KR102409599B1 - Osteoclast inhibitors for pain - Google Patents

Abstract

Described herein are methods of safe administration of an imidazole or imidazolium compound, and conditions that can be treated by the methods.

Description

Osteoclast inhibitor for pain {OSTEOCLAST INHIBITORS FOR PAIN}

The present invention relates to an osteoclast inhibitor for pain.

Bisphosphonate compounds are potent inhibitors of osteoclast activity and are used in bone related conditions such as osteoporosis and Paget's disease of bone; and cancer-related conditions, including multiple myeloma, and bone metastases from solid tumors (Fox et al., Use of Bisphosphonates for Pain Treatment , WO2002043738, 6 June 2002) (for review see Fleisch H 1997) Bisphosphonates clinical. In Bisphosphonates in Bone Disease. From the Laboratory to the Patient. Eds: The Parthenon Publishing Group, New York/London pp 68-163). They generally have low oral bioavailability (Leonard, Solid Oral Dosage Form Containing An Enhancer , US7704977, 27 April 2010).

Spotted osteoporosis and bone marrow edema can result from osteoclast hyperactivity. Zoledronic acid is a potent inhibitor of bone resorption and osteoclast activity. Nitrogen-containing bisphosphonates, such as zoledronic acid, also interfere with normal osteoclast activity by inhibiting the mevalonate pathway in osteoclasts ( reviewed in Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith) JC. 2000. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88(suppl):2961-2978) (Fox et al., Use of Bisphosphonates for Pain Treatment , WO2002043738, 6 June 2002).

It has been discovered that oral formulations of bisphosphonate compounds, such as zoledronic acid, can be used for the treatment or alleviation of pain or related conditions.

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

Some embodiments are formulations comprising zoledronic acid in the disodium salt form, wherein the bioavailability of zoledronic acid in the disodium salt form in the mammal is greater than the bioavailability of zoledronic acid in the diacid form in the same formulation. include

Some embodiments are formulations comprising zoledronic acid, wherein the formulation provides an area under the plasma concentration curve of zoledronic acid from about 4 ng h/mL to about 2000 ng h/mL to a human to which the formulation is administered. formulations containing zoledronic acid in the form of the disodium salt of

Some embodiments are formulations comprising zoledronic acid in the disodium salt form, wherein the disodium salt form is present in a lower molar amount than would be present if the zoledronic acid was in the diacid form; Zoledronic acid in the disodium salt form has improved bioavailability, compared to zoledronic acid in the diacid form, to the extent that a lower molar amount of the disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the plasma of the mammal. Includes formulations with

Although oral dosage forms with improved bioavailability for the bisphosphonate compound can be used, treatment is also effective when using oral dosage forms comprising a bisphosphonate compound, such as zoledronic acid, wherein the bioavailability of the bisphosphonate is unimproved or substantially unenhanced. can be

Some embodiments provide a method of alleviating inflammatory pain comprising administering to a mammal in need thereof an oral dosage form containing zoledronic acid, wherein the mammal is in need thereof for more than 3 hours after administration of the dosage form. (significant) includes ways to experience pain relief.

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

Some embodiments include a method of treating complex regional pain syndrome comprising administering to a mammal in need thereof an oral formulation containing zoledronic acid.

Some embodiments include oral dosage forms comprising zoledronic acid, wherein the oral bioavailability of zoledronic acid is substantially unimproved. For example, in some embodiments, the oral bioavailability in the dosage form is from about 0.01% to about 4%.

Some embodiments include a pharmaceutical product comprising more than one unit of an oral dosage form described herein. In some embodiments, each unit of the oral dosage form contains from about 1 mg to about 50 mg of zoledronic acid.

Some embodiments include a method of alleviating inflammatory pain comprising administering to a mammal in need thereof an oral formulation containing zoledronic acid.

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 formulation contains from about 10 mg/m2 to about 20 mg/m2 based on the body surface area of the mammal.

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

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

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

1 is a plot of pain compression threshold in a rat model of inflammatory pain using three different doses of zoledronic acid. Measurements were taken at baseline (BL) and at various time points post-dose on designated days.
2A is a graph depicting the reversal of arthritis pain for two different doses of zoledronic acid in a rat model of arthritis pain.
2B is a graph depicting pain thresholds for two different doses of zoledronic acid in a rat model of arthritis pain.
3 is a graph summarizing the results of vehicle and zoledronic acid-treated rats in a rat model of complex regional pain syndrome.
4 depicts hind paw pain thresholds for vehicle and zoledronic acid treated rats in a rat model of complex regional pain syndrome.
5 depicts weight bearing for vehicle and zoledronic acid treated rats in a rat model of complex regional pain syndrome.
6 depicts paw thickness changes for vehicle and zoledronic acid treated rats in a rat model of complex regional pain syndrome.
Figure 7 depicts the aqueous solubility of disodium zoledronic acid tetrahydrate compared to the diacid form of zoledronic acid.
Figure 8 depicts plasma concentrations of zoledronic acid in dogs over time after administration of 150 mg of the disodium salt form of zoledronic acid and the diacid form of zoledronic acid.
Figure 9 shows the compressibility of formulations containing zoledronic acid in the disodium salt form compared to the diacid form.
10 depicts the change in VAS pain score versus placebo at 3 months of zoledronic acid treatment in patients with osteoarthritis of the knee, bone marrow lesions and different degrees of joint space narrowing.
11 depicts the change in VAS pain score compared to baseline at 3 months of zoledronic acid treatment in patients with osteoarthritis of the knee, bone marrow lesions and different degrees of joint space narrowing.
12 depicts the change in VAS pain score versus placebo at 3 months of zoledronic acid treatment in different subgroups of patients with osteoarthritis of the knee and bone marrow lesions.
13 depicts the change in BML lesion size versus placebo at 6 months of zoledronic acid treatment in patients with osteoarthritis of the knee, bone marrow lesions and different degrees of joint space narrowing.

Inhibitors of osteoclast activity include palmidronate or pamidronic acid, neridronate or neridronic acid, olpadronate or olpadronic acid, alendronate or alendronic acid, incadronate or incadronic acid. acid), ibandronate or ibandronic acid, risedronate or risedronic acid, cimadronate or cimadronic acid, zoledronate or zoledronic acid, etidronate or etidronic acid acid), a bisphosphonate compound such as clodronate or clodronic acid, tiludronate or tiludronic acid, and the like.

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

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

Inhibitors of osteoclast activity can be used for a number of medical purposes, such as alleviating pain and treating undesirable conditions or diseases. This can in many cases be achieved by administration of oral dosage forms. Generally, oral dosage forms comprising a bisphosphonate, such as zoledronic acid, are orally administered to a mammal, such as a human, at least once for the treatment of a disease or condition or for the relief of pain.

The following compounds may also be osteoclast inhibitors.

The terms “treating” or “treatment” are broadly used to refer to any type of therapeutic activity, including the diagnosis, cure, alleviation or prevention of a disease in a human or other animal, or structure or any Includes any activity that affects function.

Oral dosage forms of bisphosphonates such as zoledronic acid include inflammatory pain, arthritis pain, complex regional pain syndrome, lumbosacral pain, musculoskeletal pain, neuropathic pain, chronic pain, cancer-related pain, acute pain, post-operative pain, etc. It can be used to treat or provide relief of any type of pain without limitation. In some instances, pain relief may be palliative, or pain relief may be provided independently of the amelioration of the disease or condition, or the underlying cause of the disease or condition. For example, an individual suffering from the disease may experience pain relief, even if the underlying disease may not be ameliorated or may continue to progress. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

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

For example, zoledronic acid or other bisphosphonates may be used for low back pain and axial spondyloarthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthritis, non-articular rheumatism, periarticular disease, ankylosing spondylitis; It may be administered orally for the relief of musculoskeletal pain, including pain associated with Paget's disease, fibrodysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and the like. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

Osteoclast inhibitors such as bisphosphonates, such as zoledronic acid, may also be used in the treatment of bone fractures or to enhance bone fracture healing.

In some embodiments, zoledronic acid or other bisphosphonates are also administered orally for the relief of neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, and central pain. may be administered. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radiation therapy or chemotherapy-related neuropathy. . In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

In some embodiments, zoledronic acid or other bisphosphonates may be administered orally to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

Examples of musculoskeletal pain include back pain; and pain associated with vertebral crush fractures, fibrous dysplasia, incomplete osteogenesis, Paget's disease of bone, transient osteoporosis and transient osteoporosis of the hip.

Arthritis refers to an inflammatory joint disease that may be associated with pain. Examples of arthritic pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthritis, non-articular rheumatism, periarticular disease, neuropathic arthropathy including Charcot's foot, ankylosing spondylitis and pain associated with axial spondyloarthritis and SAPHO syndrome.

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

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

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

For the treatment of joint pain, such as arthritis or knee pain, in some embodiments, the person being treated has joint space narrowing of OARSI grade 0 or Kelgren and Lawrence grade 0 or 1.

In some embodiments, the person has a lesion, such as a bone marrow lesion. In some embodiments, the person being treated for a bone marrow lesion has normal joint space knee pain, an OARSI grade 0 or Kellgren and Lawrence grade 0 or 1 joint space narrowing.

In some embodiments, the person has a baseline pain intensity of greater than or equal to 5 as measured using a 0-10 numeric rating scale (NRS) or greater than or equal to 50 mm as measured using the 100 mm Visual Pain Scale (VAS) . In some embodiments, the person being treated for pain has normal articular space knee pain, OARSI Grade 0 or Kellgren and Lawrence Grade 0 or 1 joint space narrowing.

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

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

In some embodiments, inhibitors of osteoclast activity may be used in the treatment of bone marrow lesions.

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

Commonly used measures of pain intensity include the Visual Pain Scale (VAS) and the Numerical Pain Rating (NRS). In the VAS approach, patients grade their pain severity by marking a score on a 10 cm (or 100 mm) VAS (0=no pain, and 10=worst possible pain). In the NRS approach, patients grade their pain severity in verbal response to a 10-point NRS (0=no pain, and 10=worst possible pain). The VAS and NRS scores were found to be strongly correlated with each other (slope of the regression line, 1.01), suggesting that scores on the 10 cm VAS are equivalent to the same scores on the 10-point NRS (Bijur PE et al. Acad Emerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm) is equivalent to an NRS score of 5. Knee pain in a person with a VAS score of 5 cm or 50 mm or greater or an NRS score of 5 or greater may be referred to herein as moderate to severe knee pain.

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

For knee pain or pain associated with bone marrow lesions, in some embodiments, treatment with a nitrogen-containing bisphosphonate, such as zoledronic acid, results in a Visual Pain Scale (VAS) pain score measured using a 100 mm scale of at least about 5 mm; at least about 8 mm, at least about 10 mm, at least about 15 mm, by about 50 mm, or by about 100 mm. In some embodiments, the VAS score may be reduced by at least about 5 mm, at least about 8 mm, at least about 10 mm, at least about 15 mm, by about 50 mm, or by about 100 mm compared to placebo.

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

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

In some embodiments, a reduction in the total area of the bone marrow lesion of at least about 240 mm 2 is achieved with the use of an inhibitor of osteoclast activity. In some embodiments, the reduction in total area is at least about 220 mm2, at least about 200 mm2, at least about 150 mm2, at least about 100 mm2, or at least about 50 mm2. In some embodiments, the reduction in the size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% %, at least about 90% or about 100%, relative to baseline. In some embodiments, the reduction in area of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% %, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400 % or at least about 450% improvement over placebo. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in the size of a bone marrow lesion over time.

Joint space narrowing (JSN) is commonly graded using the Osteoarthritis Research Society International (OARSI) graphical criteria or the Kelgren and Lawrence (K/L) system. In the OARSI diagram using a 0-3 scale, reference grade JSN, grade 0 indicates the absence of JSN, and grades 1, 2, and 3 indicate mild, moderate, and severe JSN, respectively (Altman and Gold, Osteoarthritis Cartilage 2007;15 (Altman and Gold, Osteoarthritis Cartilage 2007;15) Suppl A):A1-A56). In the K/L system grade JSN using the 0-4 scale, a grade of 0 indicates the absence of JSN, a grade of 1 indicates that JSN is suspected, and grades 2, 3, and 4 indicate minimal, moderate, and moderate JSN, respectively (Kellgren and Lawrence, Ann Rheum Dis 1957;16:494-502). Based on these criteria, an OARSI rating of 0 (absence of JSN) is approximately a K/L 0-1 rating (absence or suspicious presence of JSN). Knee pain in persons with ARSI grade 0 or K/L grade 1 JSN in the knee may be referred to herein as "normal joint space knee pain".

In some embodiments for patients with OARSI grade 0 or K/L grade 0-1 JSN, a reduction in the total area of bone marrow lesions of at least about 240 mm 2 is achieved with the use of an inhibitor of osteoclast activity. In some embodiments, the reduction in total area is at least about 220 mm2, at least about 200 mm2, at least about 150 mm2, at least about 100 mm2, or at least about 50 mm2. In some embodiments, the reduction in the size of the bone marrow lesion is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% %, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%. In some embodiments, the reduction in area of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% %, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400 % or at least about 450% improvement over placebo. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in the size of a bone marrow lesion over time.

In some embodiments for patients with OARSI grade 1-2 or K/L grade 2-4 JSN, a reduction in the total area of bone marrow lesions of at least about 100 mm 2 is achieved with the use of an inhibitor of osteoclast activity. In some embodiments, the reduction in total area is at least about 50 mm2, at least about 60 mm2, at least about 80 mm2, at least about 85 mm2, at least about 90 mm2, at least about 100 mm2, at least about 105 mm2, at least about 110 mm2, or at least about 115 mm2. In some embodiments, the reduction in the size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% , showing a decrease relative to baseline of at least about 90% or about 100%. In some embodiments, the reduction in area of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% %, at least about 90%, at least about 100%, at least about 115%, at least about 125%, at least about 135%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300 %, at least about 350%, at least about 400% or at least about 450% improvement over placebo. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in the size of a bone marrow lesion over time.

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

According to some embodiments, administration of an inhibitor of osteoclast activity achieves a reduction in pain lasting at least about 1 month, 2 months, 3 months, 4 months, 6 months, or even at least about 12 months. According to some embodiments, with administration of the inhibitor of osteoclast activity, more than 3 hours after administration of the inhibitor of osteoclast activity, about 1 day, about 2 days to about 5 days, about 1 week, about 2 weeks at about 3 weeks, at about 1 month, at about 5 weeks, at about 6 weeks, at about 7 weeks, at about 2 months, at about 9 weeks, at about 10 weeks, at about 11 weeks, at about 3 months , a reduction in pain observed at about 4 months, at about 6 months, or at about 12 months is achieved.

According to some embodiments, administration of the inhibitor of osteoclast activity in more than 3 hours, but at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, A reduction in pain observed at or before 11 weeks, 12 weeks, 4 months, 5 months or 6 months is achieved.

According to some embodiments, administration of an inhibitor of osteoclast activity achieves a reduction in pain observed over 3 hours with a duration of about 3 months or less, about 4 months or less, about 5 months or less, or about 6 months or less.

According to some embodiments, after administration of the inhibitor of osteoclast activity, the area of the bone marrow lesion relative to the size before administration remains reduced by 3 months, 4 months, 5 months, 6 months, or even at least 12 months. According to some embodiments, after administration of the inhibitor of osteoclast activity, the area of the bone marrow lesion relative to the size before administration decreases at about 3 months, at about 4 months, at about 5 months, at about 6 months, or at about 12 months. do.

According to some embodiments, after administration of the inhibitor of osteoclast activity, the modic change or size of VESCs compared to the size before administration remains reduced for up to 3 months, 4 months, 5 months, 6 months, or even up to 12 months or more. maintain. According to some embodiments, after administration of the inhibitor of osteoclast activity, the modic change or the size of the VESCs compared to the size before administration is reduced at about 4 months, at about 5 months, at about 6 months, or at about 12 months.

In some embodiments, an osteoclast inhibitor such as a nitrogen-containing bisphosphonate, such as zoledronic acid, ibandronic acid or minodronic acid, is administered to complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), It may be administered for the relief of complex regional pain syndromes such as CRPS-NOS or other types of CRPS.

In some embodiments, the zoledronic acid or other bisphosphonate is administered to complex regional pain syndromes such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or other types of CRPS. It can be administered orally to relieve CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component.

Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by swelling and severe pain in the arm, which may be accompanied by autonomic, motor and sensory changes.

In some embodiments, an osteoclast inhibitor, such as a nitrogen-containing bisphosphonate, such as zoledronic acid or minodronic acid, is a nonsteroidal anti-inflammatory drug (NSAID), an opiate, or a pain, inflammation, similar condition or any condition described herein. It can be used to reduce the use of other pain medications for the patient. For example, the use of an NSAID, opiate, or other pain medication is at least about 5%, at least about 10%, at least about 15%, at least about 20%, compared to the use of an NSAID, opiate, or other pain medication without the administration of an osteoclast inhibitor. , at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% , can be reduced by about 100%. The use of an opiate, NSAID, or other pain medication is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, compared to the use of a baseline NSAID, an opiate, or other pain medication. %, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, about 100% can be reduced to

The reduction in the use of an NSAID, opioid, or other pain medication is about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months after administration of the osteoclast inhibitor. , about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year or more.

With respect to the use of oral zoledronic acid for the relief of pain associated with an inflammatory condition, the relief of pain may be short-lived, such as for a period of several hours after administration of the formulation, and/or relief of pain, such as zoledronic acid It can be long-term, lasting for days, weeks or even months after oral administration of ronic acid. In some embodiments, a mammal, such as a human, administers an oral dosage form comprising zoledronic acid for at least about 3 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 1 week. , experience significant pain relief after at least about 2 weeks, or at least about 3 weeks. In some embodiments, the mammal, such as a human, administers the oral dosage form comprising zoledronic acid from about 3 hours to about 2 weeks, from about 3 hours to about 3 weeks, from about 3 hours to about 24 hours, from about 6 hours to about Significant pain relief is experienced for at least a portion of the time of 2 weeks, or about 6 hours to about 24 hours, about 3 days to about 2 weeks, about 6 days to about 2 weeks. In some embodiments, the human being treated has significant pain relief at 3 months, 6 months, 9 months, or 1 year after administration of the most recent dose of an osteoclast inhibitor, such as zoledronic acid.

With respect to the treatment of any of the conditions 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 administration timing of the two dosage forms, with respect to the first oral dosage form and the second oral dosage form for the first oral dosage form, is 5 x T _max or more (eg, when T _max is 1 hour) , at 5 hours or more), at least 10 x T _max or more, at least about 15 x T _max or more, at least about 20 x T _max or more, at least about 50 x T _max or more, or at least about 200 x T _max or more It may be administered whenever possible, wherein T _max is the time of maximum plasma concentration for the first oral dosage form.

Some embodiments are the treatment of a condition described herein, such as inflammatory pain, arthritis or complex regional pain syndrome, wherein the treatment comprises administering to the mammal a single formulation or administering to the mammal a first formulation to treat the condition. treatment comprising administering to the mammal a second formulation after administration. When two or more dosage forms are administered, before the maximum pain relief effect of the first oral dosage form is achieved or before the peak in the pain relief effect of the first oral dosage form is experienced by the mammal fed the dosage form, the second dosage form Oral dosage forms are administered. In some embodiments, the second oral dosage form is administered before an observable pain relief effect is achieved. In some embodiments, the first oral dosage form is administered from about 12 hours to about 60 days, from about 24 hours to about 28 days, from about 24 hours to about 7 days, from about 24 hours to about 14 days, or from about 24 hours to about After 21 days a second oral dosage form is administered.

Some embodiments are for the treatment of a condition described herein, such as inflammatory pain, arthritis or complex regional pain syndrome, wherein the treatment comprises administering a first oral dosage form to the mammal followed by administering a second oral dosage form to the mammal. wherein the second oral dosage form is administered after the maximal pain relief effect of the first oral dosage form is achieved, or while the mammal is still experiencing pain relief from the first oral dosage form or the first oral dosage form treatment in which a second oral dosage form is administered while a pain-relieving effect from In some embodiments, the second dosage form is from about 12 hours to about 60 days, from about 24 hours to about 28 days, from about 24 hours to about 7 days, from about 24 hours to about 14 days, or from about 12 hours to about 60 days after the first oral dosage form is administered. It is administered after 24 hours to about 21 days.

Zoledronic acid or other bisphosphonates may also be administered orally to relieve cancer-related pain, including pain associated with multiple myeloma and bone metastases from solid tumors. In some embodiments, zoledronic acid is used in the treatment of pain that is cancer unrelated pain. For example, zoledronic acid may be used in the treatment of multiple myeloma, bone metastases from solid tumors, hypercalcemia of malignancies, giant cell tumors of bone, blood cancers or leukemias, or pain not associated with solid tumors or cancer. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

In addition to pain relief, oral administration of zoledronic acid or other bisphosphonates may also be useful in the treatment of diseases or conditions that may or may not include a pain component. For example, zoledronic acid or other bisphosphonates may be used for the treatment of any of the pain conditions or conditions described above, including treatments that do not simply relieve the pain, and treatments such that the condition is treated without occurrence of pain relief. can be useful for In addition to any pain relief that zoledronic acid or other bisphosphonates may or may not provide, zoledronic acid or other bisphosphonates may be used to treat diseases or conditions, such as metabolic diseases or conditions; inflammatory diseases or conditions, including those not associated with pain; cancer disease or condition; It can be used to treat neurological diseases or conditions, and the like. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

In some embodiments, oral administration of zoledronic acid or other bisphosphonate is also concomitant with complex regional pain syndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, axial spondyloarthritis, including ankylosing spondylitis, acute vertebral crush fracture, fibrodysplasia, SAPHO syndrome, osteoporosis , transient osteoporosis, or transient osteoporosis of the hip. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

In some embodiments, oral administration of zoledronic acid or other bisphosphate also results in hypercalcemia of a malignant tumor, multiple myeloma, bone metastasis from a solid tumor, Paget's disease of bone, giant cell tumor of bone, hematological cancer or leukemia, or It may be useful in the treatment of solid tumors or cancers. In some embodiments, improved bioavailability of zoledronic acid can be achieved in the treatment of one of these conditions by administering a formulation comprising zoledronic acid in the disodium salt form. This may enable a reduction in the molar amount of disodium salt used compared to the diacid form being used.

Some nitrogen-containing bisphosphonates may be represented by the following formula (A).

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

With respect to formula A, R ² is aminoalkyl, such as aminoethyl, aminopropyl, aminopentyl, dimethylaminoethyl, methylpentylaminoethyl, and the like; or optionally substituted heterocyclyl alkyl, such as optionally substituted imidazolylmethyl, optionally substituted pyridinylmethyl, and the like. In some embodiments, R ² is optionally substituted imidazolylalkyl.

Unless otherwise indicated, when a compound or chemical structural feature, such as a heterocyclyl alkyl, is referred to as "optionally substituted," it is either free of substituents (i.e., unsubstituted), or the feature is characterized by one or more substituents. It includes a substituted feature meant to have The term “substituent” has the broadest meaning known to one of ordinary skill in the art and includes moieties that substitute one or more hydrogen atoms in the parent compound or structural feature. The term “substitute” is used herein for convenience only and does not require that a compound be formed by substituting one atom for another. In some embodiments, the substituent has a molecular weight (eg, the sum of the atomic masses of the atoms of the substituent) from 15 g/mole to 50 g/mole, from 15 g/mole to 100 g/mole, from 15 g/mole to 150 g/mole. , any conventional organic moiety known in the art, which may be 15 g/mole to 200 g/mole, 15 g/mole to 300 g/mole or 15 g/mole to 500 g/mole. In some embodiments, the substituents have 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10 or 0-5 heteroatoms, wherein each heteroatom is independently N, O, P, S, Si, F, Cl, Br or I; provided that the substituent contains one C, N, O, P, S, Si, F, Cl, Br or I atom. In some embodiments, the substituents can independently have a molecular weight of from about 15 Da to about 600 Da, and can consist of 2-5 chemical elements, wherein the chemical elements are independently C, H, O, N, P, S, Si, F, Cl or Br. In some embodiments, the substituents are optionally substituted alkyl, -O-alkyl (eg, -OCH ₃ , -OC ₂ H ₅ , -OC ₃ H ₇ , -OC ₄ H ₉ , etc.), -S-alkyl (eg, -SCH ₃ , -SC ₂ H ₅ , -SC ₃ H ₇ , -SC ₄ H ₉ , etc.), -NR'R", -OH, -SH, -CN, -CF ₃ , -NO ₂ , perfluoro alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amine or halogen, wherein R′ and R″ are independently H or optionally substituted alkyl. Whenever a substituent is described as "optionally substituted", that substituent may be substituted with that substituent.

For convenience, the term “molecular weight” is used to refer to the sum of the atomic masses of atoms within a moiety or portion of a molecule, for a moiety or portion of a molecule, although this may not be a complete molecule.

Examples of nitrogen-containing bisphosphonates include pamidronic acid, incadronic acid, ibandronic acid, risedronic acid, minodronic acid, shimadronic acid, neridronic acid, alendronic acid, olpadronic acid, zoledronic acid, and the like; However, the present invention is not limited thereto.

Zoledronic acid has the structure shown below and is also referred to as zoledronate.

Unless otherwise indicated, any reference herein to a compound, such as zoledronic acid, by structure, name, or any other means includes pharmaceutically acceptable salts, such as the disodium salt; other solid forms such as polymorphs, solvates, hydrates, and the like; tautomer; or any other species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

In some embodiments, zoledronic acid is administered in a formulation comprising a salt form, such as a salt of a dianion of zoledronic acid. In some embodiments, zoledronic acid is administered in a formulation comprising the disodium salt form of zoledronic acid. In some embodiments, zoledronic acid is administered in the form of a sodium salt such as a monosodium salt, a disodium salt, a trisodium salt, and the like. In some circumstances, the use of a disodium salt may be desirable. For example, the disodium salt is much more soluble in water than the diacid form. As a result, in some processes, the disodium salt may be easier to work with than the diacid form. Additionally, the sodium salt may be more bioavailable and/or more rapidly absorbed upon oral ingestion compared to the diacid form.

Examples of the salt of compound 1 are shown below.

wherein X ⁻ is any suitable anion, such as F ⁻ , Br ⁻ , Cl ⁻ , I ⁻ , OH ⁻ , acetate, and the like; M ⁺ is any suitable cation, such as Na ⁺ , K ⁺ , NH ₄ ⁺ and the like. Many other salt forms are also possible.

In some embodiments, Compound 1 may be further represented by the following formula.

In some embodiments, Compound 1 may exist in the form of a hydrate.

In some embodiments, Compound 1 is administered in a formulation comprising a salt form, such as a cation, monovalent anion, divalent anion, trivalent anion, or the like, or zwitterionic form of Compound 1.

Compound 1 is less than about 100% w/w, less than about 50% w/w, less than about 20% w/w, about 10% w/w, based on the total amount of zoledronic acid, Compound 1 and Compound 2 present in the composition. less than w, less than about 1% w/w, less than about 0.1% w/w, less than about 0.07% w/w, less than about 0.05% w/w, less than about 0.04% w/w, less than about 0.03% w/w; less than about 0.02% w/w; and/or greater than 0% w/w, at least about 0.00000001% w/w, at least about 0.000001% w/w, or at least about 0.00001% w/w.

Examples of salts of compound 2 are shown below.

wherein X ⁻ is any suitable anion, such as F ⁻ , Br ⁻ , Cl ⁻ , I ⁻ , OH ⁻ , acetate, and the like; M ⁺ is any suitable cation, such as Na ⁺ , K ⁺ , NH ₄ ⁺ and the like. Many other salt forms are also possible.

In some embodiments, the salt of Compound 2 may be further represented by the following formula.

In some embodiments, compound 2 may exist in the form of a hydrate.

In some embodiments, Compound 2 is administered in a formulation comprising a salt form, such as a cation, monoanion, divalent anion, trivalent anion, or the like, or zwitterionic form of Compound 2 .

Compound 2 is less than about 100% w/w, less than about 50% w/w, less than about 20% w/w, about 10% w/w, based on the total amount of zoledronic acid, Compound 1 and Compound 2 present in the composition. less than w, less than about 1% w/w, less than about 0.3 w/w, less than about 0.2 w/w, less than about 0.1% w/w, less than about 0.08 w/w, less than about 0.07% w/w, about 0.05 less than % w/w, less than about 0.04% w/w, less than about 0.03% w/w, less than about 0.02% w/w; and/or greater than 0% w/w, at least about 0.00000001% w/w, at least about 0.000001% w/w, or at least about 0.00001% w/w.

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

In some embodiments, administration of an osteoclast inhibitor, such as a nitrogen-containing bisphosphonate, including, for example, zoledronic acid, minodronic acid, and the like, to a patient or mammal in need thereof, affects modic changes (MC). For example, any of the above compounds may be used in the treatment of neck or back pain associated with modic changes or spinal endplate signal changes (VESC) and bone marrow changes seen using magnetic resonance imaging (MRI), or modic changes.

Modic change as used herein includes its ordinary meaning in the art and refers to pathological spinal endplate and bone marrow changes seen using magnetic resonance imaging (MRI). Modic changes may also be referred to as spinal endplate signal changes (VESCs). Modic changes can be classified into various types, including type 1 (M1), type 2 (M2) and type 3 (M3) lesions or changes, any of which nitrogen bisphosphonates including, for example, zoledronic acid, minodronic acid, and the like. can be treated using osteoclast inhibitors such as Different types of modic changes can occur in the same patient, such as type 1 and type 2 modic changes (M1/2). In some cases, M1 changes are associated with back pain more than other types of modic changes.

VESCs can be found in patients with different types of back pain including but not limited to spondylitis, trauma, spondyloarthropathies including ankylosing spondylitis, Schmall's nodule, fractures, tumors, and spinal infarction. Lesions in ankylosing spondylitis include osteoarthritis and spondylolisthesis, which can be detected using MRI or other medical imaging instruments.

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

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

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

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

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

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

In some embodiments, the patient being treated has at least two levels of modic change. In some embodiments, the patient being treated has at least 3 levels of modic change. In some embodiments, greater pain relief is obtained in treating a patient having 2 levels or more than 3 levels of modic change than is obtained in treating a patient having 1 level or 2 or more levels of modic change.

In some embodiments, greater pain relief is obtained in treating a patient with 2 levels of modic change than is obtained when treating a patient with 1 level of modic change.

In some embodiments, greater pain relief is obtained upon treatment of a patient with at least 3 levels of modic change than would be obtained upon treatment of a patient with 1 level of modic change.

In some embodiments, greater pain relief is obtained in treating a patient with 3 or more levels of modic change than is obtained when treating a patient with 2 or more levels of modic change.

In some embodiments, inhibitors of osteoclast activity can be used to reduce the level of pro-inflammatory cytokines in a patient having back pain or any other type of pain or condition described herein. In some embodiments, greater pain relief may be obtained in patients with greater baseline levels of pro-inflammatory cytokines upon treatment with inhibitors of osteoclast activity, such as nitrogen-containing bisphosphonates, including, for example, zoledronic acid, minodronic acid, and the like. have. In some embodiments, greater pain relief in a patient who experiences a reduction or greater reduction in the level of pro-inflammatory cytokines upon treatment with an inhibitor of osteoclast activity, such as nitrogen-containing bisphosphonates, including, for example, zoledronic acid, minodronic acid, and the like. this can be obtained. Inflammatory cytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis alpha (TNF-alpha), interferon gamma, and the like. doesn't happen

In some embodiments, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% A modic change of , or a reduction to the baseline in the size of the VESC is achieved. In some embodiments, the magnitude of the modic change or reduction in VESC is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 150%, at least about 170%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400% or at least about 450% improvement over placebo. In some embodiments, use of an inhibitor of osteoclast activity inhibits a modic change over time or an increase in the size of VESCs.

Oral administration of zoledronic acid in the disodium salt form can improve the oral bioavailability of zoledronic acid. For example, compared to administration of zoledronic acid in its diacid form, 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% or about 200%. % can be improved.

Due to the improved bioavailability of the disodium salt, the formulation may contain less disodium salt form of zoledronic acid on a molar basis than would otherwise be administered to the diacid form of zoledronic acid or to which mammals such as humans would receive it. can For example, the dosage form may be at least about 10 mole % less, at least about 20 mole % less, at least about 40 mole % less, at least about 50 mole % less, and/or up to about 90 mole % less or up to 95 mole % less disodium salt form or the mammal may receive it have.

In some embodiments, the formulation contains an amount in the form of the disodium salt having a value of from about 0.8 n _d to about 1.2 n _d or from about 0.9 n _d to about 1.1 n _d on a molar basis or a mammal (such as a human) This amount is administered to

n _d = (b _a /b _d )(n _a )

where b _a is the bioavailability of the diacid form, b _d is the bioavailability of the disodium salt form, and na _a is the number of moles of diacid that would have been administered in a formulation containing the diacid form of zoledronic acid. For example, if the diacid form has a bioavailability (b _a ) of 0.01 and the disodium salt form has a bioavailability (b _a ) of 0.015, and the formulation usually contains 0.001 moles of diacid, then n _d is (0.01/0.015) ) (0.001 moles) or about 0.00067 moles. In some embodiments, the disodium salt is administered in an amount having a value of about n _d .

With respect to oral dosage forms comprising a reduced molar amount of a disodium salt of zoledronic acid compared to the diacid form of zoledronic acid, in some embodiments, the bioavailability of zoledronic acid in the disodium salt form is sufficiently high that the drug When administered to a mammal, at least as much zoledronic acid is present in the mammal's blood as would be present if the zoledronic acid was administered in discrete form.

With respect to oral dosage forms comprising the disodium salt form of zoledronic acid, in some embodiments, the disodium salt form is present in a lower molar amount than would be present if the zoledronic acid was in the diacid form; Zoledronic acid in the disodium salt form has improved bioavailability, compared to zoledronic acid in the diacid form, to the extent that a lower molar amount of the disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the plasma of the mammal. has

Some oral dosage forms comprising zoledronic acid have zoledronic acid and composition suitable for certain species of mammals, such as dogs, rats, humans, and the like. Such formulations may have zoledronic acid present in an amount that results in a desired range for the area under the plasma concentration curve (AUC) of zoledronic acid in a mammal of a particular species. For example, the dosage and composition of the zoledronic acid in the oral dosage form, when the oral dosage form is administered to a mammal, is from about 1 ng hr/mL to about 700 ng hr/mL, from about 3 ng hr/mL to about 30 ng hr/mL, about 3 ng hr/mL to about 10 ng hr/mL, about 50 ng hr/mL to about 700 ng hr/mL, about 130 ng hr/mL to about 180 ng hr/mL, about 300 ng hr/mL to about 450 ng hr/mL, about 300 ng hr/mL to about 350 ng hr/mL, about 300 ng hr/mL to about 310 ng hr /mL, about 340 ng hr/mL to about 350 ng hr/mL, about 370 ng hr/mL to about 420 ng hr/mL, about 380 ng hr/mL to about 390 ng hr/mL , about 405 ng hr/mL to about 415 ng hr/mL, about 140 ng hr/mL to about 160 ng hr/mL, about 140 ng hr/mL to about 150 ng hr/mL, about 150 ng hr/mL to about 160 ng hr/mL, about 140 ng hr/mL, 142 ng hr/mL, about 155 ng hr/mL, about 305 ng hr/mL, 304 ng hr AUC of zoledronic acid /mL, about 345 ng hr/mL, 343 ng hr/mL, about 385 ng hr/mL, 384 ng hr/mL, about 410 ng hr/mL, or any of these values It can result in any AUC in a range encompassed by or in between.

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

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be prepared by administering the oral dosage form to a mammal, from about 0.2 ng/mL to about 300 ng/mL, to about 0.5 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 C _max of zoledronic acid of 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 any of these values or have zoledronic acid present in an amount that results in any C _max in a range therebetween.

a range within or between the T _max of zoledronic acid or any of these values of from about 0.4 hr to about 1 hr, about 0.5 hr or about 0.75 hr for administration of the oral dosage form to a mammal of a particular species Oral formulations comprising zoledronic acid can be formulated with the dosage and composition of zoledronic acid appropriate for a particular species of mammal, to result in any T _max of .

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

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

In some embodiments, zoledronic acid is present in an oral dosage form from about 20 ng h/mL to about 700 ng h/mL, from about 50 ng h/mL to about 500 ng h/mL in a mammal to which the dosage form is administered. /mL, about 50 ng h/mL to about 400 ng h/mL, about 50 ng h/mL to about 300 ng h/mL, about 50 ng h/mL to about 200 ng h/mL , about 100 ng h/mL to about 500 ng h/mL, about 100 ng h/mL to about 400 ng h/mL, about 100 ng h/mL to about 300 ng h/mL, about 100 ng h/mL to about 200 ng h/mL, about 125 ng h/mL to about 500 ng h/mL, about 125 ng h/mL to about 400 ng h/mL, about 125 ng plasma of zoledronic acid from h/mL to about 300 ng h/mL, from about 125 ng h/mL to about 200 ng h/mL or from about 200 ng h/mL to about 300 ng h/mL It is present in an amount such that it provides an area under the concentration curve. This amount may be suitable for weekly administration of the oral dosage form or for administration of 3-5 individual doses over a period of one month. The individual doses may be given at regular intervals given during the first week or on any other schedule providing 3 to 5 doses for 1 month.

In some embodiments, zoledronic acid is present in an oral dosage form from about 4 ng h/mL to about 100 ng h/mL, from about 10 ng h/mL to about 50 ng h/mL in a mammal to which the dosage form is administered. /mL, about 10 ng h/mL to about 30 ng h/mL, 20 ng h/mL to about 700 ng h/mL, about 50 ng h/mL to about 500 ng h/mL, about 50 ng h/mL to about 400 ng h/mL, about 50 ng h/mL to about 300 ng h/mL, about 50 ng h/mL to about 200 ng h/mL, about 100 ng h/mL to about 500 ng h/mL, about 100 ng h/mL to about 400 ng h/mL, about 100 ng h/mL to about 300 ng h/mL, about 100 ng h/mL h/mL to about 200 ng h/mL, about 125 ng h/mL to about 500 ng h/mL, about 125 ng h/mL to about 400 ng h/mL, about 125 ng h/mL under the curve of the plasma concentration of zoledronic acid from about 300 ng h/mL to about 300 ng h/mL, from about 125 ng h/mL to about 200 ng h/mL or from about 200 ng h/mL to about 300 ng h/mL. It is present in an amount to provide an area. This amount may be suitable for daily administration of the oral dosage form. In some embodiments, the formulation may be administered for 2, 3, 4, 5, 6, 7, 8, 9 or 10, 5 to 10 or 6 to 10 consecutive days.

Oral administration of zoledronic acid, particularly in the disodium salt form of zoledronic acid, may result in greater sustained plasma levels of the drug compared to parenteral modes of administration such as intravenous or subcutaneous. For example, the amount of zoledronic acid in plasma can be significantly higher for oral administration of the disodium salt after about 24 hours or 48 hours or more of administration. In some embodiments, oral zoledronic acid has a 24-hour sustained plasma level factor of at least about 1, such as from about 1 to about 10, from about 1 to about 5, from about 3 to about 5, or from about 3 to about 4. In some embodiments, the orally administered formulation of zoledronic acid is at least 1.2 times, at least about 2 times, at least about 5 times, about 1.2 times to about 20 times, about 2 times to about 15 times, about 2 times to about 15 times, intravenously administered zoledronic acid. , a higher 24-hour sustained plasma level factor or a 48-hour sustained plasma level factor, such as from about 5 times to about 10 times or from about 8 to about 15 times. The "persistent plasma level factor", p _f is determined by the formula

p _f = 1000 (C _t /C _max )

where C _max is its maximum plasma concentration after administration of zoledronic acid and Ct is the plasma concentration of zoledronic acid at that time, such as 24 hours. For parenteral administration, C _max may be C ₀ , or approximately the concentration immediately after injection of the entire amount of the drug into the body. Sustained plasma level factors can also be obtained for other times, such as 48 hours, by using the plasma concentration of zoledronic acid for C _t in the formula above. For example, if the maximum plasma level of zoledronic acid after administration is 1000 ng/mL and the plasma level of zoledronic acid at 24 hours is 1 ng/mL, the 24-hour sustained plasma level factor is 1.

Oral dosage forms comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated in an amount of about 12 to about 50, about 20 to about 40, about 25 for the particular species of mammal. to about 30, from about 30 to about 35, from about 35 to about 40, from about 33 to about 30, a 12 hour lasting plasma level factor of about 35, or any of the ranges included in or between any of these values It can be configured to have a 12 hour lasting plasma level factor.

Oral formulations comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated in an amount of about 10 to about 30, about 10 to about 20, about 10 for the particular species of mammal. a 24-hour sustained plasma level factor of from about 15, about 12 to about 15 or 16, about 15 to about 20, about 14, about 12, about 15, or a range comprised between or included in any of these values. It can be configured to have any 24 hour lasting plasma level factor.

Oral dosage forms comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated in such a way that the zoledronic acid is present in an amount of about 6 to about 20, about 8 to about 15, about 9 for a particular species of mammal. to about 12 or 13, about 8 to about 10, about 11 to about 13, about 9, about 13, a 36 hour lasting plasma level factor, or any 36 in the range included in or between any of these values It can be configured to have a time lasting plasma level factor.

Oral dosage forms comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated in such a way that the zoledronic acid is in the range of about 5 to about 20, about 6 to about 15, about 7 for the particular species of mammal. or a 48 hour lasting plasma level factor of 8 to about 12 or 13, about 8 to about 10, about 11 to about 13, about 8, about 12, or any range included in or between any of these values may be configured to have a plasma level factor lasting 48 hours of

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated in such a way that the zoledronic acid is in the range of about 4 to about 20, about 5 to about 10, about 5 for the particular species of mammal. or a 72 hour lasting plasma level factor of 6 to about 10 or 11, about 5 to about 6, about 9 to about 10, about 6, about 10, or 72 in a range included in or between any of these values It can be configured to have a time lasting plasma level factor.

Oral formulations comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be formulated from about 0.5 ng/mL to about 5 ng/mL, from about 1 ng/mL to about 3 zoledronic acid for the particular species of mammal. ng/mL, about 1 ng/mL to about 2 ng/mL, about 2 ng/mL to about 3 ng/mL, about 3 ng/mL to about 4 ng/mL, about 1.2 ng/mL, about 2.6 ng/mL mL, a plasma concentration of zoledronic acid at 12 hours of about 3.2 ng/mL, or any plasma concentration in a range falling within or between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be from about 0.2 ng/mL to about 2 ng/mL, from about 0.5 ng/mL to about 1.5 for the particular species of mammal. 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 1.4 ng/mL in 24 hours plasma concentrations of zoledronic acid, or any plasma concentration in a range falling within or between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal can be from about 0.1 ng/mL to about 2 ng/mL, from about 0.2 ng/mL to about 1.5 of the particular species of mammal. ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 1 ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about 0.8 ng/mL mL, a plasma concentration of zoledronic acid at 36 hours of about 1.1 ng/mL, or any plasma concentration in a range falling within or between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal can be from about 0.1 ng/mL to about 2 ng/mL, from about 0.2 ng/mL to about 1.5 of the particular species of mammal. ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.9 ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about 0.7 ng/mL mL, a plasma concentration of zoledronic acid at 48 hours of about 1.1 ng/mL, or any plasma concentration in a range falling within or between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal may be from about 0.2 ng/mL to about 1 ng/mL, from about 0.2 ng/mL to about 1.5 for the particular species of mammal. ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.2 ng/mL, about 0.5 ng/mL mL, a plasma concentration of zoledronic acid at 72 hours of about 0.9 ng/mL, or any plasma concentration in a range falling within or between any of these values.

An oral dosage form comprising zoledronic acid having a dosage and composition of zoledronic acid suitable for a particular species of mammal has a elimination half-life of zoledronic acid in the particular species of mammal of about 30 hours to about 100 hours, about 40 hours. to about 60 hours, about 40 hours to about 50 hours, about 50 hours to about 60 hours, about 42 hours, about 51 hours, about 59 hours, or any of the ranges included in or in between any of these values It can be configured to have a half-life.

"Clearance half-life" as used herein refers to the apparent first-order terminal plasma elimination half-life obtained by non-compartmental analysis using Win-Nonlin. The terminal plasma clearance half-life is the time required to reduce the plasma concentration by one-half after reaching quasi-equilibrium, not the time required to eliminate one-half the administered dose. For orally administered drugs, the terminal plasma clearance half-life may be affected by absorption of the drug as well as plasma clearance and extent of dispersion.

In some embodiments, the disodium salt form of zoledronic acid has an improvement in bioavailability compared to the diacid form of zoledronic acid in addition to any improvement to bioavailability provided by any bioavailability enhancing agent in the formulation. to provide. In some embodiments, the disodium salt form of zoledronic acid has an improvement in bioavailability, compared to the diacid form of zoledronic acid, that is greater than any improvement to bioavailability provided by any bioavailability enhancing agent in the formulation. to provide. In some embodiments, the disodium salt form of zoledronic acid can be administered in a formulation that is substantially free of bioavailability enhancing agents.

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

In some embodiments, formulations comprising the disodium salt of zoledronic acid are used for the treatment of an inflammatory condition.

In some embodiments, formulations comprising the disodium salt of zoledronic acid are used for the treatment of arthritis.

In some embodiments, formulations comprising the disodium salt of zoledronic acid are used in the treatment of complex regional pain syndrome.

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

The disodium salt form of zoledronic acid may be more compressible than the diacid form of zoledronic acid. This may make it easier for the formulation to have the desired hardness. This may also make it easier to increase drug loading, providing smaller tablets for a given dose hardness. In some embodiments, the solid formulation of zoledronic acid, such as the diacid form of zoledronic acid or the disodium salt form of zoledronic acid, may have a hardness of about 5 kPa to about 20 kPa or about 5 kPa to about 14 kPa. .

A pharmaceutical carrier selected on the basis of the selected route of administration for zoledronic acid or other bisphosphonates and standard pharmaceutical practice, such as as described in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is incorporated herein by reference in its entirety. can be combined with The relative proportions of active ingredient and carrier can be determined, for example, by the solubility and chemical properties of the compound, the route of administration selected and standard pharmaceutical practice.

The zoledronic acid or other bisphosphonate may be administered by any means capable of bringing the active agent(s) into contact with a site or site(s) of activity within the patient's body. The compounds may be administered by any conventional means useful for use with medicaments, either as a separate therapeutic agent or in combination with a therapeutic agent. For example, it may be administered as the sole active agent in a pharmaceutical composition, or may be used in combination with other therapeutically active ingredients.

In some embodiments, the osteoclast inhibitor may be co-administered with a steroid. Suitable steroids include, for example, hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluoro Cinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, acleomethasone dipropionate, betamethasone valerate, Betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocorthilone caproate, fluocortolone pivalate and flupredniden acetate, hydrocortisone-17 -butyrate, 17-asponate, 17-buteprate and prednicarbate.

Any effective dose of the steroid may be administered to a human. In some embodiments, the dose of steroid is from about 1 mg to about 500 mg of steroid. In some embodiments, the dose of steroid does not exceed 25 mg of steroid and is at least 5 mg of steroid.

Steroids may be given orally (eg 7.5 mg prednisone) by separate infusions (eg 7.5 mg methyl prednisolone) mixed with zoledronic acid in the same infusion, or intramuscularly, subcutaneously, by intestinal suppository, by inhalation or joint It may be administered by direct infusion.

Zoledronic acid or other bisphosphonates may be administered to a human patient in a variety of forms adapted to the chosen route of administration, such as oral, rectal or parenteral administration. Parenteral administration in this aspect includes, but is not limited to, administration by the following routes: pulmonary, intrathecal, intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, sublingual and buccal; topical; nasal inhalation by inhalation; and rectal systemic.

The effective amount of zoledronic acid or other bisphosphonate will depend on a variety of factors known to the treating physician, such as the severity of the condition being treated, the route of administration, the formulation and formulation, the physical properties of the bisphosphonate compound used, and the age, weight and response of the individual patient. It will be different.

The amount of zoledronic acid or other bisphosphonate in the therapeutic composition may vary. For example, some liquid compositions contain from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% 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), from about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w) /v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w) /v) zoledronic acid.

Some solid compositions contain at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w) /w), at least about 80%, 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) to about 60% (w/w) w), from about 70% (w/w) to about 75% (w/w), from about 70% (w/w) to about 80% (w/w), or from about 80% (w/w) to about 90% (w/w) of zoledronic acid.

Any suitable amount of an osteoclast inhibitor may be used, including a nitrogen-containing bisphosphonate, such as a bisphosphonate such as zoledronic acid, minodronic acid or ibandronic acid. Some solid or liquid oral dosage forms, or units of oral dosage forms (collectively referred to herein as "oral dosage form(s)") may contain from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, about 0.5 mg. to about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about 50 mg, about 40 mg to about 60 mg, about 50 mg to about 60 mg , about 55 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to about 600 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, about 30 mg to about 800 mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg , about 50 mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about 2000 mg, about 300 mg to about 1500 mg, about 200 mg to about 1000 mg, about 100 mg to about 500 mg, or about 150 mg of zoledronic acid, or an osteoclast inhibitor in any amount ranging from or within any of these values. In some embodiments, the oral osteoclast inhibitor is administered daily, weekly, monthly, every 2 or 3 months, once a year or twice a year.

Some oral dosage forms are about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 100 mg, about 1 mg to about 1,000 mg , about 10 mg to about 50 mg, about 40 mg to about 60 mg, about 50 mg to about 60 mg, about 55 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to about 600 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 , about 30 mg to about 800 mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about 50 mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about 2000 mg, about 300 mg to about 1500 mg, about 200 mg to about 1000 mg, about 100 mg to about 500 mg or about 150 mg of an osteoclast inhibitor or any amount ranging from or within any of these values It may contain an osteoclast inhibitor. In some embodiments, the oral osteoclast inhibitor is administered daily, weekly, monthly, every 2 or 3 months, once a year, or twice a year.

In some embodiments, the oral dosage form is from about 10 mg/m to about 20 mg/m, from about 15 mg/m to about 20 mg/m, about 18 mg/m, from about 80 mg/m to about 150 mg/m , from about 90 mg/m to about 150 mg/m, from about 100 mg/m to about 150 mg/m of zoledronic acid, or any amount of sol in the range included in or between any of these values. may contain redronic acid. 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 an osteoclast inhibitor, including a nitrogen-containing bisphosphonate, such as a bisphosphonate such as zoledronic acid, minodronic acid or ibandronic acid, is from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, about from 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg, or any amount within the range of or in between any of these values. In some embodiments, the daily oral dose of the osteoclast inhibitor is less than about 35 mg/m, less than about 30 mg/m, less than about 25 mg/m, from about 1 mg/m to about 35 mg/m, about 1 mg/m m to about 30 mg/m, from about 1.5 mg/m to about 25 mg/m, from about 1.8 mg/m to about 20 mg/m, from about 10 mg/m to about 20 mg/m, from about 10 mg/m to zoledronic acid in any amount ranging from about 30 mg/m, about 15 mg/m to about 20 mg/m, about 18 mg/m, or any of these values or in between.

In some embodiments, the daily oral dose of an osteoclast inhibitor, including a nitrogen-containing bisphosphonate, such as a bisphosphonate such as zoledronic acid, minodronic acid or ibandronic acid, is from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, about an osteoclast inhibitor in any amount ranging from 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg or any of these values or in between. In some embodiments, the daily oral dose of the osteoclast inhibitor is less than about 35 mg/m, less than about 30 mg/m, less than about 25 mg/m, about 1 mg/m to about 35 mg/m, about 1 mg/m m to about 30 mg/m, from about 1.5 mg/m to about 25 mg/m, from about 1.8 mg/m to about 20 mg/m, from about 10 mg/m to about 20 mg/m, from about 10 mg/m to about 30 mg/m 2 , about 15 mg/m 2 to about 20 mg/m 2 , about 18 mg/m 2 , or any amount of an osteoclast inhibitor in the range included or in between any of these values.

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 of these values. zoledronic acid in any amount within the range included or in between. In some embodiments, the daily oral dose of zoledronic acid is less than about 35 mg/m, less than about 30 mg/m, less than about 25 mg/m, about 1 mg/m to about 35 mg/m, about 1 mg/m m to about 30 mg/m, from about 1.5 mg/m to about 25 mg/m, from about 1.8 mg/m to about 20 mg/m, from about 10 mg/m to about 20 mg/m, from about 10 mg/m to zoledronic acid in any amount within the range of about 30 mg/m 2 , about 15 mg/m 2 to about 20 mg/m 2 , about 18 mg/m 2 , or any of these values.

In some embodiments, the weekly oral dose of an osteoclast inhibitor, including a nitrogen-containing bisphosphonate, such as a bisphosphonate such as zoledronic acid, minodronic acid or ibandronic acid, is from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg, about 20 mg to about 150 mg, about 20 mg to about 60 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg, about 55 mg, about 100 mg to about 150 mg or about 30 mg to about 100 mg. In some embodiments, the weekly oral dose of the osteoclast inhibitor is less than about 250 mg/m, less than about 200 mg/m, less than about 175 mg/m, about 6 mg/m to about 250 mg/m, about 10 mg/m m to about 210 mg/m, from about 10 mg/m to about 170 mg/m, from about 4 mg/m to about 140 mg/m, from about 100 mg/m to about 140 mg/m, about 126 mg/m, or any amount in a range encompassed by or in between any of these values. The weekly oral dose may be given as a single dose given once per week, or it may be given as 2, 3, 4, 5, 6, or 7 separate doses given per week.

In some embodiments, the weekly oral dose of zoledronic acid is about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 10 mg to about 250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg, about 20 mg to about 150 mg, about 20 mg to about 60 mg, about 30 mg to about 70 mg , about 40 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg, about 55 mg, about 100 mg to about 150 mg or about 30 mg to about 100 mg. In some embodiments, the weekly oral dose of zoledronic acid is less than about 250 mg/m, less than about 200 mg/m, less than about 175 mg/m, about 6 mg/m to about 250 mg/m, about 10 mg/m m to about 210 mg/m, from about 10 mg/m to about 170 mg/m, from about 4 mg/m to about 140 mg/m, from about 100 mg/m to about 140 mg/m, about 126 mg/m, or zoledronic acid in any amount ranging between or included in any of these values. The weekly oral dose may be given as a single dose given once per week, or it may be given as 2, 3, 4, 5, 6 or 7 separate doses given per week.

In some embodiments, the monthly dose of an osteoclast inhibitor, including a nitrogen-containing bisphosphonate, such as a bisphosphonate such as zoledronic acid, minodronic acid, or ibandronic acid, or the amount of osteoclast inhibitor administered over a monthly period is about 5000 mg or less, about 4000 mg or less. 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 4,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg to about 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200 mg, about 200 mg to about 300 mg, about 250 mg to about 300 mg, or about 100 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 50 mg to about 800 mg, or from about 100 mg to about 800 mg, from about 40 mg to about 1000 mg, from about 50 mg to about 1000 mg, or from about 100 mg to about 1000 mg, or any range included in or between any of these values is the monthly capacity of In some embodiments, the monthly oral dose of the osteoclast inhibitor is less than about 1000 mg/m, less than about 800 mg/m, less than about 600 mg/m, about 10 mg/m to about 1000 mg/m, about 50 mg/m m to about 800 mg/m, from about 70 mg/m to about 700 mg/m, from about 100 mg/m to about 700 mg/m, from about 100 mg/m to about 600 mg/m, from about 50 mg/m to about 200 mg/m, about 300 mg/m to about 600 mg/m, about 450 mg/m to about 600 mg/m, about 300 mg/m to about 1000 mg/m, about 400 mg/m to about 1000 mg/m, about 500 mg/m to about 1000 mg/m, about 400 mg/m to about 700 mg/m, about 500 mg/m to about 600 mg/m, about 540 mg/m, or any of these values Any amount in a range encompassed by or in between. The monthly dose may be given as a single dose, or as two or more separate doses administered over a period of one month. In some embodiments, the monthly dose is administered in two or three weekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered as 28 to 31 daily doses. In some embodiments, the monthly dose is administered in 5 to 10 individual doses over a period of one month. The monthly dose may be administered for only one month, or may be administered repeatedly for two or more months.

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 4,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg to about 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200 mg, about 200 mg to about 300 mg, about 250 mg to about 350 mg or about 100 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 50 mg to about 800 mg or about 100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg or any monthly dose ranging from about 100 mg to about 1000 mg or any of these values or in between. In some embodiments, the monthly oral dose of zoledronic acid is less than about 1000 mg/m, less than about 800 mg/m, less than about 600 mg/m, about 10 mg/m to about 1000 mg/m, about 50 mg/m m to about 800 mg/m, from about 70 mg/m to about 700 mg/m, from about 100 mg/m to about 700 mg/m, from about 100 mg/m to about 600 mg/m, from about 50 mg/m to about 200 mg/m, about 300 mg/m to about 600 mg/m, about 450 mg/m to about 600 mg/m, about 300 mg/m to about 1000 mg/m, about 400 mg/m to about 1000 mg/m, about 500 mg/m to about 1000 mg/m, about 400 mg/m to about 700 mg/m, about 500 mg/m to about 600 mg/m, about 540 mg/m, or any of these values zoledronic acid in any amount ranging from or in between. The monthly dose may be given as a single dose or as two or more separate doses administered over a month. In some embodiments, the monthly dose is administered as two or three weekly doses. In some embodiments, the monthly dose is administered as 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28-31 daily doses. In some embodiments, the monthly dose is administered in 5 to 10 individual doses per month. The monthly dose may be administered for only one month, or it may be administered repeatedly for two or more months.

with respect to oral administration of zoledronic acid to a mammal such as a dog, rat, rabbit, monkey, ape or human, a dose of from about 0.03 mg/kg to about 10 mg/kg or any smaller range within this range; such as from about 0.4 mg/kg to about 3 mg/kg, from about 0.4 mg/kg to about 1.5 mg/kg, mg/kg, from about 0.4 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 0.6 mg /kg, about 0.6 mg/kg to about 0.7 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 0.9 mg/kg, about 0.9 mg/kg to about 1 mg/kg , about 1 mg/kg to about 1.1 mg/kg, about 1.1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.3 mg/kg, about 1.3 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.7 mg/kg, about 1.7 mg/kg to about 1.8 mg/kg, about 1.8 mg /kg to about 1.9 mg/kg, about 1.9 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.1 mg/kg, about 2.1 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.3 mg/kg, about 2.3 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.7 mg/kg, about 2.7 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 2.9 mg/kg, about 2.9 mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.1 mg /kg, about 3.1 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.3 mg/kg, about 3.3 mg/kg to about 3.4 m g/kg, about 3.4 mg/kg to about 3.5 mg/kg, about 3.5 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.7 mg/kg, about 3.7 mg/kg to about 3.8 mg/kg kg, about 3.8 mg/kg to about 3.9 mg/kg, about 3.9 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 0.7 mg/kg, about 0.7 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.3 mg/kg, about 1.3 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.9 mg/kg kg, about 1.9 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3.3 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 1 mg/kg, or about 0.5 mg/k g to about 1 mg/kg of repeated oral administration, such as from once daily to once annually, from once daily to twice annually, from once daily to three times annually, from once daily to three months dosing once daily, dosing once daily to dosing every 2 months, dosing once daily to dosing every 2 months, dosing once daily to dosing monthly, dosing once daily to dosing every 2-4 weeks, 1 daily It may be a safe dose, such as a single dose to once a week dose.

The doses mentioned in the paragraphs above for the administration of zoledronic acid to a mammal are 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 times or about 3 times. to about 10 times, once a day or less frequently, such as once a week, once every two weeks, once a month, and the like.

For once-daily to once-weekly oral administration of zoledronic acid to a mammal, such as a mouse, rat, dog, primate, or human, in some embodiments, a safely repeated dose is from about 0.03 mg/kg to about 4 mg /kg or any smaller range within this range, such as about 0.01 mg/kg to about 0.02 mg/kg, about 0.02 mg/kg to about 0.03 mg/kg, about 0.03 mg/kg to about 0.04 mg/kg, about 0.04 mg/kg to about 0.05 mg/kg, about 0.05 mg/kg to about 0.06 mg/kg, about 0.06 mg/kg to about 0.07 mg/kg, about 0.07 mg/kg to about 0.08 mg/kg, about 0.08 mg /kg to about 0.09 mg/kg, about 0.09 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.11 mg/kg, about 0.11 mg/kg to about 0.12 mg/kg, about 0.12 mg/kg to about 0.13 mg/kg, about 0.13 mg/kg to about 0.14 mg/kg, about 0.14 mg/kg to about 0.15 mg/kg, about 0.15 mg/kg to about 0.16 mg/kg, about 0.16 mg/kg to about 0.17 mg/kg, about 0.17 mg/kg to about 0.18 mg/kg, about 0.18 mg/kg to about 0.19 mg/kg, about 0.19 mg/kg to about 0.2 mg/kg, about 0.2 mg/kg to about 0.21 mg /kg, about 0.21 mg/kg to about 0.22 mg/kg, about 0.22 mg/kg to about 0.23 mg/kg, about 0.23 mg/kg to about 0.24 mg/kg, about 0.24 mg/kg to about 0.25 mg/kg , about 0.25 mg/kg to about 0.26 mg/kg, about 0.26 mg/kg to about 0.27 mg/kg, about 0.27 mg/kg to about 0.28 mg/kg, about 0.28 mg/kg to about 0.29 mg/kg, about 0.29 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.31 mg/kg, about 0.31 mg/kg to about 0.32 mg/kg, about 0.32 mg/kg to about 0.33 mg/kg, about 0.33 mg/kg to about 0.34 mg /kg, about 0.34 mg/kg to about 0.35 mg/kg, about 0.35 mg/kg to about 0.36 mg/kg, about 0.36 mg/kg to about 0.37 mg/kg, about 0.37 mg/kg to about 0.38 mg/kg , about 0.38 mg/kg to about 0.39 mg/kg, about 0.39 mg/kg to about 0.4 mg/kg, about 0.05 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg, about 0.06 mg/kg to about 0.15 mg/kg, about 0.07 mg/kg to about 0.15 mg/kg, about 0.08 mg/kg to about 0.15 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg, about 0.1 mg /kg to about 0.15 mg/kg, about 0.03 mg/kg to about 0.5 mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.1 mg/kg to about 0.2 mg/kg, about 0.4 mg to about 4 mg, about 0.4 mg/kg to about 0.6 mg/kg , about 0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2 mg /kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg /kg, about 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 4 mg/kg, about 0.5 mg/kg to about 2 mg/kg , about 0.6 mg/kg to about 2 mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to about 2 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 0.6 mg/kg to about 1.5 mg/kg, about 0.7 mg/kg to about 1.5 mg/kg, about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg to about 0.9 mg/kg, about 0.6 mg /kg to about 0.9 mg/kg, about 0.7 mg/kg to about 0.9 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 mg/kg to about 1 mg/kg, from about 0.8 mg/kg to about 1 mg/kg, or from about 0.8 mg/kg to about 0.9 mg/kg.

For once-weekly or less frequent oral administration of zoledronic acid to a mammal such as a mouse, rat, dog, primate or human, in some embodiments, a safely repeated dose is from about 0.4 mg to about 10 mg or Any smaller range within this range, such as about 0.4 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about 3.4 mg/kg to about 3.6 mg/kg kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 4 mg/kg, about 4 mg/kg to about 4.2 mg/kg, about 4.2 mg/kg to about 4.4 mg/kg, about 4.4 mg/kg to about 4.6 mg/kg, about 4.6 mg/kg to about 4.8 mg/kg, about 4.8 mg/kg to about 5 mg/kg, about 5 mg/kg to about 5.2 mg/kg, about 5.2 mg/kg to about 5.4 mg/kg, about 5.4 mg/kg to about 5.6 mg/kg, about 5.6 mg/kg to about 5.8 mg/kg, about 5.8 mg/kg to about 6 mg/kg, about 6 mg/kg kg to about 6.2 mg/kg, about 6.2 mg/kg to about 6.4 mg/kg, about 6.4 mg/kg to about 6.6 mg/kg, about 6.6 mg/kg to about 6.8 mg/kg, about 6.8 mg/kg to about 7 mg/kg, about 7 mg/kg to about 7.2 mg/kg, about 7.2 mg/kg to about 7.4 mg/kg, about 7.4 mg/kg to about 7.6 mg/kg, about 7.6 mg/kg to about 7.8 mg/kg, about 7.8 mg/kg to about 8 mg/kg, about 8 mg/kg to about 8.2 mg/kg, about 8.2 mg/kg to about 8.4 mg /kg, about 8.4 mg/kg to about 8.6 mg/kg, about 8.6 mg/kg to about 8.8 mg/kg, about 8.8 mg/kg to about 9 mg/kg, about 9 mg/kg to about 9.2 mg/kg , about 9.2 mg/kg to about 9.4 mg/kg, about 9.4 mg/kg to about 9.6 mg/kg, about 9.6 mg/kg to about 9.8 mg/kg, about 9.8 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.6 mg/kg to about 2 mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to about 2 mg/kg, about 0.5 mg /kg to about 1.5 mg/kg, about 0.6 mg/kg to about 1.5 mg/kg, about 0.7 mg/kg to about 1.5 mg/kg, about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 mg/kg to about 1 mg/kg, about 0.8 mg/kg to about 1 mg/kg, or about 0.8 mg/kg to about 0.9 mg/kg.

In some embodiments, the osteoclast inhibitor comprises zoledronic acid, wherein the oral zoledronic acid, or disodium salt thereof, is administered parenterally, such as intravenously, from about 0.1 mg to about 10 mg of zoledronic acid or its It may be administered with a salt. In some embodiments, about 50 mg, about 100 mg, or about 150 mg of the disodium salt of zoledronic acid is administered orally with 1 mg of zoledronic acid for parenteral use, such as intravenously. 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 an osteoclast inhibitor, such as zoledronic acid, minodronic acid, ibandronic acid or other bisphosphonates, for the treatment of pain associated with inflammation, arthritis, CRPS, or any other condition described herein, an osteoclast inhibitor may be The mammal or human to be administered has food for at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours or at least about 12 hours before the osteoclast inhibitor is administered. It may be helpful not to eat or drink (other than any water needed to swallow the oral dosage form). The mammal or human to which the osteoclast inhibitor is administered does not eat or drink food or drink 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 after the osteoclast inhibitor is administered. Not doing so can also help. In some embodiments, the human being administered the zoledronic acid avoids lying down or sits upright or upright for at least about 30 minutes or about 1 hour after receiving the formulation containing the osteoclast inhibitor. Avoiding food or beverages before or after oral administration of the osteoclast inhibitor may improve the bioavailability of the osteoclast inhibitor.

The oral bioavailability of an osteoclast inhibitor in a formulation may vary. Some formulations may have ingredients added to improve bioavailability. However, improved bioavailability is not required to make an oral dosage form effective. In some embodiments, the formulation is substantially free of bioavailability enhancing agents. In some embodiments, the oral dosage form has an oral bioavailability of an osteoclast inhibitor such as zoledronic acid, minodronic acid, ibandronic acid from about 0.01% to about 10%, from about 0.1% to about 7%, from about 0.1% to about 5% or the like. Without ingredients or other means to enhance bioavailability, bisphosphonates such as zoledronic acid typically have low bioavailability in oral dosage forms. In some embodiments, the bioavailability of zoledronic acid is unimproved or substantially unimproved. For example, the oral bioavailability of zoledronic acid can be from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5%, about 0.3% to about 1%, about 1% to about 3%, about 1.2% to about 3.5%, about 1.2% to about 3%, about 1 % to about 4%, about 1.5% to about 4.5%, about 0.1% 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%, from about 1.5% to about 1.6%, from about 1.6% to about 1.8%, from about 1.8% to about 2%, or from about 2% to 2.5%.

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

In some embodiments, the oral bioavailability of the osteoclast inhibitor in the formulation is about 0.01% to about 5%, about 0.1% to about 7%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% to about 2%, from about 0.2% to about 2%, from about 0.2% to about 1.5%, from about 0.3% to about 1.5%, or from about 0.3% to about 1.0%.

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

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

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

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

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

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

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

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

In some embodiments, the oral bioavailability of zoledronic acid in the formulation 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, minodronic acid, or ibandronic acid, which is administered daily for from about 2 to about 15 consecutive days. This regimen is for once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once a year, or It can be repeated 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, minodronic acid, or ibandronic acid for about 2 days to about 15 consecutive days. It is administered daily for one day. This prescription plan is for once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once a year, or every 2 years. It can be repeated once.

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, minodronic acid, or ibandronic acid for about 5 to about 10 consecutive days. It is administered daily for one day. This prescription plan is for once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once a year, or every 2 years. It can be repeated once.

In some embodiments, the oral dosage form comprises about 40 mg to about 150 mg of zoledronic acid, minodronic acid, or ibandronic acid, which is administered daily for about 5 to about 10 consecutive days. This prescription plan is for once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once a year, or every 2 years. It can be repeated once.

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

Osteoclast inhibitors such as zoledronic acid, minodronic acid or ibandronic acid may be formulated for oral administration, for example with an inert diluent or edible carrier, or they may be sealed in hard or soft shell gelatin capsules compressed into tablets or It can be incorporated directly into diet foods. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, powders, suspensions, solutions, syrups, wafers, patches, and the like.

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

Some compositions or formulations may be liquids or may include a solid phase dispersed in a liquid.

Osteoclast inhibitors such as zoledronic acid, minodronic acid or ibandronic acid may be formulated for parenteral or intraperitoneal administration. Solutions of the active compounds as free acids or pharmaceutically acceptable salts can be prepared in water by appropriate mixing with a surfactant such as hydroxypropylcellulose. Powders may also have oils dispersed in or dispersed in glycerol, liquid polyethylene glycols and mixtures thereof. Under normal conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms.

In some embodiments, oral dosage forms may include silicified microcrystalline cellulose such as Prosolv. For example, from about 20% (wt/wt) to about 70% (wt/wt), from about 10% (wt/wt) to about 20% (wt/wt), from 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) ) to about 50% (wt/wt) of silicified microcrystalline cellulose may be present in the oral dosage form or unit of the oral dosage form.

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

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

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

An oral dosage form comprising zoledronic acid or another bisphosphonate or an osteoclast inhibitor may be included in a pharmaceutical product comprising more than one unit of the oral dosage form.

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

A pharmaceutical product containing an oral dosage form for weekly use may contain 4 or 5 units of an oral dosage form for a one-month supply. A weekly supply of approximately two months may contain 8 or 9 units of the oral dosage form. An approximately 6 week weekly supply may contain about 6 units of the oral dosage form. A weekly supply of approximately 3 months may contain 12, 13 or 14 units of the oral dosage form. A weekly supply of approximately 6 months may contain 22-30 units of oral dosage form. A weekly supply of approximately one year may contain 45-60 units of oral dosage form.

The pharmaceutical product may accommodate other dosing regimens. For example, the pharmaceutical product may contain 5 to 10 units of an oral dosage form, wherein each unit of the oral dosage form contains from about 40 mg to about 150 mg of zoledronic acid, minodronic acid, or ibandronic acid. contains Some pharmaceutical products may contain from 1 to 10 units of an oral dosage form, wherein the product contains from about 200 mg to about 2000 mg of zoledronic acid, minodronic acid or ibandronic acid. For such products, each unit of the oral dosage form may be taken daily for 1 to 10 days or 5 to 10 days for a month as at the beginning of the month.

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

Useful doses for antibodies to RANK or RANKL, such as denosumab, are from about 0.1 mg/kg to about 20 mg/kg, from about 0.75 mg/kg to about 7.5 mg/kg, from about 0.1 mg/kg to about 5 mg/kg. , about 1 mg/kg to about 2 mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 to about 17 mg/kg, about 15 mg/kg to about 20 mg/kg, about 1 mg/kg kg, from about 1 mg/kg to about 10 mg/kg, or any value within or in between these ranges based on the body weight of the mammal. The selected dose may be repeated, particularly for chronic conditions, or the amount per dose may be increased or decreased as treatment progresses. The selected dose may be administered one or more times per week, monthly, every two months, every three months, every six months or annually.

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

There are a number of methods by which a portion of Compound 1 and/or Compound 2 can be removed from the zoledronic acid product. For example, HPLC, preparative TLC, crystallization, sublimation or zone purification can be used. Solvents that may be useful for HPLC, TLC or crystallization include water or organic solvents such as hexane, diethyl ether, ethyl acetate, methyl acetate, acetone, acetic acid, acetonitrile, tetrahydrofuran, ethanol, methanol, isopropyl alcohol, chloroform , diethyl ether, toluene, dimethylformamide, benzene, and the like. Gradient or two-solvent systems may also be used. For example, HPLC separation can be started by elution with water, after several hours of elution with water, an organic solvent such as acetonitrile, methanol, ethanol, ethyl acetate, acetone, acetic acid, methyl acetate or other solvent is gradually added to the water Alternatively, water may be substituted entirely. Similarly, crystallization or recrystallization may use a single solvent or a combination of solvents. For example, zoledronic acid or a salt thereof such as a disodium salt may be recrystallized from water, ethanol, methanol, diethyl ether, methyl acetate, acetic acid, and the like, or combinations of these solvents or others. In some embodiments, zoledronic acid or a salt thereof such as a disodium salt is dissolved in water or a solvent such as acetic acid, hexane, diethyl ether, chloroform, dichloromethane, ethyl acetate, methyl acetate, acetic acid, ethanol, The crystallization may be carried out in a second solvent or solvent system, such as methanol or a combination thereof. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of hexane. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of diethyl ether. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of chloroform. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of dichloromethane. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of ethyl acetate. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of methyl acetate. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of acetic acid. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of ethanol. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by addition of methanol. In embodiments using water and a second solvent, the ratio of water to second solvent (water:second solvent) is from about 1:100 to about 100:1, from about 1:10 to about 1:5; about 1:5 to about 1:4, about 1:4 to about 1:3, about 1:3 to about 1:2, about 1:2 to about 1:1, about 1:1 to about 2:1, from about 2:1 to about 3:1, from about 3:1 to about 4:1, from about 4:1 to about 5:1, or from about 1:1 to about 10:1.

In some embodiments, a combination of the two methods described in the paragraph above, such as HPLC or TLC and crystallization, may be used. In some embodiments, methods such as HPLC, preparative TLC, crystallization, sublimation or zone purification may be repeated. In some embodiments, the purification method described in the paragraph above can be performed twice. In some embodiments, the purification method described in the paragraph above can be performed 3 or 4 times.

In the examples below, zoledronic acid was administered in the form of the disodium salt as disodium zoledronic acid tetrahydrate. No bioavailability enhancers were used in the test compositions.

Example 1

Effect of Orally Administered Zoledronic Acid in a Rat Model of Inflammatory Pain

Way:

The effect of orally administered zoledronic acid on inflammatory pain was tested using a rat complete Freund's adjuvant (CFA) model. On day 0, 100% CFA was injected into the left hind paw of Sprague-Dawley rats in a volume of 75 μl to induce inflammatory pain, and then evaluated on days 1 to 3. Animals were given vehicle (control), zoledronic acid 18 mg/m (or 3 mg/kg), zoledronic acid 120 mg/m (or 20 mg/kg), or zoledronic acid 900 mg/m (or 150 mg/kg). kg) was orally administered daily on days 1-3. The drug was dissolved in distilled water and prepared fresh daily. Animals were fasted prior to dosing. Under current FDA guidelines for extrapolating starting doses from animals to humans, doses expressed in mg/m 2 are considered equivalent between mammalian species. Thus, for example, 18 mg/m2 in a rat is considered equivalent to 18 mg/m2 in a human, whereas 3 mg/kg in a rat may not be equivalent to 3 mg/kg in a human.

Values for inflammatory pain (mechanical hyperalgesia) in vehicle and drug treated animals were obtained at baseline and after treatment on day 0 before CFA injection and on days 1-3. Pain was assessed using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). The animals were placed in the restraint bandages that hung them, leaving their hind limbs available for testing. Paw compression thresholds were measured by placing a dome-shaped tip between the third and fourth ulna and applying an increase in pressure to the plantar surface of the hind paw. Pressure was applied gradually over approximately 10 seconds. Measurements were made from the first observed nocifensive behavior of vocalization, writhing or withdrawal. A cutoff value of 300 g was used to prevent damage to animals.

The reversal of inflammatory pain was calculated according to the formula:

Reversal (%) = (post-treatment - baseline after CFA)/(baseline before CFA - baseline after CFA) x 100.

Experiments were conducted using 9 to 10 animals per group.

result:

Oral administration of zoledronic acid significantly improved the inflammatory pain threshold compared to vehicle. Pain threshold measurements taken at various times are shown in FIG. 1 . The foot compression threshold in the 18 mg/m 2 group was higher than for vehicle during the entire measurement period 30 minutes after initiation of treatment. At day 3, the paw compression thresholds for both the 18 mg/m and 900 mg/m groups were greater than for vehicle. An improvement in pain threshold of 49% and 83% from baseline was observed for the 18 mg/m 2 and 900 mg/m 2 groups, respectively.

Orally administered zoledronic acid produced 29% reversal of inflammatory pain at the 18 mg/m 2 dose and 49% reversal at the 900 mg/m 2 dose. The magnitude of this effect is comparable to that obtained with clinical doses of commercially available NSAIDs when tested in similar models of inflammatory pain. Under current FDA guidelines, the standard body surface area for an adult human is 1.62 m2. Thus, a daily dose of 18 mg/m2 corresponds to a monthly dose of about 500-560 mg/m2 or a human dose of about 800-900 mg.

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

Example 2

Effect of Orally Administered Zoledronic Acid in a Rat Model of Arthritic Pain

Way:

The effect of orally administered zoledronic acid on arthritis pain was tested in a rat complete Freund's adjuvant (CFA) model of arthritis pain. In this model, arthritic pain was developed for a period of 10-14 days after injection of 100% complete Freund's adjuvant (CFA) in a volume of 75 μl in the left hind paw. Vehicle (control), zoledronic acid 54 mg/m2 (or 9 mg/kg) or zoledronic acid 360 mg/m2 (or 60 mg/kg) divided into three equal doses daily on the first 3 days after CFA injection into animals. was orally administered. The drug was dissolved in distilled water and prepared fresh daily. Animals were fasted prior to dosing.

Arthritic pain (mechanical hyperalgesia) in vehicle and drug treated animals was assessed 14 days after CFA injection using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). The animals were placed in the restraint bandages that hung them, leaving their hind limbs available for testing. Paw compression thresholds were measured by placing a dome-shaped tip between the third and fourth ulna and applying a pressure increase to the plantar surface of the hind paw. Pressure was applied gradually over approximately 10 seconds. Measurements were taken from the first observed nocifensive behavior of vocalization, writhing or withdrawal. A cutoff value of 300 g was used to prevent damage to animals.

The reversal of arthritis pain in the ipsilateral (CFA injection) paw was calculated according to the following equation:

Reversal (%) = (ipsilateral drug threshold - ipsilateral vehicle threshold)/(contralateral vehicle threshold - ipsilateral vehicle threshold) x 100.

Experiments were conducted using 7 to 10 animals per group.

result:

Oral administration of zoledronic acid significantly improved arthritic pain threshold compared to vehicle. As shown in Figures 2A and 2B, orally administered zoledronic acid produced a dose-dependent reversal of arthritis pain. A reversal of 33% was observed in the 54 mg/m 2 group and a reversal of 54% in the 360 mg/m 2 group. Under current FDA guidelines, the standard body surface area for an adult human is 1.62 m2. Thus, 54 mg/m2 in rats is equivalent to referring to a human dose of about 87 mg, and 360 mg/m2 in rats is equivalent to referring to a human dose of about 583 mg.

Example 3. Treatment of Complex Local Pain Syndrome with Orally Administered Zoledronic Acid

The effect of orally administered zoledronic acid was examined in a rat tibia fracture model of complex regional pain syndrome (CRPS). See Guo TZ et al. (Pain. 2004;108:95-107), CRPS was induced in rats by fracture of the right distal tibia in animals and a cast on the fractured hind paw for 4 weeks. This animal model has been shown to recapitulate the inciting trauma, natural course, signs, symptoms and pathological changes observed in human CRPS patients (Kingery WS et al., Pain. 2003;104:75-84). .

Animals were orally administered vehicle (control) or zoledronic acid at a dose of 18 mg/m/day (3 mg/kg/day) for 28 days starting on the day of fracture and cast. The drug was dissolved in distilled water and administered by feeding. Animals were fasted for 4 hours before dosing and 2 hours after dosing. At the end of the 28 day period, the cast was removed and the next day, the rats were tested for hindpaw pain, edema and warmth.

pain assessment

Pain was assessed by measuring hyperalgesia and weight bearing.

To measure hyperalgesia, an up-down von Frey test paradigm was used. Rats were placed in a clear plastic cylinder (20 cm in diameter) with a wire mesh bottom and allowed to acclimate for 15 minutes. The paws were tested with one series of eight von Frey hairs ranging in stiffness from 0.41 g to 15.14 g. Von Frey hairs were applied against the plantar skin of the hind paws approximately in the middle of the plantar, being careful to avoid tori pads. The fiber was pushed until it was slightly bent, and then it was gently shaken in that position for 6 seconds. Stimuli were given every few seconds. Hindpaw withdrawal from fibers was considered a positive response. The initial fiber serving was 2.1 g, and the fiber was fed according to Dickson's up-down method to produce 6 responses in the immediate vicinity of the 50% threshold. Stimuli were given every few seconds.

Postural effects of hind paw weight bearing and pain were measured using an incapacitance device (IITC Inc. Life Science, Woodland, CA, USA). The hind paws were placed on each metal scale plate and the rats were manually held in an upright position on the device, and the entire weight of the rats was supported on the hind paws. The duration of each measurement was 6 s, and 10 consecutive measurements were taken at 60 s intervals. Eight readings (excluding the highest and lowest) were averaged to calculate both hindpaw weight bearing values. Weight bearing data were analyzed as the ratio ((2R/(R+L))×100%) between right (fracture) and left hind paw weight bearing values.

Edema evaluation

The dorsal-ventral thickness of the hind paws was measured using laser sensor technology. Before the baseline test, two to three mm dots were tattooed on the dorsal skin above the midpoint of the third metatarsal on both hind paws. For laser measurements, each rat was briefly anesthetized with isoflurane and then held upright so that the hind paw rests on a table top under the laser. The foot was gently placed flat on the table while a small metal rod was applied to the top of the ankle joint. Using optical triangulation, the distance from the tattoo site to the top of the hind paw and the distance to the top of the table were measured using a laser with a distance measuring sensor, and the difference was used to calculate the dorsal-ventral paw thickness. The measuring sensor device used in this experiment (4381 Precicura, Limab, Gothenburg, Sweden) had a measuring range of 200 mm and a resolution of 0.01 mm.

hind paw temperature measurement

The temperature of the hind paw was measured using a fine wire thermocouple (Omega, Stanford, Connecticut, USA) applied to the paw skin. Six sites per hind paw were tested. Six measurements for each hind paw were averaged to be the average temperature.

result

As shown in Figure 3, treatment with orally administered zoledronic acid reversed pain, restored weight bearing and prevented edema compared to vehicle treated animals.

As shown in FIG. 4 , the von Frey pain threshold for the right (fracture) hindpaw was reduced by 72% compared to the contralateral (normal) hindpaw in vehicle treated animals. Zoledronate treatment reversed fracture-induced pain by 77% compared to vehicle treatment.

As shown in FIG. 5 , the reduction in weight bearing and the postural effect of pain were significantly higher in the vehicle treatment group than in the zoledronic acid treatment group. The weight bearing on the fractured hindlimb was reduced to 55% of normal in the vehicle treated group. Zoledronate treatment significantly restored hindlimb weight bearing compared to vehicle treatment (86% of normal).

As shown in Figure 6, the expected increase in hindpaw thickness was greater in the vehicle-treated group compared to the zoledronic acid-treated group, reflecting the development of edema. Zoledronate treatment reduced hindpaw edema by 60% compared to vehicle treatment.

Zoledronic acid reduced hindpaw warm angle by 5% compared to vehicle treatment.

The daily dose in this experiment was 18 mg/m 2 /day. Under current FDA guidelines, the standard body surface area for an adult human is 1.62 m2. Thus, a daily dose of 18 mg/m2 corresponds to a monthly dose of about 500-560 mg/m2 or a human dose of about 800-900 mg.

Example 6. Solubility of the disodium salt of zoledronic acid

The aqueous solubility of zoledronic acid and disodium zoledronic acid tetrahydrate was determined. 1 g of test compound was weighed into a beaker. Deionized water (pH 5.5) was then added to the test compound in small increments and the mixture was subjected to ultrasound. The procedure was continued until complete dissolution was achieved. It was determined that complete dissolution was reached when a clear solution was provided with no visible material. Solubility values expressed in grams per 100 ml were calculated using the volume of water required to reach complete dissolution. The procedure was performed for each compound.

result

As shown in FIG. 7 , the aqueous solubility of disodium zoledronic acid tetrahydrate was approximately 50 times that of zoledronic acid. Disodium zoledronic acid tetrahydrate had a solubility of 12.5 g/100 ml, whereas the solubility of zoledronic acid was only 0.25 g/100 ml.

Example 7. Bioavailability of Orally Administered Zoledronic Acid and Disodium Zoledronic Acid

Tablets containing zoledronic acid or a disodium salt of zoledronic acid (disodium zoledronic acid tetrahydrate) were prepared. Both tablet types contained 50 mg of zoledronic acid equivalent per tablet. The same excipient was used for both tablet types, and the amount was adjusted to account for the difference in molecular weight between acid and disodium.

Beagles were orally administered tablets containing 150 mg of zoledronic acid equivalent in the form of disodium zoledronic acid (group 1) or pure zoledronic acid (group 2). Each animal was given three 50 mg equivalent tablets (150 mg total), which were administered together. Before placing the tablet on the back of the animal's tongue, the animal's mouth was wetted with water. Animals were fasted before and after dosing. Animals were 6-9 months old and weighed 6-10 kg on the day of dosing. There were 3 dogs per group.

Sequential blood samples were collected from each animal by jugular venipuncture at each time point after administration for determination of plasma concentrations of zoledronic acid. Blood samples were collected in a cooling tube containing K ₂ EDTA as an anticoagulant. The samples were then centrifuged at approximately 3000 rpm at +4° C. for 10 minutes for plasma induction. Plasma concentrations of zoledronic acid were determined using the LC/MS/MS method.

result

The average plasma concentrations of zoledronic acid for each group of dogs are summarized in Table 1 and shown in FIG. 8 . Detectable plasma levels of zoledronic acid were observed for the entire 48 hours measured.

Disodium zoledronic acid produced significantly higher plasma levels of zoledronic acid than pure zoledronic acid, suggesting improved oral absorption using the salt form. As measured using peak plasma concentrations (C _max ), the disodium salt resulted in a 119% actual increase and a 74% weight adjusted increase in bioavailability compared to pure zoledronic acid. As measured using the area under the plasma concentration curve (AUC _0-∞ ), the bioavailability was 84% and 46% greater on an actual basis and a weight-adjusted basis, respectively, with disodium salt than pure zoledronic acid. The mean AUC _0-∞ for the disodium salt was 4073 ng hr/mL and the mean AUC _0-∞ for the diacid was 2217 ng hr/mL. AUC _0-∞ was found to be dose proportional. Thus, for beagle dogs similar to those tested, about 3 mg to about 4 mg of disodium salt is expected to result in an AUC _0-∞ of about 100 ng hr/mL, and about 7 mg to about 8 mg It is expected that the disodium salt will result in an AUC _0-∞ of about 200 ng·hr/mL.

Example 8

Tablets were prepared by blending the free acid or zoledronic acid in disodium form with the same excipients. For formulations with higher amounts of active, the amount of excipient was reduced proportionally to keep the weight of the tablet at about 100 mg. After blending, the components were compressed at varying pressures followed by film coating. Then, about the resulting tablets, Dr. The hardness was tested using a Schleuniger Pharmatron 8M Tablet Hardness Tester. The results are shown in Table 2 and Fig. 9 below.

Example 9

Some embodiments relating to joint pain, bone marrow lesions and osteoarthritis were considered as a result of interpretation of data from clinical studies. Some of the results of this study were reported by the literature (Laslett et. al. in Ann Rheum Dis 2012;71:1322-1328). Some of the descriptions and data reported below were not published prior to filing this application. Fifty-two patients with clinical knee osteoarthritis and knee bone marrow lesions (BML) were randomized to receive either intravenous zoledronic acid (5 mg) or placebo in a double-blind manner. All patients had at least one bone marrow lesion (BML) in the knee on magnetic resonance imaging (MRI). All patients had an X-ray of the knee for measurement of joint space narrowing (JSN) graded according to the International Association for Osteoarthritis Research (OASI) schematics. The patient had articular space narrowing (OARSI grade 1 and grade 2) of greater than or equal to no joint space narrowing (OARSI grade 0). Twenty-six patients were treated with zoledronic acid (8, 6 and 12 with OARSI grades 0, 1 and 2, respectively). Twenty-six patients received placebo (8, 8 and 12 with OARSI grades 0, 1 and 2, respectively).

Pain intensity was assessed at baseline and at 3 months using the 100 mm Visual Pain Scale (VAS), with 0 representing no pain and 100 representing extreme pain. Changes in pain intensity from baseline to 3 months were calculated.

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

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

Zoledronic acid treatment resulted in a significant reduction in pain compared to placebo in patients with baseline VAS pain intensity scores ≥ 50 mm, but not in patients with baseline VAS scores <50 mm. As shown in Table 4, patients with baseline VAS ≥ 50 mm had a 9 mm decrease in mean VAS score compared to placebo, whereas patients with baseline VAS < 50 mm reduced only 0.6 compared to placebo.

As summarized in Table 5 and shown in Figure 12, the pain reduction was greater in patients with baseline VAS ≥ 50 mm, greater in patients with joint space narrowing at OARSI grade 0, baseline VAS ≥ 50 mm and OARSI. It was maximal in patients with both grade 0 joint space narrowing.

BML was assessed using proton density weighed fat saturated MR images. BML was scored using Osiris software (University of Geneva, Switzerland). The maximum size was measured in mm 2 using a software cursor applied to the largest area of each lesion. If there were more than 1 lesion in the same site, the lesion with the highest score was used. Each patient was given a BML score (mm 2 ) at each of the 4 sites (medial tibia, medial femoral, lateral tibia and lateral femur), and these were summed to give a total BML score (mm 2 ). Changes in total area of BML from baseline to 6 months were calculated.

Zoledronic acid treatment reduced the size of BML. As shown in FIG. 13 and Table 6, the mean BML area in the OARSI grade 0 group decreased by approximately 190 mm 2 compared to placebo, but only 33 mm 2 decreased in the patients with OARSI grade 1-2 compared to placebo.

Example 10

Way

A study was conducted to evaluate the efficacy of a single intravenous infusion of 5 mg ZA in comparison with an intravenous placebo infusion among patients with chronic low back pain (LBP) and modic changes on MRI. This study was a double-blind, randomized, placebo-controlled clinical trial in patients with low back pain (LBP). The patient has an LBP of at least 6 on the 10 cm Visual Pain Scale (VAS) or an Oswestry Low Back Pain Disorder Index (ODI) of at least 30% for at least 3 months, and an MRI performed within the last 6 months immediately prior to enrollment. Patients with low back pain symptoms of M1 type, M1/2 mixed type or M2 type change were included in the study.

Kidney damage, hypocalcemia, known as hypersensitivity to zoledronic acid or other bisphosphonates or components of the infusion, red, in which the patient has a reduced, estimated glomerular filtration rate (eGFR) of less than 40 ml/min, creatinine clearance, red Patients were excluded from the study if they had the presence of a red flag, neuromuscular entrapment, or an early retirement physician. Premenopausal women of childbearing potential were also excluded. Blood samples were taken prior to infusion for assessment of serum concentrations of calcium and creatinine. Clinical examinations included medical history and clinical evaluation of lumbar flexibility, tendon cues, and motor and sensory tests.

After eligibility determination, patients were randomized to receive a single intravenous infusion of 5 mg of zoledronic acid (n=20) or 100 ml saline as placebo (n=20) over a 15-minute period. Information on the use of concomitant medications and hospital access permits was recorded. Blood samples were taken for evaluation of stability, inflammatory mediators and bone turnover rate at baseline, 1 month and 1 year.

Clinical evaluations were performed at 14 days prior to enrollment (screening visit), and at follow-up visits at 1 month and 1 year post-infusion. The primary outcome was the change in intensity of LBP on the VAS. Secondary outcomes included leg pain intensity, ODI, RAND-36-related health-related quality of life, patient-reported sick leave, and back flexibility. These outcome measures were evaluated at baseline and at each follow-up. Waist flexibility was evaluated using finger-palm and trunk lateral flexion measurements (cm). The % of patients undergoing 20% relative improvement, the proportion of patients achieving a VAS score of 40 or less at the primary outcome, and patient acceptable symptom status (PASS) were also assessed. The use of pain medication was required around the time during the follow-up visit.

result

Zoledronic acid treatment resulted in a significant improvement in LBP intensity at 1 month compared to placebo treatment. In addition, patients who received zoledronic acid reported significantly less frequent use of NSAIDs at 1 year than those in the placebo group. Overall, the improvement in most of the parameters evaluated was greater than the zoledronic acid group throughout the follow-up period.

The clinical characteristics of study participants at baseline are presented in Table 6. The mean LBP duration was 293 days, the initial LBP intensity on the VAS was 6.7, the leg pain on the VAS was 2.9, and the ODI score was 32%. All 19 patients in the ZA group and 18 patients in the placebo group had M1/2 lesions. Modic changes located at L4/5 or L5/S1 were most common (70%). The zoledronic acid and placebo groups were similar with respect to the demographic and background characteristics of all patients at baseline (Table 6).

The mean difference (MD) between treatment groups in primary outcome, the intensity of LBP, was significantly favorable to zoledronic acid at 1 month (MD 1.4; 95% CI 0.01 to 2.9), but no significant difference was observed at 1 year. (MD 0.7; 95% CI - 1.0 to 2.4; Table 7). The proportion of patients with at least a 20% improvement in both the strength of PASS and LBP was favorable to zoledronic acid treatment at 1 month: 55% zoledronic acid versus 25% placebo (p=0.105) and 50% zoledronic acid and 50% zoledronic acid respectively (p=0.105) and placebo 20% (p=0.096).

For patients treated with zoledronic acid, as shown in Table 9, the reduction in pain intensity was greater than those with greater baseline pain intensity. The mean pain reduction from baseline was 3.4 for patients with baseline pain intensity ≧7, compared to only 0.1 for patients with baseline pain intensity <6.

Among secondary outcomes, improvement in ODI was favorable for zoledronic acid at 1 month [adjusted-group difference was 6.0% (95% CI - 0.6 to 13)], but not at 1 year (Table 7). Similarly, lateral flexion (to the right and left) was favorable for zoledronic acid treatment at 1 month, but not at 1 year (Table 7). Table 8 shows the changes in total RAND-36 and in the physical and mental components of RAND-36.

At baseline, there were no differences in self-reported use of non-steroidal anti-inflammatory drugs (NSAIDs) between treatment groups, but at 1 year, only 20% of patients in the ZA group used NSAIDs compared to 60% of patients in the placebo group.

[Table 6]

Example 11

1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9). Methyl chloroacetate ( 2 ; 29.8 mL, 338.6 mmol, 2.0 equiv) was added dropwise to 1-(trimethylsilyl)-1H-imidazole ( 8 ; 25.0 mL, 169.3 mmol). The mixture was heated at 60° C. for 24 h. The mixture was cooled to room temperature, washed with Et ₂ O (3x500 mL) and dried in vacuo to give 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.

1,3-bis(carboxymethyl)1H-imidazol-3-ium chloride (10). 1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride ( 9 ; 41.00 g, 164.88 mmol, 1 equiv) was dissolved in 37% aqueous HCl (30.03 mL, 362.74 mmol, 2.2 equiv). The mixture was stirred at reflux for 0.5 h. The mixture was concentrated and the remaining solid was washed with acetone (2x200 mL) and Et ₂ O (3x200 mL). Drying in vacuo gave 10 (31.89 g, 144.55 mmol, 87.7%) as a white solid.

Compound 1: Compound 10 was reacted with an equimolar amount of phosphoric acid and then reacted with an equimolar amount of phosphorus trichloride and an excess of water to form Compound 1, which was precipitated from ethanol.

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

The following embodiments are specifically contemplated:

Embodiment 1. A method of alleviating inflammatory pain comprising administering to a mammal in need thereof an oral dosage form containing zoledronic acid, wherein the mammal has about 800 body surface area based on the mammal's body surface area. A method of receiving a total monthly dose of zoledronic acid of no more than mg/m2.

Embodiment 2. The method of embodiment 1, wherein the mammal is a human receiving a total monthly dose of zoledronic acid from about 30 mg/m 2 to about 700 mg/m 2 .

Embodiment 3. The method of embodiment 2, wherein the total monthly dose is administered in 4 or 5 weekly doses.

Embodiment 4. The method of embodiment 2, wherein the total monthly dose is administered in 28 to 31 daily doses.

Embodiment 5. The method of embodiment 2, wherein the total monthly dose is administered in 5 to 10 individual doses during one month.

Embodiment 6. The method of embodiment 1, wherein the mammal is a human receiving a total weekly dose of zoledronic acid from about 10 mg to about 300 mg.

Embodiment 7. The method of embodiment 6, wherein the total weekly dose is a single dose administered once a week.

Embodiment 8. The method of embodiment 6, wherein the total weekly dose is administered in 2-7 individual doses during 1 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 of any preceding embodiment, wherein the mammal experiences significant pain relief more than 3 hours after administration of the formulation.

Embodiment 11. The method of embodiment 10, wherein the mammal experiences significant pain relief for at least a portion of the time from about 3 hours to about 24 hours after administration of the formulation.

Embodiment 12. The method of embodiment 10, wherein the mammal experiences significant pain relief for at least a portion of the time from about 3 hours to about 3 weeks after administration of the formulation.

Embodiment 13. A method for alleviating inflammatory pain comprising administering to a mammal in need thereof an oral dosage form containing zoledronic acid, wherein the oral dosage form is administered based on the mammal's body surface area. 10 mg/m 2 to about 20 mg/m 2 zoledronic acid.

Embodiment 14. The method of embodiment 13, wherein the oral dosage form contains from about 15 mg/m 2 to about 20 mg/m 2 zoledronic acid based on the body surface area of the mammal.

Embodiment 15. A method of treating inflammatory pain comprising orally administering to a mammal in need thereof from about 300 mg/m to about 600 mg/m of zoledronic acid per month based on the body surface area of the mammal. mitigation method.

Embodiment 16. The method of embodiment 15, comprising orally administering to the mammal from about 450 mg/m to about 600 mg/m of zoledronic acid per month based on the body surface area of the mammal.

Embodiment 17. The method of any preceding embodiment, wherein the mammal does not suffer from bone metastases.

Embodiment 18. The method of any preceding embodiment, wherein the mammal does not have cancer.

Embodiment 19. The method of any preceding embodiment, wherein the zoledronic acid is administered as a salt of the divalent anion of zoledronic acid.

Embodiment 20. A method for alleviating pain associated with arthritis, comprising administering to a human in need thereof an oral dosage form containing zoledronic acid.

Embodiment 21. The method of embodiment 20, wherein the human receives a total monthly dose of about 40 mg to about 2000 mg of zoledronic acid.

Embodiment 22. The method of embodiment 21, wherein the total monthly dose is administered in 4 or 5 weekly doses.

Embodiment 23. The method of embodiment 21, wherein the total monthly dose is administered in 28-31 daily doses.

Embodiment 24. The method of embodiment 21, wherein the total monthly dose is administered in 5 to 10 individual doses during one month.

Embodiment 25. 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. The method of embodiment 25, wherein the total weekly dose is a single dose administered once a week.

Embodiment 27. The method of embodiment 25, wherein the total weekly dose is administered in 2-7 individual doses during one week.

Embodiment 28. 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 of any one of embodiments 20-28, wherein the human experiences significant pain relief more than 3 hours after administration of the formulation.

Embodiment 30. The method of embodiment 29, wherein the human experiences significant pain relief for at least a portion of the time from about 3 hours to about 24 hours after administration of the formulation.

Embodiment 31. The method of embodiment 29, wherein the human experiences significant pain relief for at least a portion of the time from about 3 hours to about 3 weeks after administration of the formulation.

Embodiment 32. The method of any one of embodiments 20-31, wherein the dosage form contains from about 10 mg/m to about 20 mg/m of zoledronic acid based on human body surface area.

Embodiment 33. The method of embodiment 32, wherein the dosage form contains from about 15 mg/m to about 20 mg/m of zoledronic acid based on human body surface area.

Embodiment 34. The method of any one of embodiments 20-33, wherein from about 50 mg/m 2 to about 200 mg/m 2 zoledronic acid per month, based on the human body surface area, is orally administered.

Embodiment 35. The method of any one of embodiments 20-31, wherein the dosage form contains from about 80 mg/m to about 150 mg/m of zoledronic acid based on human body surface area.

Embodiment 36. The method of embodiment 35, wherein from about 300 mg/m to about 1000 mg/m of zoledronic acid per month based on human body surface area is orally administered.

Embodiment 37. The method of any one of embodiments 20-36, wherein the human does not suffer from bone metastases.

Embodiment 38. The method according to any one of embodiments 20-37, wherein the human does not have cancer.

Embodiment 39. The method of any preceding embodiment, wherein the zoledronic acid is in the form of the disodium salt.

Embodiment 40. An oral dosage form comprising zoledronic acid, wherein the oral bioavailability of zoledronic acid in the dosage form is from about 0.01% to about 4%.

Embodiment 41. The oral dosage form of embodiment 40, wherein the oral dosage form contains from about 10 mg to about 300 mg of zoledronic acid.

Embodiment 42. The oral dosage form of embodiment 40, wherein the oral dosage form contains from about 10 mg to about 50 mg of zoledronic acid.

Embodiment 43. The oral dosage form of 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 more than one unit of the oral dosage form of embodiment 40.

Embodiment 45. The pharmaceutical product of 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 of embodiment 45, comprising 28, 29, 30 or 31 units of the oral dosage form for a total of about 28 mg to about 1600 mg of zoledronic acid administered in about 1 month. .

Embodiment 47. The pharmaceutical product of embodiment 45, comprising 85-95 units of the oral dosage form for a total of about 85 mg to about 4800 mg of zoledronic acid administered at about 3 months.

Embodiment 48. The pharmaceutical product of embodiment 45, comprising 170-200 units of the oral dosage form for a total of about 170 mg to about 10000 mg of zoledronic acid administered at about 6 months.

Embodiment 49. The pharmaceutical product of embodiment 45, comprising 350-380 units of the oral dosage form for a total of about 350 mg to about 19000 mg of zoledronic acid administered per year.

Embodiment 50. The pharmaceutical product of embodiment 44, wherein each unit of the oral dosage form contains from about 10 mg to about 300 mg.

Embodiment 51. The pharmaceutical product of embodiment 50, comprising 4 or 5 units of the oral dosage form for a total of about 40 mg to about 1500 mg of zoledronic acid administered within a period of about 1 month.

Embodiment 52. The pharmaceutical product of embodiment 50, comprising 8 or 9 units of the oral dosage form for a total of about 80 mg to about 2700 mg of zoledronic acid administered at about 2 months.

Embodiment 53. The pharmaceutical product of embodiment 50, comprising 12, 13 or 14 units of the oral dosage form for a total of about 120 mg to about 4200 mg of zoledronic acid administered at about 3 months.

Embodiment 54. The pharmaceutical product of embodiment 50, comprising 22-30 units of the oral dosage form for a total of about 220 mg to about 9000 mg of zoledronic acid administered at about 6 months.

Embodiment 55. The pharmaceutical product of embodiment 50, comprising 45-60 units of the oral dosage form for a total of about 450 mg to about 18000 mg of zoledronic acid administered per year.

Embodiment 56. The pharmaceutical product of embodiment 44, comprising 1 to 10 units of the oral dosage form, wherein the product contains from about 200 mg to about 2000 mg of zoledronic acid.

Embodiment 57. The oral dosage form according to any preceding embodiment, wherein the zoledronic acid is in the form of the sodium salt.

Embodiment 58. The oral dosage form of any preceding embodiment, wherein the zoledronic acid is in a form of greater than 1% (w/v) water solubility.

Embodiment 59. The oral dosage form of any preceding embodiment, wherein the zoledronic acid is in a form of about 5% (w/v) to about 50% (w/v) water solubility.

Embodiment 60. An oral dosage form comprising zoledronic acid and an excipient, wherein the zoledronic acid is present in a form of greater than 1% (w/v) water solubility.

Embodiment 61. The oral dosage form of embodiment 60, wherein the zoledronic acid is in a form of about 5% (w/v) to about 50% (w/v) water solubility.

Embodiment 62. A method of treating complex regional pain syndrome comprising administering to a mammal in need thereof an oral dosage form containing zoledronic acid.

Embodiment 63. The method of embodiment 62, wherein the mammal is a human receiving an amount of zoledronic acid from about 30 mg/m to about 700 mg/m for a period of 1 month or less.

Embodiment 64. The method of embodiment 63, wherein 4 or 5 weekly doses are administered over a period of 1 month or less.

Embodiment 65. The method of embodiment 63, wherein 28 to 31 daily doses are administered for a period of up to 1 month.

Embodiment 66. The method of embodiment 63, wherein 5 to 10 individual doses are administered for a period of up to 1 month.

Embodiment 67. The method of embodiment 63, wherein about 30 mg/m to about 700 mg/m of zoledronic acid is administered for only one month.

Embodiment 68. The method of embodiment 63, wherein about 30 mg/m to about 700 mg/m of zoledronic acid is administered for a period of up to one month for at least two consecutive months.

Embodiment 69. The method of embodiment 62, wherein the mammal receives from about 10 mg/m 2 to about 30 mg/m 2 zoledronic acid per day.

Embodiment 70. The method of embodiment 62, wherein the mammal is a human receiving a total weekly dose of zoledronic acid from about 10 mg to about 300 mg.

Embodiment 71. The method of embodiment 70, wherein the total weekly dose is a single dose administered once a week.

Embodiment 72. The method of embodiment 70, wherein the total weekly dose is administered in 2-7 individual doses during one week.

Embodiment 73. The method according to any one of embodiments 62-72, wherein the complex regional pain syndrome is complex regional pain syndrome type I.

Embodiment 74 The method according to any one of embodiments 62-72, wherein the complex regional pain syndrome is complex regional pain syndrome type II.

Embodiment 75. The method of any preceding embodiment, wherein the zoledronic acid is in the form of a salt.

Embodiment 76. The method of any one of embodiments 62-75, wherein the formulation contains from about 10 mg/m 2 to about 20 mg/m 2 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 zoledronic acid based on the body surface area of the mammal.

Embodiment 78. A method of treating complex regional pain syndrome, comprising administering pamidronic acid to a human in need thereof.

Embodiment 79. A method of treating complex regional pain syndrome, comprising administering neridronic acid to a human being in need thereof.

Embodiment 80. A method of treating complex regional pain syndrome, comprising administering olpadronic acid to a human being in need thereof.

Embodiment 81. A method of treating complex regional pain syndrome, comprising administering alendronic acid to a human being in need thereof.

Embodiment 82. A method of treating complex regional pain syndrome, comprising administering incadronic acid to a human being in need thereof.

Embodiment 83. A method of treating complex regional pain syndrome, comprising administering ibandronic acid to a human being in need thereof.

Embodiment 84. A method of treating complex regional pain syndrome, comprising administering risedronic acid to a human being in need thereof.

Embodiment 85. A method of treating pain comprising administering pamidronic acid to a human being in need thereof.

Embodiment 86. A method of treating pain comprising administering neridronic acid to a human being in need thereof.

Embodiment 87. A method of treating pain comprising administering olpadronic acid to a human being in need thereof.

Embodiment 88. A method of treating pain comprising administering alendronic acid to a human being in need thereof.

Embodiment 89. A method of treating pain comprising administering incadronic acid to a human being in need thereof.

Embodiment 90. A method of treating pain comprising administering ibandronic acid to a human being in need thereof.

Embodiment 91. A method of treating pain comprising administering risedronic acid to a human being in need thereof.

Embodiment 92. A method of treating arthritis pain, comprising administering pamidronic acid to a human being in need thereof.

Embodiment 93. A method of treating arthritic pain comprising administering to a human in need thereof neridronic acid.

Embodiment 94. A method of treating arthritis pain, comprising administering olpadronic acid to a human being in need thereof.

Embodiment 95. A method of treating arthritis pain, comprising administering alendronic acid to a human being in need thereof.

Embodiment 96. A method of treating arthritis pain, comprising administering incadronic acid to a human being in need thereof.

Embodiment 97. A method of treating arthritis pain, comprising administering ibandronic acid to a human being in need thereof.

Embodiment 98. A method of treating arthritis pain, comprising administering risedronic acid to a human being in need thereof.

Embodiment 99. A method of treating inflammatory pain comprising administering pamidronic acid to a human being in need thereof.

Embodiment 100. A method of treating inflammatory pain comprising administering neridronic acid to a human being in need thereof.

Embodiment 101. A method of treating inflammatory pain comprising administering to a human in need thereof olpadronic acid.

Embodiment 102. A method of treating inflammatory pain comprising administering alendronic acid to a human being in need thereof.

Embodiment 103. A method of treating inflammatory pain comprising administering incadronic acid to a human being in need thereof.

Embodiment 104. A method of treating inflammatory pain comprising administering ibandronic acid to a human being in need thereof.

Embodiment 105. A method of treating inflammatory pain comprising administering risedronic acid to a human being in need thereof.

Embodiment 106. A method of treating complex regional pain syndrome, comprising administering etidronic acid to a human being in need thereof.

Embodiment 107. A method of treating pain, comprising administering etidronic acid to a human being in need thereof.

Embodiment 108. A method of treating arthritis pain, comprising administering etidronic acid to a human being in need thereof.

Embodiment 109. A method of treating inflammatory pain comprising administering etidronic acid to a human being in need thereof.

Embodiment 110. A method of treating complex regional pain syndrome, comprising administering clodronic acid to a human being in need thereof.

Embodiment 111. A method of treating pain, comprising administering clodronic acid to a human being in need thereof.

Embodiment 112. A method of treating arthritis pain, comprising administering clodronic acid to a human being in need thereof.

Embodiment 113. A method of treating inflammatory pain comprising administering to a human in need thereof clodronic acid.

Embodiment 114. A method of treating complex regional pain syndrome, comprising administering tiludronic acid to a human being in need thereof.

Embodiment 115. A method of treating pain comprising administering tiludronic acid to a human being in need thereof.

Embodiment 116. A method of treating arthritis pain comprising administering tiludronic acid to a human being in need thereof.

Embodiment 117. A method of treating inflammatory pain comprising administering tiludronic acid to a human being in need thereof.

Embodiment 118. The method according to any one of embodiments 78-117, wherein the active compound is administered orally.

Embodiment 119 The method according to any one of embodiments 78-117, wherein the active compound is administered parenterally.

Embodiment 120. A method of enhancing the oral bioavailability of zoledronic acid comprising orally administering a formulation containing zoledronic acid in the form of a disodium salt.

Embodiment 121 The zoledronic acid of embodiment 120, wherein the zoledronic acid in the disodium salt form is in addition to any improvement on bioavailability provided by any bioavailability enhancing agent in the formulation, compared to the zoledronic acid in the diacid form. A method of providing an improvement to bioavailability.

Embodiment 122. The method of embodiment 120, wherein the formulation is substantially free of bioavailability enhancing agents.

Embodiment 123. The method of embodiment 120, wherein the zoledronic acid in the disodium salt form is administered to the mammal from about 4 ng h/mL to about 2000 ng h/mL per administration of zoledronic acid as the disodium salt. A method of administering to a mammal in an amount that provides an area under the curve of the plasma concentration of zoledronic acid.

Embodiment 124. The method of embodiment 123, wherein the zoledronic acid in disodium salt form is administered to the mammal from about 100 ng h/mL to about 2000 ng h/mL per administration of zoledronic acid in disodium salt form. wherein the amount is administered at intervals of about 3 to about 4 weeks in an amount to provide an area under the curve of the plasma concentration of zoledronic acid.

Embodiment 125. The method of embodiment 123, wherein the zoledronic acid in disodium salt form is administered to the mammal from about 20 ng h/mL to about 700 ng h/mL per administration of zoledronic acid in disodium salt form. 3 to 5 times weekly or monthly in an amount providing an area under the curve of the plasma concentration of zoledronic acid.

Embodiment 126. The method of embodiment 123, wherein the zoledronic acid in the disodium salt form is administered to the mammal from about 4 ng h/mL to about 100 ng h/mL per administration of zoledronic acid in the disodium salt form. wherein the method is administered daily in an amount providing an area under the curve of the plasma concentration of zoledronic acid.

Embodiment 127. The method of embodiment 120, wherein the formulation is a solid.

Embodiment 128. The method of embodiment 120, 121, 122, 123, 124, 125, 126 or 127, wherein the bioavailability of zoledronic acid is improved by at least about 20% as compared to administration of zoledronic acid in the diacid form.

Embodiment 129. The molar basis of embodiment 120, 121, 122, 123, 124, 125, 126, 127 or 128, wherein the diacid form of zoledronic acid would be administered to achieve the same plasma level of zoledronic acid. The method further comprising administering less zoledronic acid in the form of the disodium salt as

Embodiment 130. The method of embodiment 129, wherein at least about 10 mole % less disodium form is administered relative to the amount of zoledronic acid in the diacid form that would have been administered to achieve the same plasma level of zoledronic acid.

Embodiment 131. The method of embodiment 129, wherein the disodium salt form is administered in an amount having a value of from about 0.8 n _d to about 1.2 n _d on a molar basis, wherein

n _d= (b _a /b _d )(n _a )

, where b _a is the bioavailability of the diacid form, b _d is the bioavailability of the disodium salt form, and na _is the amount of zoledronic acid in the diacid form that would have been administered to achieve the same plasma level of zoledronic acid. How to forfeit.

Embodiment 132. The method of embodiment 131, wherein the disodium salt is administered in an amount having a value of about n _d .

Embodiment 133 The method of any one of embodiments 120-132, wherein the zoledronic acid is used for the treatment of an inflammatory condition.

Embodiment 134. The method of embodiment 133, wherein the zoledronic acid is used for the treatment of arthritis.

Embodiment 135. The method of embodiment 133, wherein the zoledronic acid is used in the treatment of complex regional pain syndrome.

Embodiment 136. The method according to any one of embodiments 1-39, 62-77 and 120-135,

A first oral dosage form is administered;

A second oral dosage form is administered;

wherein, relative to the first oral dosage form, the second oral dosage form is administered at least 10 x T _max , wherein T _max is the time of maximum plasma concentration for the first oral dosage form.

Embodiment 137. A dosage form comprising zoledronic acid in the disodium salt form, wherein the bioavailability of zoledronic acid in the disodium salt form in the mammal is greater than the bioavailability of zoledronic acid in the diacid form in the same dosage form.

Embodiment 138. A dosage form comprising zoledronic acid in the form of a disodium salt, wherein the dosage form is administered under a curve of plasma concentration of zoledronic acid from about 4 ng h/mL to about 2000 ng h/mL in a human to which the dosage form is administered. A formulation containing zoledronic acid in the form of the disodium salt in an amount to provide an area.

Embodiment 139. The dosage form of embodiment 138, wherein the dosage form provides an area under the plasma concentration curve of zoledronic acid from about 100 ng h/mL to about 2000 ng h/mL to a human to whom the dosage form is administered, disodium Formulations containing zoledronic acid in salt form.

Embodiment 140. The dosage form of embodiment 138, wherein the dosage form provides an area under the plasma concentration curve of zoledronic acid from about 20 ng h/mL to about 700 ng h/mL to a human to which the dosage form is administered, disodium Formulations containing zoledronic acid in salt form.

Embodiment 141. The dosage form of embodiment 138, wherein the dosage form provides an area under the plasma concentration curve of zoledronic acid from about 4 ng h/mL to about 100 ng h/mL to a human to which the dosage form is administered, disodium Formulations containing zoledronic acid in salt form.

Embodiment 142. A formulation comprising zoledronic acid in the form of a disodium salt, comprising:

The disodium salt form is present in a lower molar amount than would be present if the zoledronic acid was in the diacid form;

Zoledronic acid in the disodium salt form has improved bioavailability, compared to zoledronic acid in the diacid form, to the extent that a lower molar amount of the disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the plasma of the mammal. Formulation having.

Embodiment 143. The dosage form according to embodiment 137, 138, 139, 140, 141 or 142, wherein the dosage form is a solid.

Embodiment 144. The formulation of embodiment 142 or 143, wherein the bioavailability of zoledronic acid in the disodium salt form is improved by at least about 10% as compared to another identical formulation containing zoledronic acid in the diacid form.

Embodiment 145. The formulation of embodiment 142, 143 or 144, which contains at least about 20 mole % less disodium form compared to the amount of zoledronic acid in diacid form that would be present if zoledronic acid in diacid form.

Embodiment 146. The method of embodiment 142, wherein the disodium salt form is present in an amount having a value of from about 0.9 n _d to about 1.1 n _d on a molar basis, wherein

n _d= (b _a /b _d )(n _a )

wherein b _a is the bioavailability of the diacid form, _{b d} is the bioavailability of the disodium salt form, and na is the number of moles of the diacid form that would have been present if zoledronic acid was in the diacid form.

Embodiment 147. The formulation of embodiment 146, wherein the disodium salt is administered in an amount having a value of about n _d .

Embodiment 148. The method according to any one of embodiments 1-39, 62-77 and 120-136,

only one oral dosage form is administered; or

A first oral dosage form is administered, and a second oral dosage form is administered after the first oral dosage form, wherein the second oral dosage form is administered or observable before the maximum pain relief effect of the first oral dosage form is achieved. A method wherein the second oral dosage form is administered before the pain relief effect is achieved.

Embodiment 149. The method of embodiment 148, wherein the second oral dosage form is administered before an observable pain relief effect is achieved.

Embodiment 150. The method of any one of embodiments 1-39, 62-77 and 120-132, wherein the first dosage form is administered followed by the second dosage form, wherein the maximal pain relief effect of the first oral dosage form is achieved and then the second dosage form is administered, and the second oral dosage form is administered while the pain relief effect from the first oral dosage form is observable.

Embodiment 151 . The method of embodiments 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 of any one of embodiments 20-39, wherein the human is from about 30 years old to about 75 years old.

Embodiment 153. The method of any one of embodiments 20-39, wherein the human is about 1 year old to about 16 years old.

Embodiment 154. The method of any one of embodiments 20-39, wherein the human is from about 80 years old to about 95 years old.

Embodiment 155. The method of any one of embodiments 20-39, wherein the human has suffered from arthritis for at least 2 months.

Embodiment 156 . The method of any one of embodiments 20-39, wherein the arthritis affects the knee, elbow, wrist, shoulder or hip.

Embodiment 157. The mammal or human according to any one of embodiments 1-44, 62-133 and 144-156, wherein the mammal or human to which the zoledronic acid is administered does not eat or drink food or drink for at least 1 hour prior to administering the zoledronic acid. how not to.

Embodiment 158. The method of embodiment 157, wherein the mammal or human to which zoledronic acid is administered does not eat or drink for at least 2 hours prior to administration of zoledronic acid.

Embodiment 159. The method of embodiment 158, wherein the mammal or human to which zoledronic acid is administered does not eat or drink for at least 4 hours prior to administration of zoledronic acid.

Embodiment 160. The method of embodiment 159, wherein the mammal or human to which zoledronic acid is administered does not eat or drink for at least 6 hours prior to administration of zoledronic acid.

Embodiment 161 The method of any one of embodiments 157-160, wherein the mammal or human to which the zoledronic acid is administered does not eat or drink for at least 30 minutes after administration of the zoledronic acid.

Embodiment 162. The method of embodiment 161, wherein the mammal or human to which zoledronic acid is administered does not eat or drink for at least 1 hour after administration of zoledronic acid.

Embodiment 163 The method of embodiment 161, wherein the mammal or human to which zoledronic acid is administered does not eat or drink for at least 2 hours after administration of zoledronic acid.

Embodiment 164. The method, dosage form or article of any preceding embodiment, wherein the zoledronic acid in the oral dosage form has a plasma level factor that is at least about 1 or greater.

Embodiment 165. The method, formulation or article of any preceding embodiment, wherein the zoledronic acid in the oral dosage form has a higher 24-hour sustained plasma level factor than the intravenously administered zoledronic acid.

Embodiment 166. The method, dosage form or article of any preceding embodiment, wherein the oral dosage form is a solid having a hardness of from about 5 kPa to about 20 kPa.

Embodiment 167. A method of treating a bone marrow lesion comprising: selecting a patient having a bone marrow lesion, and an OARSI grade 0 joint space narrowing, and administering an inhibitor of osteoclast activity to the patient for treatment of the bone marrow lesion. step.

Embodiment 168. The method of embodiment 167, wherein the inhibitor of osteoclast activity is administered at least twice.

Embodiment 169 The method of embodiment 167, wherein the inhibitor of osteoclast activity is administered about every 3 months or more.

Embodiment 170. The method of embodiment 167, wherein the inhibitor of osteoclast activity comprises a nitrogen containing bisphosphonate.

Embodiment 171. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises zoledronic acid.

Embodiment 172. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises pamidronic acid.

Embodiment 173. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises neridronic acid.

Embodiment 174. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises olpadronic acid.

Embodiment 175. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises alendronic acid.

Embodiment 176. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises incadronic acid.

Embodiment 177. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises ibandronic acid.

Embodiment 178. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises risedronic acid.

Embodiment 179. The method of any one of embodiments 167-178, wherein the inhibitor of osteoclast activity is administered orally.

Embodiment 180. The method of any one of embodiments 167-178, wherein the inhibitor of osteoclast activity is administered intravenously.

Embodiment 181. The method of any one of embodiments 167-180, wherein the patient experiences a reduction in bone marrow lesion size that is at least about 100% greater than the reduction in bone marrow lesion size achieved with placebo.

Embodiment 182. The method of any one of embodiments 167-180, wherein the patient experiences a reduction in bone marrow lesion size that is at least about 150% greater than the reduction in bone marrow lesion size achieved with placebo.

Embodiment 183 The method of any one of embodiments 167-182, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.

Embodiment 184. The method of any one of embodiments 167-183, wherein the inhibitor of osteoclast activity is administered once weekly for a period of 6 weeks.

Embodiment 185. The method of any one of embodiments 167-184, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is from about 25 mg to about 75 mg.

Embodiment 186. A method of treating knee pain, comprising: selecting a patient having knee pain and joint space narrowing of OARSI grade 0, and administering to the patient an inhibitor of osteoclast activity for the treatment of knee pain. .

Embodiment 187. The method of embodiment 186, wherein the inhibitor of osteoclast activity is administered at least twice.

Embodiment 188. The method of any one of embodiments 186-187, wherein the inhibitor of osteoclast activity is administered about every 3 months or more.

Embodiment 189. The method of any one of embodiments 186-188, wherein the inhibitor of osteoclast activity comprises a nitrogen containing bisphosphonate.

Embodiment 190. The method of any one of embodiments 186-189, wherein the patient experiences pain relief 3 months after administration of the inhibitor of osteoclast activity.

Embodiment 191 The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises zoledronic acid.

Embodiment 192. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises pamidronic acid.

Embodiment 193. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises neridronic acid.

Embodiment 194. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises olpadronic acid.

Embodiment 195. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises alendronic acid.

Embodiment 196. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises incadronic acid.

Embodiment 197. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises ibandronic acid.

Embodiment 198. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast activity is or comprises risedronic acid.

Embodiment 199. The method of any one of embodiments 186-198, wherein the patient experiences a decrease in pain intensity of at least about 20 using the 100 mm visual pain scale.

Embodiment 200. A method of treating a bone marrow lesion of the knee, comprising: selecting a patient having a bone marrow lesion of the knee, and an OARSI grade 0 or Kelgren and Lawrence grade 0 or grade 1 joint space narrowing, and a bone marrow lesion administering an inhibitor of osteoclast activity to the patient for the treatment of

Embodiment 201. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered at least twice.

Embodiment 202. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered about every 3 months or more.

Embodiment 203. The method of embodiment 200, wherein the inhibitor of osteoclast activity comprises a nitrogen containing bisphosphonate.

Embodiment 204. The method of embodiment 203, wherein the inhibitor of osteoclast activity is zoledronic acid.

Embodiment 205. The method of embodiment 203, wherein the inhibitor of osteoclast activity is pamidronic acid.

Embodiment 206. The method of embodiment 203, wherein the inhibitor of osteoclast activity is neridronic acid.

Embodiment 207. The method of embodiment 203, wherein the inhibitor of osteoclast activity is olpadronic acid.

Embodiment 208. The method of embodiment 203, wherein the inhibitor of osteoclast activity is minodronic acid.

Embodiment 209. The method of embodiment 203, wherein the inhibitor of osteoclast activity is incadronic acid.

Embodiment 210. The method of embodiment 203, wherein the inhibitor of osteoclast activity is ibandronic acid.

Embodiment 211. The method of embodiment 203, wherein the inhibitor of osteoclast activity is risedronic acid.

Embodiment 212. The method of embodiment 203, wherein the inhibitor of osteoclast activity is alendronic acid.

Embodiment 213. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered orally.

Embodiment 214. The method of embodiment 200, wherein the inhibitor of osteoclast activity is administered intravenously.

Embodiment 215. The method of embodiment 200, wherein the patient experiences a reduction in bone marrow lesion size of at least about 15% within about 6 months after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 216. The method of embodiment 200, wherein the patient experiences a reduction in bone marrow lesion size by at least about 25% within about 6 months after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 217. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.

Embodiment 218. The method of embodiment 201, wherein the inhibitor of osteoclast activity is administered once weekly for a period of 6 weeks.

Embodiment 219. The method of embodiment 218, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is from about 25 mg to about 75 mg.

Embodiment 220. A method of treating knee pain comprising:

a. knee pain, and

i. OARSI Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1 joint space narrowing, or

ii. 0-10 Pain intensity of 5 or more when measured using NRS, or 5 cm or more when measured using 10 cm VAS

selecting a patient with and

b. administering to the patient an inhibitor of osteoclast activity.

Embodiment 221. The method of embodiment 220, comprising selecting a patient having joint space narrowing of OARSI Grade 0 or Kelgren and Lawrence Grade 0 or Grade 1.

Embodiment 222. The method of embodiment 220 or 221, comprising selecting a patient having a pain intensity of at least 5 as measured using a 0-10 NRS, or at least 5 cm as measured using a 10 cm VAS.

Embodiment 223. The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered at least twice.

Embodiment 224. The method of embodiment 223, wherein the inhibitor of osteoclast activity is administered about every 3 months or more.

Embodiment 225. The method of embodiment 220, wherein the inhibitor of osteoclast activity comprises a nitrogen containing bisphosphonate.

Embodiment 226. The method of embodiment 220, wherein the patient experiences pain relief within about 3 months after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 227. The method of embodiment 226, wherein the patient experiences pain relief at least 24 hours after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 228. The method of embodiment 220, wherein the inhibitor of osteoclast activity is zoledronic acid.

Embodiment 229. The method of embodiment 220, wherein the inhibitor of osteoclast activity is minodronic acid.

Embodiment 230. The method of embodiment 220, wherein the inhibitor of osteoclast activity is neridronic acid.

Embodiment 231. The method of embodiment 220, wherein the inhibitor of osteoclast activity is olpadronic acid.

Embodiment 232. The method of embodiment 220, wherein the inhibitor of osteoclast activity is alendronic acid.

Embodiment 233. The method of embodiment 220, wherein the inhibitor of osteoclast activity is incadronic acid.

Embodiment 234. The method of embodiment 220, wherein the inhibitor of osteoclast activity is ibandronic acid.

Embodiment 235. The method of embodiment 220, wherein the inhibitor of osteoclast activity is risedronic acid.

Embodiment 236. The method of embodiment 220, wherein the patient experiences a decrease in pain intensity of at least about 5 using the 100 mm visual pain scale.

Embodiment 237. The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.

Embodiment 238. The method of embodiment 220, wherein the inhibitor of osteoclast activity is administered once weekly for a period of 6 weeks.

Embodiment 239 The method of embodiment 238, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is from about 25 mg to about 75 mg.

Embodiment 240. A method of treating moderate to severe knee pain, comprising administering to a person suffering from moderate to severe knee pain an inhibitor of osteoclast activity.

Embodiment 241 The method of embodiment 240, wherein the person suffering from moderate to severe knee pain has normal joint space in the knee.

Embodiment 242. The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered at least twice.

Embodiment 243. The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered about every 3 months or more.

Embodiment 244. The method of embodiment 240, wherein the inhibitor of osteoclast activity comprises a nitrogen containing bisphosphonate.

Embodiment 245. The method of embodiment 240, wherein the patient experiences pain relief within about 3 months after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 246. The method of embodiment 245, wherein the patient experiences pain relief at least 24 hours after the inhibitor of osteoclast activity is administered to the patient.

Embodiment 247. The method of embodiment 240, wherein the inhibitor of osteoclast activity is zoledronic acid.

Embodiment 248. The method of embodiment 240, wherein the inhibitor of osteoclast activity is minodronic acid.

Embodiment 249. The method of embodiment 240, wherein the inhibitor of osteoclast activity is neridronic acid.

Embodiment 250. The method of embodiment 240, wherein the inhibitor of osteoclast activity is olpadronic acid.

Embodiment 251 . The method of embodiment 240, wherein the inhibitor of osteoclast activity is alendronic acid.

Embodiment 252. The method of embodiment 240, wherein the inhibitor of osteoclast activity is incadronic acid.

Embodiment 253. The method of embodiment 240, wherein the inhibitor of osteoclast activity is ibandronic acid.

Embodiment 254. The method of embodiment 240, wherein the inhibitor of osteoclast activity is risedronic acid.

Embodiment 255. The method of embodiment 240, wherein the patient experiences a reduction in pain intensity of at least about 5 using the 100 mm visual pain scale.

Embodiment 256. The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered at least twice over a period of at least 4 weeks.

Embodiment 257. The method of embodiment 240, wherein the inhibitor of osteoclast activity is administered once weekly for a period of 6 weeks.

Embodiment 258. The method of embodiment 257, wherein the inhibitor of osteoclast activity comprises zoledronic acid and the weekly dose is from about 25 mg to about 75 mg.

Embodiment 259. A method for safely delivering zoledronic acid to the blood of a mammal via repeated oral administration, comprising:

orally administering to the mammal from about 0.4 mg/kg to about 4 mg/kg of zoledronic acid less frequently than once a day and more often than once a week; or

Oral administration of about 0.4 mg/kg to about 10 mg/kg to the mammal once a week or less frequently.

Embodiment 260. The method of any preceding embodiment, such as embodiment 259, wherein from about 0.5 mg/kg to about 2 mg/kg is orally administered to the mammal daily.

Embodiment 261 The method of any preceding embodiment , such as embodiment 260, wherein about 0.6 mg/kg to about 0.9 mg/kg is orally administered to the mammal daily.

Embodiment 262. The method of any preceding embodiment, such as embodiment 259, wherein about 0.5 mg/kg to about 2 mg/kg is orally administered to the mammal weekly.

Embodiment 263 The method of any preceding embodiment, such as embodiment 263, wherein about 0.6 mg/kg to about 0.9 mg/kg is orally administered to the mammal weekly.

Embodiment 264. The method of any preceding embodiment, such as embodiments 259, 260, 261, 262 or 263, wherein the zoledronic acid is administered orally about 3 to about 10 times.

Embodiment 265. The method of any of the preceding embodiments, such as embodiments 259, 260, 261, 262, 263 or 264, wherein the zoledronic acid is administered orally in a dosage form comprising greater than about 10% by weight of zoledronic acid.

Embodiment 266. The method of any of the preceding embodiments, such as embodiments 259, 260, 261, 262, 263, 264 or 265, wherein the zoledronic acid is from about 50 ng h/mL to about A method of administration in a manner and in an amount that results in a mammal having an AUC _0-24 of zoledronic acid of 500 ng·h/mL.

Embodiment 267. The AUC of zoledronic acid according to any preceding embodiment, such as embodiment 266, wherein the zoledronic acid is from about 100 ng h/mL to about 500 ng h/mL with each administration of the zoledronic acid. A method in which a mammal having _0-24 is administered in a manner and in an amount.

Embodiment 268. A method for preparing an oral dosage form that is safe for repeated administration to a mammal, comprising zoledronic acid together with a pharmaceutically acceptable excipient to the mammal, wherein the amount of zoledronic acid combined with the excipient comprises: wherein the redronic acid is present in the oral dosage form in an amount from 0.4 mg/kg to about 10 mg/kg, based on the body weight of the mammal.

Embodiment 269 The method of any preceding embodiment, such as embodiment 268, wherein the amount of zoledronic acid combined with the excipient is an amount wherein the oral dosage form comprises greater than about 10% by weight zoledronic acid.

Embodiment 270. The method of any preceding embodiment, such as embodiment 268 or 269, wherein the amount of zoledronic acid combined with the excipient is from 0.4 mg/kg to about 3 mg/kg of zoledronic acid, based on the body weight of the mammal. A method in an amount present in an oral dosage form in an amount of phosphorus.

Embodiment 271. The method of any preceding embodiment, such as embodiment 270, wherein the amount of zoledronic acid combined with the excipient is such that the zoledronic acid is from 0.4 mg/kg to about 1.5 mg/kg of body weight of the mammal. as an amount present in an oral dosage form.

Embodiment 272. The method of any preceding embodiment, such as embodiment 270, wherein the amount of zoledronic acid combined with the excipient is such that the zoledronic acid is from 0.6 mg/kg to about 0.9 mg/kg of body weight of the mammal. as an amount present in an oral dosage form.

Embodiment 273. The method of any preceding embodiment, such as embodiments 268, 269, 270, 271 or 272, wherein the oral dosage form is safe for once daily administration of the oral dosage form for about 3 days to about 10 days. .

Embodiment 274. The method of any preceding embodiment, such as embodiments 268, 269, 270, 271 or 272, wherein the oral dosage form is safe for once weekly administration of the oral dosage form for about 3 weeks to about 10 weeks.

Embodiment 275. Orally administering to the mammal from about 0.05 mg/kg to about 4 mg/kg of zoledronic acid less frequently than once a day and more often than once a week; or

orally administering to a mammal from about 0.1 mg/kg to about 10 mg/kg once a week or less frequently.

A method of safely delivering zoledronic acid to the blood of a mammal through repeated oral administration comprising:

wherein the zoledronic acid is administered orally at least 5 times.

Embodiment 276. The method of any preceding embodiment, such as embodiment 275, wherein the zoledronic acid is administered orally about 5 to about 10 times.

Embodiment 277. The method of any of the preceding embodiments, such as embodiments 275 or 276, wherein the zoledronic acid is administered orally in a dosage form comprising greater than about 10% by weight of zoledronic acid.

embodiment 278. any preceding embodiment, such as embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276 or 277 The method of claim 1 , wherein the mammal is a human.

embodiment 279. any previous embodiment, such as embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277 or 278, wherein about 50 mg to about 350 mg of oral zoledronic acid is administered to the mammal per month.

embodiment 280. any preceding embodiment, such as embodiments 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277 , an oral dosage form prepared by the method of 278 or 279.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and other used in the specification and claims, are intended to refer to both the exact values shown and values modified by the term “about”. case should be understood. Accordingly, unless indicated to the contrary, the numerical parameters recited in the specification and appended claims are approximations which may vary depending upon the desired properties desired. At the very least, and not as an attempt to limit the application of the teachings of equivalents to the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary ordinary skill in the art.

The terms "a", "an", "the" and similar designations used in the context of describing the invention (especially in the context of the claims that follow), unless otherwise indicated herein or otherwise clearly contradicted by context, It should be construed to cover both the singular and the plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of exemplary language (eg, “such as”) or any and all examples provided herein is merely to better explain the invention and is not intended to limit the scope of the claims. No language in the specification should be construed as referring to any non-claimed element essential for the practice of the invention.

The groupings of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and claimed as such, individually or in any combination with other members or other elements of the group described herein. It is contemplated that one or more members of a group may be included in or withdrawn from a group for reasons of convenience and/or patentability. In the event of any such inclusions or deletions, the specification is intended to include groups that complete the written description of all Markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, modifications to these described embodiments will become apparent to those skilled in the art upon reading the above description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Also, any combination in all possible variations of the elements described above is contemplated unless indicated herein or otherwise clearly contradicted by context.

Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other variations that may be employed are within the scope of the claims. Thus, by way of example and not limitation, alternative embodiments may be employed in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments as precisely presented and described.

Claims (30)

A pharmaceutical composition comprising zoledronic acid for the treatment of modic variation type 1 in a human, wherein the human has a baseline visual pain scale (VAS) of 6 or greater, wherein the human experiences pain relief at 3 months after administration of zoledronic acid. a pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the zoledronic acid is administered orally. The pharmaceutical composition according to claim 2, wherein 50 mg to 600 mg of zoledronic acid is administered orally. The pharmaceutical composition according to claim 2, wherein 200 mg to 400 mg of zoledronic acid is administered orally. The pharmaceutical composition according to claim 2, wherein 400 mg to 500 mg of zoledronic acid is administered orally. The pharmaceutical composition according to claim 2, wherein 150 mg to 200 mg of zoledronic acid is administered orally. The pharmaceutical composition according to claim 2, wherein the zoledronic acid in a dose of 100 mg to 200 mg is orally administered twice or three times within one month. The pharmaceutical composition according to claim 2, wherein 50 to 60 mg of zoledronic acid in the form of the disodium salt is administered orally weekly. 9. The pharmaceutical composition of claim 8, wherein the zoledronic acid is administered weekly for 6 weeks. The pharmaceutical composition according to claim 2, wherein the zoledronic acid is administered orally weekly for 1 month or 2 months. The pharmaceutical composition according to claim 2, wherein the zoledronic acid is administered orally weekly for 6 weeks. The pharmaceutical composition of claim 1 , wherein the modic change is located at C1/2, C2/3, C3/4, C4/5, C5/6, or C6/7. 2. The method of claim 1, wherein the modic change is C7/T1, T1/2, T2/3, T3/4, T4/5, T5/6, T6/7, T7/8, T8/9, T9/10, T10. /11, or a pharmaceutical composition located at T11/12. The pharmaceutical composition of claim 1 , wherein the modic change is located at T12/L1, L1/2, L2/3, L3/4, L4/5, or L5/S1. The pharmaceutical composition of claim 1 , wherein the human achieves a size reduction of modic variation type 1 of at least 5% relative to baseline prior to administration of zoledronic acid. The pharmaceutical composition of claim 1 , wherein the human has at least two levels of modic variation type 1 . The pharmaceutical composition of claim 1 , wherein the zoledronic acid is administered orally in such a way that 4 mg of zoledronic acid results in a plasma level factor that is at least twice that of when administered intravenously. The pharmaceutical composition of claim 1 , wherein the zoledronic acid is administered orally in a manner such that 1 mg of zoledronic acid results in a 48 hour lasting plasma level factor that is at least twice that when administered intravenously. The pharmaceutical composition of claim 1 , wherein the zoledronic acid is administered orally in such a way as to result in a bioavailability of at least 1.1%. The pharmaceutical composition according to claim 2, wherein the zoledronic acid is administered orally in such a way as to result in a bioavailability of 1.3% to 3%. The pharmaceutical composition of claim 1 , wherein the human experiences pain relief for at least 3 weeks. The pharmaceutical composition of claim 1 , wherein the human experiences pain reduction lasting for at least 3 months. 3. The pharmaceutical composition of claim 2, wherein the human fasts for at least 2 hours prior to oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human fasts for at least 30 minutes after oral administration of zoledronic acid. The pharmaceutical composition according to claim 2, wherein the human fasts for at least 1 hour after oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human fasts for at least 4 hours prior to oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human fasts for at least 8 hours prior to oral administration of zoledronic acid. The pharmaceutical composition according to claim 2, wherein the human is upright or sitting upright for at least 30 minutes after oral administration of zoledronic acid. The pharmaceutical composition according to claim 2, wherein the magnitude of modic change type 1 with respect to baseline before administration is reduced and maintained for at least 3 months after oral administration of zoledronic acid. The pharmaceutical composition according to claim 2, wherein the magnitude of modic change type 1 with respect to baseline before administration is decreased 3 months after oral administration of zoledronic acid.

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