JP6802245B2 - Oral pharmaceutical compositions with enhanced oral bioavailability - Google Patents

Description

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

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

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said zoledronic acid being an oral dosage form for a particular species of mammal. Upon administration, it is characterized by being present in an amount that provides an area under the zoledronic acid plasma concentration curve (AUC) of about 50 ng · hour / mL to about 700 ng · hour / mL.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said zoledronic acid being an oral dosage form for a particular species of mammal. Upon administration, it is characterized by being present in an amount that results in a _maximum C of about 5 ng / mL to about 300 ng / mL zoledronic acid.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form being an oral dosage form for a particular species of mammal. Administration of zoledronic acid is configured to result in a T- _maximum of zoledronic acid for about 0.4 to about 12 hours.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form in which the zoledronic acid is used to identify the mammal. It is characterized by being configured to have a 12-hour sustained plasma concentration factor of about 1 to about 50 per species.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form in which the zoledronic acid is used to identify the mammal. It is characterized by being configured to have a 24-hour sustained plasma concentration factor of about 10 to about 30 relative to the species.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form in which the zoledronic acid is used to identify the mammal. It is characterized by being configured to have a 36-hour sustained plasma concentration factor of about 6 to about 20 relative to the species.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form in which the zoledronic acid is used to identify the mammal. It is characterized by being configured to have a 48-hour sustained plasma concentration factor of about 5 to about 20 relative to the species.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form in which the zoledronic acid is used to identify the mammal. It is characterized by being configured to have a 72-hour sustained plasma concentration factor of about 4 to about 20 relative to the species.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form for a particular species of mammal for 12 hours. It is characterized in that it is configured to have a plasma concentration of zoledronic acid of about 0.5 ng / mL to about 5 ng / mL.

Some embodiments include an oral dosage form comprising zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal, said oral dosage form of zoledronic acid in a particular species of mammal. It is characterized in that the excretion half-life is configured to be about 30 hours to about 100 hours.

Some embodiments include administering an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. Including a method of treating a symptom of zoledronic acid, said zoledronic acid to the oral dosage form in an amount that results in an AUC of about 50 ng hours / mL to about 700 ng hours / mL of zoledronic acid upon administration of the oral dosage form to a mammal. It is characterized by being present.

Some embodiments include administering an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The zoledronic acid is present in the oral dosage form in an amount that results in a C _maximal of about 5 ng / mL to about 300 ng / mL of zoledronic acid upon administration of the oral dosage form to a mammal. It is characterized by doing.

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating symptoms associated with such that administration of the oral dosage form to a particular species of mammal results in a T- _maximum of zoledronic acid of about 0.4 hours to about 1 hour. It is characterized by being done.

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a symptom related to, characterized in that the zoledronic acid is configured to have a 12-hour sustained plasma concentration factor of about 12 to about 50 for a mammal. ..

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a symptom related to, characterized in that the zoledronic acid is configured to have a 24-hour sustained plasma concentration factor of about 10 to about 30 for a mammal. ..

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a condition relating to, characterized in that the zoledronic acid is configured to have a 36-hour sustained plasma concentration factor of about 6 to about 20 relative to a mammal. ..

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a symptom related to, characterized in that the zoledronic acid is configured to have a 48-hour sustained plasma concentration factor of about 5 to about 20 relative to a mammal. ..

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a symptom related to, characterized in that the zoledronic acid is configured to have a 72-hour sustained plasma concentration factor of about 4 to about 20 relative to a mammal. ..

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating symptoms associated with such that a particular species of mammal has a plasma concentration of zoledronic acid of about 0.5 ng / mL to about 5 ng / mL in 12 hours. It is characterized by being.

Some embodiments include administration of an oral dosage form containing zoledronic acid to a mammal in need of treatment for a disease or bone, cancer, or pain-related condition, the disease or bone, cancer, or pain. The oral dosage form comprises a method of treating a condition relating to zoledronic acid, characterized in that the excretion half-life of zoledronic acid in a particular species of mammal is configured to be from about 30 hours to about 100 hours.

Some embodiments include methods of enhancing the oral bioavailability of zoledronic acid, including oral administration of a dosage form containing zoledronic acid in the form of a disodium salt.

Some embodiments include a dosage form containing zoledronic acid in the disodium salt form, the bioavailability of zoledronic acid in the disodium salt form in mammals being zoledronic acid in the diacid form in the same dosage form. It is characterized in that it is larger than the bioavailability of.

Some embodiments include dosage forms containing zoledronic acid in the form of a disodium salt, said dosage forms ranging from about 4 ng · h / mL to about 2000 ng · h / to the human to whom the dosage form is administered. It is characterized by containing the amount of zoledronic acid in the form of a disodium salt that results in the area under the plasma concentration curve of mL zoledronic acid.

Some embodiments include dosage forms containing zoledronic acid in the disodium salt form, present in less molar amount than would exist if zoledronic acid were assumed to be in the diacid form, and the disodium salt. The form of zoledronic acid was improved compared to the diacid form of zoledronic acid to the extent that even a smaller molar amount of the disodium salt in the dosage form did not reduce the amount of zoledronic acid delivered to the 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 in which the bioavailability of bisphosphonates is not enhanced or substantially not enhanced. Treatments using oral dosage forms that include may also be effective.

Some embodiments are methods of relieving inflammatory pain, comprising administering an oral dosage form containing zoledronic acid to a mammal in need thereof, the mammal after administration of the dosage form. After 3 hours, experience significant pain relief.

Some embodiments are methods of relieving pain associated with arthritis, comprising administering an oral dosage form containing zoledronic acid to a person 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 oral dosage forms containing zoledronic acid, and 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 pharmaceuticals comprising multiple units of the oral dosage forms described herein. In some embodiments, each unit in the oral dosage form contains from about 1 mg to about 50 mg of zoledronic acid.

Some embodiments are methods of relieving 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 of 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 relieving inflammatory pain, including oral administration of zoledronic acid to mammals in need thereof.

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

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

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 at BL (baseline, baseline) and on the indicated dates. 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 pain thresholds 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 solvent and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 4 is a diagram showing hind paw pain thresholds for rats treated with solvent and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 5 is a diagram showing body weight loading for rats treated with solvent and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 6 is a diagram showing changes in paw thickness for rats treated with solvent and zoledronic acid in a rat model of complex regional pain syndrome. FIG. 7 is a diagram showing the water solubility of disodium zoledronic acid tetrahydrate compared with the diacid form of zoledronic acid. FIG. 8 is a diagram showing plasma concentrations of zoledronic acid in dogs with respect to the time after administration of 150 mg of the disodium salt form of zoledronic acid and the diacid form of zoledronic acid. FIG. 9 is a diagram showing the compressibility of the dosage form containing zoledronic acid in the disodium salt form as compared with the diacid form.

Pamidronate or pamidronic acid, neridronate or neridronate, orpadronate or orpadronate, alendronate or alendronate, incadronate or incadronic acid, ibandronate or ibandronate, lysedronate or lysedronate, zoledronic acid or zoledronic acid, etidronate or etidronate Bisphosphonate compounds, such as acids, clodronic acid or clodronic acid, or tildronic acid or tildronic acid, can be used for a number of medical purposes, such as the treatment of unwanted symptoms or disorders, including pain relief. This can often be achieved by administration in oral dosage form. Generally, oral dosage forms containing bisphosphonates such as zoledronic acid are orally administered to mammals such as humans at least once to treat a disease or condition or to relieve pain. ..

The term "treat" or "treatment" refers to any type of therapeutic activity, including diagnosis, cure, alleviation or prevention of disease in humans or other animals, or the structure of the human or other animal's body or It broadly includes any activity that has other effects on any function.

Oral forms of bisphosphonates such as zoredronate are not limited, but are limited to inflammatory pain, arthritis pain, complex local pain syndrome, lumbosacral pain, musculoskeletal pain, neurogenic pain, chronic pain, cancer-related pain, It can be used to treat or relieve any type of pain, including acute pain and postoperative pain. In some cases, pain relief can be temporary relief or can be provided independently of the amelioration of the disease or symptom or the underlying cause of the disease or symptom. For example, the underlying disease may not improve or may continue to progress, but the pain of an individual suffering from the disease can be relieved. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve the treatment of one of these symptoms by administering a dosage form containing zoledronic acid in the form of a disodium salt. This may allow it to 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, as well as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoporosis, diffuse osteoporosis, seronegative (non-rheumatic) arthropathy, rheumatoid arthritis, periarthritis, tonicity. Relieves musculoskeletal pain, including pain associated with axial spondyloarthritis, including spondyloarthritis, Paget's disease, fibrous osteodysplasia, SAPHO syndrome, transient low back mutant arthropathy, crushed spinal fractures and osteoporosis, etc. Therefore, it can be administered orally. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve the treatment of one of these symptoms by administering a dosage form containing zoledronic acid in the form of a disodium salt. This may allow it to be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

Bisphosphonates such as zoledronic acid can be used to treat fractures or enhance fracture healing.

In some embodiments, zoledronic acid or another bisphosphonate relieves 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 include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation or chemotherapy-related neuropathy. Including cancer. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve the treatment of one of these symptoms by administering a dosage form containing zoledronic acid in the form of a disodium salt. This may allow it to 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 relieve inflammatory pain, including musculoskeletal pain, arthritic pain and complex regional pain syndrome. In some embodiments, the enhanced bioavailability of zoledronic acid can achieve the treatment of one of these symptoms by administering a dosage form containing zoledronic acid in the form of a disodium salt. This may allow it to 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 crushed fractures of the spinal column, fibrous dysplasia, osteogenesis imperfecta, bone Paget's disease, transient osteoporosis and transient osteoporosis of the lumbar region. ..

Bisphosphonates, such as zoledronic acid, can also be used to treat low back pain, or other musculoskeletal or inflammatory symptoms with bone changes detected by MRI or other medical imaging devices. For example, bisphosphonates such as zoledronic acid can be used to treat low back pain associated with modic changes, or changes in vertebral endplate signal (VESC) and bone marrow changes viewed using magnetic resonance imaging (MRI). Can be used. Modic changes can be classified into various types, including type 1 (M1), type 2 (M2) and type 3 (M3) lesions or changes, one of which can be treated with bisphosphonates such as zoledronic acid. .. VESC can be found in patients with different types of low back pain, including, but not limited to, spondylitis, trauma, and ankylosing spondylitis, small nodules, fractures, tumors, and spondyloarthropathies including spinal cord infarction. Lesions in ankylosing spondylitis include osteotis and vertebral discitis that can be detected using MRI or other medical imaging devices.

Bisphosphonates such as zoledronic acid also cause knee osteoarthritis such as knee osteoarthritis associated with bone marrow lesions (BML) containing BML that can be detected using MRI or other medical imaging devices. Can be used to treat. In some embodiments, bisphosphonates such as zoledronic acid treat osteoarthritis of the knee associated with bone marrow edema (BME), including BME that can be detected using MRI or other medical imaging devices. Can be used for.

Arthritis means an inflammatory joint disease that can be painful. Examples of arthritic pain include osteoarthritis, diffuse osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-rheumatoid arthritis, periarticular disorders, neuropathic arthropathy including Charcoal foot , Axial spondyloarthritis, including tonic spondylitis, and pain associated with SAPHO syndrome.

In some embodiments, a human being treated for a disease or condition such as an inflammatory disease (eg, arthritis) by an oral dosage form of zoledronic acid is about 10 to about 90 years old, about 20 to about 80 years old. , About 30 to about 75 years old, about 40 to about 70 years old, about 1 to about 16 years old, or about 80 to about 95 years old.

In some embodiments, a human being treated for a disease or condition such as an inflammatory disease (eg, arthritis) by an oral dosage form of zoledronic acid is at least 1 month, at least 2 months, at least 6 months, or at least 1 I have been suffering from arthritis for years.

In some embodiments, a disease or condition such as an inflammatory disease (eg, arthritis) affects the knees, elbows, fingers, wrists, shoulders, or hips.

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. Can be administered orally to relieve complex regional pain syndrome, such as. CRPS is a type of inflammatory pain. 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 with edema, as well as changes in autonomic nerves, movement and sensation.

With respect to the use of oral zoledronic acid to relieve pain associated with inflammatory symptoms, pain relief can be short-term, eg, a period of several hours after administration of the dosage form, and / or long-term, eg, After oral administration of zoledronic acid, it can be sustained for days, weeks or even months. In some embodiments, mammals such as humans have 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 the oral dosage form containing zoledronic acid. Experience significant pain relief for at least about 1 week, at least about 2 weeks, or at least about 3 weeks. In some embodiments, mammals such as humans will have at least about 3 hours to about 2 weeks, about 3 hours to about 3 weeks, about 3 hours to about 24 after administration of the oral dosage form containing zoledronic acid. Significant pain relief during hours, 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 at least one part of the time from about 6 days to about 2 weeks. To experience.

For the treatment of any of the symptoms 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: regarding the first oral dosage form, the second oral dosage form and the second oral dosage form regarding the first oral dosage form are 5 × T _maximum or more (for example, if the T _maximum is 1 hour). Administered at least 10 x T _maximum or higher, at least about 15 x T _maximum or higher, at least about 20 x T _maximum or higher, at least about 50 x T _maximum or higher, or at least about 200 x T _maximum or higher (in 5 hours or longer). The _maximum T is the time of the maximum plasma concentration of the first oral dosage form).

Some embodiments include treatment of the symptoms described herein, such as inflammatory pain, arthritis, or complex regional pain syndrome, the treatment of which is 1 for mammals to treat the symptoms. It is characterized by comprising either administering only the dosage form or administering the first dosage form to the mammal followed by the second dosage form to the mammal. When two or more dosage forms are administered, the second oral dosage form has a peak in the pain-relieving effect of the first oral dosage form before the maximum pain-relieving effect of the first oral dosage form is achieved. Administered before being experienced by the shaped mammal. In some embodiments, the second oral dosage form is administered before the observed pain-relieving effect 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. Is administered from about 14 days, or from about 24 hours to about 21 days.

Some embodiments include treatment of the symptoms described herein, such as symptomatic pain, arthritis, or complex local pain syndrome, the treatment of administering the first dosage form to the mammal and then feeding. The second dosage form comprises administering the second dosage form to the animal, the second dosage form is administered after the maximum pain-relieving effect of the first dosage form is achieved, and the second oral dosage form is the first oral dosage form for the mammal. It is administered while the pain relief from the form is still being experienced, 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. Is administered from about 14 days, or from about 24 hours to about 21 days.

Zoledronic acid or another bisphosphonate can also be administered orally to relieve 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 can be used in multiple myeloma, bone metastases from solid tumors, hypercalcemia in malignant tumors, giant cell tumors of bone, hematological 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 to treat one of these symptoms by administering a dosage form containing zoledronic acid in the disodium salt form. This may allow it to 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 may also be beneficial for treating diseases or conditions that may or may not contain a pain component. For example, zoledronic acid or another bisphosphonate may include treatments that do not simply relieve the pain of the symptoms, and treatments that are performed in a way that the symptoms are treated without pain relief. It can be beneficial to treat any of the types of symptoms 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 disorder or symptom, a painless inflammatory disorder or symptom. It can be used to treat diseases or symptoms such as inflammatory diseases or symptoms, cancer diseases or symptoms, and neurological diseases or symptoms, including. In some embodiments, enhanced bioavailability of zoledronic acid can be achieved by treating one of these symptoms by administering a dosage form containing zoledronic acid in the disodium salt form. This may allow it to 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 results in axial spondylitis, including complex regional pain syndrome, rheumatoid arthritis, osteoporosis, diffuse osteoporosis, ankylosing spondylitis, and acute spinal dissection. It can also be beneficial for treating fractures, fibrous osteodysplasia, SAPHO syndrome, osteoporosis, transient osteoporosis, or lumbar transient osteoporosis. In some embodiments, enhanced bioavailability of zoledronic acid can be achieved by treating one of these symptoms by administering a dosage form containing zoledronic acid in the disodium salt form. This may allow it to 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 causes hypercalcemia of malignancies, multiple myeloma, bone metastases from solid tumors, Paget's disease of bone, giant cell tumor of bone, blood. It can also be beneficial for treating cancer or leukemia, or solid tumors or cancer. In some embodiments, enhanced bioavailability of zoledronic acid can be achieved by treating one of these symptoms by administering a dosage form containing zoledronic acid in the disodium salt form. This may allow it to be used with a reduced molar amount of disodium salt compared to that used in the diacid form.

In some embodiments, bisphosphonates such as zoledronic acid can be used to treat otosclerosis.

Zoledronic acid has the structure shown below and is also referred to as 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 a disodium salt. Alternative solid forms such as solvates or hydrates, tautomers, or any that can be rapidly converted to the compounds herein under the conditions in which the compounds are used herein. Includes other chemical species.

In some embodiments, zoledronic acid is administered in a dosage form comprising a salt form, such as a salt of the dianion 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 sodium salt form, such as monosodium salt, disodium salt or trisodium salt. Under certain circumstances, the use of disodium salts may be desired. For example, disodium salts are more soluble in water than diacid forms. As a result, in certain steps, the disodium salt can act together more easily than in the diacid form. Further, the disodium salt is more bioavailable and / or can be absorbed more rapidly when taken orally as compared to the diacid form.

Some oral dosage forms include zoledronic acid having a dose and form of zoledronic acid suitable for a particular species of mammal (eg, dog, rat, human, etc.). Such dosage forms may have zoledronic acid present in an amount that provides the desired range of area under the plasma concentration curve (AUC) of zoledronic acid in certain species of mammal. For example, the dose of zoledronic acid and the composition of the oral dosage form are about 1 ng · hour / mL to about 700 ng · hour / mL, about 3 ng · hour / mL to about 30 ng · hour / hour in administration of the oral dosage form to mammals. 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 From about 450 ng / hour / mL, about 300 ng / hour / mL to about 350 ng / hour / mL, about 300 ng / hour / mL to about 310 ng / hour / mL, about 340 ng / hour / mL to about 350 ng / hour / 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 to about 415 ng / hour / mL, about 140 ng / hour / mL to about 160 ng / hour / mL, about 140 ng / hour / mL to about 150 ng / hour / mL, about 150 ng / hour / mL to about 160 ng / hour / mL, about 140 ng / hour / 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 / hour / mL, about 410 ng / hour / mL, Or it can result in any AUC in the range bounded by these arbitrary values, or any AUC between these arbitrary values, zoledronic acid.

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

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal are from about 0.2 ng / mL to about 300 ng / mL, about 0 in administration of the oral dosage form to mammals. .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, about 97 ng / mL or amount that can result in C _maximum any zoledronic acid between any arbitrary C _maximum range bounded or these, by any of these values, May include zoledronic acid present in.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that administration of the oral dosage form to a particular species of mammal is about 0.4 hours to about 1 hour. about 0.5 hours, or about 0.75 hours, or be configured to provide any of the _maximum T of zoledronic acid between _maximum any T any or these, in the range bounded by any of these values obtain.

The oral bioavailability of zoledronic acid can be enhanced by oral administration of zoledronic acid in the form of a disodium salt. 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 up to about 100% compared to administration of the diacid form of zoledronic acid. , Or can be improved up to about 200.

Due to the improved bioavailability of the disodium salt, the dosage form may contain less zoledronic acid disodium salt than when the diacid form zoledronic acid is administered, or mammals such as humans. Can receive less disodium salt of zoledronic acid on a molar basis than if zoledronic acid in the diacid form is administered. At least about 10 mol% compared to the amount of zoledronic acid in the diacid form, such as the molar amount when zoledronic acid in the diacid form is administered to achieve the same plasma concentration of zoledronic acid. The dosage form may include less than, at least less than about 20 mol%, at least less than about 40 mol%, at least less than about 50 mol%, and / or a disodium salt up to less than 90 mol% or more than 95 mol%. Or mammals can receive it.

In some embodiments, where included in the dosage form, or a mammalian (e.g., human) at which it is administered, the amount of the disodium salt form of on a molar basis is from about 0.8n _d about 1.2n having about 1.1 n _d of _d, or about 0.9n _{d, where,} n _d = a _{(b a / b d) (} n a), b a is an bioavailability of diacid form , b _d is the bioavailability of the disodium salt form, n _a is the number of moles of diacid when administered dosage forms comprising diacid form of zoledronic acid. For example, the diacid form has a bioavailability _{(b a)} of 0.01, disodium form has a 0.015 bioavailability _{(b d),} the dosage form is 0.001 moles of diacid Is usually included, _nd is (0.01 / 0.015) (0.001 mol), or 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, the bioavailability of zoledronic acid in the disodium salt form is that of an oral dosage form containing a reduced molar amount of the disodium salt of zoledronic acid as compared to the diacid form of zoledronic acid. When the drug is administered to a mammal, the amount of zoledronic acid is high enough to be present in the mammalian blood at least as much as it would be if zoledronic acid was administered in the diacid form.

For oral dosage forms containing the disodium salt form of zoledronic acid, in some embodiments, the disodium salt form is present in a smaller molar amount than would be present if zoledronic acid was assumed to be in the disodium form. However, the zoledronic acid in the disodium salt form is such that even a smaller molar amount of zoledronic acid in the dosage form does not reduce the amount of zoledronic acid delivered to the mammalian plasma. Has improved bioavailability compared to.

In some embodiments, the disodium salt form of zoledronic acid is in oral dosage form to the mammal each time zoledronic acid is administered in the disodium salt from about 4 ng · hour / mL to about 2000 ng · hour / hour. It is present in an amount that provides an area under the plasma concentration curve (AUC) of mL zoledronic acid. In some embodiments, the disodium salt form of zoredronic acid has an oral dosage form of about 100 ng · hour / mL to about 2000 ng · hour / mL, about 100 ng · hour / mL in the mammal to which the dosage form is administered. To provide an area under the plasma concentration curve of zoledronic acid from about 1000 ng · hour / mL, about 500 ng · hour / mL to about 1000 ng · hour / mL, or about 500 ng · hour / mL to about 700 ng · hour / mL. Exists in quantity. This amount may be suitable for administration of oral dosage forms approximately every 3 to 4 weeks.

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

In some embodiments, the disodium salt form of zoredronic acid has an oral dosage form of about 4 ng · hour / mL to about 100 ng · hour / mL, about 10 ng · hour / mL in the mammal to which the dosage form is administered. To provide an area under the plasma concentration curve of zoledronic acid from about 50 ng · hour / mL, or about 10 ng · hour / mL to about 30 ng · hour / mL. This amount may be suitable for daily administration of oral dosage forms.

Oral administration of zoledronic acid, in particular oral administration in the form of a disodium salt of zoledronic acid, can result in more sustained plasma concentrations of the drug compared to parenteral modes such as intravenous or subcutaneous. For example, the amount of zoledronic acid in plasma can be much higher for oral administration of disodium salt for about 24 hours, or 48 hours, or longer after administration. In some embodiments, oral zoledronic acid produces about 1 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, more than the 24-hour or 48-hour sustained plasma concentration factor of parenteral administration of zoredronic acid. 24-hour continuous plasma concentration factor 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. The "sustained plasma concentration factor", p _f, is defined by the formula p _f = 1000 (C _t / C _maximum ), where C _maximum is the maximum plasma concentration of zoledronic acid after administration, and C _t is 24. The plasma concentration of zoledronic acid at a time of interest, such as time. For parenteral administration, the _maximum C can be about C ₀ , or the concentration immediately after infusion of the total amount of the drug into the body. Sustained plasma concentration factor, obtained using the plasma concentrations of zoledronic acid in C _t in the above formula, for example, obtained for other time such as 48 hours. 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 continuous plasma concentration factor is 1.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that 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 these can be configured.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal, the zoledronic acid is about 10 to about 30, about 10 to about 10 to about 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 sustained plasma in the range bounded by any of these values. It can be configured to have a concentration factor, or any 24-hour sustained plasma concentration factor between these.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that 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 may be configured to have any 36-hour sustained plasma concentration factor between these.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that 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 can be configured to have a factor, or any 48-hour sustained plasma concentration factor between any of these.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal, 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 can be configured to have a factor, or any 72-hour sustained plasma concentration factor between any of these.

Oral dosage forms containing zoledronic acid having the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that the particular species of mammal is from about 0.5 ng / mL to about 5 ng / mL, about 1 ng / mL. From about 3 ng / mL, from about 1 ng / mL to about 2 ng / mL, from about 2 ng / mL to about 3 ng / mL, from 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 zoredronic acid at about 3.2 ng / mL, or any plasma concentration in the range bounded by any of these, or any 12 hours between these.

Oral dosage forms containing zoledronic acid having the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that the particular species of mammal is from about 0.2 ng / mL to about 2 ng / mL, about 0.5 ng. / 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 .4 ng / mL, or any plasma concentration in the range bounded by any of these values, or any 24 hours between these.

Oral dosage forms containing zoledronic acid having the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that the particular species of mammal is from about 0.1 ng / mL to about 2 ng / mL, about 0.2 ng. From / mL to about 1.5 ng / mL, from about 0.2 ng / mL to about 0.5 ng / mL, from about 0.5 ng / mL to about 1 ng / mL, from about 1 ng / mL to about 1.3 ng / mL, about 0 .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 zoledronic acid in any 36 hours between these. Can be configured to have a plasma concentration of.

Oral dosage forms containing zoledronic acid having the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that the particular species of mammal is from about 0.1 ng / mL to about 2 ng / mL, about 0.2 ng. From / mL to about 1.5 ng / mL, from about 0.2 ng / mL to about 0.5 ng / mL, from about 0.5 ng / mL to about 0.9 ng / mL, from about 0.9 ng / mL to about 1.3 ng / mL Any plasma concentration in the range bounded by mL, about 0.3 ng / mL, about 0.7 ng / mL, about 1.1 ng / mL, or any of these, or any 48 between any of these. It can be configured to have a plasma concentration of zoledronic acid over time.

Oral dosage forms containing zoledronic acid having the appropriate amount and morphology of zoledronic acid for a particular species of mammal are such that the particular species of mammal is from about 0.2 ng / mL to about 1 ng / mL, about 0.2 ng. From / mL to about 1.5 ng / mL, from about 0.1 ng / mL to about 0.3 ng / mL, from about 0.3 ng / mL to about 0.6 ng / mL, from about 0.6 ng / mL to about 1 ng / mL, At any plasma concentration in the range bounded by about 0.2 ng / mL, about 0.5 ng / mL, about 0.9 ng / mL, or any of these, or any 72 hours between these. It can be configured to have a plasma concentration of zoledronic acid.

Oral dosage forms containing zoledronic acid with the appropriate amount and morphology of zoledronic acid for a particular species of mammal have a half-life of zoledronic acid excretion in a particular species of mammal from about 30 hours to about 100 hours. 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 of the ranges bounded by any of these values. Can be configured to have a half-life of, or any value between these.

As used herein, "half-life of excretion" refers to the apparent half-life of primary terminal plasma excretion obtained by non-compartmental analysis using Win-Nonlin. The terminal phase plasma excretion 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 orally administered drugs, the terminal phase plasma excretion half-life can be affected by the degree of drug absorption, as well as plasma clearance and distribution.

In some embodiments, the disodium salt form of zoledronic acid is compared to the diacid form of zoledronic acid, which facilitates any enhancement to the bioavailability provided by any bioavailability enhancer in the dosage form. Provide enhancements to bioavailability, such as. In some embodiments, the disodium salt form of zoledronic acid is to be compared to the diacid form of zoledronic acid that is greater in dosage form than any enhancement to the bioavailability provided by any bioavailability enhancer. It provides 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 containing the disodium salt of zoledronic acid is solid.

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

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

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

In some embodiments, 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 exists in a form having water solubility, which means.

The form of the disodium salt 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 may also facilitate increasing the drug load of the dosage form, as smaller tablets obtain a given dose intensity. In some embodiments, solid dosage forms of zoledronic acid, such as the diacid form of zoledronic acid or the disodium salt form of zoledronic acid, can have hardnesses 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 based on the route of administration and standard pharmaceutical practices. 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 the active ingredient and carrier can be determined, for example, by the solubility and chemistry of the compound, the route of administration and standard pharmaceutical practices.

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

Zoledronic acid or another bisphosphonate can be administered to a human patient, for example, in various forms adapted to the alternative route of oral, rectal or parenteral administration. Parenteral administration here includes, but is not limited to, administration by the following route. Transepithelial, local, nasal inhalation via insufflation, and whole rectum, including lung, intramedullary, intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, subdermal, sublingual and buccal.

The effective amount of zoledronic acid or another bisphosphonate is the severity of the symptoms being treated, the route of administration, the formulation and dosage form, the physical properties of the bisphosphonate compound used, and the age, weight and response to irritation of the individual patient. Will vary depending on various factors known to the therapist, such as.

The amount of zoledronic acid or another bisphosphonate in the therapeutic composition can vary. For example, some liquid compositions are about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0. From 0.01% (w / v) to about 10% (w / v), from about 0.001% (w / v) to about 1% (w / v), from 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% ( From w / v) to about 7% (w / v), from about 7% (w / v) to about 10% (w / v), from 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 may contain from about 40% (w / v) to about 50% (w / v) of zoledronic acid.

Some solid compositions are 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 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) From w) to about 60% (w / w), from about 70% (w / w) to about 75% (w / w), from about 70% (w / w) to about 80% (w / w), or It may contain from about 80% (w / w) to about 90% (w / w) of zoledronic acid.

Some solid compositions containing bisphosphonates such as zoledronic acid can contain from about 1 mg to about 5 mg or 8 mg bisphosphonates, with total dosage forms of less than about 9 mg, about 10 mg, about 11 mg, or about 15 mg. possible.

Some solid compositions containing bisphosphonates, such as zoledronic acid, may contain from about 5 mg to about 10 mg or 15 mg of bisphosphonates, with total dosage forms of less than about 15 mg, about 17 mg, about 21 mg, or about 29 mg. possible.

Some solid compositions containing bisphosphonates such as zoledronic acid may contain from about 10 mg to about 50 mg or 80 mg of bisphosphonates, with total dosage forms of less than about 77 mg, about 85 mg, about 110 mg, or about 150 mg. possible.

Some solid compositions containing bisphosphonates such as zoledronic acid can contain from about 100 mg to about 200 mg or 290 mg of bisphosphonates, and the total mass of the dosage form is about 280 mg, about 315 mg, about 360 mg, about 430 mg or about 570 mg. Can be less than.

Some solid compositions containing bisphosphonates such as zoledronic acid can contain from about 200 mg to about 300 mg or 430 mg of bisphosphonates, and the total mass of the dosage form is about 430 mg, about 500 mg, about 570 mg, about 640 mg or about 710 mg. Can be less than.

Any suitable amount of zoledronic acid can be used. A solid or liquid oral dosage form, or unit of oral dosage form (collectively referred to herein as "oral dosage form" (s)) is from about 0.005 mg to about 20 mg, about 0.1 mg. From 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 1 mg to about 75 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 30 mg to about 150 mg, about 1 mg to about 1000 mg, about 10 mg to about 50 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg From about 100 mg, about 40 mg to about 150 mg, about 40 mg to about 220 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 800 mg, about 25 mg to about 800 mg, from 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 Approximately 150 mg of zoledronic acid, or any amount of zoledronic acid, within the range bounded by any of these values, or between any of these values, may be contained. In some embodiments, oral zoledronic acid is administered daily, weekly, monthly, once every two or three months, annually, or twice a year.

In some embodiments, the oral dosage form is 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. Zoredronic acid from / 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 , or within the range bounded by any of these numbers, or any of these. Any amount of zoledronic acid may be contained between the values of. All dosage 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 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 these arbitrary numbers, or between these arbitrary numbers. In some embodiments, the daily oral dose 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 , 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 within the range bounded by any of these numbers, or these Any amount of zoledronic acid, between any numbers.

In some embodiments, weekly oral doses of zoledronic acid are 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. It is about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg, about 20 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 zoredronic acid within the range bounded by any of these numbers, or between any of these numbers. The weekly oral dose may be given as a single dose given once a week, or given in units of 2, 3, 4, 5, 6 or 7 during the week. May be done.

In some embodiments, the monthly dose of zoledronic acid, or the amount of zoledronic acid administered over a one-month period, 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 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, 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 monthly amount within the range bounded by these arbitrary numbers, or between these arbitrary numbers. In some embodiments, monthly oral doses of zoledronic acid are 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 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 / m ² , about 500 mg / m ² to about 600 mg / m ² , about 540 mg / m ² , Alternatively, any amount of zoredronic acid within or between these arbitrary numbers bounded by these arbitrary numbers. The monthly dose may be given as a single dose, or may be given as two or more individual doses administered during the 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 a daily dose of 28-31. In some embodiments, the monthly dose is administered in doses of 5 to 10 units over a month. The monthly dose may be administered for only one month, or may be administered repeatedly for two months or longer.

In some embodiments, the 6-week dose of zoledronic acid can be from about 200 mg to about 500 mg, from about 300 mg to about 450 mg, or about 300 mg. In some embodiments, the 6-week dose of zoledronic acid can be administered only once. In some embodiments, the 6-week dose of zoledronic acid can be administered at a 6-week dose, eg, about 35 mg to about 80 mg or about 50 mg to about 75 mg at each weekly dose.

Oral zoledronic acid or a disodium salt thereof may be administered in combination with about 0.1 mg to about 10 mg of zoledronic acid or a salt thereof administered parenterally, such as intravenously. In some embodiments, about 50 mg, about 100 mg or about 150 mg of zoledronic acid disodium salt is orally administered in combination with parenteral 1 mg zoledronic acid, such as intravenous. In some embodiments, the parenteral dose of zoledronic acid is from about 0.25 mg to about 25 mg, from about 0.25 mg to about 10 mg or from about 0.5 mg to about 7.5 mg.

With respect to oral administration of zoledronic acid, or other bisphosphonates, at least about before zoledronic acid is administered for the treatment of pain associated with inflammation, arthritis, CRPS, or any other condition described herein. 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 Zoledronic acid-administered mammals or humans do not eat or drink It can be useful if you do not drink (other than any water needed to swallow the oral dosage form). Also, mammals or humans receiving zoledronic acid do not eat food 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 zoledronic acid is administered. Or it can be useful if you don't drink. In some embodiments, the human being administered zoledronic acid avoids lying down for at least about 30 minutes or about 1 hour after receiving the dosage form containing zoledronic acid, or remains upright or sits upright. Avoiding food or drink before or after oral administration of zoledronic acid may improve the bioavailability of zoledronic acid.

The oral bioavailability of zoledronic acid in dosage form can vary. Some dosage forms may have components added to enhance bioavailability. However, enhanced bioavailability is not always necessary for effective oral dosage forms. In some embodiments, the dosage form is substantially free of bioavailability enhancers. In some embodiments, the oral dosage form is the oral bioavailability of zoledronic acid, such as about 0.01% to about 10%, about 0.1% to about 7%, or about 0.1% to about 5%. Can have. Zoledronic acid typically has low bioavailability in oral dosage forms, even in the absence of ingredients or other methods for enhancing bioavailability. In some embodiments, the oral bioavailability of zoledronic acid is not enhanced or substantially not enhanced. For example, the oral bioavailability of zoredronic acid is about 0.01% to about 5%, about 1.1% to about 4%, about 1.1% to about 3.1%, about 1.1% to about. 3.5%, about 1.5% to about 4%, about 1.5% to about 3.1%, about 1.5% to about 3.5%, about 2% to about 3%, about 3% From about 4%, 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% From about 1.5%, about 0.3% to about 1.5%, about 0.3% to about 1%, about 0.1% to about 0.5%, about 0.3% to about 0. 5%, about 0.5% to about 1%, about 0.6% to about 0.7%, 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%, about 1.3% to about 1.4% , About 1.4% to about 1.5%, about 1.5% to about 1.6%, about 1.6% to about 1.8%, or about 1.8% to about 2%. obtain.

One embodiment is a pharmaceutical composition comprising zoledronic acid, the oral bioavailability of zoledronic acid in dosage form is from about 0.01% to about 10%.

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 from 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 comprises from about 10 mg to about 300 mg of zoledronic acid and is administered daily for about 2 to about 15 consecutive days. This medication plan (regime) 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 a year or once every two years.

In some embodiments, the oral dosage form comprises from about 10 mg to about 150 mg or from about 10 mg to about 100 mg of zoledronic acid and is administered daily for about 2 to about 15 consecutive days. This medication plan (regime) 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 a year or once every two years.

In some embodiments, the oral dosage form comprises from about 10 mg to about 150 mg or from about 10 mg to about 100 mg zoledronic acid and is administered daily for about 5 to about 10 consecutive days. This medication plan (regime) 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 a year or once every two years.

In some embodiments, the oral dosage form comprises from about 40 mg to about 150 mg of zoledronic acid and is administered daily for about 5 to about 10 consecutive days. This medication plan (regime) 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 a year or once every two years.

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

Zoledronic acid can be formulated and formulated for oral administration, for example, with an inert diluent or edible carrier. Alternatively, it may be encapsulated in a hard or soft shell gelatin capsule, compressed in a tablet, or incorporated directly into the dietary food. For oral therapeutic administration, the active compound may be incorporated with excipients, orally ingested tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches. Can be used in such forms.

Tablets, troches, pills, capsules and the like may also contain one or more of the following: Binders such as tragacanth gum, 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 Sweeteners such as sucrose, or flavors such as peppermint, winter green oil or cherry flavors. If the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings, for example tablets, pills or capsules can be coated with shellac, sugar or both. The syrup or elixir may contain active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, pigments, and flavors such as cherry or orange flavors. It may be desired that the material in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amount used.

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

Zoledronic acid can be formulated for parenteral or intraperitoneal administration. Solutions of active compounds, such as free acids or pharmaceutically acceptable salts, can be prepared in water appropriately mixed with surfactants such as hydroxypropyl cellulose. The dispersion can also have oil dispersed in or in glycerol, liquid polyethylene glycol and mixtures thereof. Under normal storage and use conditions, these formulations may contain preservatives to prevent the growth of microorganisms.

In some embodiments, the oral dosage form may include silicified microcrystalline cellulose such as prosolve. 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) About 50% (wt / wt) of silicified microcrystalline cellulose from wt) may be present in the oral or oral dosage form unit.

In some embodiments, the oral dosage form may comprise crosslinked polyvinylpyrrolidone, such as crospovidone. For example, about 1% (wt / wt) to about 10% (wt / wt), about 1% (wt / wt) to about 5% (wt / wt), or about 1% (wt / wt) to about. 3% (wt / wt) crosslinked polyvinylpyrrolidone may be present in the oral or oral dosage form unit.

In some embodiments, the oral dosage form may 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). From wt / wt) to about 0.6% (wt / wt) of fumed silica may be present in the oral or oral dosage form unit.

In some embodiments, the oral dosage form may comprise 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). Approximately 0.6% (wt / wt) of magnesium stearate (wt / wt) may be present in the oral or oral dosage form unit.

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

Pharmaceutical products containing oral dosage forms for daily use can contain 28, 29, 30 or 31 units of such oral dosage forms for monthly supply. A supply of about 6 weeks for daily use can contain 40 to 45 units of the oral dosage form. A supply for about 3 months in daily use can contain 85-95 units of the oral dosage form. A supply for about 6 months in daily use can contain 170-200 units of the oral dosage form. A supply for about one year in daily use can contain 350 to 380 units of the oral dosage form.

Pharmaceutical products containing oral dosage forms used weekly may contain 4 or 5 units of such oral dosage form for monthly supply. A supply for about 2 months in weekly use can contain 8-9 units of the oral dosage form. A supply of about 6 weeks for weekly use can contain 6 units of the oral dosage form. A supply for about 3 months in weekly use can contain 12, 13 or 14 units of the oral dosage form. A supply for about 6 months in weekly use can contain 22 to 30 units of the oral dosage form. A supply for about one year of weekly use can contain 45 to 60 units of the oral dosage form.

Pharmaceutical products may be adapted to other dosing regimens. For example, a pharmaceutical product may contain 5 to 10 units of the oral dosage form, and each unit of the oral dosage form contains about 40 mg to about 150 mg of zoledronic acid. Some pharmaceutical products 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. In such products, each unit of the oral dosage form may be taken daily at the beginning of the month, eg, for 1 to 10 days or 5 to 10 days in a month.

Certain oral dosage forms, including zoledronic acid or salts thereof, may have an enteric coating or a film coating.

In the following examples, zoledronic acid was administered in disodium salt form as zoledronic acid disodium tetrahydrate. No bioavailability enhancer was used in the test composition.

Example 1
Effect of oral administration of zoledronic acid on a rat model of inflammatory pain Method The effect of oral administration of zoledronic acid on inflammatory pain was investigated using a rat complete Freund's adjuvant (CFA) model. Inflammatory pain was induced by injecting a 75 μL volume of 100% CFA into the left hind paw of Sprague-Dawley rats on day 0, followed by evaluation on days 1-3. .. For animals, daily on days 1 to 3, 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 freshly prepared daily. Animals were fasted prior to administration. Under current FDA guidelines for extrapolating starting doses from animals to humans, the 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, while 3 mg / kg in rats cannot be equivalent to 3 mg / kg in humans.

Obtained values of inflammatory pain (mechanical hyperalgesia) in solvent- and drug-treated animals at baseline and Post-treatment on days 0 before CFA infusion and days 1-3. It was. Pain was evaluated using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). Animals were placed in restraint slings, leaving the hind limbs used for the test. The foot compression threshold was measured by applying a pressure increase to the bottom of the hind paw using a dome-shaped tip located between the third and fourth metatarsals. The pressure was gradually applied over a period of about 10 seconds. Measurements were taken from the first observed defensive behavior of vocalization, struggle or withdrawal. A cutoff value of 300 g was used to prevent damage to the animals.

Recovery of inflammatory pain was calculated according to the following formula.
% Recovery = (Post-Treatment-Post-CFA Baseline) / (Pre-CFA Baseline-Post-CFA Baseline) x 100

Experiments were performed using 9 to 10 animals per group.

Results Oral administration of zoledronic acid significantly improved the threshold for inflammatory pain compared to the solvent. The pain thresholds measured at various times are shown in FIG. The foot compression threshold in the 18 mg / m ² group was higher than the solvent from 30 minutes after the start of treatment for the entire measurement period. On day 3, the foot compression thresholds in both the 18 mg / m ² and 900 mg / m ² groups were higher than in 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 commercially available clinical doses of NSAIDs when tested in similar models of inflammatory pain. Under current FDA guidelines, the reference body surface area for human adults 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 lower thresholds than the solvent in 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, with significant toxicity that forced euthanasia of all animals in this group 2 days after discontinuation. ..

Example 2
Effect of Oral Zoledronic Acid Administration in Rat Models of Arthritis Pain The effect of oral administration of zoledronic acid in arthritis pain was investigated in a complete Freund's Adjuvant (CFA) model of rats with arthritis pain. In this model, a 75 μL volume of 100% Complete Freund's Adjuvant (CFA) was injected into the left hind paw for a period of 10 to 14 days to develop arthritic pain. Animals were given three solvents (controls), 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 procedure. The dose was orally divided into equal daily doses. The drug was dissolved in distilled water and freshly prepared daily. Animals were fasted prior to administration.

Solvent and drug treatment Arthritis pain (mechanical hyperalgesia) in animals was treated with a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA) 14 after CFA infusion procedure. Evaluated on the day. Animals were placed in restraint slings, leaving the hind limbs used for the test. The foot compression threshold was measured by applying a pressure increase to the bottom of the hind paw using a dome-shaped tip located between the 3rd and 4th metatarsals. The pressure was gradually applied over a period of about 10 seconds. Measurements were taken from the first observed infringement defense behavior of vocalization, struggle or withdrawal. A cutoff value of 300 g was used to prevent damage to the animals.

Recovery of arthritic pain in the ipsilateral (CFA-injected) foot was calculated according to the following equation:
% Recovery = (ipsilateral 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 arthritic pain threshold compared to the solvent. As shown in FIGS. 2A and 2B, oral administration of zoledronic acid resulted in dose-dependent recovery of arthritic pain. 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 reference body surface area for human adults 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 Regional Pain Syndrome with Oral Administration of Zoledronic Acid The effect of oral administration of zoledronic acid was investigated in a rat tibial fracture model of complex regional pain syndrome (CRPS). CRPS, as disclosed by Guo TZ et al. (Pain. 2004; 108: 95-107), crushes and fractures the right distal tibia of a rat and molds the fractured hind paw in 4 weeks (casts). This led to rats. This animal model has been shown to reproduce the incitement trauma, natural history, signs, symptoms and pathological changes observed in human CRPS patients (Kingery WS et al., Pain. 2003; 104: 75). -84).

Starting on the day of fracture and molding, animals were orally administered either solvent (control) or zoledronic acid at a dose of 18 mg / m ² / day (3 mg / kg / day) for 28 days. The drug was dissolved in distilled water and administered by gastrointestinal nutrition. Animals were fasted 4 hours before and 2 hours after dosing. At the end of the 28-day period, the mold was removed and the next day rats were tested for hind paw pain, edema and warmth.

Pain evaluation Pain was evaluated by measuring hyperalgesia and weight bearing.

The up-down von Freytest paradigm was used to assess hyperalgesia. Rats were placed in a clear plastic cylinder (20 cm in diameter) with a wire mesh bottom and acclimatized for 15 minutes. Feet were tested using one of eight series of von Frey hairs in the stiffness range of 0.41 g to 15.14 g. Von Frey hair was applied approximately to the hind plantar skin in the midsole, taking care to avoid the ring pad. The fiber was pressed until it was slightly bent and then rocked in that position for 6 seconds. The stimulus was applied at intervals of a few seconds. The withdrawal of the hind legs from the fiber was considered to have been a positive reaction. The initial fiber presentation pressure was 2.1 g and the fibers were applied according to Dixon's up-down method so that 6 reactions occurred in the immediate vicinity of the 50% threshold. The stimulus was applied at intervals of a few seconds.

An in-capacitance device (IITC Inc. Life Sciences Woodland, CA, USA) was used to measure hindfoot weight load and postural effects of pain. With the hind paw stationary on separate metal scale plates, the rat was manually held in a vertical position across the device to support the entire weight of the rat on the hind paw. The duration of each measurement was 6 seconds, and 10 consecutive measurements were taken at 60 second intervals. Eight measurements (excluding the highest and lowest) were averaged to calculate bilateral hindfoot weight loadings. The weight load data was analyzed as the ratio of the hind paw weight load 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 the baseline test, tattoos of 2-3 mm spots were placed on both hind paws on the dorsal skin beyond the midpoint of the third metatarsal bone. In laser measurements, each rat was briefly anesthetized with isoflurane and then held vertically on the upper table under the laser so that the hind paws were resting. 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, a laser with a ranging sensor is used to measure the distance to the top of the table and the top of the hind paw at the tattooed area, and the distance is the dorsal-ventral paw. Used to calculate the thickness. The measurement sensor devices used in this experiment (4381 Precicura, Limab, Gothenburg, Sweden) have a measurement range of 200 mm with a resolution of 0.01 mm.

Hindfoot temperature measurement Hindfoot temperature was measured using a thin thermocouple (Omega, Standford, CT, USA) applied to the skin of the foot. Six sites were tested per hind paw. Six measurements on each hind paw were averaged as average temperature.

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

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

As shown in FIG. 5, the reductions in body weight loading and postural effects of pain were significantly greater in the solvent-treated group than in the zoledronic acid-treated group. Weight loading in the hind limbs of the fracture was reduced to 55% of normal in the solvent treated group. Zoledronic acid treatment significantly restored hindlimb weight load compared to solvent treatment (86% of normal).

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

Zoledronic acid reduced hindfoot warmth by 5% with respect to solvent treatment.

The daily dose in the above experiment was 18 mg / m ² / day. Under current FDA guidelines, the reference body surface area for human adults 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
Sodium solubility of zoledronic acid disodium salt The water solubility of zoledronic acid and disodium zoledronic acid tetrahydrate was measured. 1 gram of test compound was measured in a beaker. Then, desalinated water (pH 5.5) was added little by little to the test compound, and sonication was applied to the mixture. The procedure was continued until it was completely dissolved. It was determined that complete dissolution was reached when there were no visible substances 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 disodium zoledronic acid tetrahydrate is about 50 times that of zoledronic acid. Zoledronic acid disodium tetrahydrate has a solubility of 12.5 g / 100 mL as 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 a disodium salt of zoledronic acid (disodium zoledronic acid tetrahydrate) were produced. Both types of tablets had a zoledronic acid equivalent of 50 mg per tablet. The same excipient was used in both types of tablets in an amount prepared taking into account the difference in molecular weight between the acid and the disodium salt.

Tablets with a zoledronic acid equivalent of 150 mg, either in the form of disodium zoledronic acid (Group 1) or in the form of pure zoledronic acid (Greep 2), were orally administered to beagle dogs. Each animal was given three 50 mg equivalent tablets (150 mg total), which were administered together. The animal's oral cavity was moistened with water before placing the tablet on the back under the animal. Animals were fasted before and after administration. Animals weighed 6 to 10 kg 6 to 9 months of age on the day of administration. There were 3 dogs per group.

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

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

Disodium zoledronic acid produced much higher plasma concentrations of zoledronic acid than pure zoledronic acid and showed improved oral absorption in salt form. Measured using peak plasma concentration ( _maximum C), the disodium salt resulted in a de facto 119% increase in bioavailability and a 74% weight adjustment increase in bioavailability compared to pure zoledronic acid. Bioavailability was measured using the area under the plasma concentration curve (AUC _0-inf ), with the disodium salt being 84% and 46% greater than pure zoledronic acid, respectively, in effect and by weight adjustment criteria. The average AUC _0-∞ of the disodium 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 the dogs tested, about 3 mg to about 4 mg of disodium salt is expected to yield about 100 ng · hour / mL AUC _0-∞ , about 7 mg to about 8 mg of disodium. Salt would be expected to result in an AUC of about 200 ng · hour / mL _0-∞ .

The excretion half-life of dogs receiving a 150 mg acid equivalent of disodium salt was 20.5 ± 5.2 hours.

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

The following embodiments are specifically intended.
(Embodiment 1)
A way to relieve inflammatory pain
Including administration of an oral dosage form containing zoledronic acid to a mammal in need thereof.
A method in which the mammal receives a total monthly dose of zoledronic acid, which is about 800 mg / m ² or less, based on the body surface area of the mammal.
(Embodiment 2)
The method of embodiment 1, wherein the mammal is a human receiving a total monthly dose of zoledronic acid ranging from about 30 mg / m ² to about 700 mg / m ² .
(Embodiment 3)
The method according to embodiment 2, wherein the total monthly dose is administered in 4 or 5 weekly doses.
(Embodiment 4)
The method according to embodiment 2, wherein the total monthly dose is administered at a daily dose of 28 to 31 times.
(Embodiment 5)
The method of embodiment 2, wherein the total monthly dose is administered in unit doses of 5 to 10 times during the month.
(Embodiment 6)
The method of embodiment 1, wherein the mammal is a human receiving a total weekly dose of about 10 mg to about 300 mg of zoledronic acid.
(Embodiment 7)
The method according to 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 weekly total dose is administered in unit doses of 2 to 7 times during the week.
(Embodiment 9)
The method of embodiment 1, wherein the mammal is a human receiving a total weekly dose of about 10 mg to about 150 mg of zoledronic acid.
(Embodiment 10)
The method according to any one of embodiments 1-9, wherein the mammal experiences significant pain relief 3 hours after administration of the dosage form.
(Embodiment 11)
10. The method of embodiment 10, wherein the mammal experiences significant pain relief for at least one portion of the time from about 3 hours to about 24 hours after administration of the dosage form.
(Embodiment 12)
10. The method of embodiment 10, wherein the mammal experiences significant pain relief for at least one portion of the time from about 3 hours to about 3 weeks after administration of the dosage form.
(Embodiment 13)
A way to relieve inflammatory pain
Including administration of an oral dosage form containing zoledronic acid to a mammal in need thereof.
The method, wherein the oral dosage form contains from about 10 mg / m ² to about 20 mg / m ² of zoledronic acid, based on the body surface area of the mammal.
(Embodiment 14)
13. The method of embodiment 13, wherein the oral dosage form contains from about 15 mg / m ² to about 20 mg / m ² of zoledronic acid, based on the body surface area of the mammal.
(Embodiment 15)
A way to relieve inflammatory pain
A method comprising orally administering to a mammal in need thereof about 300 mg / m ² to about 600 mg / m ² of zoledronic acid per month based on the body surface area of the mammal.
(Embodiment 16)
13. The method of embodiment 15, wherein the mammal is orally administered with about 450 mg / m ² to about 600 mg / m ² of zoledronic acid per month based on the body surface area of the mammal.
(Embodiment 17)
The method according to any one of embodiments 1-16, wherein the mammal does not suffer from bone metastasis.
(Embodiment 18)
The method according to any one of embodiments 1-17, wherein the mammal does not suffer from cancer.
(Embodiment 19)
The method according to any one of embodiments 1-18, wherein the zoledronic acid is administered as a salt of the dianion of zoledronic acid.
(Embodiment 20)
A way to relieve pain associated with arthritis
A method comprising administering an oral dosage form containing zoledronic acid to a person in need thereof.
(Embodiment 21)
20. The method of embodiment 20, wherein the human receives a total monthly dose of zoledronic acid, which is about 40 mg to about 2000 mg.
(Embodiment 22)
21. The method of embodiment 21, wherein the total monthly dose is administered in 4 or 5 weekly doses.
(Embodiment 23)
21. The method of embodiment 21, wherein the total monthly dose is administered at a daily dose of 28 to 31 times.
(Embodiment 24)
21. The method of embodiment 21, wherein the total monthly dose is administered in unit doses of 5 to 10 times during the month.
(Embodiment 25)
20. The method of embodiment 20, wherein the human receives a total weekly dose of about 100 mg to about 300 mg of zoledronic acid.
(Embodiment 26)
25. The method of embodiment 25, wherein the total weekly dose is a single dose and is administered once a week.
(Embodiment 27)
25. The method of embodiment 25, wherein the weekly total dose is administered in unit doses of 2 to 7 times during the week.
(Embodiment 28)
20. The method of embodiment 20, wherein the human receives a total weekly dose of about 10 mg to about 100 mg of zoledronic acid.
(Embodiment 29)
The method according to any one of embodiments 20-28, wherein the human experiences significant pain relief after 3 hours after administration of the dosage form.
(Embodiment 30)
29. The method of embodiment 29, wherein the human experiences significant pain relief for at least one portion of the time from about 3 hours to about 24 hours after administration of the dosage form.
(Embodiment 31)
29. The method of embodiment 29, wherein the human experiences significant pain relief for at least one portion of the time from about 3 hours to about 3 weeks after administration of the dosage form.
(Embodiment 32)
The method according to any one of embodiments 20-31, wherein the dosage form contains about 10 mg / m ² to about 20 mg / m ² of zoledronic acid based on the human body surface area.
(Embodiment 33)
32. The method of embodiment 32, wherein the dosage form contains about 15 mg / m ² to about 20 mg / m ² of zoledronic acid based on the human body surface area.
(Embodiment 34)
The method according to any one of embodiments 20-33, wherein about 50 mg / m ² to about 200 mg / m ² of zoledronic acid is orally administered per month based on the human body surface area.
(Embodiment 35)
The method according to any one of embodiments 20-31, wherein the dosage form contains about 80 mg / m ² to about 150 mg / m ² of zoledronic acid based on the human body surface area.
(Embodiment 36)
Based on body surface area of said human, one month zoledronic acid per month to about 300 mg / ^{m 2} to about 1000 mg / ^{m 2} is administered orally, method of embodiment 35.
(Embodiment 37)
The method according to any one of embodiments 20-36, wherein the human does not suffer from bone metastasis.
(Embodiment 38)
The method according to any one of embodiments 20-37, wherein the human does not suffer from cancer.
(Embodiment 39)
The method according to any one of embodiments 1-38, wherein the zoledronic acid is in the form of a disodium salt.
(Embodiment 40)
Contains zoledronic acid
The oral bioavailability of zoledronic acid in the dosage form is from about 0.01% to about 4%, the oral dosage form.
(Embodiment 41)
The oral dosage form of embodiment 40, comprising from about 10 mg to about 300 mg of zoledronic acid.
(Embodiment 42)
The oral dosage form of embodiment 40, comprising from about 10 mg to about 50 mg of zoledronic acid.
(Embodiment 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)
A pharmaceutical product comprising a plurality of units of the oral dosage form according to embodiment 40.
(Embodiment 45)
The pharmaceutical product according to embodiment 44, wherein each unit of the oral dosage form contains from 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 the oral dosage form for zoledronic acid administered in a total of about 28 mg to about 1600 mg over a period of about one month.
(Embodiment 47)
The pharmaceutical product according to embodiment 45, comprising 85 to 95 units of the 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 the oral dosage form for zoledronic acid administered in a total of about 170 mg to about 10000 mg over a period of about 6 months.
(Embodiment 49)
The pharmaceutical product according to embodiment 45, comprising 350 to 380 units of the oral dosage form for zoledronic acid administered in a total of about 350 mg to about 19000 mg in about one 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 the oral dosage form for zoledronic acid administered in total from about 40 mg to about 1500 mg over a period of about 1 month.
(Embodiment 52)
The pharmaceutical product according to embodiment 50, comprising 8 or 9 units of the oral dosage form for zoledronic acid administered in a total of about 80 mg to about 2700 mg over a period of about 2 months.
(Embodiment 53)
The pharmaceutical product according to embodiment 50, comprising 12, 13 or 14 units of the oral dosage form for zoledronic acid administered in a total of about 120 mg to about 4200 mg over a period of about 3 months.
(Embodiment 54)
50. The pharmaceutical product of embodiment 50, comprising 22 to 30 units of the 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)
50. The pharmaceutical product of embodiment 50, comprising 45 to 60 units of the oral dosage form for zoledronic acid administered in a total of about 450 mg to about 18000 mg in about one year.
(Embodiment 56)
Contains 1 to 10 units of the oral dosage form
The pharmaceutical product according to embodiment 44, wherein the 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 to 43, wherein the zoledronic acid is in the form of a sodium salt.
(Embodiment 58)
The oral dosage form according to any one of embodiments 40-43 or 57, wherein the zoledronic acid has a water solubility greater than 1% (w / v).
(Embodiment 59)
The oral preparation according to any one of embodiments 40 to 43, 57 or 58, wherein the zoledronic acid has a water solubility of about 5% (w / v) to about 50% (w / v). form.
(Embodiment 60)
Contains zoledronic acid and excipients
The zoledronic acid is an oral dosage form in which it has a water solubility greater than 1% (w / v).
(Embodiment 61)
The oral dosage form according to embodiment 60, wherein the zoledronic acid has a water solubility of about 5% (w / v) to about 50% (w / v).
(Embodiment 62)
A method of treating complex regional pain syndrome
A method comprising administering an oral dosage form containing zoledronic acid to a mammal in need thereof.
(Embodiment 63)
62. The method of embodiment 62, wherein the mammal is a human receiving an amount of zoledronic acid ranging from about 30 mg / m ² to about 700 mg / m ² over a period of less than one month.
(Embodiment 64)
63. The method of embodiment 63, wherein 4 or 5 weekly doses are administered for a period of up to 1 month.
(Embodiment 65)
The method of embodiment 63, wherein the daily doses of 28 to 31 times are administered within a period of one month.
(Embodiment 66)
63. The method of embodiment 63, wherein a dose of 5 to 10 units is administered for a period of up to 1 month.
(Embodiment 67)
63. The method of embodiment 63, wherein zoledronic acid of about 30 mg / m ² to about 700 mg / m ² is administered for only one month.
(Embodiment 68)
63. The method of embodiment 63, wherein about 30 mg / m ² to about 700 mg / m ² of zoledronic acid is administered continuously for 2 months or longer and within 1 month.
(Embodiment 69)
62. The method of embodiment 62, wherein the mammal receives about 10 mg / m ² to about 30 mg / m ² of zoledronic acid daily.
(Embodiment 70)
62. The method of embodiment 62, wherein the mammal is a human receiving a total weekly dose of about 10 mg to about 300 mg of zoledronic acid.
(Embodiment 71)
The method according to embodiment 70, wherein the total weekly dose is a single dose and is administered once a week.
(Embodiment 72)
The method of embodiment 70, wherein the weekly total dose is administered in unit doses of 2 to 7 times during the week.
(Embodiment 73)
The method according to any one of embodiments 62 to 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 to 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 the zoledronic acid is in salt form.
(Embodiment 76)
The method according to any one of embodiments 62-75, wherein the dosage form contains about 10 mg / m ² to about 20 mg / m ² of zoledronic acid based on the body surface area of the mammal.
(Embodiment 77)
The method of embodiment 76, wherein the dosage form contains from about 15 mg / m ² to about 20 mg / m ² of zoledronic acid based on the body surface area of the mammal.
(Embodiment 78)
A method of treating complex regional pain syndrome
A method comprising administering pamidronic acid to a person in need thereof.
(Embodiment 79)
A method of treating complex regional pain syndrome
A method comprising administering neridronic acid to a person in need thereof.
(Embodiment 80)
A method of treating complex regional pain syndrome
A method comprising administering orpadronic acid to a person in need thereof.
(Embodiment 81)
A method of treating complex regional pain syndrome
A method comprising administering alendronic acid to a person in need thereof.
(Embodiment 82)
A method of treating complex regional pain syndrome
A method comprising administering incadronic acid to a person in need thereof.
(Embodiment 83)
A method of treating complex regional pain syndrome
A method comprising administering ibandronic acid to a person in need thereof.
(Embodiment 84)
A method of treating complex regional pain syndrome
A method comprising administering risedronic acid to a person in need thereof.
(Embodiment 85)
A way to treat pain
A method comprising administering pamidronic acid to a person in need thereof.
(Embodiment 86)
A way to treat pain
A method comprising administering neridronic acid to a person in need thereof.
(Embodiment 87)
A way to treat pain
A method comprising administering orpadronic acid to a person in need thereof.
(Embodiment 88)
A way to treat pain
A method comprising administering alendronic acid to a person in need thereof.
(Embodiment 89)
A way to treat pain
A method comprising administering incadronic acid to a person in need thereof.
(Embodiment 90)
A way to treat pain
A method comprising administering ibandronic acid to a person in need thereof.
(Embodiment 91)
A way to treat pain
A method comprising administering risedronic acid to a person in need thereof.
(Embodiment 92)
A way to treat arthritic pain
A method comprising administering pamidronic acid to a person in need thereof.
(Embodiment 93)
A way to treat arthritic pain
A method comprising administering neridronic acid to a person in need thereof.
(Embodiment 94)
A way to treat arthritic pain
A method comprising administering orpadronic acid to a person in need thereof.
(Embodiment 95)
A way to treat arthritic pain
A method comprising administering alendronic acid to a person in need thereof.
(Embodiment 96)
A way to treat arthritic pain
A method comprising administering incadronic acid to a person in need thereof.
(Embodiment 97)
A way to treat arthritic pain
A method comprising administering ibandronic acid to a person in need thereof.
(Embodiment 98)
A way to treat arthritic pain
A method comprising administering risedronic acid to a person in need thereof.
(Embodiment 99)
A way to treat inflammatory pain
A method comprising administering pamidronic acid to a person in need thereof.
(Embodiment 100)
A way to treat inflammatory pain
A method comprising administering neridronic acid to a person in need thereof.
(Embodiment 101)
A way to treat inflammatory pain
A method comprising administering orpadronic acid to a person in need thereof.
(Embodiment 102)
A way to treat inflammatory pain
A method comprising administering alendronic acid to a person in need thereof.
(Embodiment 103)
A way to treat inflammatory pain
A method comprising administering incadronic acid to a person in need thereof.
(Embodiment 104)
A way to treat inflammatory pain
A method comprising administering ibandronic acid to a person in need thereof.
(Embodiment 105)
A way to treat inflammatory pain
A method comprising administering risedronic acid to a person in need thereof.
(Embodiment 106)
A method of treating complex regional pain syndrome
A method comprising administering etidronic acid to a person in need thereof.
(Embodiment 107)
A way to treat pain
A method comprising administering etidronic acid to a person in need thereof.
(Embodiment 108)
A way to treat arthritic pain
A method comprising administering etidronic acid to a person in need thereof.
(Embodiment 109)
A way to treat inflammatory pain
A method comprising administering etidronic acid to a person in need thereof.
(Embodiment 110)
A method of treating complex regional pain syndrome
A method comprising administering clodronic acid to a person in need thereof.
(Embodiment 111)
A way to treat pain
A method comprising administering clodronic acid to a person in need thereof.
(Embodiment 112)
A way to treat arthritic pain
A method comprising administering clodronic acid to a person in need thereof.
(Embodiment 113)
A way to treat inflammatory pain
A method comprising administering clodronic acid to a person in need thereof.
(Embodiment 114)
A method of treating complex regional pain syndrome
A method comprising administering tildronic acid to a person in need thereof.
(Embodiment 115)
A way to treat pain
A method comprising administering tildronic acid to a person in need thereof.
(Embodiment 116)
A way to treat arthritic pain
A method comprising administering tildronic acid to a person in need thereof.
(Embodiment 117)
A way to treat inflammatory pain
A method comprising administering tildronic acid to a person in need thereof.
(Embodiment 118)
The method according to any one of embodiments 78 to 117, wherein the active compound is orally administered.
(Embodiment 119)
The method according to 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, which comprises oral administration of a dosage form containing zoledronic acid in the form of a disodium salt.
(Embodiment 121)
The zoledronic acid in the disodium salt form, as compared to the zoledronic acid in the diacid form, is a bioavailability that facilitates enhancements to any bioavailability provided by any bioavailability enhancer in the dosage form. 120. The method of embodiment 120, which provides an enhancement against.
(Embodiment 122)
The method of embodiment 120, wherein the dosage form is substantially free of bioavailability enhancers.
(Embodiment 123)
The zoledronic acid in the disodium salt form is a zoledronic acid plasma concentration curve of about 4 ng · hour / mL to about 2000 ng · hour / mL each time the zoledronic acid in the disodium salt form is administered to the mammal. 120. The method of embodiment 120, wherein the mammal is administered in an amount that provides a lower area.
(Embodiment 124)
The zoledronic acid in the disodium salt form is a plasma concentration curve of zoledronic acid from about 100 ng · hour / mL to about 2000 ng · hour / mL each time the zoledronic acid in the disodium salt form is administered. 12. The method of embodiment 123, which is administered at intervals of about 3 to about 4 weeks in an amount that provides a lower area.
(Embodiment 125)
The zoledronic acid in the disodium salt form is below the plasma concentration curve of zoledronic acid from about 20 ng · hour / mL to about 700 ng · hour / mL each time the zoledronic acid in the disodium form is administered. 12. The method of embodiment 123, which is administered 3 to 5 times weekly or monthly in an amount that provides area.
(Embodiment 126)
The zoledronic acid in the disodium salt form is a plasma concentration curve of zoledronic acid from about 4 ng · hour / mL to about 100 ng · hour / mL each time the zoledronic acid in the disodium salt form is administered. 12. The method of embodiment 123, which is administered daily in an amount that provides a lower area.
(Embodiment 127)
The method of embodiment 120, wherein the dosage form is solid.
(Embodiment 128)
The method according to 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)
An embodiment further comprising administering on a molar basis, in a smaller amount than the amount of zoledronic acid in the diacid form, in the form of the disodium salt, in order to achieve the same plasma concentration of zoledronic acid. 120, 121, 122, 123, 124, 125, 126, 127 or 128.
(Embodiment 130)
129. Embodiment 129, wherein an amount of at least about 10 mol% less than the amount of zoledronic acid in said diacid form administered is administered in order to achieve the same plasma concentration of zoledronic acid. the method of.
(Embodiment 131)
The disodium salt form, on a molar basis, is administered in an amount from about 0.8n _d has a value of about 1.2 N _d,
satisfies n _d = a _{(b a / b d) (} n a),
b _a is the bioavailability in the diacid form, b _d is the bioavailability in the disodium salt form, and n _a is the said dosed to achieve the same plasma concentration of zoledronic acid. 129. The method of embodiment 129, which is the number of moles of zoledronic acid in the diacid form.
(Embodiment 132)
The disodium salt is administered in an amount having a value of approximately n _d, method of embodiment 131.
(Embodiment 133)
The method according to any one of embodiments 120 to 132, wherein the zoledronic acid is used to treat inflammatory symptoms.
(Embodiment 134)
13. The method of embodiment 133, wherein the zoledronic acid is used to treat arthritis.
(Embodiment 135)
13. The method of embodiment 133, wherein zoledronic acid is used to treat complex regional pain syndrome.
(Embodiment 136)
Zoledronic acid is for the treatment of inflammatory symptoms, arthritis, or complex regional pain syndrome.
The first oral dosage form was administered
A second oral dosage form was administered
With respect to the first oral dosage form, the second oral dosage form is administered at 10 × T _up above, T _maximum, the first oral dosage form is for a period of time the maximum plasma concentration, Embodiment 1 39, 62 to 77 and 120 to 135 according to any one of the methods.
(Embodiment 137)
The bioavailability of zoledronic acid in the disodium salt form in mammals is greater than the bioavailability of zoledronic acid in the diacid form of the same dosage form, comprising the zoledronic acid in the disodium salt form.
(Embodiment 138)
A dosage form containing zoledronic acid in the form of the disodium salt.
The dosage form of the zoledronic acid in the disodium salt form provides an area under the plasma concentration curve of zoledronic acid of about 4 ng · hour / mL to about 2000 ng · hour / mL for the human to whom the dosage form is administered. Dosage form, including quantity.
(Embodiment 139)
The dosage form comprises the amount of zoledronic acid in the disodium salt form that provides the area under the plasma concentration curve of zoledronic acid from about 100 ng · hour / mL to about 2000 ng · hour / mL to the person to whom the dosage form is administered. , The dosage form according to embodiment 138.
(Embodiment 140)
The dosage form comprises the amount of zoledronic acid in the disodium salt form that provides the area under the plasma concentration curve of zoledronic acid from about 20 ng · hour / mL to about 700 ng · hour / mL to the person to whom the dosage form is administered. , The dosage form according to embodiment 138.
(Embodiment 141)
The dosage form comprises the amount of zoledronic acid in the disodium salt form that provides the area under the plasma concentration curve of zoledronic acid from about 4 ng · hour / mL to about 100 ng · hour / mL to the person to whom the dosage form is administered. , The dosage form according to embodiment 138.
(Embodiment 142)
A dosage form containing the diacid form of zoledronic acid.
The disodium salt form is present in a smaller molar amount than would exist if the zoledronic acid was assumed to be in the diacid form, and the zoledronic acid in the disodium salt form is more than the dosage form. An agent having improved bioavailability as compared to the zoledronic acid form of the diacid form to the extent that even a small molar amount of the disodium salt does not reduce the amount of zoledronic acid delivered to the mammalian plasma. form.
(Embodiment 143)
The dosage form according to embodiment 137, 138, 139, 140, 141 or 142, wherein the dosage form is solid.
(Embodiment 144)
13. The bioavailability of zoledronic acid in the sodium diacid form is improved by at least about 10% as compared to other identical dosage forms containing zoledronic acid in the diacid form, according to embodiment 142 or 143. Dosage form.
(Embodiment 145)
Embodiments 142, 143 or comprising the disodium salt form which is at least about 20 mol% lower than the amount of zoledronic acid in the diacid form present when the zoledronic acid is assumed to be in the diacid form. The dosage form according to 144.
(Embodiment 146)
The disodium salt form, on a molar basis, present in an amount from about 0.9n _d has a value of about 1.1 N _d,
satisfies n _d = a _{(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, when the zoledronic acid is assumed to the diacids forms The dosage form according to embodiment 142, which is the number of moles of the diacid form present.
(Embodiment 147)
The disodium salt form is administered in an amount having a value of approximately n _d, dosage form according to embodiment 146.
(Embodiment 148)
Zoledronic acid is for the treatment of inflammatory symptoms, arthritis, or complex regional pain syndrome.
The oral dosage form is given only once, or
The first oral dosage form is administered, followed by the first oral dosage form and the second oral dosage form.
The second oral dosage form is administered before the maximum pain-relieving effect of the first oral dosage form is achieved, or the second oral dosage form is administered before the observable pain-relieving effect is achieved. The method according to any one of embodiments 1 to 39, 62 to 77 and 120 to 136.
(Embodiment 149)
148. The method of embodiment 148, wherein the second oral dosage form is administered before an observable pain-relieving effect is achieved.
(Embodiment 150)
Zoledronic acid is for the treatment of inflammatory symptoms, arthritis, or complex regional pain syndrome.
The first oral dosage form is administered, followed by the second oral dosage form,
The second oral dosage form is administered after the maximum pain-relieving effect of the first oral dosage form is achieved, and the second oral dosage form can observe the pain-relieving effect from the first oral dosage form. The method according to any one of 1 to 39, 62 to 77 and 120 to 132, which is administered in the meantime.
(Embodiment 151)
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)
The method according to any one of embodiments 20 to 39, wherein the human is about 30 to about 75 years old.
(Embodiment 153)
The method according to any one of embodiments 20 to 39, wherein the human is about 1 to about 16 years old.
(Embodiment 154)
The method according to any one of embodiments 20 to 39, wherein the human is about 80 to about 95 years old.
(Embodiment 155)
The method of any one of embodiments 20-39, wherein the human has been suffering from arthritis for at least 2 months.
(Embodiment 156)
The method of any one of embodiments 20-39, wherein the arthritis affects the knees, elbows, fingers, wrists, shoulders, or hips.
(Embodiment 157)
From Embodiments 1-44, 62-133 and 144, wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 1 hour prior to administration of the zoledronic acid. The method according to any one of 156.
(Embodiment 158)
157. The method of embodiment 157, wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 2 hours prior to administration of the zoledronic acid.
(Embodiment 159)
157. The method of embodiment 157, wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 4 hours prior to administration of the zoledronic acid.
(Embodiment 160)
157. The method of embodiment 157, wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 6 hours prior to administration of the zoledronic acid.
(Embodiment 161)
157-160 according to any one of embodiments 157-160, wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 30 minutes after administration of zoledronic acid. Method.
(Embodiment 162)
161. The method of embodiment 161 wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank a drink for at least 1 hour after administration of zoledronic acid.
(Embodiment 163)
161. The method of embodiment 161 wherein the mammal or human to whom zoledronic acid is administered has not eaten or drank food for at least 2 hours after administration of zoledronic acid.
(Embodiment 164)
The method, dosage form or product according to any one of embodiments 1 to 163, wherein the zoledronic acid in the oral dosage form has a 24-hour sustained plasma concentration factor of about 1 or more.
(Embodiment 165)
The oral dosage form of zoledronic acid according to any one of embodiments 1 to 164, wherein the zoledronic acid has a 24-hour plasma concentration factor that is higher than the intravenously administered 24-hour plasma concentration factor of zoledronic acid. Method, dosage form or product.
(Embodiment 166)
The method, dosage form, or product according to 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)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the zoledronic acid is from about 50 ng · hour / mL to about 50 ng · hour / mL in administration of the oral dosage form to the particular species. The method, dosage form, or product according to any one of embodiments 1 to 166, which is present in an amount that results in an AUC of 700 ng · hour / mL zoledronic acid.
(Embodiment 168)
167. The method of embodiment 167, wherein the zoledronic acid is present in an amount that results in an AUC of about 130 ng · hour / mL to about 180 ng · hour / mL of the zoledronic acid upon administration of the oral dosage form to the particular species. Dosage form or product.
(Embodiment 169)
167. The method of embodiment 167, wherein the zoledronic acid is present in an amount that results in an AUC of about 300 ng · hour / mL to about 450 ng · hour / mL of the zoledronic acid upon administration of the oral dosage form to the particular species. Dosage form or product.
(Embodiment 170)
167. The method of embodiment 167, wherein the zoledronic acid is present in an amount that results in an AUC of about 300 ng · hour / mL to about 350 ng · hour / mL of the zoledronic acid upon administration of the oral dosage form to the particular species. Dosage form or product.
(Embodiment 171)
167. The method of embodiment 167, wherein the zoledronic acid is present in an amount that results in an AUC of about 370 ng · hour / mL to about 420 ng · hour / mL of the zoledronic acid upon administration of the oral dosage form to the particular species. Dosage form or product.
(Embodiment 172)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the zoledronic acid is from about 5 ng / mL to about 300 ng / mL in administration of the oral dosage form to a particular species. The method, dosage form, or product according to any one of embodiments 1 to 171 that is present in an amount that results in the C _maximum of zoledronic acid.
(Embodiment 173)
The method, dosage form, or dosage form according to embodiment 172, wherein the zoledronic acid is present in an amount that results in a C _maximal amount of about 5 ng / mL to about 50 ng / mL of zoledronic acid upon administration of the oral dosage form to a particular species. Product.
(Embodiment 174)
The zoledronic acid according to any one of embodiments 1 to 171 which is present in an amount that results in a C _maximal amount of about 50 ng / mL to about 200 ng / mL of zoledronic acid upon administration of the oral dosage form to a particular species. Method, dosage form, or product.
(Embodiment 175)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that administration of the oral dosage form to the particular species of mammal is about 0. The method, dosage form, or product according to any one of embodiments 1 to 174, which is configured to provide a T- _maximum of zoledronic acid for 4 to about 1 hour.
(Embodiment 176)
The method of embodiment 175, wherein the oral dosage form is configured such that administration of the oral dosage form to said particular species of mammal results in a T _maximal of zoledronic acid for about 0.5 hours. Dosage form or product.
(Embodiment 177)
The method of embodiment 175, wherein the oral dosage form is configured such that administration of the oral dosage form to said particular species of mammal results in a T _maximal of zoledronic acid for about 0.75 hours. Dosage form or product.
(Embodiment 178)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that zoledronic acid is about 12 to about 50 for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 177, which is configured to have a 12-hour sustained plasma concentration factor.
(Embodiment 179)
The method, agent according to embodiment 178, wherein the oral dosage form is configured such that zoledronic acid has a 12-hour sustained plasma concentration factor of about 20 to about 40 for the particular species of mammal. Shape, or product.
(Embodiment 180)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that zoledronic acid is about 10 to about 30 for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 179, which is configured to have a 24-hour sustained plasma concentration factor.
(Embodiment 181)
The method, agent according to embodiment 180, wherein the oral dosage form is configured such that zoledronic acid has a 24-hour sustained plasma concentration factor of about 10 to about 20 for the particular species of mammal. Shape, or product.
(Embodiment 182)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that zoledronic acid is about 6 to about 20 for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 181, which is configured to have a 36-hour sustained plasma concentration factor.
(Embodiment 183)
The method, agent according to embodiment 182, wherein the oral dosage form is configured such that zoledronic acid has a 36-hour sustained plasma concentration factor of about 8 to about 15 for the particular species of mammal. Shape, or product.
(Embodiment 184)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that zoledronic acid is about 5 to about 20 for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 183, which is configured to have a 48-hour sustained plasma concentration factor.
(Embodiment 185)
The method, agent according to embodiment 184, wherein the oral dosage form is configured such that zoledronic acid has a 48-hour sustained plasma concentration factor of about 6 to about 15 for the particular species of mammal. Shape, or product.
(Embodiment 186)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is such that zoledronic acid is about 4 to about 20 for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 186, which is configured to have a 72-hour sustained plasma concentration factor.
(Embodiment 187)
The method, agent according to embodiment 186, wherein the oral dosage form is configured such that zoledronic acid has a 72-hour sustained plasma concentration factor of about 5 to about 10 for the particular species of mammal. Shape, or product.
(Embodiment 188)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is from about 0.5 ng / mL to about 5 ng of the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 187, which is configured to have a plasma concentration of zoledronic acid at / mL for 12 hours.
(Embodiment 189)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is from about 0.2 ng / mL to about 2 ng of the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 188, which is configured to have a plasma concentration of zoledronic acid at / mL for 24 hours.
(Embodiment 190)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is from about 0.1 ng / mL to about 2 ng for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 189, which is configured to have a plasma concentration of zoledronic acid at / mL for 36 hours.
(Embodiment 191)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is from about 0.1 ng / mL to about 2 ng for the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 190, which is configured to have a plasma concentration of zoledronic acid at / mL for 48 hours.
(Embodiment 192)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form is from about 0.2 ng / mL to about 1 ng of the particular species of mammal. The method, dosage form, or product according to any one of embodiments 1 to 191 which is configured to have a plasma concentration of zoledronic acid at 72 hours / mL.
(Embodiment 193)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form has the elimination half-life of zoledronic acid in the particular species of mammal of about 30. The method, dosage form, or product according to any one of embodiments 1 to 192, which is configured to be about 100 hours from time.
(Embodiment 194)
The oral dosage form containing zoledronic acid comprises a dose and form suitable for a particular species of mammal, and the oral dosage form has the elimination half-life of zoledronic acid in the particular species of mammal of about 40. The method, dosage form, or product according to any one of embodiments 1 to 193, which is configured to be about 60 hours from time.
(Embodiment 195)
An oral dosage form containing zoledronic acid having the appropriate dose and form for a particular species of mammal.
The amount of zoledronic acid such that the administration of the oral dosage form to the particular species of mammal provides an area under the plasma concentration curve (AUC) of zoledronic acid from about 50 ng · hour / mL to about 700 ng · hour / mL. An oral dosage form present in.
(Embodiment 196)
The zoledronic acid is present in an amount such that it provides an area under the AUC of zoledronic acid from about 130 ng · hour / mL to about 180 ng · hour / mL in administration of the oral dosage form to said particular species of mammal. The oral dosage form according to form 195.
(Embodiment 197)
The zoledronic acid is present in an amount such that it provides an area under the AUC of zoledronic acid from about 300 ng · hour / mL to about 450 ng · hour / mL in administration of the oral dosage form to said particular species of mammal. The oral dosage form according to form 195.
(Embodiment 198)
The zoledronic acid is present in an amount such that it provides an area under the AUC of zoledronic acid from about 300 ng · hour / mL to about 350 ng · hour / mL in administration of the oral dosage form to said particular species of mammal. The oral dosage form according to form 195.
(Embodiment 199)
The zoledronic acid is present in an amount such that it provides an area under the AUC of zoledronic acid from about 370 ng · hour / mL to about 420 ng · hour / mL in administration of the oral dosage form to said particular species of mammal. The oral dosage form according to form 195.
(Embodiment 200)
An oral dosage form containing zoledronic acid having the appropriate dose and form for a particular species of mammal.
The oral dosage form in which the zoledronic acid is present in an amount that results in a C _maximal of about 5 ng / mL to about 300 ng / mL of zoledronic acid upon administration of the oral dosage form to said particular species of mammal.
(Embodiment 201)
20. The embodiment 200, wherein the zoledronic acid is present in an amount such that it results in a C _maximal of about 5 ng / mL to about 50 ng / mL of zoledronic acid upon administration of the oral dosage form to the particular species of mammal. Oral dosage form.
(Embodiment 202)
20. The embodiment 200, wherein the zoledronic acid is present in an amount such that it results in a C _maximal of about 50 ng / mL to about 200 ng / mL of zoledronic acid upon administration of the oral dosage form to the particular species of mammal. Oral dosage form.
(Embodiment 203)
An oral dosage form containing zoledronic acid having the appropriate dose and form for a particular species of mammal.
The oral dosage form is an oral dosage form that is present in such an amount that administration of the oral dosage form to a particular species of mammal results in a T- _maximum of zoledronic acid for about 0.4 hours to about 1 hour.
(Embodiment 204)
The oral dosage form according to embodiment 203, wherein the oral dosage form is present in such an amount that administration of the oral dosage form to a particular species of mammal results in a _maximum T of zoledronic acid for about 0.5 hours. ..
(Embodiment 205)
The oral dosage form according to embodiment 203, wherein the oral dosage form is present in such an amount that administration of the oral dosage form to a particular species of mammal results in a _maximum T of zoledronic acid for about 0.75 hours. ..
(Embodiment 206)
An oral dosage form containing zoledronic acid having the appropriate dose and form for a particular species of mammal.
The oral dosage form is an oral dosage form in which the zoledronic acid is configured to have a 12-hour sustained plasma concentration factor of about 12 to about 50 for the particular species of mammal.
(Embodiment 207)
The oral dosage form is an oral dosage form in which the zoledronic acid is configured to have a 12-hour sustained plasma concentration factor of about 20 to about 40 for the particular species of mammal.
(Embodiment 208)
The oral dosage form according to embodiment 206 or 207, wherein the zoledronic acid is configured to have a 24-hour sustained plasma concentration factor of about 10 to about 30 for the particular species of mammal. Oral dosage form.
(Embodiment 209)
The oral dosage form is any of embodiments 206-208, wherein the zoledronic acid is configured to have a 24-hour sustained plasma concentration factor of about 10 to about 20 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 210)
The oral dosage form is any of embodiments 206-209, wherein the zoledronic acid is configured to have a 36-hour sustained plasma concentration factor of about 6 to about 20 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 211)
The oral dosage form is any of embodiments 206-210, wherein the zoledronic acid is configured to have a 36-hour sustained plasma concentration factor of about 8 to about 15 for said particular species of mammal. The oral dosage form according to one.
(Embodiment 212)
The oral dosage form is any of embodiments 206 to 211, wherein the zoledronic acid is configured to have a 48-hour sustained plasma concentration factor of about 5 to about 20 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 213)
The oral dosage form is any of embodiments 206-212, wherein the zoledronic acid is configured to have a 48-hour sustained plasma concentration factor of about 6 to about 15 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 214)
The oral dosage form is any of embodiments 206-213, wherein the zoledronic acid is configured to have a 72-hour sustained plasma concentration factor of about 4 to about 20 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 215)
The oral dosage form is any of embodiments 206-213, wherein the zoledronic acid is configured to have a 72-hour sustained plasma concentration factor of about 5 to about 10 for the particular species of mammal. The oral dosage form according to one.
(Embodiment 216)
The oral dosage form is configured such that the particular species of mammal has zoledronic acid with a plasma concentration of zoledronic acid in 12 hours, from about 0.5 ng / mL to about 5 ng / mL. The oral dosage form according to any one of 206 to 215.
(Embodiment 217)
The oral dosage form is configured such that the particular species of mammal has zoledronic acid with a plasma concentration of zoledronic acid at about 0.2 ng / mL to about 2 ng / mL for 24 hours. The oral dosage form according to any one of 206 to 216.
(Embodiment 218)
The oral dosage form is configured such that the particular species of mammal has zoledronic acid with a plasma concentration of zoledronic acid at 36 hours from about 0.1 ng / mL to about 2 ng / mL. The oral dosage form according to any one of 206 to 217.
(Embodiment 219)
The oral dosage form is configured such that the particular species of mammal has zoledronic acid with a plasma concentration of zoledronic acid at 48 hours from about 0.1 ng / mL to about 2 ng / mL. The oral dosage form according to any one of 206 to 218.
(Embodiment 220)
The oral dosage form is configured such that the particular species of mammal has zoledronic acid with a plasma concentration of zoledronic acid at 72 hours from about 0.2 ng / mL to about 1 ng / mL. The oral dosage form according to any one of 206 to 219.
(Embodiment 221)
The oral dosage form is any of embodiments 206-220, wherein the excretion half-life of zoledronic acid in said particular species of mammal is configured to be 24 hours, which is about 30 hours to about 100 hours. The oral dosage form according to one.
(Embodiment 222)
The oral dosage form is any of embodiments 206-221, wherein the excretion half-life of zoledronic acid in said particular species of mammal is configured to be 24 hours, which is about 40 to about 60 hours. The oral dosage form according to one.

Unless otherwise stated, properties such as component weight, molecular weight, reaction conditions, and all numbers representing such as used herein and in the claims are the exact numbers shown. It should be understood in all cases as indicating both a value and a value that is modified by the term "about". Thus, unless the opposite is indicated, the numerical parameters described herein and in the appended claims are approximate values that can vary depending on the conditions under which the desired properties can be obtained. .. At a minimum, it does not limit the application of the doctrine of equivalents in terms of claims, with each numerical parameter at least in light of the number of significant figures reported and applying conventional rounding techniques. Should be interpreted by.

The terms "one", "corresponding" and similar references used in the context of describing the invention (particularly in the context of the following claims) are specifically shown herein. If not, or if there is no apparent contradiction in the context, it should be interpreted to include both singular and plural. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or where there is no apparent contradiction in the context. The use of any and all examples or exemplary languages provided herein (eg, "such as") is solely intended to make the invention more explicit. This does not limit the scope of any claim. The language herein should not be construed as indicating any unclaimed element essential to the practice of the present invention.

The group of alternative elements or embodiments disclosed herein should not be construed in a limited way. Members of each group may be indicated and claimed individually or in combination with other members of the group or other elements found herein. It is expected that one or more members of the group may be included in or removed from the group for convenience and / or for patent reasons. If any such inclusion or deletion occurs, the specification is considered to include a group modified to meet the description of all Markush groups used in the appended claims.

Specific embodiments are described herein, including the best known embodiments of the present inventor for carrying out the present invention. Of course, variations of these described embodiments will be apparent to those skilled in the art by reading the above description. The inventor anticipates that those skilled in the art will use such modifications as appropriate, and intends that the present invention will be practiced outside of those specifically described herein. .. Thus, the claims include all variations and equivalents of the subject matter indicated in the claims, as permitted by applicable law. Moreover, any combination of the above elements in all possible variations thereof is considered, unless otherwise indicated herein or is clearly inconsistent with the context.

Finally, it should be understood that the embodiments disclosed herein exemplify the principles of the claims. Other variations that may be used are within the scope of the claims. Thus, as an example, but not limited to, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the scope of claims is not limited to the exact embodiments shown and described.

Claims (22)

An oral pharmaceutical composition comprising the zoledronic acid disodium tetrahydrate form of zoledronic acid and an excipient.
The zoledronic acid disodium tetrahydrate form of zoledronic acid in the oral pharmaceutical composition is an oral pharmaceutical composition having enhanced oral bioavailability in mammals as compared to the diacid form of zoledronic acid. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition is administered to the mammal for the treatment of pain. The oral pharmaceutical composition is administered to a person in need thereof, who receives a total amount of 200 mg to 500 mg of the zoledronic acid disodium disodium tetrahydrate form of the zoledronic acid within a period of 6 weeks. The oral pharmaceutical composition according to claim 2. The oral pharmaceutical composition according to claim 2, wherein the pain is inflammatory pain. The oral pharmaceutical composition according to claim 2, wherein the pain is associated with arthritis. The oral pharmaceutical composition according to claim 2, wherein the pain is associated with complex regional pain syndrome. The oral pharmaceutical composition according to claim 2, wherein the pain is low back pain. The oral pharmaceutical composition according to claim 3, wherein the total amount of the zoledronic acid disodium tetrahydrate form of zoledronic acid is given in a 6-week dose administered during 6 weeks. The oral pharmaceutical composition according to claim 3, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered 2 to 5 times a month. The oral pharmaceutical composition according to claim 3, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is administered monthly. The oral pharmaceutical composition according to claim 3, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered weekly. The oral pharmaceutical composition according to claim 11, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered weekly for 1 or 2 months. The oral pharmaceutical composition according to claim 3, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered daily. The oral pharmaceutical composition according to claim 3, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered weekly in an amount of 10 mg to 100 mg. The oral pharmaceutical composition according to claim 2, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is administered in an oral pharmaceutical composition in an amount of 30 mg to 100 mg. The oral pharmaceutical composition according to claim 2, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is administered in an oral pharmaceutical composition in an amount of 50 mg. The oral pharmaceutical composition according to claim 2, wherein 50 mg to 75 mg of the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered weekly. The oral pharmaceutical composition according to claim 2, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered weekly for 6 weeks. The oral pharmaceutical composition according to claim 1, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered in an amount of 10 mg to 100 mg daily. The oral pharmaceutical composition according to claim 19, wherein the zoledronic acid disodium tetrahydrate form of zoledronic acid is orally administered for 5 to 10 consecutive days. The oral pharmaceutical composition according to claim 2, wherein the oral pharmaceutical composition contains at least about 10% (w / w) of the zoledronic acid disodium tetrahydrate form of the zoledronic acid . The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition does not contain a bioavailability enhancer.