are specifically indicated herein. If not, or unless clearly contradicted by context, it should be construed to include both singular and plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Use of any and all examples or exemplary languages (e.g., "like") provided herein are intended merely to clarify the present invention. And does not limit the scope of any claims. The language herein should not be construed as indicating any non-claimed element essential to the practice of the invention.

  Alternative elements or groups of embodiments disclosed herein are not to be construed as limiting. Each group member may be shown and claimed individually or in any combination with other group members or other elements found herein. It is to be expected that one or more members of a group may be included in or removed from the group for convenience and / or for patent reasons. In the event of any such inclusion or deletion, the specification is deemed to include groups that have been modified to meet the description of all Markush groups used in the appended claims.

  Particular embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor anticipates that those skilled in the art will use such variations as appropriate, and that the invention is intended to be practiced otherwise than as specifically described herein. . Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, any combination of the above-described elements in all possible variations thereof is contemplated unless specifically indicated herein or otherwise clearly contradicted by context.

  Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other variations that may be used are within the scope of the claims. As such, by way of example and not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the precise embodiments shown and described.

(Appendix)
(Appendix 1)
A mammal in need of pain treatment is administered a compound that is a RANK / RANKL antagonist, an inhibitor of osteoclast activity, or a bisphosphonate to alleviate pain, a musculoskeletal condition, or a condition associated with bone or joints A method of treating pain comprising:

(Appendix 2)
The method according to appendix 1, wherein the mammal is a human.

(Appendix 3)
Acute pain, central pain, radiation therapy or chemotherapy-related neuropathy, ankylosing spondylitis, arthritis, axonal spondyloarthritis, blood cancer, fracture, bone metastasis from solid tumor, bone metastasis, breast cancer, cancer, central multiple Sclerosis pain, Charcot's foot, chronic pain, complex local pain syndrome, diabetic peripheral neuropathy, erosive osteoarthritis, excessive bone resorption, fibrous dysplasia, giant cell tumor of bone, HIV-related neuropathy, malignant tumor hypercalcemia, inflammatory pain, juvenile rheumatoid arthritis, leukemia, back pain, lumbar root compression, lumbosacral pain, lung cancer, metastatic bone cancer, monoradosis, multiple myeloma , Musculoskeletal pain, neuropathic arthropathy, neuropathic pain, rheumatoid arthritis, osteoarthritis, osteogenesis imperfecta, osteoporosis, Paget's disease, Paget's disease of bone, periarticular disorder, phantom limb pain, postherpetic Neuralgia, postoperative pain, post-stroke pain , Prostate cancer, rheumatoid arthritis, SAPHO syndrome, seronegative (non-rheumatic) arthropathy, solid tumor or cancer, spinal cord injury, systemic lupus erythematosus, temporary hip osteoarthritis, temporary osteoporosis, hip joint 3. The method of claim 1 or 2, comprising treating transient osteoporosis, trigeminal neuralgia, tumor-induced hypocalcemia, or vertebral fracture.

(Appendix 4)
The method according to appendix 1 or 2, comprising treating arthritis.

(Appendix 5)
The method of claim 3, comprising alleviating pain associated with arthritis.

(Appendix 6)
The method of claim 5, wherein the arthritis affects the knee, elbow, wrist, shoulder, or waist.

(Appendix 7)
The method of claim 6, wherein the arthritis affects the knee.

(Appendix 8)
The method according to appendix 1 or 2, comprising treating musculoskeletal pain.

(Appendix 9)
The method according to appendix 1 or 2, comprising treating a bone marrow lesion.

(Appendix 10)
The method of claim 9, wherein the mammal is a human who experiences a bone marrow lesion size reduction of at least about 15% within about 6 months after the inhibitor of osteoclast activity is administered to the human.

(Appendix 11)
The method of claim 9, wherein the mammal is a human who experiences a bone marrow lesion size reduction of at least about 25% within about 6 months after the inhibitor of osteoclast activity is administered to the human.

(Appendix 12)
The method of claim 9, 10 or 11, wherein the bone marrow lesion affects the knee.

(Appendix 13)
Treating the bone marrow lesion of the knee by selecting a patient having a bone marrow lesion of the knee and an OARSI grade 0 or Kellgren and Lawrence grade 0 or grade 1 of joint stenosis; 13. The method of appendix 9, 10, 11 or 12, comprising administering the compound to the patient for the treatment of bone marrow lesions.

(Appendix 14)
The method according to appendix 1 or 2, comprising treating osteoarthritis.

(Appendix 15)
15. The method of claim 14, wherein the osteoarthritis affects the knee.

(Appendix 16)
16. The method of appendix 14 or 15, comprising treating an osteolytic lesion associated with osteoarthritis.

(Appendix 17)
17. The method of appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 comprising treating knee pain.

(Appendix 18)
18. The method of claim 17, comprising treating moderate to severe knee pain.

(Appendix 19)
The method according to appendix 17 or 18, wherein the mammal is a human having a normal joint space in the knee.

(Appendix 20)
c. Knee pain and
iii. With OARSI grade 0 or Czergren and Lawrence grade 0 or grade 1 of joint stenosis, or
iv. Pain intensity of 5 or more measured using 0-10 NRS or pain intensity of 5 cm or more measured using 10 cm VAS;
Selecting patients with
d. Administering the compound to the patient;
18. The method of claim 17, comprising treating knee pain by:

(Appendix 21)
21. The method of appendix 20, comprising selecting patients with OARSI grade 0 or Czergren and Lawrence grade 0 or grade 1 of joint space stenosis.

(Appendix 22)
21. The method of claim 20, comprising selecting a patient having a pain intensity of 5 or more measured using 0-10 NRS or a pain intensity of 5 cm or more measured using 10 cm VAS.

(Appendix 23)
23. The method of clause 20, 21, or 22, wherein the patient experiences a reduction in pain intensity of at least about 5 mm when using a 100 mm visual analog scale.

(Appendix 24)
Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 further comprising administering a second therapeutic agent indicated for the treatment of pain or other neurological diseases , 13, 14, 15, 16, or 17.

(Appendix 25)
The method according to appendix 1 or 2, comprising treating musculoskeletal pain.

(Appendix 26)
The method according to appendix 1 or 2, comprising treating inflammatory pain.

(Appendix 27)
The method according to appendix 1 or 2, comprising treating back pain.

(Appendix 28)
28. The method of appendix 27, wherein the back pain includes low back pain.

(Appendix 29)
29. The method of appendix 28, wherein the back pain is associated with vertebral changes.

(Appendix 30)
The method of claim 1 or 2, comprising treating type 1 modic changes or type 1 and type 2 modic changes.

(Appendix 31)
The method of claim 30, wherein the modic change is located at C1 / 2, C2 / 3, C3 / 4, C4 / 5, C5 / 6, or C6 / 7.

(Appendix 32)
The modic change is C7 / T1, T1 / 2, T2 / 3, T3 / 4, T4 / 5, T5 / 6, T6 / 7, T7 / 8, T8 / 9, T9 / 10, T10 / 11, or 31. The method according to appendix 30, located at T1 / 12.

(Appendix 33)
The method of claim 30, wherein the Modic change is located at T12 / L1, L1 / 2, L2 / 3, L3 / 4, L4 / 5, or L5 / S1.

(Appendix 34)
The method according to appendix 1 or 2, comprising treating peripheral pain.

(Appendix 35)
The method according to appendix 1 or 2, comprising treating joint pain.

(Appendix 36)
The method according to appendix 1 or 2, comprising treating myalgia.

(Appendix 37)
The method according to appendix 1 or 2, comprising treating neuropathic pain.

(Appendix 38)
The method according to appendix 1 or 2, comprising treating complex regional pain syndrome.

(Appendix 39)
39. The method of appendix 38, wherein the complex regional pain syndrome is complex regional pain syndrome type I.

(Appendix 40)
39. The method of appendix 38, wherein the complex regional pain syndrome is complex regional pain syndrome type II.

(Appendix 41)
The method according to appendix 1 or 2, comprising treating Paget's disease of bone.

(Appendix 42)
The method according to appendix 1 or 2, comprising treating multiple myeloma.

(Appendix 43)
The method according to appendix 1 or 2, comprising treating ankylosing spondylitis.

(Appendix 44)
The compound is a RANK / RANKL antagonist and is a polypeptide, protein, or nucleic acid. Supplementary notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 40, 41, 42, or 43.

(Appendix 45)
Said compound is a RANK / RANKL antagonist and is a small molecule, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42. The method according to 42 or 43.

(Appendix 46)
The compound is a RANK / RANKL antagonist and has a molecular weight of less than about 1000 Daltons, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. A method according to 40, 41, 42 or 43.

(Appendix 47)
The compounds include ibrutinib, benzo [b] thiophene-2-carboxamide, N- [3- [6-[[4-[(2R) -1,4-dimethyl-3-oxo-2-piperazinyl] phenyl] amino ] -4,5-dihydro-4-methyl-5-oxo-2-pyrazinyl] -2-methylphenyl] -4,5,6,7-tetrahydro-, benzamide, 4- (1,1-dimethylethyl) -N- [3- [8- (Phenylamino) imidazo [1,2-a] pyrazin-6-yl] phenyl]-, benzamide, N- [3- [4,5-dihydro-4-methyl-6 -[[4- (4-morpholinylcarbonyl) phenyl] amino] -5-oxo-2-pyrazinyl] -2-methylphenyl] -4- (1,1-dimethylethyl)-, 2-propenamide, N- [3-[[5 Fluoro-2-[[4- (2-methoxyethoxy) phenyl] amino] -4-pyrimidinyl] amino] phenyl]-, 2-pyridinecarboxamide, 4- [4-[[5-fluoro-4-[[3 -[(1-oxo-2-propen-1-yl) amino] phenyl] amino] -2-pyrimidinyl] amino] phenoxy] -N-methyl-, AVL-101, AVL-291, AVL-292, [N -(2-Chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide] (dasatinib ), Zoledronic acid, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-ibromophenyl) propenamide,
Appendices 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, The method according to 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43.

(Appendix 48)
48. The method of appendix 47, wherein the RANK / RANKL antagonist is ibrutinib.

(Appendix 49)
48. The method of appendix 47, wherein the compound is zoledronic acid.

(Appendix 50)
50. The method of appendix 49, comprising orally administering a steroid and zoledronic acid to the mammal.

(Appendix 51)
51. The method of appendix 50, wherein the steroid is prednisone.

(Appendix 52)
Supplementary note 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 wherein the compound is a nitrogen-containing bisphosphonate , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 Method.

(Appendix 53)
Additional compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, wherein the compound is pamidronic acid 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 54)
The compound is neridronic acid, additional notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 55)
Additional Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, wherein the compound is olpadronic acid 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 56)
Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 Method.

(Appendix 57)
Additional Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, wherein the compound is incadrotonic acid 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 58)
The compound is ibandronic acid, additional notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 59)
The compound is risedronic acid, additional notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 60)
The compound is etidronic acid, supplementary notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 61)
Supplementary note 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, the compound is clodronic acid 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 62)
The compound is simadronic acid, additional notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 63)
The compound is minodronic acid, additional notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 64)
Supplementary note 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, the compound is tiludronic acid 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 .

(Appendix 65)
The compound is administered at a frequency of about every 3 months or more. Supplementary notes 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 61, 62, 63, or 64.

(Appendix 66)
66. The method of appendix 65, wherein the compound is administered intravenously.

(Appendix 67)
68. The method of appendix 65, wherein the compound such as zoledronic acid is administered orally.

(Appendix 68)
Including orally administering zoledronic acid to a mammal in need of treatment with zoledronic acid, wherein zoledronic acid is administered only once or for a period of about 24 hours to about 2 years between administrations of the multiple dosage forms A method of delivering zoledronic acid to mammalian blood.

(Appendix 69)
Orally administering a salt-enhanced dosage form to a mammal to be treated with zoledronic acid,
The salt-enhanced dosage form comprises the disodium salt form of zoledronic acid with enhanced oral bioavailability in beagle dogs compared to the diacid form of zoledronic acid,
A method of delivering zoledronic acid systemically.

(Appendix 70)
A method for enhancing the oral bioavailability of zoledronic acid comprising orally administering a dosage form containing zoledronic acid in disodium salt form.

(Appendix 71)
About 0.05 mg / kg to about 4 mg / kg of zoledronic acid is orally administered to the mammal at a frequency of no more than once a day and more than once a week, or about 0. Orally administering 1 mg / kg to about 10 mg / kg to said mammal at a frequency of no more than once a week;
Zoledronic acid is orally administered at least 5 times,
A method of safely delivering zoledronic acid to mammalian blood by repeated oral administration.

(Appendix 72)
About 0.4 mg / kg to about 4 mg / kg zoledronic acid is orally administered to the mammal at a frequency of no more than once a day and more than once a week, or about 0. Orally administering 4 mg / kg to about 10 mg / kg to the mammal at a frequency of not more than once a week;
A method of safely delivering zoledronic acid to mammalian blood by repeated oral administration comprising:

(Appendix 73)
73. The method of appendix 65, 66, 67, 68, 69, 70, 71, or 72, wherein about 0.5 mg / kg to about 2 mg / kg zoledronic acid is orally administered daily to the mammal.

(Appendix 74)
74. The method of appendix 73, wherein about 0.6 mg / kg to about 0.9 mg / kg zoledronic acid is orally administered daily to the mammal.

(Appendix 75)
73. The method of clause 65, 66, 67, 68, 69, 70, 71, or 72, wherein about 0.5 mg / kg to about 2 mg / kg of zoledronic acid is orally administered to the mammal weekly.

(Appendix 76)
76. The method of appendix 75, wherein about 0.6 mg / kg to about 0.9 mg / kg zoledronic acid is orally administered to the mammal weekly.

(Appendix 77)
77. The appendix 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76, wherein the mammal experiences pain relief at least 24 hours after the compound is administered to the mammal. Method.

(Appendix 78)
78. The method of appendix 77, wherein the mammal experiences pain relief 3 months after the compound is administered.

(Appendix 79)
79. The method of appendix 78, wherein the mammal receives about 40 mg to about 700 mg of the compound within one month.

(Appendix 80)
79. The method of appendix 78, wherein the human experiences pain relief that lasts at least 48 hours after administration of the compound.

(Appendix 81)
79. The method of appendix 78, wherein the human does not receive the compound less frequently than once a day.

(Appendix 82)
81. The method of appendix 78 or 80, wherein there is a period of about 24 hours to about 7 days between administration of the dosage form.

(Appendix 83)
84. The method of appendix 82, wherein the compound is administered weekly.

(Appendix 84)
81. The method of appendix 80, wherein there is a period of about 14 days to about 28 days between administration of the dosage form.

(Appendix 85)
81. The method of appendix 80, wherein there is a period of at least 1 month between administration of the dosage form.

(Appendix 86)
81. The method of appendix 80, wherein about 10 mg to about 100 mg of the compound is administered to the mammal weekly.

(Appendix 87)
81. The method of appendix 80, wherein about 10 mg to about 250 mg of the compound is administered to the mammal monthly.

(Appendix 88)
78. The method of appendix 77, wherein about 100 mg to about 1000 mg of the compound is administered to the mammal daily.

(Appendix 89)
81. The method of appendix 80, wherein there is a period of about 7 days to about 14 days between administration of the dosage form.

(Appendix 90)
81. The method of appendix 80, wherein the compound is administered more than once.

(Appendix 91)
90. The method of appendix 90, wherein zoledronic acid is orally administered to a human to provide 1.2 to about 3% bioavailability in the human.

(Appendix 92)
94. The method of appendix 90, wherein the zoledronic acid is administered to provide 1.5-3% bioavailability in a human.

(Appendix 93)
94. The method of appendix 90, wherein the zoledronic acid is administered daily for 2 to 7 consecutive days.

(Appendix 94)
94. The method of appendix 90, wherein the compound is administered weekly for a period of 6 weeks.

(Appendix 95)
90. The method of appendix 90, wherein the compound comprises zoledronic acid and the weekly dosage is from about 25 mg to about 75 mg.

(Appendix 96)
90. The method of appendix 90, wherein about 10 mg to about 100 mg of zoledronic acid is orally administered daily.

(Appendix 97)
90. The method of appendix 90, wherein about 40 mg to about 50 mg of zoledronic acid is orally administered daily.

(Appendix 98)
90. The method of appendix 90, wherein about 50 mg of zoledronic acid is orally administered daily.

(Appendix 99)
90. The method of appendix 90, wherein about 50 mg to about 100 mg of zoledronic acid is orally administered daily.

(Appendix 100)
Zoledronic acid is administered with Compound 1 and / or Compound 2, Compound 1 is less than 0.1% of the total weight of zoledronic acid, Compound 1 and Compound 2, and Compound 2 comprises zoledronic acid, Compound 1 and Compound 101. The method of any one of appendices 1 to 99, wherein the method is less than 0.1% of the total weight of 2.

(Appendix 101)
formula
A compound represented by
In which X ⁻ is F ⁻ , Br ⁻ , Cl ⁻ , I ⁻ , OH ⁻ or acetate,
A compound wherein M ⁺ is Na ⁺ , K ⁺ or NH ₄ ⁺ .

(Appendix 102)
formula
102. The compound according to appendix 101, further represented by:

(Appendix 103)
105. The compound according to appendix 102, wherein the compound is in a hydrate form.

(Appendix 104)
A dosage form comprising the compound according to appendix 101, 102, or 103.

(Appendix 105)
105. The dosage form of claim 104, wherein the compound is less than 0.1% (w / w) of the total amount of therapeutically effective agent in the dosage form.

(Appendix 106)
The dosage form of claim 104, wherein the compound is at least 20% of the total amount of therapeutically effective agent in the dosage form.

(Appendix 107)
The dosage form of claim 104, wherein the compound is at least 90% of the total amount of therapeutically effective agent in the dosage form.

(Appendix 108)
formula
A compound represented by
A compound wherein M ⁺ is Na ⁺ , K ⁺ or NH ₄ ⁺ .

(Appendix 109)
The compound has the formula
109. The compound according to appendix 108, further represented by:

(Appendix 110)
110. The compound according to appendix 109, wherein the compound is in a hydrate form.

(Appendix 111)
A dosage form comprising the compound according to appendix 108, 109, or 110.

(Appendix 112)
112. The dosage form of claim 111, wherein the compound is less than 0.1% (w / w) of the total amount of therapeutically effective agent in the dosage form.

(Appendix 113)
112. The dosage form of clause 111, wherein the compound is at least 20% of the total amount of therapeutically effective agent in the dosage form.

(Appendix 114)
112. The dosage form of claim 111, wherein the compound is at least 90% of the total amount of therapeutically effective agent in the dosage form.

Claims (10)

(1) knee pain and
(2) OARSI grade 0 or Czergren and Lawrence grade 0 or grade 1 for joint space stenosis ;
Selecting patients with
( 3 ) A pharmaceutical composition used in treating knee pain by administering the pharmaceutical composition to a patient in need of the pharmaceutical composition,
Said pharmaceutical composition comprises a bisphosphonate.   2. The pharmaceutical composition of claim 1, wherein the patient has a bone marrow lesion. 0 used in treating knee pain by -10cmVAS selecting a patient having a 5cm or more pain intensity measured using a pharmaceutical composition according to claim 1. 4. The pharmaceutical composition of claim 3 , wherein the patient experiences a reduction in pain intensity of at least about 0.5 cm when using the 0-10 cm VAS. The pharmaceutical composition according to any one of claims 1 to 4 , wherein the bisphosphonate is zoledronic acid. 6. The pharmaceutical composition of claim 5 , wherein the zoledronic acid is orally administered to a human so as to provide a bioavailability of 1.2% to about 3% in the human. 7. The pharmaceutical composition according to claim 6 , wherein the zoledronic acid is administered weekly for a period of 6 weeks. 8. The pharmaceutical composition of claim 7 , wherein the weekly dose of zoledronic acid is about 25 mg to about 75 mg. 9. The pharmaceutical composition according to claim 8 , wherein the zoledronic acid is in the disodium salt form. The pharmaceutical composition according to any one of claims 1 to 4 , wherein the bisphosphonate is neridronic acid.