KR20190010728A - Osteoclast inhibitors for pain - Google Patents

Abstract

Methods of safe administration of imidazole or imidazolium compounds and conditions which can be treated by this method are described herein.

Description

OSTEOCLAST INHIBITORS FOR PAIN}

The present invention relates to pain osteoclast inhibitors.

Bisphosphonate compounds are potent inhibitors of osteoclast activation, bone related conditions such as osteoporosis and Paget's disease of bone; And for the treatment of bone metastasis 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 , US 7704977, 27 April 2010).

Spot osteoporosis and myelodysplasia can result from osteoclast hyperactivity. Zoledronic acid is an effective inhibitor of bone resorption and osteoclast activity. Nitrogen-containing bisphosphonates, such as zoledronic acid, also inhibit the mevalonate pathway in osteoclasts and inhibit normal osteoclast function ( reviewed in Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, 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 found that oral formulations of bisphosphonate compounds such as zoledronic acid can be used in the treatment or alleviation of pain or related conditions.

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

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

Some embodiments are formulations comprising zoledronic acid, wherein the formulation is an amount that provides the area under the plasma concentration curve of zoledronic acid from about 4 ng · h / mL to about 2000 ng · h / mL for a human to which the formulation is administered Lt; RTI ID = 0.0 > of zoledronic acid < / RTI > in the form of its sodium salt.

Some embodiments include formulations comprising zoledronic acid in the form of a sodium salt, wherein the sodium salt form is present in a lower molar amount than present when the zoledronic acid is in the discrete form; The zoledronic acid in the form of its sodium salt has an improved bioavailability such that the lower molar amount of disodium disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the mammalian plasma compared to disolinated zoledronic acid ≪ / RTI >

Although oral formulations with improved bioavailability for bisphosphonates can be used, treatment with the oral formulations comprising a bisphosphonate compound, such as zoledronic acid, in which the bioavailability of bisphosphonates is not improved or substantially improved, is also effective Lt; / RTI >

Some embodiments are methods of alleviating inflammatory pain comprising administering to a mammal in need of relief of inflammatory pain an oral dosage form comprising zoledronic acid, wherein the mammal has a significant lt; RTI ID = 0.0 > of < / RTI > significant pain relief.

Some embodiments include a method of alleviating pain associated with arthritis, including administering an oral formulation containing zoledronic acid to a human in need of relief of pain associated with arthritis.

Some embodiments include a method of treating a complex localized pain syndrome comprising administering to a mammal in need of such treatment a complex topical pain syndrome, an oral formulation comprising zoledronic acid.

Some embodiments include oral formulations with zoledronic acid, wherein the oral bioavailability of the zoledronic acid is substantially improved. For example, in some embodiments, the oral bioavailability in the formulation is from about 0.01% to about 4%.

Some embodiments include a pharmaceutical product comprising more than one unit of the oral dosage forms 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 of relief of inflammatory pain an oral formulation comprising zoledronic acid.

In some embodiments, the mammal receives a monthly dose of zoledronic acid less than or equal to about 800 mg / m 2.

In some embodiments, the formulation contains from about 10 mg / m 2 to about 20 mg / m 2 based on the mammalian body surface area.

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

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

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

Figure 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 after dosing on designated days.
Figure 2A is a graph showing the reversal of arthritis pain for two different doses of zoledronic acid in a rat model of arthritic pain.
Figure 2B is a graph showing the pain threshold for two different doses of zoledronic acid in a rat model of arthritic pain.
Figure 3 is a graph summarizing the results for vehicle and zoledronic acid treatment rats in a rat model of complex local pain syndrome.
Figure 4 shows the rump pain threshold for vehicle and zoledronic acid treatment rats in a rat model of complex local pain syndrome.
Figure 5 shows the weight bearing for vehicle and zoledronic acid treated rats in a rat model of complex local pain syndrome.
Figure 6 shows paw thickness changes for vehicle and zoledronic acid treated rats in a rat model of complex local pain syndrome.
Figure 7 shows the solubility of disodium zoledronic acid dihydrate compared to the discrete form of zoledronic acid.
Figure 8 shows the plasma concentration of zoledronic acid in dogs over time following administration of the disodium form of zoledronic acid and the discrete form of zoledronic acid 150 mg.
Figure 9 shows the compressibility of formulations containing zoledronic acid in the form of a disodium salt, compared to the discrete form.
Figure 10 shows the change in VAS pain score versus placebo at 3 months of treatment with zoledronic acid in patients with osteoarthritis, bone marrow lesion and different degrees of joint space narrowing of the knee.
Figure 11 shows the change in VAS pain score versus baseline at 3 months of treatment with zoledronic acid in patients with osteoarthritis of the knee, bone marrow lesion, and different degrees of joint space narrowing.
Figure 12 shows changes in VAS pain scores versus placebo at 3 months of treatment with zoledronic acid in patients of different subgroups with osteoarthritis of the knee and bone marrow lesions.
Figure 13 shows the change in BML lesion size versus placebo at 6 months of treatment with zoledronic acid in patients suffering from osteoarthritis of the knee, bone marrow lesion and a different degree of joint space narrowing.

Inhibitors of osteoclast activity include, but are not limited to, palimodonate or pamidronic acid, neridronate or neridronic acid, olefadronate or olpadronic acid, alendronate or alendronate, incadronate or incadronic acid acid, ibandronate or ibandronic acid, risedronate or risedronic acid, cimadronic acid or cimadronic acid, zoledronate or zoledronic acid, etidronate or etidronic acid, acid, clodronic acid, clodronic acid, tyluronate or tiludronic acid, and the like.

RANK / RANKL antagonists may be inhibitors of osteoclast activity. The RANK / RANKL antagonist can be selected from the group consisting of OPG (osteoproterenin) or a variant thereof, an anti-RANKL antibody such as denosumab, a monoclonal anti-RANKL antibody, a small interfering RNA, a microRNA, a precursor molecule, a ribozyme, an antisense nucleic acid, But are not limited thereto. An abasic cell inhibitor that targets antibodies, small molecules, small interfering RNAs, microRNAs, precursor molecules such as AB-25E9, ribozymes, antisense nucleic acids or cell surface proteins Siglec-15.

Some Bruton tyrosine kinase (BTK) inhibitors may be inhibitors of osteoclast activity. BTK inhibitors include ONO-4059; Ibrutinib; 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); Methyl-6 - [[4- (4-morpholinylcarbonyl) phenyl] amino] -5-oxo-2-pyrazinyl] - 2-methylphenyl] -4- (1,1-dimethylethyl) - (CGI-1746CAS registry number 910232-84-7); HM-71224; Amino] -4-pyrimidinyl] amino] phenyl] - (CC (2-methoxyphenyl) -292, CAS registration number 1202757-89-8); 2-pyridinecarboxamide, 4- [4 - [[5-fluoro-4 - [[3- 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- (2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide] (dasatinib), alpha-cyano-beta-hydroxy- , 5-ibromophenyl) propenamide (LFM-A13) and ONO-WG-307.

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

The following compounds may also be osteoclast inhibitors.

The term " treating " or " treatment " broadly encompasses any type of therapeutic activity, including diagnosis, healing, alleviation or prevention of disease in humans or other animals, Includes any activity that affects functionality.

Oral formulations of bisphosphonates such as zoledronic acid include, but are not limited to, inflammatory pain, arthritic pain, complex local pain syndrome, urinary sacral pain, musculoskeletal pain, neuropathic pain, chronic pain, cancer related pain, acute pain, Can be used in the treatment or alleviation of any type of pain that is not limited. In some cases, the pain relief may be palliative, or pain relief may be provided independently of the improvement of the disease or condition, or the underlying cause of the disease or condition. For example, an individual suffering from a disease may experience pain relief, even if the underlying disease can not be improved or may continue to progress. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

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

For example, zoledronic acid or other bisphosphonates may be used for the treatment and / or prevention of low back pain, such as back pain and rheumatoid arthritis, pediatric rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, serum negative (non- rheumatoid) arthritis, May be administered orally to alleviate musculoskeletal pain, including pain associated with Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral fracture fracture, osteoporosis, and the like. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

An osteoclast inhibitor, such as a bisphosphonate, such as zoledronic acid, may also be used for the treatment of bone fractures or for the improvement of bone fracture healing.

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

In some embodiments, the zoledronic acid or other bisphosphonate may be orally administered to alleviate inflammatory pain, including musculoskeletal pain, arthritic pain, and complex local pain syndrome. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

Examples of musculoskeletal pain include back pain; And pain associated with vertebral crush fracture, fibrous dysplasia, imperfect bone formation, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip.

Arthritis refers to inflammatory arthropathy that can be associated with pain. Examples of arthritic pain include, but are not limited to, osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, rheumatoid arthritis, serum-negative (non-rheumatoid) arthritic disease, nonarticular rheumatism, periarticular disease, neuropathic arthropathy including Charcot's foot, ≪ / RTI > and pain associated with SAPHO syndrome.

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

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

In some embodiments, arthritis affects the knees, elbows, fingers, wrists, shoulders, ankles, spine or hips.

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

In some embodiments, the person has a baseline pain intensity of greater than or equal to 50 mm when measured using a numerical rating scale (NRS) of 5 or more or a 100 mm visual pain scale (VAS) . In some embodiments, the person being treated for pain has normal joint space knee pain, OARSI 0 grade or Kelgren and Lawrence 0 or 1 grade joint space narrowing.

Bone marrow lesions (BML) involve local bone marrow signal intensity changes on magnetic resonance imaging (MRI). BML can be present in the knee and can be an important feature of osteoarthritis of the knee. BML is also 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, for example, a person who is treated with arthritis with zoledronic acid has osteoarthritis of the knee associated with bone marrow lesions.

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

In some embodiments, an inhibitor of osteoclast activity can be used in the treatment of bone marrow lesions of the knee, shoulder, ankle, wrist, hand, finger, spine, or hips.

Commonly used measures of pain intensity include visual pain scale (VAS) and numeric pain rating (NRS). In the VAS approach, the patient marks the severity of their pain by marking a score on the 10 cm (or 100 mm) VAS (0 = no pain, and 10 = worst possible pain). In the NRS approach, the patient responds verbally to a 10-point NRS (0 = no pain, and 10 = possible worst pain) to grade their moderate pain. VAS and NRS scores were found to be highly correlated (slope of the regression line, 1.01), suggesting that the score on the 10-cm VAS is equivalent to the same score 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 greater or 50 or more or an NRS score of 5 or greater may be referred to herein as moderate to severe knee pain.

In some embodiments, a patient suffering from pain, inflammation, a similar condition, or any of the conditions described herein has an NRS of 5 or greater or a VAS of 5 cm or greater. In some embodiments, the patient has at least 4 NRS or at least 4 cm VAS. In some embodiments, the patient has a NRS of 6 or more or a VAS of 6 cm or more. In some embodiments, the patient has a NRS of 7 or more or a VAS of 7 cm or more. In some embodiments, the patient has about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 NRS. 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 pain associated with knee pain or bone marrow lesions, in some embodiments, treatment with a nitrogen containing bisphosphonate, such as zoledronic acid, results in a visual acuity 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, up to about 50 mm, or up to about 100 mm. In some embodiments, the VAS score may be reduced to at least about 5 mm, at least about 8 mm, at least about 10 mm, at least about 15 mm, up to about 50 mm, or about 100 mm, compared to placebo.

Treatment with a nitrogen containing bisphosphonate such as zoledronic acid may be achieved by administering a number pain rating (NRS) pain score 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, 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, up to about 5, or about 10,

In some embodiments, an inhibitor of osteoclast activity can be used to reduce the size of the bone marrow lesion. The area of the 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 the 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, the use of an inhibitor of osteoclast activity results in a reduction in the total area of bone marrow lesions of at least about 240 mm < 2 >. In some embodiments, the reduction in total area is at least about 220 mm 2, at least about 200 mm 2, at least about 150 mm 2, at least about 100 mm 2, or at least about 50 mm 2. In some embodiments, the decrease in size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% %, At least about 90%, or about 100%. In some embodiments, the reduction in area of 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 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% % Or at least about 450%. 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 usually graded using the Osteoarthritis Research Society International (OARSI) chart standard or the Korgren and Lawrence (K / L) system. In the OARSI scale with 0-3 scale, in the baseline grade JSN, grade 0 indicates absence of JSN, grade 1, 2, and 3 indicate mild, moderate, and severe JSN, respectively (Altman and Gold, Osteoarthritis Cartilage 2007; Suppl A: A1-A56). In a K / L system class JSN using 0-4 scale, class 0 indicates absence of a JSN, class 1 indicates a suspected JSN, class 2, 3 and 4 indicate a minimum, moderate, and medium JSN, respectively (Kellgren and Lawrence, Ann Rheum Dis 1957; 16: 494-502). Based on these criteria, OARSI grade 0 (absence of JSN) is approximately K / L 0-1 grade (absence or suspicious presence of JSN). Knee pain in a person with an ARSI 0 grade or a K / L grade 1 JSN in the knee may be referred to herein as " normal joint space knee pain ".

In some embodiments for a patient having an OARSI grade 0 or a K / L 0-1 grade JSN, the use of an inhibitor of osteoclast activity achieves a reduction in the total area of bone marrow lesions of at least about 240 mm < 2 >. In some embodiments, the reduction in total area is at least about 220 mm 2, at least about 200 mm 2, at least about 150 mm 2, at least about 100 mm 2, or at least about 50 mm 2. In some embodiments, the decrease in 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 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 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 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% % Or at least about 450%. 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 a patient having an OARSI 1-2 Grade or a K / L 2-4 Grade JSN, the use of an inhibitor of osteoclast activity achieves a reduction in the total area of bone marrow lesions of at least about 100 mm 2. In some embodiments, the reduction in total area is at least about 50 mm 2, at least about 60 mm 2, at least about 80 mm 2, at least about 85 mm 2, at least about 90 mm 2, at least about 100 mm 2, at least about 105 mm 2, At least about 115 mm < 2 >. In some embodiments, the decrease in size of the bone marrow lesion is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% , At least about 90%, or about 100%. In some embodiments, the reduction in area of 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 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 350%, at least about 400%, or at least about 450%. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in the size of a bone marrow lesion over time.

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

According to some embodiments, 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 is achieved with the administration of an inhibitor of osteoclast activity. According to some embodiments, administration of an inhibitor of osteoclast activity may be followed by administration of an inhibitor of osteoclast activity at a level of greater than 3 hours, from about 1 day, from about 2 days to about 5 days, at about 1 week, at about 2 weeks About 3 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months , A reduction in pain observed at about 4 months, at about 6 months, or at about 12 months is achieved.

In some embodiments, the administration of an inhibitor of osteoclast activity may be administered at more than 3 hours, but at 1, 2, 3, 4, 5, 6, 7, 8, 9, 11 weeks, 12 weeks, 4 months, 5 months or 6 months.

According to some embodiments, 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 upon administration of an inhibitor of osteoclast activity is achieved.

Following administration of the inhibitor of osteoclast activity, the area of the bone marrow lesion relative to the size prior to administration remains reduced to 3, 4, 5, 6, or even 12 months or more, according to some embodiments. According to some embodiments, after administration of the inhibitor of osteoclast activity, the area of the bone marrow lesion relative to the size prior to administration is reduced 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 activation, the size of the VESC or mordic change relative to the size prior to 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 amount of mordic change or VESC relative 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, the osteoclast inhibitor, such as a nitrogen-containing bisphosphonate, such as zoledronic acid, ibandronic acid or minodronic acid, is administered to a patient suffering from multiple local pain syndrome type I (CRPS-I), multiple localized pain syndrome type II (CRPS- 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 selected from the group consisting of Complex Regional Pain Syndrome Type I (CRPS-I), Complex Regional Pain Syndrome Type II (CRPS-II), CRPS-NOS or other types of Complex Pain Syndrome ≪ / RTI > CRPS is a type of inflammatory pain. CRPS may also have neuropathic components.

Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the arm, which may be accompanied by edema and 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 administered to a patient suffering from a nonsteroidal anti-inflammatory drug (NSAID), opiate, or pain, inflammation, May be used to reduce the use of other pain medications for the patient. At least about 10%, at least about 15%, at least about 20%, at least about 5%, at least about 15%, at least about 20%, 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% , And can be reduced to about 100%. At least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 10%, at least about 20%, at least about 25% At least about 60%, at least about 70%, at least about 80%, or at least about 90%, at least about 100%, at least about 30%, at least about 35% Lt; / RTI >

A reduction in the use of an NSAID, opiate or other pain medication may be 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 in relieving pain associated with inflammatory conditions, relief of pain can be, for example, short-lived for several hours after administration of the formulation, and / or relief of pain, It may be an organ that lasts for days, weeks, or even months after oral administration of lonic acid. In some embodiments, the mammal, such as a human, is administered an oral dosage form comprising zoledronic acid and administered 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 2 weeks, or at least about 3 weeks. In some embodiments, the mammal, such as a human, is administered for about 3 hours to about 2 weeks, for about 3 hours to about 3 weeks, for about 3 hours to about 24 hours, for about 6 hours to about 2 weeks, or about 6 hours to about 24 hours, about 3 days to about 2 weeks, about 6 days to about 2 weeks. In some embodiments, the treated human has significant pain relief at 3 months, 6 months, 9 months, or 1 year after administration of the most recent dose of 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. Two administration time of the formulation if the first dosage form, the first with respect to the formulation for the second orally for formulations for oral use, the second dosage form is 5 x T over _max oral (e.g., oral T _max 1 hour At least about 10 x T _max , at least about 15 x T _max , at least about 20 x T _max , at least about 50 x T _max, or at least about 200 x T _max or more , Wherein T _max is the time of the maximum plasma concentration for the first oral dosage form.

Some embodiments are methods of treating conditions described herein, such as inflammatory pain, arthritis or multiple localized pain syndromes, wherein the treatment includes administering to the mammal only one formulation to treat the condition, or administering the first formulation to the mammal And administering the second formulation to the mammal after administration. Before two or more formulations 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 being fed the formulation, Oral formulations are administered. In some embodiments, a second oral dosage form is administered before an observable pain relief effect is achieved. In some embodiments, the first oral dosage form is administered and about 12 hours to about 60 days, about 24 hours to about 28 days, about 24 hours to about 7 days, about 24 hours to about 14 days, or about 24 hours to about After 21 days the second oral dosage form is administered.

Some embodiments are methods of treating conditions described herein, such as inflammatory pain, arthritis or complex localized pain syndrome, wherein the treatment comprises administering to the mammal a second oral dosage form after administration of the first oral dosage form Wherein the second oral dosage form is administered after the maximum pain relief effect of the first oral dosage form is achieved, or the mammal is still experiencing pain relief from the first oral dosage form, or the first oral dosage form Lt; RTI ID = 0.0 > a < / RTI > second oral dosage form is observable. In some embodiments, the second formulation is administered to a first oral dosage form and 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, 24 hours to about 21 days.

Zoledronic acid or other bisphosphonates may also be orally administered to alleviate cancer-related pain, including pain associated with bone metastasis from multiple myeloma and solid tumors. In some embodiments, zoledronic acid is used in the treatment of pain, which is cancer related pain. For example, zoledronic acid can be used in the treatment of multiple myeloma, bone metastases from solid tumors, hypercalcemia of malignant tumors, giant cell tumors of the bone, blood or leukemia, or pain not associated with solid tumors or cancer. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form 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 pain factors. For example, zoledronic acid or other bisphosphonates may be used in combination with any of the pain conditions or treatments that do not simply alleviate the pain of the conditions of the type described above, and treatments of these conditions, including those conducted in such a way that the condition is treated without pain relief . ≪ / RTI > In addition to any pain relief that zoledronic acid or other bisphosphonates may or may not provide, zoledronic acid or other bisphosphonates may be useful in the treatment of diseases or conditions such as metabolic diseases or conditions; Inflammatory diseases or conditions including inflammatory diseases or conditions not associated with pain; Cancer disease or condition; Nervous system diseases or conditions. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

In some embodiments, oral administration of zoledronic acid or other bisphosphonates may also be useful for the treatment of multiple sclerosis, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, osteoarthritis including ankylosing spondylitis, acute vertebral crush fracture, fibrous dysplasia, SAPHO syndrome, osteoporosis , Transient osteoporosis, or transient osteoporosis of the hips. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

In some embodiments, oral administration of zoledronic acid or other bisphosphate may also be useful in the treatment of hypercalcemia, multiple myeloma, bone marrow from solid tumors, Paget's disease of bone, giant cell tumor of bone, blood cancer or leukemia, May be useful for the treatment of solid tumors or cancers. In some embodiments, improved bioavailability of zoledronic acid in the treatment of one of these conditions can be achieved by administering a formulation comprising zoledronic acid in the form of the sodium salt. This may allow a reduction in the molar amount of the disodium salt used compared to the discrete form used.

Some nitrogen-containing bisphosphonates can 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 heterocyclylalkyl, 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, such as a heterocyclylalkyl, or chemical structural feature is referred to as "optionally substituted", it may be a substituent-free (ie, unsubstituted) feature, Lt; RTI ID = 0.0 > a < / RTI > 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 for parent compounds or structural features. The term " substituted " is used herein for convenience only, and the compound is not necessarily formed by substituting one atom for another. In some embodiments, the substituent has a molecular weight (eg, the sum of the atomic mass of the atoms of the substituents) of from 15 g / mole to 50 g / mole, from 15 g / mole to 100 g / mole, from 15 g / mole to 150 g / , From 15 g / mole to 200 g / mole, from 15 g / mole to 300 g / mole or from 15 g / mole to 500 g / mole, as is known in the art. In some embodiments, the substituent is selected from the group consisting of 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; However, the substituent includes 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 about 15 Da to about 600 Da and can consist of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, P, S, Si, F, Cl or Br. In some embodiments, the substituent is an optionally substituted alkyl, -O- alkyl _{(e.g., -OCH 3, -OC 2 H 5} , -OC 3 H 7, -OC 4 H 9 , etc.), -S- alkyl (e.g., as _{-SCH 3, -SC 2 H 5,} -SC 3 H 7, -SC 4 H 9 , etc.), -NR'R ", -OH, -SH , -CN, -CF 3, -NO 2, perfluoroalkyl 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 referred to as " optionally substituted ", the substituent may be substituted with the substituent.

For convenience, the term " molecular weight " is used to refer to the sum of the atomic mass of a molecule or a moiety of a molecule, relative to the moiety or portion of the molecule, although it may not be a complete molecule.

Examples of the nitrogen-containing bisphosphonate include pamidronic acid, incadronic acid, ibandronic acid, risedronic acid, munidolonic acid, simardronic acid, neridronic acid, alendronic acid, olefadronic acid, zoledronic acid, But is not limited thereto.

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

Unless otherwise indicated, any designation for a compound such as zoledronic acid, by structure, name or any other means herein, includes pharmaceutically acceptable salts, such as disodium salt; Other solid forms, such as polymorphs, solvates, hydrates and the like; Tautomers; Or any other species that can be rapidly converted to the compounds described herein under conditions where the compounds are used as described herein.

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

Examples of the salt of Compound 1 are shown below.

Wherein, X ^- is any suitable anion, for example, ^{F -, Br -, Cl -} , I -, OH -, acetate or the like; M ⁺ is any suitable cation such as _{^{Na +, K +, NH 4}} + or the like. Many other salt forms are possible.

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

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

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

Compound 1 is less than about 100% w / w, less than about 50% w / w, less than about 20% w / w, less than about 10% 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 / 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 the salt of the compound 2 are shown below.

Wherein, X ^- is any suitable anion, for example, ^{F -, Br -, Cl -} , I -, OH -, acetate or the like; M ⁺ is any suitable cation such as _{^{Na +, K +, NH 4}} + or the like. Many other salt forms are possible.

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

In some embodiments, compound 2 may be present in the hydrate form.

In some embodiments, compound 2 is administered in a formulation comprising a salt form such as a salt of compound 2, a monovalent anion, a divalent anion, a salt such as a trivalent anion, or an amphoteric ion form.

Compound 2 is less than about 100% w / w, less than about 50% w / w, less than about 20% w / w, less than about 10% w / w, 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 / 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, such as, for example, zoledronic acid, munidolonic acid, and the like, to a patient or mammal in need thereof affects the mordic change (MC). For example, any of the above compounds may be used in the treatment of mock changes or spinal endometriosis changes (VESC) and bone marrow changes seen using magnetic resonance imaging (MRI), or neck pain or back pain associated with mocking changes.

As used herein, the Mocking variation includes its conventional meaning in the art and refers to pathological vertebral endplates and bone marrow changes visible using magnetic resonance imaging (MRI). Modic changes may also be referred to as vertebral endplate signal changes (VESC). Mocking changes can be classified into various types including type 1 (M1), type 2 (M2) and type 3 (M3) lesions or changes, some of which include nitrogen bisphosphonates including zoledronic acid, Lt; RTI ID = 0.0 > osteoclast < / RTI > Different types of mocking changes may occur in the same patient, such as type 1 and type 2 mock changes (M1 / 2). In some cases, M1 changes are associated with back pain over other types of mock changes.

VESC can be found in patients with different types of back pain, including, but not limited to, spondylitis, trauma, spondyloarthropathies including spondyloarthropathies, small nodules, fractures, tumors, and spinal cord infarction. Lesions in ankylosing spondylitis include osteitis and spinal discitis that can be detected using MRI or other medical imaging devices.

Mordic changes can be found in the neck, chest, waist, and sacrum vertebrae. The modic shifts can be performed in the order of C1 / 2, C2 / 3, C3 / 4, C4 / 5, C5 / 6, C6 / 7, C7 / T1, T1 / 2, T2 / 3, T3 / 4, T4 / Such as T6 / 7, T7 / 8, T8 / 9, T9 / 10, T10 / 11, T11 / 12, T12 / L1, L1 / 2, L2 / 3, L3 / 4, L4 / 5, Can be found at various vertebral levels and some of which can be treated using osteoclast inhibitors such as, for example, nitrogen bisphosphonates, including zoledronic acid, munidolonic acid, and the like.

In some embodiments, the mocking change being treated is located at L2 / 3. In some embodiments, the mocking change to be treated is located at L3 / 4. In some embodiments, the mocking change to be treated is located at L4 / 5. In some embodiments, the mocking changes being treated are located at L5 / S1.

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

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

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

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

In some embodiments, the treated patient has two or more levels of mocking changes. In some embodiments, the treated patient has three or more levels of mocking changes. In some embodiments, greater pain relief is obtained at the time of treatment of a patient with two or more levels of mocking changes than is obtained during treatment of a patient with one or two levels of mocking changes.

In some embodiments, greater pain relief is obtained at the time of treatment of the patient with two levels of Mordic change than is obtained during treatment of the patient with one level of Mordic change.

In some embodiments, greater pain relief is obtained at the time of treatment of a patient with three or more levels of mordic change than is obtained during treatment of a patient with one level of mordic change.

In some embodiments, greater pain relief is obtained at the time of treatment of a patient with three or more levels of the mordic change than is achieved during treatment of the patient with two levels of Mordic change.

In some embodiments, an inhibitor of osteoclast activity can be used to effect a reduction in the level of 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 inflammatory cytokines when treated with inhibitors of osteoclast activity, such as, for example, nitrogen containing bisphosphonates, such as zoledronic acid, munidolonic acid, have. In some embodiments, a greater pain relief in a patient experiencing a reduction or greater reduction in inflammatory cytokine levels in treatment with an inhibitor of osteoclast activity, such as, for example, a nitrogen containing bisphosphonate, such as zoledronic acid, Can be obtained. Inflammatory cytokines include IL-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis alpha It does not.

In some embodiments, an inhibitor of osteoclast activity, such as a nitrogen containing bisphosphonate, including zoledronic acid, munidolonic acid, and the like, is administered to a patient or mammal in need thereof by at least about 5%, at least about 10% At least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of at least about 15%, at least about 20%, at least about 25% Lt; / RTI > change in the magnitude of the VESC is achieved. In some embodiments, the reduced size of the mordic change or 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 70%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120% 300%, at least about 350%, at least about 400%, or at least about 450%. In some embodiments, the use of an inhibitor of osteoclast activity inhibits an increase in the size of the VESC or a modic change over time.

Oral administration of zoledronic acid in the form of its sodium salt can improve oral bioavailability of zoledronic acid. For example, the bioavailability of zoledronic acid may be 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% %. ≪ / RTI >

Due to the improved bioavailability of the sodium salt, the formulations may otherwise contain less sodium disodium form of zoledronic acid on a molar basis than the discrete form of zoledronic acid administered, or the mammal, such as a human, . For example, the formulation can be at least about 10 mole% less, at least about 10 mole% less, or even at least about 10 mole% less, compared to the amount of disaccharide administered differently, At least about 40 mole%, at least about 50 mole%, and / or up to about 90 mole% or up to 95 mole% of the disodium salt form, have.

In some embodiments, the formulation is a mole basis to about 0.8n _d and about _d, or about 1.2n to 0.9n _d containing the amount of the sodium salt form with a value of about 1.1n or _d (such as a human) mammals Lt; RTI ID = 0.0 >

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

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

With respect to oral formulations comprising a reduced molar amount of disodium salt of zoledronic acid relative to the discrete form of zoledronic acid, in some embodiments, the bioavailability of the zoledronic acid in the form of the sodium salt is sufficiently high such that the drug When administered to a mammal, there are as many zoledronic acid in the blood of the mammal as would have existed, at least when the zoledronic acid was administered in a discrete form.

With respect to oral formulations comprising di-sodium salt forms of zoledronic acid, in some embodiments, the di-sodium salt forms are present in a lower molar amount than present when zoledronic acid is in discrete form; The zoledronic acid in the form of its sodium salt has an improved bioavailability such that the lower molar amount of disodium disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the mammalian plasma compared to disolinated zoledronic acid Respectively.

Some oral formulations, including zoledronic acid, have a zoledronic acid and configuration suitable for certain species of mammals, such as dogs, rats, humans, and the like. Such formulations may have zoledronic acid in an amount that results in a desired range for the area under the plasma concentration curve (AUC) of zoledronic acid in a particular species of mammal. For example, the dosage and composition of the oral formulation of zoledronic acid may be in the range of about 1 ng · hr / mL to about 700 ng · hr / mL, about 3 ng · hr / mL to about 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 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 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 140 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 / 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, / mL, about 345 ng · hr / mL, 343 ng · hr / mL, about 385 ng · hr / mL, 384 ng · hr / mL, about 410 ng · hr / option Or may result in any AUC of the range in between.

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

Oral dosage forms comprising zoledronic acid with a dose and composition of zoledronic acid suitable for the mammal of a particular species may be in the range of about 0.2 ng / mL to about 300 ng / mL, about 0.5 ng 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 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 50 ng / Or a C _max of about 100 ng / mL, about 50 ng / mL to about 200 ng / mL, about 40 ng / mL, about 95 ng / mL, about 97 ng / mL zoledronic acid Lt; RTI ID = 0.0 > C- _max < / RTI >

Administration of an oral dosage form to a mammal of a particular species comprises the T _max of zoledronic acid from about 0.4 hr to about 1 hr, about 0.5 hr, or about 0.75 hr, or a range Oral < / RTI > formulations with zoledronic acid dosage and composition suitable for mammals of particular species can be constructed to result in an arbitrary _Tmax of < RTI ID = 0.0 >

In some embodiments, the zoledronic acid in the form of the sodium salt is administered to the mammal in an amount of about 4 ng · h / mL to about 2000 ng · h / mL per day for each oral administration of the zoledronic acid in the sodium salt Lt; RTI ID = 0.0 > zoledronic acid < / RTI >

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

In some embodiments, the zoledronic acid is present in the mammal to which the formulation is administered in an amount of about 20 ng · h / mL to about 700 ng · h / mL, about 50 ng · h / mL to about 500 ng · h 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 / , 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 / From about 100 ng · h / mL to about 200 ng · h / mL, from about 125 ng · h / mL to about 500 ng · h / mL, from about 125 ng · h / mL to about 400 ng · h / Plasma of zoledronic acid at a concentration of from about 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 / Concentration curve < / RTI > This amount may be appropriate for weekly administration of oral formulations or for administration of 3 to 5 individual doses per month. The individual doses may be provided at regular intervals provided during the first week or in any other schedule providing three to five doses over a month.

In some embodiments, the zoledronic acid is present in the mammal to which the formulation is administered in an amount of about 4 ng · h / mL to about 100 ng · h / mL, about 10 ng · h / mL to about 50 ng · h / 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 / From about 50 ng · h / mL to about 400 ng · h / mL, from about 50 ng · h / mL to about 300 ng · h / mL, from about 50 ng · h / from about 100 ng · h / mL to about 500 ng · h / mL, from about 100 ng · h / mL to about 400 ng · h / mL, from about 100 ng · h / 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 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 under a plasma concentration curve of zoledronic acid Lt; RTI ID = 0.0 > area. ≪ / RTI > This amount may be appropriate for daily administration of oral dosage forms. In some embodiments, the formulations 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, especially in the form of its disodium salt of zoledronic acid, may result in a greater sustained plasma level of the drug compared to parenteral modes such as intravenous or subcutaneous. For example, the amount of zoledronic acid in plasma may be significantly higher for oral administration of disodium salt after about 24 hours or 48 hours or more after administration. In some embodiments, the oral zoledronic acid has a plasma plasma level factor of about 1 or more, such as about 1 to about 10, about 1 to about 5, about 3 to about 5, or about 3 to about 4. In some embodiments, the orally administered formulation of zoledronic acid is at least 1.2 times, at least about 2 times, at least about 5 times, from about 1.2 times to about 20 times, from about 2 times to about 15 times , A higher 24 hour sustained plasma level factor or a 48 hour sustained plasma level factor, such as about 5-fold to about 10-fold or about 8 to about 15-fold. The "sustained plasma level factor", p _f , is determined by the following equation:

p _f = 1000 (C _t / C _max )

Where C _max is its maximum plasma concentration after administration of zoledronic acid and C t is the plasma concentration of zoledronic acid at that time, such as 24 hours. For parenteral administration, C _max may be the concentration at C ₀ , or just after the entire dose of the drug is injected 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 in C _t in the above equation. 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 formulations comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal include those in which zoledronic acid is present in the range of about 12 to about 50, about 20 to about 40, about 25 To about 30, about 30 to about 35, about 35 to about 40, about 33, about 30, about 35, or any of the ranges contained in or intervening any of these values And may be configured to have a plasma level factor of 12 hours duration.

An oral dosage form comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal is characterized in that the zoledronic acid is present in the range of about 10 to about 30, about 10 to about 20, about 10 To about 15, from about 12 to about 15 or 16, from about 15 to about 20, from about 14 to about 12, from about 15 to about 24 hours of plasma level factor, And may be configured to have any 24 hour sustained plasma level factor.

An oral dosage form comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal is characterized in that the zoledronic acid is present in the range of about 6 to about 20, about 8 to about 15, about 9 To 36 hours duration plasma level factor of about 12 or 13, about 8 to about 10, about 11 to about 13, about 9, about 13, or any of the ranges contained in or intervening any of these values. May be configured to have a time duration plasma level factor.

An oral dosage form comprising zoledronic acid with a dosage and configuration of zoledronic acid suitable for a particular species of mammal is characterized in that the zoledronic acid is present in the range of about 5 to about 20, about 6 to about 15, about 7 Or a 48 hour sustained plasma level factor of 8 to about 12 or 13, about 8 to about 10, about 11 to about 13, about 8, or about 12, or any of the ranges included in or between any of these values Lt; / RTI > plasma level factor of 48 hours.

An oral dosage form comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal is characterized in that the zoledronic acid is present in the range of about 4 to about 20, about 5 to about 10, about 5 Or a 72 hour sustained 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 a range of 72 May be configured to have a time duration plasma level factor.

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

An oral dosage form comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal comprises about 0.2 ng / mL to about 2 ng / mL of a particular species of mammal, about 0.5 ng / mL to about 1.5 at about 24 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 / The plasma concentration of zoledronic acid, or any plasma concentration in the range comprised within or between any of these values.

Oral formulations comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal may be administered at a dose of from about 0.1 ng / mL to about 2 ng / mL, from about 0.2 ng / mL to about 1.5 about 0.3 ng / mL, about 0.8 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, plasma concentration of zoledronic acid at 36 hours of about 1.1 ng / mL, or any plasma concentration in the range comprised within or between any of these values.

Oral formulations comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal may be administered at a dose of from about 0.1 ng / mL to about 2 ng / mL, from about 0.2 ng / mL to about 1.5 about 0.3 ng / mL, about 0.7 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, plasma concentration of zoledronic acid at 48 hours of about 1.1 ng / mL, or any plasma concentration in the range comprised within or between any of these values.

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

Oral formulations comprising zoledronic acid with a dose and composition of zoledronic acid suitable for a particular species of mammal include those wherein the elimination half-life of zoledronic acid in a particular species of mammal is 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 these values Can be configured to be half-life.

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

In some embodiments, the diatomic form of zoledronic acid has an improved bioavailability, in addition to any improvement in bioavailability provided by any bioavailability enhancer in the formulation compared to the discrete form of zoledronic acid to provide. In some embodiments, the disodium salt form of zoledronic acid has an improvement over bioavailability that is greater than any improvement in bioavailability provided by any bioavailability enhancer in the formulation, compared to the discrete form of zoledronic acid to provide. In some embodiments, the diatomic salt form of zoledronic acid may be administered in a formulation substantially free of bioavailability enhancers.

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

In some embodiments, a formulation comprising a disodium salt of zoledronic acid is used in the treatment of an inflammatory condition.

In some embodiments, a formulation comprising a disodium salt of zoledronic acid is used in the treatment of arthritis.

In some embodiments, a formulation comprising a disodium salt of zoledronic acid is used in the treatment of a complex localized pain syndrome.

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

The disodium salt form of zoledronic acid may be more compressible than the discrete form of zoledronic acid. This can make the formulation more easily have a predetermined hardness. This can also make it easier to increase the drug load, thus providing a smaller tablet for a given dose hardness. In some embodiments, solid formulations of zoledronic acid, such as the discrete form of zoledronic acid or the disodium salt form of zoledronic acid, may have a hardness from about 5 kPa to about 20 kPa or from about 5 kPa to about 14 kPa .

The zoledronic acid or other bisphosphonate can be administered to a selected pharmacological carrier based on the selected route of administration and standard pharmaceutical practice as described, for example, in the disclosure cited herein in its entirety (Remington ' s Pharmaceutical Sciences, 2005) ≪ / RTI > The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature 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 contacting the active site (s) with a given site or site (s) in the patient ' s body. The compounds may be administered as an individual therapeutic agent or together with a therapeutic agent by any conventional means useful for use with a medicament. For example, it can be administered as a sole active agent in a pharmaceutical composition, or it can be used 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, Dexamethasone sodium phosphate, dexamethasone sodium phosphate, fluorocortolone, hydrocortisone-17-valerate, acleomethasone dipropionate, betamethasone valerate, betamethasone sodium phosphate, But are not limited to, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluorocortilone caproate, fluorocortolone pivalate and fluoprednidene acetate, Tison 17-butyrate, and a 17-fibroblast carbonate, 17 parts tapes rate and Fred you carboxylic bait.

Any effective dose of 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 the steroid does not exceed 25 mg of steroid, and is greater than 5 mg of steroid.

Steroids may be provided orally (e.g., 7.5 mg prednisone) by an individual injection (e.g., 7.5 mg of methylprednisolone) mixed with zoledronic acid in the same injection, or by intramuscular, subcutaneous, intrathecal, Can be administered by direct injection.

Zoledronic acid or other bisphosphonates can be administered to human patients in a variety of forms adapted to the chosen route of administration, e.g. oral, rectal or parenteral administration. In this respect, parenteral administration includes, but is not limited to, administration by the following routes: pulmonary, intrathecal, intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal, including transdermal, Sublingual and ball; Topography; Inhaled nasal aspiration; And rectal systemic.

The effective amount of zoledronic acid or other bisphosphonates 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 characteristics of the bisphosphonate compound employed, and the age, It will be different.

The amount of zoledronic acid or other bisphosphonates in the therapeutic composition can vary. For example, some liquid compositions may contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v) (w / v), about 0.001% (w / v) to about 1% (w / v), about 0.1% (W / v), about 3% (w / v) to about 5% (w / v), about 5% about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v) (W / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% / v) < / RTI > zoledronic acid.

Some solid compositions comprise at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / (W / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / (w / w), about 70% (w / w) to about 75% (w / w), about 70% And 90% (w / w) of zoledronic acid.

An osteoclast inhibitor can be used, including any suitable amount of a nitrogen containing bisphosphonate, such as zoledronic acid, mynodronic acid or a bisphosphonate such as ibandronic acid. Some solid or liquid oral formulations or units of oral dosage form (collectively referred to herein as "oral dosage form (s)") contain from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg About 10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 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, From about 10 mg to about 50 mg, from about 40 mg to about 60 mg, from about 50 mg to about 60 mg, from about 20 mg to about 150 mg, from about 30 mg to about 100 mg, from about 1 mg to about 1000 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 100 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 600 mg, about 40 mg to about 2000 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 Zoledronic acid, or an osteoclast inhibitor of any amount in the range comprised within or between 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 formulations contain from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg, from about 1 mg to about 500 mg, From about 10 mg to about 250 mg, from about 100 mg to about 300 mg, from about 20 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 100 mg, from about 1 mg to about 1,000 mg , From about 10 mg to about 50 mg, from about 40 mg to about 60 mg, from about 50 mg to about 60 mg, from about 55 mg, from about 10 mg to about 300 mg, from about 10 mg to about 150 mg, from 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, From about 300 mg to about 1500 mg, from about 200 mg to about 1000 mg, from about 100 mg to about 500 mg, or An osteoclast inhibitor of about 150 mg, or an osteoclast inhibitor of any amount in the range comprised within or between any of these values. In some embodiments, the oral osteoclast inhibitor is administered daily, weekly, monthly, every two or three months, once a year, or twice a year.

In some embodiments, the oral dosage form comprises from about 10 mg / m2 to about 20 mg / m2, from about 15 mg / m2 to about 20 mg / m2, from about 18 mg / m2, from about 80 mg / m2 to about 150 mg / , From about 90 mg / m 2 to about 150 mg / m 2, from about 100 mg / m 2 to about 150 mg / m 2 of zoledronic acid, or any amount in the range comprised within or between any of these values It may contain redronic acid. All dose ranges or amounts expressed in mg / m 2 are based on the mammalian body surface area.

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

In some embodiments, the daily oral dose of an osteoclast inhibitor, including a nitrogen-containing bisphosphonate, such as zoledronic acid, mynodronic acid, or a bisphosphonate, such as ibandronate, is from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, 0.0 > mg, < / RTI > from about 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg, or any amount in the range comprised within or between any of these values. In some embodiments, the daily oral dosage of the osteoclast inhibitor is less than about 35 mg / m 2, less than about 30 mg / m 2, less than about 25 mg / m 2, about 1 mg / m 2 to about 35 mg / M 2 to about 20 mg / m 2, from about 10 mg / m 2 to about 30 mg / m 2, from about 1.5 mg / m 2 to about 25 mg / m 2, from about 1.8 mg / An osteoclast inhibitor of any amount in 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 daily oral dose of zoledronic acid is from about 0.005 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 0.2 mg to about 5 mg, Or any amount of zoledronic acid in the range therebetween. In some embodiments, the daily oral dose of zoledronic acid is less than about 35 mg / m 2, less than about 30 mg / m 2, less than about 25 mg / m 2, about 1 mg / m 2 to about 35 mg / M 2 to about 20 mg / m 2, from about 10 mg / m 2 to about 30 mg / m 2, from about 1.5 mg / m 2 to about 25 mg / m 2, from about 1.8 mg / About 30 mg / m 2, about 15 mg / m 2 to about 20 mg / m 2, about 18 mg / m 2, or any value in the range comprised within or between any of these values.

In some embodiments, the weekly oral dose of an osteoclast inhibitor, including a nitrogen containing bisphosphonate, such as zoledronic acid, mynodronic acid, or a bisphosphonate, such as ibandronic acid, is from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, From about 10 mg to about 300 mg, from about 10 mg to about 100 mg, from about 10 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 300 mg, from about 20 mg To about 50 mg, to about 55 mg, to about 100 mg to about 50 mg, to about 150 mg, to about 20 mg to about 60 mg, to about 30 mg to about 70 mg, to about 40 mg to about 60 mg, 150 mg or about 30 mg to about 100 mg. In some embodiments, the weekly oral dose of osteoclast inhibitor is less than about 250 mg / m 2, less than about 200 mg / m 2, less than about 175 mg / m 2, about 6 mg / m 2 to about 250 mg / From about 10 mg / m 2 to about 170 mg / m 2, from about 4 mg / m 2 to about 140 mg / m 2, from about 100 mg / m 2 to about 140 mg / Or any amount of the range contained within or between any of these values. Oral doses may be provided as a single dose once a week, or as individual doses of 2, 3, 4, 5, 6, or 7 times a week.

In some embodiments, the weekly oral dose of zoledronic acid is from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 10 mg to about 250 mg, from about 100 mg to about 300 mg, from about 10 mg to about 100 mg, 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 2, less than about 200 mg / m 2, less than about 175 mg / m 2, about 6 mg / m 2 to about 250 mg / From about 10 mg / m 2 to about 170 mg / m 2, from about 4 mg / m 2 to about 140 mg / m 2, from about 100 mg / m 2 to about 140 mg / m 2, from about 126 mg / And any amount of zoledronic acid in the range contained within or between any of these values. The weekly oral dose may be provided as a single dose given once a week or may be provided in 2, 3, 4, 5, 6 or 7 individual doses over a week.

In some embodiments, the monthly dose of an osteoclast inhibitor, including a nitrogen containing bisphosphonate, such as zoledronic acid, mynodronic acid or a bisphosphonate, such as ibandronate, or the amount of osteoclast inhibitor administered over a period of one month is less than about 5000 mg, From about 1 mg to about 1000 mg, from about 10 mg to about 1000 mg, and up to about 1000 mg, up to about 2000 mg, up to about 1000 mg, up to about 700 mg, up to about 600 mg, About 50 mg to about 200 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 50 mg to about 1000 mg, about 10 mg to about 600 mg, About 40 mg to about 800 mg, about 50 mg to about 800 mg, or about 200 mg to about 300 mg, or about 250 mg to about 300 mg, or about 100 mg to about 600 mg, or about 40 mg to about 2000 mg, About 100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50 Mg to about 1000 mg, or about 100 mg to about 1000 mg, or any monthly amount in the range comprised within or between any of these values. In some embodiments, the monthly oral dosage of osteoclast inhibitor is less than about 1000 mg / m 2, less than about 800 mg / m 2, less than about 600 mg / m 2, about 10 mg / m 2 to about 1000 mg / From about 100 mg / m 2 to about 600 mg / m 2, from about 50 mg / m 2 to about 800 mg / m 2, from about 70 mg / m 2 to about 700 mg / From about 300 mg / m 2 to about 1000 mg / m 2, from about 400 mg / m 2 to about 1000 mg / m 2, from about 300 mg / m 2 to about 600 mg / From about 500 mg / m 2 to about 600 mg / m 2, from about 500 mg / m 2 to about 1000 mg / m 2, from about 400 mg / m 2 to about 700 mg / Is any amount of range included in or between any of the ranges. Monthly doses may be provided as a single dose or as two or more separate doses administered over a period of one month. In some embodiments, monthly doses are administered in two or three weekly doses. In some embodiments, monthly doses are administered at 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in a daily dose of 28 to 31 times. In some embodiments, monthly doses are administered at 5-10 individual doses over a month. Monthly doses can be administered for only one month, or repeatedly for more than two months.

In some embodiments, the monthly dose of zoledronic acid or the amount of zoledronic acid administered over a period of one month is less than or equal to about 5000 mg, less than about 4000 mg, less than about 3000 mg, less than about 2000 mg, less than about 1000 mg, less than about 700 about 1 mg to about 1000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg or less, about 600 mg or less, about 1 mg to about 4000 mg, about 50 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, From about 40 mg to about 2000 mg, from about 40 mg to about 800 mg, from 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 monthly amount in the range comprised within or between any of these values. In some embodiments, the monthly oral dose of zoledronic acid is less than about 1000 mg / m 2, less than about 800 mg / m 2, less than about 600 mg / m 2, about 10 mg / m 2 to about 1000 mg / From about 100 mg / m 2 to about 600 mg / m 2, from about 50 mg / m 2 to about 800 mg / m 2, from about 70 mg / m 2 to about 700 mg / From about 300 mg / m2 to about 600 mg / m2, from about 450 mg / m2 to about 600 mg / m2, from about 300 mg / m2 to about 1000 mg / m2, from about 400 mg / from about 500 mg / m2 to about 600 mg / m2, from about 500 mg / m2 to about 1000 mg / m2, from about 400 mg / m2 to about 700 mg / m2, from about 500 mg / Or any amount of zoledronic acid in the range therebetween. Monthly doses may be provided as a single dose or as two or more individual doses administered over a month. In some embodiments, the monthly dose is administered in two or three weekly doses. In some embodiments, monthly doses are administered in four or five weekly doses. In some embodiments, monthly doses are administered at 28 to 31 daily doses. In some embodiments, monthly doses are administered at 5-10 individual doses per month. Monthly doses may be administered for only one month, or repeatedly for two or more months.

With respect to oral administration of zoledronic acid to mammals such as dogs, rats, rabbits, monkeys, apes or humans, dosages of 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, from about 0.4 mg / kg to about 0.5 mg / kg, from about 0.5 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 / 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 / From about 1.5 mg / kg to about 1.6 mg / kg, from about 1.6 mg / kg to about 1.7 mg / kg, from about 1.7 mg / kg to about 1.8 mg / / kg to about 1.9 mg / kg, from about 1.9 mg / kg to about 2 mg / kg, from about 2 mg / kg to about 2.1 mg / kg, from about 2.1 mg / kg to about 2.2 mg / To about 2.3 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 to about 2.8 mg / kg, from about 2.8 mg / kg to about 2.9 mg / kg, from about 2.9 mg / kg to about 3 mg / kg, from about 3 mg / kg to about 3.1 mg / 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 mg / kg, about 3.4 mg / kg to about 3.5 mg / About 3.6 mg / kg to about 3.7 mg / kg, about 3.7 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 3.9 mg / 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 / 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 / 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 / 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 0.7 mg / kg, from about 0.7 mg / kg to about 3.6 mg / kg, from about 3.6 mg / kg to about 3.8 mg / kg, from about 3.8 mg / kg to about 4 mg / From about 1 mg / kg to about 1.3 mg / kg, from about 1.3 mg / kg to about 1.6 mg / kg, from about 1.6 mg / kg to about 1.9 mg / 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, from about 3.6 mg / kg to about 4 mg / kg, from about 0.4 mg / kg to about 1 mg / kg, or from about 0.5 mg / kg to about 1 mg / kg is repeatedly orally administered, Once daily or twice a year, once daily or three times a year, once daily or once every three months, once daily or once every two months, once daily It may be safe dosage for about every 2 to 4 months, every once to every month, every once to every 2 to 4 weeks, once for every day, or once for every week.

The dosages mentioned in the preceding paragraph for the administration of zoledronic acid to mammals 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 or less frequently once a day, once a week, once every two weeks, once a month, and the like.

For once daily or weekly oral administration of zoledronic acid to a mammal such as a mouse, rat, dog, primate, or human, in some embodiments, the safely repeated dose is about 0.03 mg / kg to about 4 mg / kg or any smaller range within this range, such as from about 0.01 mg / kg to about 0.02 mg / kg, from about 0.02 mg / kg to about 0.03 mg / kg, from about 0.03 mg / kg to about 0.04 mg / From about 0.04 mg / kg to about 0.05 mg / kg, from about 0.05 mg / kg to about 0.06 mg / kg, from about 0.06 mg / kg to about 0.07 mg / kg, from about 0.07 mg / kg to about 0.08 mg / / kg to about 0.09 mg / kg, from about 0.09 mg / kg to about 0.1 mg / kg, from about 0.1 mg / kg to about 0.11 mg / kg, from about 0.11 mg / kg to about 0.12 mg / 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 / 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 About 0.2 mg / kg to about 0.23 mg / kg, from about 0.2 mg / kg to about 0.21 mg / kg, from about 0.21 mg / kg to about 0.22 mg / about 0.24 mg / kg to about 0.27 mg / kg, from about 0.24 mg / kg to about 0.25 mg / kg, from about 0.25 mg / kg to about 0.26 mg / kg to about 0.31 mg / kg, from about 0.31 mg / kg to about 0.28 mg / kg, from about 0.28 mg / kg to about 0.29 mg / kg, from about 0.29 mg / kg to about 0.3 mg / 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 / about 0.37 mg / kg to about 0.37 mg / kg, about 0.37 mg / kg to about 0.37 mg / kg, about 0.37 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 / About 0.08 mg / kg to about 0.15 mg / kg, about 0.09 mg / kg About 0.1 mg / kg, 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 0.08 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 to about 0.6 mg / kg, from about 0.6 mg / kg to about 0.8 mg / kg, from about 0.8 mg / kg to about 1 mg / kg, from about 1 mg / kg to about 1.2 mg / 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 / From about 2.2 mg / kg to about 2.4 mg / kg, from about 2.4 mg / kg to about 2.6 mg / kg, from about 2.6 mg / kg to about 2.8 mg / kg, from about 2.8 mg / 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 / 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 0.6 mg / kg to about 1.5 mg / kg, about 0.7 mg / kg to about 2 mg / kg, about 0.8 mg / kg to about 2 mg / 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 / from about 0.5 mg / kg to about 1 mg / kg, from about 0.6 mg / kg to about 1 mg / kg, from about 0.7 mg / kg to about 1 mg / kg, from about 0.8 mg / kg to about 1 mg / kg or about 0.8 mg / kg to about 0.9 mg / kg.

For oral administration of zoledronic acid once per week or less frequently to mammals such as mice, rats, dogs, primates or humans, in some embodiments, the safely repeated dose is about 0.4 mg to about 10 mg or less Any smaller range within this range, such as from about 0.4 mg / kg to about 0.6 mg / kg, from about 0.6 mg / kg to about 0.8 mg / kg, from about 0.8 mg / kg to about 1 mg / kg to about 1.2 mg / kg, from about 1.2 mg / kg to about 1.4 mg / kg, from about 1.4 mg / kg to about 1.6 mg / kg, from about 1.6 mg / kg to about 1.8 mg / From about 2 mg / kg to about 2.2 mg / kg, from about 2.2 mg / kg to about 2.4 mg / kg, from about 2.4 mg / kg to about 2.6 mg / about 3 mg / kg to about 3.2 mg / kg, about 3.2 mg / kg to about 3.4 mg / kg, about 3.4 mg / kg to about 3.6 mg / kg, about 3.6 mg / kg to about 3.8 mg / kg, about 3.8 mg / kg to about 4 mg / kg, about 4 mg / kg to about 4.2 mg / 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 / About 5.2 mg / kg to about 5.4 mg / kg, from about 5.4 mg / kg to about 5.6 mg / kg, from about 5.6 mg / kg to about 5.8 mg / kg, from about 5.8 mg / kg to about 6 mg / kg, about 6 mg / kg to about 6.2 mg / kg, about 6.2 to about 6.4 mg / kg, about 6.4 to about 6.6 mg / kg, about 6.6 to about 6.8 mg / 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 / From about 7.8 mg / kg to about 7.8 mg / kg, from about 7.8 mg / kg to about 8 mg / kg, from about 8 mg / kg to about 8.2 mg / kg, from about 8.2 mg / kg to about 8.4 mg / / kg to about 8.6 mg / kg, from about 8.6 mg / kg to about 8.8 mg / kg, from about 8.8 mg / kg to about 9 mg / kg, from about 9 mg / kg to about 9.2 mg / 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 / From about 0.5 mg / kg to about 2 mg / kg, from about 0.6 mg / kg to about 2 mg / kg, from about 0.7 mg / kg to about 2 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 / 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 / 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 a disodium salt thereof, is administered parenterally, such as intravenously, about 0.1 mg to about 10 mg of zoledronic acid, or ≪ / RTI > salt. In some embodiments, about 50 mg, about 100 mg, or about 150 mg of the disodium salt of zoledronic acid is orally administered with 1 mg of zoledronic acid for parenteral such as intravenous. In some embodiments, the parenteral dose of zoledronic acid is from about 0.25 mg to about 25 mg, from about 0.25 mg to about 10 mg, or from about 0.5 mg to about 7.5 mg.

For the treatment of pain associated with inflammation, arthritis, CRPS or any other condition described herein with respect to oral administration of an osteoclast inhibitor, such as zoledronic acid, mnodronic acid, ibandronate or other bisphosphonates, an osteoclast inhibitor The mammal or human to be administered may be a foodstuff 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 Or drinking a drink (other than any water necessary to swallow the oral dosage form) may be helpful. A mammal or a human to which an osteoclast inhibitor is administered may be fed a 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 administration of the osteoclast inhibitor It can also help. In some embodiments, a human to whom zoledronic acid is administered avoids lying, or is upright or sitting upright for at least about 30 minutes or about 1 hour after receiving a formulation containing an osteoclast inhibitor. Avoiding food or drinks before or after oral administration of osteoclast inhibitors may improve the bioavailability of osteoclast inhibitors.

Oral bioavailability of the osteoclast inhibitor in a formulation may vary. Some formulations may have ingredients added to improve bioavailability. However, bioavailability enhancement is not necessary to make oral formulations effective. In some embodiments, the formulation is substantially free of bioavailability enhancers. In some embodiments, the oral dosage form has an oral bioavailability of about 0. 01% to about 10%, about 0.1% to about 7%, about 0.1% to about 10%, or about 0.01% to about 10%, of an osteoclast inhibitor such as zoledronic acid, 5%. Without a component or other means to improve bioavailability, bisphosphonates such as zoledronic acid are typically poorly bioavailable in oral formulations. In some embodiments, the bioavailability of the zoledronic acid is non-enhanced or substantially non-improved. For example, the oral bioavailability of zoledronic acid may range 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% 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 0.5% to about 0.5%, about 0.5% to about 1%, about 0.6% to about 0.7%, about 0.7% to about 0.5% 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% % To about 1.5%, about 1.5% to about 1.6%, about 1.6% to about 1.8%, about 1.8% to about 2%, or about 2% to about 2.5%.

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

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

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

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

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

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

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

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

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

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

In some embodiments, the oral bioavailability of the 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, munidolonic acid or ibandronate, administered daily for a consecutive day of about 2 days to about 15 days. This regimen may be administered once a month, once every two months, once every three months, once every four months, once every five months, once every six 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, munidolonic acid or ibandronic acid, which may be from about 2 days to about 15 days of continuous Lt; / RTI > This prescription plan is administered once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year, or every two years 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, munidolonic acid or ibandronate, which may be from about 5 days to about 10 days of continuous Lt; / RTI > This prescription plan is administered once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year, or every two years Can be repeated once.

In some embodiments, the oral dosage form comprises from about 40 mg to about 150 mg of zoledronic acid, munidolonic acid or ibandronate, administered daily for a consecutive day of about 5 days to about 10 days. This prescription plan is administered once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year, or every two years Can be repeated once.

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

An osteoclast inhibitor, such as zoledronic acid, munidolonic acid or ibandronic acid, may be formulated for oral administration, for example, with an inert diluent or an edible carrier, or it may be enclosed in a hard or soft shell gelatin capsule compressed with a tablet, Can be incorporated directly into diet foods. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of peptic tablets, oral tablets, coated tablets, troches, capsules, elixirs, powders, suspensions, solutions, syrups, wafers, patches and the like.

Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as 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 flavoring agents, such as peppermint, oil or cherry flavor of a presser foot paste. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the materials of this type. Various other materials may be present as coatings, for example tablets, pills or capsules coated with shellac, sugar or both. Syrups or elixirs may contain flavoring agents such as active compounds, sugars as sweeteners, methyl and propyl parabens as preservatives, dyes, and cherry or orange flavors. The materials in the formulations or pharmaceutical compositions may be desired to be pharmaceutically pure and substantially non-toxic to the amount employed.

Some compositions or formulations may be liquid or may comprise a solid phase that is dispersed in a liquid.

An osteoclast inhibitor, such as zoledronic acid, munidolonic acid or ibandronic acid, may be formulated for parenteral or intraperitoneal administration. A solution of the active compound as the free acid or a pharmacologically acceptable salt can be prepared in water by appropriately mixing with a surfactant such as hydroxypropylcellulose. The 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 a preservative to prevent the growth of microorganisms.

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

In some embodiments, the oral dosage form may comprise a cross-linked polyvinylpyrrolidone such as crospovidone. (Wt / wt) to about 10% (wt / wt), about 1% (wt / wt) to about 5% (wt / wt), or about 1% % (wt / wt) of crosslinked polyvinylpyrrolidone may be present in the unit for oral or oral dosage form.

In some embodiments, the oral dosage form may comprise fumed silica, such as Aerosil. (Wt / wt) to about 10% (wt / wt), about 0.1% (wt / wt) to about 1% (wt / wt), or about 0.4% % (wt / wt) of fumed silica may be present in units of oral or oral formulations.

In some embodiments, the oral dosage form may comprise magnesium stearate. (Wt / wt) to about 10% (wt / wt), about 0.1% (wt / wt) to about 1% (wt / wt), or about 0.4% % (wt / wt) magnesium stearate may be present in the unit for oral or oral formulations.

Oral formulations comprising zoledronic acid or other bisphosphonates or osteoclast inhibitors may be included in a pharmaceutical product comprising an oral dosage form of more than one unit.

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

Pharmaceutical products containing oral formulations for use on a weekly basis may include four or five unit oral formulations for one month supply. Approximately 2 months The weekly feed may include 8 or 9 unit oral formulations. Approximately 6 weeks The weekly feed may contain about 6 units of oral dosage form. Approximately 3 months The weekly feed may include 12, 13 or 14 unit oral formulations. Approximately 6 months The weekly feed may contain 22 to 30 unit oral formulations. Approximately one year The weekly feed may include 45 to 60 unit oral formulations.

The pharmaceutical product can accommodate different dosing regimens. For example, the pharmaceutical product may comprise from 5 to 10 unit oral formulations, wherein each unit of oral dosage form comprises from about 40 mg to about 150 mg of zoledronic acid, munidolonic acid or ibandronate . 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, munidolonic acid or ibandronic acid. In these products, each unit of the oral dosage form may be taken daily for 1 to 10 days or for 5 to 10 days for one month as at the beginning of the month.

Some oral formulations, including osteoclast inhibitors (such as suitable bisphosphonates, such as zoledronic acid, mnodonic acid or ibandronate or salts thereof, may have enteric coatings or membrane coatings. In some embodiments, an oral dosage form of an osteoclast inhibitor comprises a tablet having an enteric coating. In some embodiments, an oral dosage form of an osteoclast inhibitor comprises a capsule having an enteric coating. In some embodiments, an oral formulation of an osteoclast inhibitor comprises a tablet having a membrane coating. In some embodiments, an oral formulation of an 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 / 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, about 1 mg / kg to about 10 mg / kg, or any range of values included in or between these ranges based on the weight of the mammal. The selected dose may be repeatedly administered, especially for chronic conditions, or it may increase or decrease the amount per dose as treatment proceeds. Selected doses may be administered more than once per week, monthly, every 2 months, every 3 months, every 6 months or annually.

In some embodiments, 60 mg of demosurf is administered subcutaneously to a patient in need of such treatment. In some embodiments, the administration is repeated every six months.

There are a number of ways in which compounds 1 and / or a portion of compound 2 can be removed from the zoledronic acid product. For example, HPLC, preparative TLC, crystallization, sublimation or zone purification can be used. Solvents which 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 may be initiated by elution with water, followed by the gradual addition of an organic solvent such as acetonitrile, methanol, ethanol, ethyl acetate, acetone, acetic acid, methyl acetate or other solvent to water, Or replace the water as a whole. Similarly, crystallization or recrystallization may use a single solvent or a combination of solvents. For example, salts thereof such as zoledronic acid or disodium salt can be recrystallized from water, ethanol, methanol, diethyl ether, methyl acetate, acetic acid, etc. or a combination of these solvents or others. In some embodiments, a salt thereof, such as zoledronic acid or disodium salt, is dissolved in one solvent such as water or acetic acid, and the solvent is removed in a solvent such as hexane, diethyl ether, chloroform, dichloromethane, ethyl acetate, methyl acetate, Methanol or a combination thereof. ≪ / RTI > In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then hexane is added to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then diethyl ether is added to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then chloroform is added to effect crystallization. In some embodiments, the disodium salt of zoledronic acid is dissolved in water, followed by the addition of dichloromethane to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water and then crystallized by the addition of ethyl acetate. In some embodiments, the disodium salt of zoledronic acid is dissolved in water followed by the addition of methyl acetate to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water followed by the addition of acetic acid to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water, followed by the addition of ethanol to crystallize. In some embodiments, the disodium salt of zoledronic acid is dissolved in water, followed by the addition of methanol to crystallize. 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, From about 1: 1 to about 2: 1, from about 1: 2 to about 1: 1, from about 1: 3 to about 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 preceding paragraph, such as HPLC or TLC and crystallization, may be used. In some embodiments, methods such as HPLC, preparative TLC, crystallization, sublimation, or zone purification can be repeated. In some embodiments, the purification method described in this paragraph can be performed twice. In some embodiments, the purification method described in the paragraph can be performed three or four times.

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

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 proin adjuvant (CFA) model. On day 0, 100% CFA was injected into the left hind paw of the Sprague-Dole rats in a volume of 75 μl to induce inflammatory pain and evaluated on days 1-3. (Or control), zoledronic acid 18 mg / m 2 (or 3 mg / kg), zoledronic acid 120 mg / m 2 (or 20 mg / kg), or zoledronic acid 900 mg / Kg) was orally administered daily on days 1-3. The drug was dissolved in distilled water and made fresh every day. Animals were fasted prior to administration. Under current FDA guidelines for extrapolating the starting dose from animal to human, the dose expressed in mg / m 2 is considered equivalent among mammalian species. Thus, for example, 18 mg / m 2 in rats is considered equivalent to 18 mg / m 2 in humans, whereas 3 mg / kg in rats may not be equivalent to 3 mg / kg in humans.

Values for inflammatory pain (mechanical hyperalgesia) in vehicle and drug treated animals were obtained at baseline and after treatment on days 0 and 1 to 3 before CFA injection. Pain was assessed using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). The animal was placed on an arresting bandage hanging the animal, with the back limb being available for testing. A dome-shaped tip was placed between the third and fourth vertebrae and a pressure increase was applied to the plantar surface of the hind paw to measure the foot compression threshold. The pressure was gradually applied over approximately 10 seconds. Measurements were taken from the nocifensive behavior initially observed of vocalization, wobble or withdrawal. A cut-off value of 300 g was used to prevent damage to the animal.

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

Inversion (%) = (after treatment - baseline after CFA) / (CFA pre-baseline - baseline after CFA) x 100.

Experiments were carried out using 9-10 animals per group.

result:

Oral administration of zoledronic acid significantly improved the inflammatory pain threshold compared to vehicle. The pain threshold measurement taken at various times is shown in Fig. The foot compression threshold in the 18 mg / m 2 group was higher for the vehicle over the entire measurement period after 30 minutes of treatment initiation. On day 3, the foot compression threshold for both the 18 mg / m2 and 900 mg / m2 groups was greater for the vehicle. Improvements in pain thresholds of 49% and 83% from the baseline were observed for the 18 mg / m2 and 900 mg / m2 groups, respectively.

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

Surprisingly, a lower threshold than the vehicle on the first two days of dosing at two higher doses resulted. The 120 mg / m 2 group was approximately equal to or less than the vehicle at all time points during the evaluation period. Although the 900 mg / m2 group showed efficacy on day 3, this result was accompanied by significant toxicity, requiring euthanasia of all animals in this group at 2 days after discontinuation of administration.

Example 2

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

Way:

The effect of orally administered zoledronic acid on arthritic pain was tested in a rat complete propinergic agent (CFA) model of arthritis pain. In this model, arthritis pain was induced for 10-14 days after injection of 100% complete Freund's adjuvant (CFA) in 75 μl volume on the left hind paw. (Or control), zoledronic acid 54 mg / m 2 (or 9 mg / kg) or zoledronic acid 360 mg / m 2 (or 60 mg / kg) divided into three equal daily doses on the first three days after CFA injection, Were orally administered. The drug was dissolved in distilled water and made fresh every day. Animals were fasted prior to administration.

Arthritis pain (mechanical hyperalgesia) in the vehicle and in the drug treated animals was assessed using a digital Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA, USA) 14 days after CFA injection. The animal was placed on an arresting bandage hanging the animal, with the back limb being available for testing. A dome-shaped tip was placed between the third and fourth ulna and a pressure increase was applied to the plantar surface of the hind paw to measure the foot compression threshold. The pressure was gradually applied over approximately 10 seconds. Measurements were taken from the first observed nociceptive behavior of utterance, struggle or withdrawal. A cut-off value of 300 g was used to prevent damage to the animal.

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

Inversion (%) = (eastbound drug threshold - eastbound vehicle critical) / (contralateral vehicle critical - eastbound vehicle critical) x100.

Experiments were conducted using 7 to 10 animals per group

result:

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

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

The effect of orally administered zoledronic acid in the rat tibial fracture model of Complex Regional Pain Syndrome (CRPS) was examined. Guo TZ et al. (Pain. 2004; 108: 95-107), and CRPS was induced in rats by fracture of the right distal tibia of the animal and casting on the hind paw fractured for 4 weeks. This animal model has been found to repeat the inciting trauma, natural history, 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 2 / day (3 mg / kg / day) for 28 days beginning with fracture and Gibbs work. Drugs were dissolved in distilled water and administered by feeding. The animals were fasted 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, rats were tested for back pains, swelling and warmth.

Pain assessment

Pain was assessed by measuring hyperalgesia and weight loading.

To measure hyperalgesia, an up-down von Frey test paradigm was used. The rats were placed in a clear plastic cylinder (diameter 20 cm) with a wire mesh bottom and allowed to acclimate for 15 minutes. The feet were tested with one of eight bobshear hair series with stiffness ranging from 0.41 g to 15.14 g. The frayed hair was applied to the paw skin of the hind paw approximately in the middle of the foot, being careful to avoid the circular tori pad. Pour the fiber until it bends slightly, then shake it gently at that location for 6 seconds. Stimulation was provided at intervals of several seconds. The back of the foot from the fiber was considered as a positive reaction. The initial fiber delivery was 2.1 g, and fibers were provided according to Dixon's up-down method to generate six reactions in the immediate vicinity of the 50% threshold. Stimulation was provided at intervals of several seconds.

(IITC Inc. Life Science, Woodland, Calif., USA) was used to measure the posterior foot weight load and positional effects of pain. The hind paw was placed on each metal balance plate, the rats were manually held in a vertical position on the device, and the entire weight of the rats was supported by the hind paw. The duration of each measurement was 6 seconds and 10 consecutive measurements were taken at 60 second intervals. Eight readings (except the highest and lowest) were averaged to yield both hind weight loads. The weight load data was analyzed as the ratio ((2R / (R + L)) x 100% between the right side (fracture) and the left hind weight load value.

Edema evaluation

We measured the dorsal - toe thickness of the hind paw using laser sensor technology. Before the baseline test, 2 to 3 mm points were tattooed on the dorsal skin above the midpoint of the third metatarsal on both hind feet. For laser measurements, each rat was briefly anesthetized with isoflurane and held vertically, allowing the hind paw to rest on the top of the table below the laser. A small metal rod was applied to the top of the ankle joint and the foot was placed flat on the table. Using optical triangulation, the distance between the back of the tattoo and the top of the table was measured using a laser with a distance sensor, and the dorsal - toe foot thickness was calculated using the difference. The measuring sensor device (4381 Precicura, Limab, Gothenburg, Sweden) used in this experiment had a measuring range of 200 mm and a resolution of 0.01 mm.

Rear foot temperature measurement

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

result

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

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

As shown in FIG. 5, the weight reduction and the posture effect of pain were significantly higher in the vehicle-treated group than in the zoledronic acid-treated group. The weight load on the fracture posterior limb was reduced to 55% of normal in the vehicle treated group. Zoledronate treatment significantly restored the back limb weight load (86% of normal) compared to vehicle treatment.

As shown in Figure 6, the predicted increase in hind paw thickness was greater in the vehicle treated group than in the zoledronic acid treated group, reflecting the occurrence of edema. Zoledronate treatment reduced hindpaw edema by 60% compared to vehicle treatment.

Zoledronic acid reduced the hind paw warming by 5% compared to vehicle treatment.

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

Example 6. Solubility of disodium salt of zoledronic acid

The solubility of zeolite and zephloronate disodium tetrahydrate was measured. 1 g of the test compound was measured in a beaker. Deionized water (pH 5.5) was then added in small increments to the test compound and the mixture was sonicated. The procedure was continued until complete dissolution was achieved. It was determined that complete dissolution was reached when a clear solution was provided without visible material. The solubility value in g per 100 ml was calculated using the volume of water required to reach complete dissolution. Procedures were performed for each compound.

result

As shown in FIG. 7, the water solubility of disodium zoloiodic acid dihydrate was about 50 times that of zoledronic acid. The solubility of the disodium zoloidic acid dihydrate was 12.5 g / 100 ml, whereas solubility of zoledronic acid was only 0.25 g / 100 ml.

Example 7. Bioavailability of disodium zoledronic acid and disodium zoledronic acid administered orally

Tablets containing disodium salt of zoledronic acid or zoledronic acid (disodium zoledronic acid disodium) 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 count molecular weight differences between acid and disodium.

The beagle dog was orally administered a tablet containing 150 mg of zoledronic acid equivalent in the form of disodium zoledronic acid (Group 1) or pure zoledronic acid (Group 2). Each animal received three 50 mg equivalent tablets (total of 150 mg), which were administered together. Before placing the tablets on the back of the animal's tongue, the animal's mouth was soaked with water. Animals were fasted before and after administration. The animals were 6 to 9 months old and weighed between 6 and 10 kg on the day of administration. There were three dogs per group.

Sequential blood samples were collected from each animal by venipuncture of the jugular vein at each time point after administration for determination of the plasma concentration 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. The plasma concentration of zoledronic acid was measured 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. The detectable plasma levels of zoledronic acid were monitored for a total of 48 hours as measured.

Disodium zoledronic acid produced significantly higher plasma levels of zoledronic acid than pure zoledronic acid, suggesting improved oral absorption using the salt form. When measured using the peak plasma concentration (C _max ), the sodium salt resulted in an actual increase in bioavailability of 119% and a 74% weight gain increase over pure zoledronic acid. The bioavailability was 84% and 46% greater than the pure sodium zoledronic acid, respectively, when measured using the area under the plasma concentration curve (AUC _0-∞ ) based on the actual reference and weight adjustment standards, respectively. The mean AUC _0-∞ for this sodium salt was 4073 ng · hr / mL and the mean AUC _0-∞ for discrete was 2217 ng · hr / mL. AUC _0-∞ was found to be proportional to dose. Thus, for beagle dogs similar to those tested, it is expected that from about 3 mg to about 4 mg of disodium salt will result in an AUC _0-∞ of about 100 ng · hr / mL, and about 7 mg to about 8 mg of This sodium salt is expected to bring about an AUC _0-∞ of about 200 ng · hr / mL.

Example 8

The tablets were prepared by blending zoledronic acid in the form of free acid or disodium with the same excipient. For more active agent amounts, the amount of excipient was proportionally reduced to maintain the tablet weight at about 100 mg. After blending, the components were compressed at varying pressures and then film coated. Then, for the resulting tablets, The hardness was tested using a Schleuniger Pharmatron 8M Tablet Hardness Tester. The results are shown in Table 2 and FIG.

Example 9

Some embodiments related to joint pain, bone marrow lesions and osteoarthritis have been considered as the interpretation of data from clinical studies. Some of the results of this study have been reported by Laslett et al. In Ann Rheum Dis 2012; 71: 1322-1328. Some of the explanations and data reported below have not been published before the present application. 52 patients with clinical knee osteoarthritis and knee osteoarthritis (BML) were randomized to receive intravenous zoledronic acid (5 mg) or placebo in a double blind fashion. All patients had at least one bone marrow lesion (BML) on their knees on magnetic resonance imaging (MRI). All patients underwent X-ray of the knee to measure the grade of joint space narrowing (JSN) according to the International Osteoarthritis Study Association (OASI) guideline. The patient had a joint space narrowing (OARSI grade 1 and grade 2) greater than or equal to no narrowing of the joint space (OARSI grade 0). Twenty-six patients were treated with zoledronic acid (8, 6, and 12 patients with OARSI 0, 1, and 2, respectively). Twenty-six patients received placebo (eight, eight, and twelve, respectively, with OARSI 0, 1, and 2 ratings).

The 100-mm visual pain scale (VAS) was used to assess pain at baseline and at 3 months, with 0 indicating no pain and 100 indicating severe pain. The change in pain intensity from baseline to 3 months was calculated.

Treatment with zoledronic acid significantly reduced pain compared to placebo in patients with no narrowed joint space (OARSI grade 0), but not with patients with narrowed joint space (OARSI 1-2 grade). As shown in Table 3 and FIG. 10, the mean VAS score was reduced by 15 mm in the OARSI 0 grade group compared to placebo, but decreased by 0.28 million in patients with OARSI 1-2 grade compared with placebo.

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

Treatment with zoledronic acid significantly reduced pain pain compared with placebo in patients with baseline VAS pain intensity scores greater than 50 mm, but not in patients with a baseline VAS score less than 50 mm. As shown in Table 4, in patients with baseline VAS ≥ 50 mm, the mean VAS score was reduced by 9 mm compared to placebo, but decreased by 0.6 mg compared to placebo in baseline VAS <50 mm.

As shown in Table 5 and shown in FIG. 12, pain reduction was greater in patients with baseline VAS? 50 mm, greater in patients with OARSI grade 0 joint space narrowing, and baseline VAS? 50 mm and OARSI And 0 in the patients with both narrowed joint space.

BML was assessed using proton density saturation fat saturated MR images. BML was scored using Osiris software (University of Geneva, Geneva, Switzerland). The maximum size was measured in mm 2 using a software cursor applied to the largest area of each lesion. If more than 1 lesion is present in the same region, lesions with the highest score are used. Each patient was given a BML score (㎟) at 4 sites (medial tibialis, medial femur, lateral tibia, and lateral femoral region), and combined to give a total BML score (㎟). The change in total area of BML from baseline to 6 months was calculated.

Treatment with zoledronic acid reduced the size of the BML. As shown in Figure 13 and Table 6, the mean BML area in the OARSI 0 grade group was reduced by about 190 mm 2 compared to placebo but decreased by 33 mm 2 in patients with OARSI 1-2 grade compared with placebo.

Example 10

Way

Studies were performed to evaluate the efficacy of single intravenous infusion of 5 mg ZA in comparison with intravenous placebo infusion among patients with chronic low back pain (LBP) and mock changes on MRI. This study was a double blind, randomized, placebo controlled trial in patients with low back pain (LBP). Wherein the patient has at least 6 LBP or at least 30% Oswestry Low Back Pain Disability Index (ODI) on a 10 cm visual pain scale (VAS) for at least 3 months, and on MRI performed within the last 6 months immediately prior to registration Patients were included in the study if they had back pain symptoms of M1 type, M1 / 2 mixed type or M2 type change.

The patient has renal impairment with a creatinine clearance defined as reduced estimated glomerular filtration rate (eGFR) of less than 40 ml / min, hypocalcemia known as hypersensitivity to components of zoledronic acid or other bisphosphonates or infusions, red Patients were excluded from the study if they had the presence of a flag (red flag), neuromuscular seizure, or early retirement intent. Pre-menopausal women who were pregnant were also excluded. Blood samples were taken prior to injection to assess serum concentrations of calcium and creatinine. Clinical examination included history and waist flexibility, tendon signals and clinical evaluation of exercise and sensory tests.

After qualification, the patients were randomly given a single intravenous infusion of 5 mg of zoledronic acid (n = 20) or 100 ml of saline (n = 20) as placebo over a 15 minute period. Information on concurrent medications and use of hospital access permits. Blood samples were collected at baseline, at 1 month and 1 year for stability, inflammatory mediators and bone conversion rates.

Clinical evaluations were performed on follow-up visits on the 14th day before enrollment (screening visit) and 1 month and 1 year after the injection. The primary outcome was the intensity change of the LBP on the VAS. Secondary outcomes included leg pain intensity, ODI, health-related quality of life associated with RAND-36, patient reporting sick leave and waist flexibility. These outcome measures were evaluated at baseline and each follow-up. Flexibility of the waist was evaluated using finger-to-floor and body side bend measurements (cm). The percentage of patients who underwent 20% relative improvement, the percentage of patients who reached a VAS score of 40 or less in the primary outcome, and the patient's acceptable symptom status (PASS) were also assessed. During the follow-up visit, the use of pain medication was required.

result

Treatment with zoledronic acid resulted in a significant improvement in LBP intensity at 1 month compared with placebo treatment. In addition, patients receiving zoledronic acid reported significantly less frequent NSAID use at one year than placebo. Overall, the improvement in most of the evaluated parameters was greater in the follow-up period than in the zoledronic acid group.

The clinical characteristics of study participants at baseline are shown 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%. Nineteen patients in the ZA group and 18 patients in the placebo group had M1 / 2 lesions. Modic alterations located in L4 / 5 or L5 / S1 were most common (70%). The zoledronic acid and placebo groups were similar in demographic and background characteristics of all patients at baseline (Table 6).

The mean difference between the treatment groups (MD) and the intensity of LBP in the primary outcome was fairly 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% Cl - 1.0 to 2.4; Table 7). The proportion of patients with at least 20% improvement in both PASS and LBP intensities was favorable for treatment with zoledronic acid at 1 month: 55% versus 25% (p = 0.105) of zoledronic acid and 50% of zoledronic acid Placebo 20% (p = 0.096).

In 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 the secondary outcomes, improvement in ODI was favorable to zoledronic acid at one month [6.0% (95% CI - 0.6-13) difference between adjusted groups, but not one year (Table 7). Similarly, side bending (right and left) was favorable for treatment with zoledronic acid at 1 month, but not at 1 year (Table 7). Changes in total RAND-36 and in the physical and mental components of RAND-36 are shown in Table 8.

At baseline, there was no difference in self-reporting use of nonsteroidal 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-yl chloride (9). Methyl chloroacetate ( 2 ; 29.8 mL, 338.6 mmol, 2.0 eq) was added dropwise to 1- (trimethylsilyl) -1 H-imidazole ( 8 ; 25.0 mL, 169.3 mmol). The mixture was heated at 60 [deg.] C for 24 hours. The mixture was cooled to room temperature, washed with Et ₂ O ( 3 x 500 mL) and dried in vacuo to afford 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.

1,3-bis (carboboxymethyl) 1H-imidazol-3-yl chloride (10). ( 9) (41.00 g, 164.88 mmol, 1 eq.) Was dissolved in 37% aqueous HCl (30.03 mL, 362.74 mmol, 2.2 eq.). The mixture was stirred and refluxed for 0.5 hour. The mixture was concentrated and the remaining solid was washed with acetone ( ₂ x 200 mL) and Et ₂ O ( ₃ x 200 mL). Drying in vacuo afforded 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 excessive water to form Compound 1, which was precipitated from ethanol.

Compound 2: 1,3-bis (carboxymethyl) -1H-imidazol-3-yl chloride ( 10 , 2.00 g, 9 mmol, 1.0 eq.) And H ₃ PO ₃ (7.37 g, 90 mmol, Dissolved in toluene (10 mL) and heated to 70 &lt; 0 &gt; C. The reaction mixture was stirred at this temperature for 20 min and then PCl ₃ (16 mL, 180 mmol, 20 eq.) Was added within 30 min. The reaction mixture was then heated to 95 &lt; 0 &gt; C and stirred at this temperature for 2 hours. Then aqueous HCl (30 mL, 37% HCl and 5 mL H ₂ O) was added. The reaction mixture was heated to 100 &lt; 0 &gt; C, stirred at this temperature for 7 hours, stirred at room temperature for 2 days and then filtered. The filtrate was cooled in an ice bath and added to dry EtOH (90 mL) within 45 min. The resulting cloudy solution was stirred at room temperature for 1 h and then the solid was filtered. 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 specific examples are contemplated:

1. A method of alleviating inflammatory pain comprising administering to a mammal in need of relief of inflammatory pain an oral dosage form comprising zoledronic acid, wherein the mammal has a body surface area of about 800 &lt; RTI ID = 0.0 &gt;&Lt; / RTI &gt; mg / m &lt; 2 &gt; of zoledronic acid.

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.

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

Embodiment 4: The method according to embodiment 2, wherein the total monthly dose is administered at a daily dose of 28 to 31 days.

Embodiment 5: The method according to embodiment 2, wherein the total monthly dose is administered at 5 to 10 individual doses per month.

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 daily dose is a single dose administered once a week.

8. The method of embodiment 6 wherein the total daily dose is administered at 2 to 7 separate doses for one week.

9. The method of embodiment 1 wherein the mammal is a human receiving a total daily dose of about 10 mg to about 150 mg of zoledronic acid.

Embodiment 10. In any of the previous embodiments, the mammal experiences significant pain relief in excess of 3 hours following administration of the formulation.

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

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

13. A method of alleviating inflammatory pain comprising administering to a mammal in need of relief of inflammatory pain an oral dosage form comprising zoledronic acid, wherein the oral dosage form comprises about &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt; to about 20 mg / m &lt; 2 &gt; of zoledronic acid.

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

15. A method of treating inflammatory pain, comprising orally administering to a mammal in need of relief of inflammatory pain zoledronic acid of about 300 mg / m 2 to about 600 mg / m 2 per month based on the mammal's body surface area Mitigation method.

16. The method of embodiment 15 wherein the mammal is orally administered zoledronic acid at about 450 mg / m 2 to about 600 mg / m 2 per month based on the mammal's body surface area.

Embodiment 17. In any of the previous embodiments, the mammal is not suffering from bone metastasis.

Embodiment 18. The method of any preceding embodiment, wherein the mammal is not suffering from cancer.

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

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

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

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

23. The method of embodiment 21 wherein the total monthly dose is administered at a daily dosage of 28 to 31 days.

Embodiment 24. The method of embodiment 21 wherein the total monthly dose is administered at a dosage of 5 to 10 times a month.

25. The method of embodiment 20 wherein the human receives a total daily dose of about 100 mg to about 300 mg of zoledronic acid.

Embodiment 26. The method of embodiment 25 wherein the total daily dose is a single dose administered once a week.

Embodiment 27. The method according to embodiment 25, wherein the total daily dose is administered in two to seven separate doses for one week.

Embodiment 28. The method of embodiment 20 wherein the human receives a total daily 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 is experiencing significant pain relief in excess of 3 hours after administration of the formulation.

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

31. The method of embodiment 29 wherein the human is experiencing significant pain relief during at least a portion of a time period of from about 3 hours to about 3 weeks after administration of the formulation.

32. The method as in any one of embodiments 20-31, wherein the formulation contains from about 10 mg / m 2 to about 20 mg / m 2 of zoledronic acid based on the human body surface area.

33. The method of embodiment 32 wherein the formulation contains from about 15 mg / m 2 to about 20 mg / m 2 of zoledronic acid based on the human body surface area.

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

Embodiment 35. The method as in any one of embodiments 20-31, wherein the formulation contains from about 80 mg / m 2 to about 150 mg / m 2 of zoledronic acid based on the human body surface area.

36. The method of embodiment 35 wherein zoledronic acid is administered orally from about 300 mg / m 2 to about 1000 mg / m 2 per month based on the human body surface area.

37. The method of any one of embodiments 20-36, wherein the human is not suffering from bone metastasis.

39. The method of any one of embodiments 20-37, wherein the human is not suffering from cancer.

Embodiment 39. The method according to any of the preceding embodiments, wherein the zoledronic acid is present in the form of a disodium salt.

Embodiment 40. An oral dosage form comprising zoledronic acid, wherein the oral bioavailability of the zoledronic acid in the formulation 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.

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

39. The oral dosage form of any one of embodiments 40-42 wherein the oral bioavailability of the zoledronic acid in the formulation is from about 0.1% to about 2%.

Embodiment 44. A pharmaceutical product comprising an oral dosage form of Embodiment 40 of more than one unit.

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 composition of embodiment 45, wherein the pharmaceutical product comprises 28, 29, 30, or 31 units of oral dosage form for a total of about 28 mg to about 1600 mg of Zoledronic acid administered in about a month. .

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

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

49. The pharmaceutical product of embodiment 45 comprising 350 to 380 units of oral dosage form for a total of about 350 mg to about 19000 mg of zoledronic acid to be administered in about a year.

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

[0321 ] Embodiment 51. A pharmaceutical product, as described in embodiment 50, comprising four or five units of an oral dosage form for a total of about 40 mg to about 1500 mg of Zoledronic acid to be administered within a period of about one month.

[0215 ] Embodiment 52. A pharmaceutical product, as described in embodiment 50, comprising 8 or 9 units of oral dosage form for a total amount of about 80 mg to about 2700 mg of zoledronic acid administered in about 2 months.

Embodiment 53. A pharmaceutical product according to embodiment 50 comprising 12, 13 or 14 units of oral dosage form for a total of about 120 mg to about 4200 mg of Zoledronic acid to be administered in about 3 months.

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

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

56. The pharmaceutical product of embodiment 44, wherein the product comprises from 1 to 10 unit oral formulations, wherein the product contains from about 200 mg to about 2000 mg of zoledronic acid.

Embodiment 57. The oral dosage form of any of the previous embodiments, wherein the zoledronic acid is present in the form of a sodium salt.

58. The method of embodiment 58 , wherein in any of the previous embodiments, the zoledronic acid is present in a form having a water solubility in excess of 1% (w / v).

Embodiment 59. In any of the previous embodiments, the zoledronic acid is present in the 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 having a water solubility in excess of 1% (w / v).

[0323 ] Embodiment 61. The oral formulations of Embodiment 60 wherein the zoledronic acid is present in a form having a water solubility in the range of about 5% (w / v) to about 50% (w / v).

Embodiment 62. A method of treating a complex local pain syndrome comprising administering to a mammal in need of such treatment a complex topical pain syndrome, an oral formulation comprising zoledronic acid.

63. The method of embodiment 62 wherein the mammal is a human receiving from about 30 mg / m 2 to about 700 mg / m 2 of zoledronic acid for a period of one month or less.

[0322] 74. The method of embodiment 63, wherein four or five weekly doses are administered for a period of one month or less.

[ 0321] Embodiment 65. The method of Embodiment 63 wherein 28 to 31 daily doses are administered for a period of one month or less.

[0215 ] Embodiment 66. The Embodiment 63 of Embodiment 63, wherein 5-10 individual doses are administered for a period of not more than 1 month.

Spheres 67. The method of embodiment 63 wherein from about 30 mg / m 2 to about 700 mg / m 2 of zoledronic acid is administered for only one month.

68. The method of embodiment 63, wherein from about 30 mg / m 2 to about 700 mg / m 2 of zoledronic acid is administered over a period of at least 2 months for two or more consecutive months.

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

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 weekly.

Embodiment 72. The method of embodiment 70, wherein the total daily dose is administered in two to seven separate doses for one week.

73. The method of any one of embodiments 62-72, wherein the complex local pain syndrome is complex localized pain syndrome type I.

74. The method of any one of embodiments 62-72, wherein the complex local pain syndrome is complex localized pain syndrome type II.

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

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 of zoledronic acid based on the mammalian body surface area.

77. The method of embodiment 76, wherein the formulation contains from about 15 mg / m 2 to about 20 mg / m 2 of zoledronic acid based on the mammalian body surface area.

Embodiment 78. A method of treating a complex local pain syndrome comprising administering pemidronic acid to a human in need of treatment for multiple localized pain syndromes.

Embodiment 79. A method of treating a complex local pain syndrome, comprising administering neridronic acid to a human in need of treatment for multiple localized pain syndromes.

Embodiment 80. A method of treating a complex local pain syndrome, comprising administering olanzapride acid to a human in need of treatment for multiple localized pain syndromes.

Embodiment 81. A method of treating a complex local pain syndrome comprising administering to a human in need of treatment of multiple localized pain syndromes allendronic acid.

Embodiment 82. A method of treating a complex local pain syndrome, comprising administering incadronate to a human in need of treatment for multiple localized pain syndromes.

Embodiment 83. A method for treating a complex local pain syndrome comprising administering ibandronate to a human in need of treatment for multiple localized pain syndromes.

Embodiment 84. A method of treating a complex local pain syndrome comprising administering risedronate to a human in need of treatment for multiple localized pain syndromes.

Embodiment 85. A method of treating pain, comprising administering pemidronic acid to a human in need of treatment for pain.

Embodiment 86. A method of treating pain, comprising administering neridronic acid to a human in need of treatment for pain.

Embodiment 87. A method of treating pain, comprising administering olanzapride to a human in need of such treatment.

Embodiment 88. A method of treating pain, comprising administering alendronate to a human in need of treatment for pain.

Embodiment 89. A method of treating pain, comprising administering incadronate to a human in need of such treatment.

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

Embodiment 91. A method of treating pain, comprising administering risedronate to a human in need of such treatment.

Embodiment 92. A method of treating arthritic pain comprising administering pemidronic acid to a human in need of treatment for arthritis pain.

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

Embodiment 94. A method of treating arthritic pain comprising administering olanzapride acid to a human in need of treatment for arthritis pain.

Embodiment 95. A method of treating arthritic pain comprising administering to a human in need of treatment of arthritic pain allendronate .

Embodiment 96. A method of treating arthritic pain comprising administering to a human in need of treatment of arthritic pain incadronate.

Embodiment 97. A method of treating arthritic pain comprising administering to a human in need thereof a treatment with arthritic pain.

Embodiment 98. A method of treating arthritic pain comprising administering risedronate to a human in need of treatment for arthritis pain.

Embodiment 99. A method of treating inflammatory pain comprising administering pemidronic acid to a human in need of treatment for inflammatory pain.

Embodiment 100. A method of treating inflammatory pain comprising administering neuritic acid to a human in need of treatment for inflammatory pain.

Embodiment 101. A method of treating inflammatory pain comprising administering olanzapride acid to a human in need of such treatment for inflammatory pain.

Embodiment 102. A method of treating inflammatory pain, comprising administering alendronate to a human in need of treatment for inflammatory pain.

Embodiment 103. A method of treating inflammatory pain comprising administering incadronate to a human in need of treatment for inflammatory pain.

Embodiment 104. A method of treating inflammatory pain comprising administering ibandronate to a human in need of treatment for inflammatory pain.

Embodiment 105. A method of treating inflammatory pain comprising administering lysedronic acid to a human in need of treatment for inflammatory pain.

Embodiment 106. A method of treating a complex localized pain syndrome comprising administering to a human in need thereof a treatment for multiple localized pain syndromes.

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

108. A method of treating arthritic pain comprising administering to a human in need of treatment for arthritis pain an etidronate .

109. A method of treating inflammatory pain comprising administering to a human in need of treatment of inflammatory pain an etidronic acid.

Embodiment 110. A method of treating a complex localized pain syndrome, comprising administering to a human in need of such treatment a complex localized pain syndrome.

111. The method of treating pain, comprising administering claudronic acid to a human in need of treatment for pain.

Embodiment 112. A method of treating arthritic pain comprising administering claudronic acid to a human in need of treatment for arthritis pain.

Embodiment 113. A method of treating inflammatory pain comprising administering claudronic acid to a human in need of treatment for inflammatory pain.

Embodiment 114. A method of treating a complex localized pain syndrome comprising administering tylurdronic acid to a human in need of treatment for multiple localized pain syndromes.

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

Embodiment 116. A method of treating arthritic pain comprising administering tylurdronic acid to a human in need thereof.

Embodiment 117. A method of treating inflammatory pain comprising administering tyluronic acid to a human in need of treatment for inflammatory pain.

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

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

Embodiment 120. A method for improving oral bioavailability of zoledronic acid, comprising orally administering a formulation containing zoledronic acid in the form of a sodium salt.

121. Embodiment 120. The method of embodiment 121 wherein the zoledronic acid in the form of a sodium salt is added to any of the bioavailability provided by any of the bioavailability enhancers in the formulation A method of providing improved bioavailability.

128. Embodiment 122. The method of embodiment 120 wherein the formulation is substantially free of a bioavailability enhancer.

Embodiment 123. The method of embodiment 123 , wherein the sodium salt form of zoledronic acid is administered to the mammal from about 4 ng · h / mL to about 2000 ng · h / mL Wherein the amount of zoledronic acid is administered to the mammal in an amount that provides an area under the plasma concentration curve of zoledronic acid.

124. The method of embodiment 123, wherein the sodium salt form of zoledronic acid is administered to the mammal in an amount of from about 100 ng · h / mL to about 2000 ng · h / mL Of the zoledronic acid in an amount that provides an area under the plasma concentration curve of about 3 to about 4 weeks.

125. Embodiment 125. The method of embodiment 123, wherein the sodium salt form of zoledronic acid is administered to the mammal at a rate of from about 20 ng · h / mL to about 700 ng · h / mL Of the zoledronic acid is administered three to five times a week or every month in an amount that provides the area under the plasma concentration curve.

126. Embodiment 126. The method of embodiment 123, wherein the sodium salt form of zoledronic acid is administered to the mammal in an amount of from about 4 ng · h / mL to about 100 ng · h / mL Lt; RTI ID = 0.0 &gt; of zoledronic acid &lt; / RTI &gt;

127. The process of embodiment 120 wherein the formulation is a solid.

128. The method of embodiment 128, 121, 122, 123, 124, 125, 126 or 127 wherein the bioavailability of zoledronic acid is improved by at least about 20% over the administration of zoledronic acid in its discrete form.

Embodiment 129. The method of embodiment 120, 121, 122, 123, 124, 125, 126, 127 or 128 wherein the discrete form of zoledronic acid is administered to achieve the same plasma level of zoledronic acid, Lt; RTI ID = 0.0 &gt; of zoledronic acid &lt; / RTI &gt;

130. The method of embodiment 129 wherein at least about 10 mole% of the disodium form is administered relative to the amount of disolinated form of zoledronic acid to be administered to achieve the same plasma level of zoledronic acid.

In the specific example embodiments 131. 129, a form of sodium salt is administered in an amount having a value of about 0.8n _d to about 1.2n that the ratio of _d, in which

n _{d =} (b _a / b _d ) (n _a )

Wherein b _a is the bioavailability of the discrete form, b _d is the bioavailability of the sodium salt form, and n _a is the disodium form of zoledronic acid to be administered to achieve the same plasma level of zoledronic acid How to confiscate.

132. The process of embodiment 131 wherein the sodium salt is administered in an amount having a value of about n _d .

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

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

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

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

The first oral dosage form is administered;

A second oral dosage form is administered;

Wherein for a first oral dosage form, the second oral dosage form is administered at 10 x T _max or greater, wherein T _max is the time of the maximum plasma concentration for the first oral dosage form.

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

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

139. The method of embodiment 138 wherein the formulation is administered to a human to which the formulation is administered in an amount of from about 100 ng · h / mL to about 2000 ng · h / mL of a disodium salt Formulation containing zoledronic acid in salt form.

Embodiment 140. The method of embodiment 138 wherein the formulation is administered to a human to which the formulation is administered in an amount of from about 20 ng · h / mL to about 700 ng · h / mL, Formulation containing zoledronic acid in salt form.

Embodiment 141. The method of embodiment 138 wherein the formulation is administered to a human to which the formulation is administered in an amount of from about 4 ng · h / mL to about 100 ng · h / mL of an amount of disodium Formulation containing zoledronic acid in salt form.

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

The sodium salt form is present in a lower molar amount than that present when the zoledronic acid is in the discrete form;

The zoledronic acid in the form of its sodium salt has an improved bioavailability such that the lower molar amount of disodium disodium salt in the formulation does not reduce the amount of zoledronic acid delivered to the mammalian plasma compared to disolinated zoledronic acid &Lt; / RTI &gt;

143. The formulation of embodiments 137, 138, 139, 140, 141 or 142 wherein the formulation is solid.

144. The formulation of embodiment 142 or 143 wherein the bioavailability of the zoledronic acid in the form of said sodium salt is improved by at least about 10% over other identical formulations containing zoledronic acid in its discrete form.

145. The formulation of embodiment 142, 143 or 144, wherein the formulation comprises at least about 20 mole% disodium form relative to the amount of disolinated form of zoledronic acid that would have been present when the zoledronic acid was in the discrete form.

In the specific example embodiments 146. 142, a form of sodium salt and is present in an amount having a value of about 0.9n _d to about 1.1n that the ratio of _d, in which

n _{d =} (b _a / b _d ) (n _a )

Wherein b _a is the bioavailability of the discrete form, b _d is the bioavailability of the sodium salt form, and n _a is the number of moles of the discrete form that would have been present if the zoledronic acid was in the discrete form.

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

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

Only one oral dosage form is administered; or

The first oral dosage form is administered and the second oral dosage form is administered after the first oral dosage form wherein the second oral dosage form is administered before the maximum pain relief effect of the first oral dosage form is achieved, Wherein the second oral dosage form is administered before the pain relief effect is achieved.

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

150. The method of any one of embodiments 1-39, 62-77 and 120-132 wherein the second formulation is administered after the first formulation is administered wherein the maximum pain relief effect of the first oral dosage form is achieved Wherein 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.

Specific Example 151 . Wherein in the Embodiment 148, 149 or 150, the first oral dosage form is administered and the second oral dosage form is administered from about 24 hours to about 28 days.

Embodiment 152. The method of any one of embodiments 20-39, wherein the human is about 30 to about 75 years of age.

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

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

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

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

Embodiment 157. The method of any one of embodiments 1-44, 62-133, and 144-156, wherein the mammal or the human to which zoledronic acid is administered is fed at least one hour prior to the administration of zoledronic acid, Not the way.

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

Embodiments according to the embodiment 159. 158. A method Zoledronic acid is a mammal or human administration is not drinking the Zoledronic acid administration before eating the food or drink for at least four hours.

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

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

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

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

168. Embodiment 164. In any of the previous embodiments, the zoledronic acid in the oral dosage form has a plasma level factor of about 1 or more for 24 hours.

165. Embodiment 166. In any of the previous embodiments, the zoledronic acid in the oral dosage form has a 24 hour sustained plasma level factor that is higher than the intravenously administered zoledronic acid.

168. Embodiment 166. In any preceding embodiment, 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 with a bone marrow lesion, and an OARSI 0 grade joint space narrowing, and administering an inhibitor of osteoclast activity to the patient for treatment of a bone marrow lesion step.

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

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

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

A method according to any one of embodiments 167-170 171. embodiments, an inhibitor of osteoclast activity method or Zoledronic acid or contains it.

Embodiment 172. A method according to any one of embodiments 167-170, an inhibitor of osteoclast activity method or wave imide acid or contains it.

A method according to any one of embodiments 167-170 173. embodiments, an inhibitor of osteoclast activity may be a four lead-acid or a method comprising the same.

Embodiment 174. Specific examples according to any one of 167-170, an inhibitor of osteoclast activity may be a come-Pas acid or comprises this.

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

In the embodiment 176. any one of embodiments 167-170, an inhibitor of osteoclast activity comprises Inca acid or drones or them.

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

In the embodiment 178. any one of embodiments 167-170, an inhibitor of osteoclast activity comprising risedronic acid, or or them.

In the embodiment 179. any one of embodiments 167-178, an inhibitor of osteoclast activity is how the oral administration.

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

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

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

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.

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

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

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

In the specific example embodiments 187. 186, an inhibitor of osteoclast activity is how to be administered at least twice.

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

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

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

A method according to any one of embodiments 186-190 191. embodiments, an inhibitor of osteoclast activity method or Zoledronic acid or contains it.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

206. The method of embodiment 203 wherein the inhibitor of osteoclast activity is neuridonic acid.

207. The method of embodiment 203 wherein the inhibitor of osteoclast activity is oleadic acid.

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

209. The method of embodiment 203, wherein the inhibitor of osteoclast activity is incadronate.

210. The method of embodiment 203 wherein the inhibitor of osteoclast activity is ibandronate.

211. The method of embodiment 203, wherein the inhibitor of osteoclast activity is risedronate.

212. The method of embodiment 203 wherein the inhibitor of osteoclast activity is alendronate.

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

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

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

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

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.

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

219. The method of embodiment 218 wherein the inhibitor of osteoclast activity comprises zoledronic acid and the daily 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 Kelloggren and Lawrence grade 0 or grade 1 joint space narrowing, or

ii. 0-10 Measured using NRS 5 or more, or 10 cm VAS measured 5 cm or more pain intensity

Selecting a patient having the patient; And

b. Administering an inhibitor of osteoclast activation to the patient.

221. The method of embodiment 220 comprising selecting a patient having a joint space narrowing of OARSI 0 grade or Kelgene and Lawrence 0 grade or 1 grade.

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

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

203. The method of embodiment 223 wherein the inhibitor of osteoclast activity is administered about every 3 months or more frequently.

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

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

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.

228. The process of embodiment 220 wherein the inhibitor of osteoclast activity is zoledronic acid.

229. The process of embodiment 220 wherein the inhibitor of osteoclast activity is minodronic acid.

230. The process of embodiment 220 wherein the inhibitor of osteoclast activity is neuridonic acid.

231. The process of embodiment 220, wherein the inhibitor of osteoclast activity is oleadic acid.

232. The method of embodiment 220, wherein the inhibitor of osteoclast activity is alendronate.

203. The process of embodiment 220 wherein the inhibitor of osteoclast activity is incadronate.

203. The process of embodiment 220 wherein the inhibitor of osteoclast activity is ibandronic acid.

235. The process of embodiment 220 wherein the inhibitor of osteoclast activity is risedronate.

[0082] Embodiment 236. The method of embodiment 220 wherein the subject experiences a reduction in pain intensity of at least about 5 using a 100 mm visual pain scale.

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

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

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

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

241. The method according to embodiment 240, wherein the person with moderate to severe knee pain has normal joint space in the knee.

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

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

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

248. The method of embodiment 240 wherein the patient experiences pain relief within about 3 months after administration of the inhibitor of osteoclast activity to the patient.

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.

247. The process of embodiment 240 wherein the inhibitor of osteoclast activity is zoledronic acid.

248. The process of embodiment 240 wherein the inhibitor of osteoclast activity is minodronic acid.

249. The process of embodiment 240 wherein the inhibitor of osteoclast activity is neuritonic acid.

250. The method of embodiment 240 wherein the inhibitor of osteoclast activity is oleadic acid.

Example 251 . The method of embodiment 240 wherein the inhibitor of osteoclast activity is alendronate.

252. The process of embodiment 240 wherein the inhibitor of osteoclast activity is incadronate.

255. The process of embodiment 240 wherein the inhibitor of osteoclast activity is ibandronate.

255. The process of embodiment 240 wherein the inhibitor of osteoclast activity is risedronate.

255. The method of embodiment 240 wherein the patient experiences a reduction in pain intensity of at least about 5 using a 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.

257. The process of embodiment 240 wherein the inhibitor of osteoclast activity is administered once a week for a period of 6 weeks.

198. The process of embodiment 257 wherein the inhibitor of osteoclast activity comprises zoledronic acid and the daily 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 through repeated oral administration comprising:

Oral administration of zoledronic acid from about 0.4 mg / kg to about 4 mg / kg of the mammal 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 once a week or less frequently to a mammal.

Embodiment 260. The method of any preceding embodiment, e.g. Example 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, e.g. 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 according to any of the preceding embodiments, e.g. Example 259, wherein from about 0.5 mg / kg to about 2 mg / kg is administered orally to the mammal every week.

Embodiment 263. The method of any preceding embodiment, e.g. Embodiment 263, wherein from about 0.6 mg / kg to about 0.9 mg / kg is administered orally to the mammalian body every week.

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

Embodiment 265. The method of any of the preceding embodiments, e.g., Examples 259, 260, 261, 262, 263, or 264, wherein the zoledronic acid is orally administered to a formulation comprising greater than about 10 weight percent zoledronic acid.

In any of the previous embodiments, such as Examples 259, 260, 261, 262, 263, 264 or 265, the zoledronic acid is administered at a dose of about 50 ng · h / _Wherein the method is administered in the manner and amount such that a mammal having an AUC _0-24 of zoledronic acid of 500 ng · h / mL emerges.

Embodiment 267. In any of the previous embodiments, e. G. Example 266, the zoledronic acid has an AUC of about 100 ng · h / mL to about 500 ng · h / mL of zoledronic acid for each administration of zoledronic acid _Lt ; RTI ID = 0.0 &gt; _0-24 &lt; / RTI &gt;

Embodiment 268. A method of making an oral dosage form safe for repeated administration to a mammal comprising zoledronic acid in association with a pharmaceutically acceptable excipient in a mammal, wherein the amount of zoledronic acid to be combined with the excipient Wherein the redron acid is present in the oral dosage form in an amount from 0.4 mg / kg to about 10 mg / kg, based on the weight of the mammal.

269. Embodiments 269. In any of the previous embodiments, e.g. Example 268, the amount of zoledronic acid to be combined with the excipient is an amount wherein the oral dosage form comprises greater than about 10% by weight of zoledronic acid.

Embodiment 270. In any of the previous embodiments, e. G. Examples 268 or 269, the amount of zoledronic acid to be combined with the excipient is such that the zoledronic acid is present in the amount of 0.4 mg / kg to about 3 mg / kg Lt; RTI ID = 0.0 &gt; oral &lt; / RTI &gt; formulation.

Example 271. In any of the previous embodiments, e.g., Example 270, the amount of zoledronic acid to be combined with the excipient is such that the amount of zoledronic acid is from 0.4 mg / kg to about 1.5 mg / kg, based on the weight of the mammal In the oral dosage form.

Embodiment 272. In any of the previous embodiments, such as Embodiment 270, the amount of zoledronic acid to be combined with the excipient is such that the amount of zoledronic acid is from 0.6 mg / kg to about 0.9 mg / kg, based on the weight of the mammal In the oral dosage form.

Example 273. In any of the previous embodiments, e.g., Examples 268, 269, 270, 271, or 272, the oral dosage form is formulated in a safe manner for once-daily dosing of the oral dosage form for about 3 days to about 10 days .

Embodiment 274. The method of any preceding embodiment, e.g., Examples 268, 269, 270, 271, or 272, wherein the oral dosage form is safe for administration once a week for about 3 to about 10 weeks of oral dosage form.

Embodiment 275. Orally administering to a mammal 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

Oral administration of about 0.1 mg / kg to about 10 mg / kg to a mammal once a week or less frequently

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

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

278. Embodiment 276. The method of any preceding embodiment, e.g. Embodiment 275, wherein the zoledronic acid is administered orally from about 5 times to about 10 times.

Detailed Description 277. In any of the previous embodiments, such as Examples 275 or 276, the zoledronic acid is orally administered to a formulation comprising greater than about 10% by weight of zoledronic acid.

278. Specific examples any of the previous embodiments, such as embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276 or 277 Wherein the mammal is a human.

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

Embodiments 280. Any previous embodiments, such as Examples 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277 , &Lt; / RTI &gt; 278 or 279. &lt; RTI ID = 0.0 &gt;

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are intended to refer to both the exact value shown and the value modified by the term " about " Should be understood. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and the appended claims are approximations that may vary depending upon the particular characteristics sought to be obtained. At the very least, and not as an attempt to limit the application of the teaching of equivalents to the claims, each numerical parameter should at least be construed in light of the number of significant digits reported and by applying ordinary ordinary skill.

The terms " a ", " an ", " the ", and the like, used in the context of describing the invention (especially in the context of the following claims), unless otherwise indicated herein or otherwise clearly contradicted by context, Should be construed to cover both the singular and the plural. All methods described herein may be performed in any suitable order unless otherwise stated herein or otherwise clearly contradicted by context. The use of the exemplary expressions provided herein (e.g., " such as ") or any and all instances is intended merely to better illuminate the invention and is not intended to limit the scope of the claims. The expression in the specification should not be construed as indicating any non-claimed element which is essential for the practice of the invention.

The groupings of alternative elements or embodiments disclosed in the present invention should not be construed as limiting. Each group member may be referred to individually, or in any combination with other members or other elements of the group described herein, and so claimed. It is anticipated that one or more members of the group may be included or excluded from the county for reasons of convenience and / or patentability. Where there are any such inclusions or deletions, the specification intends to include a group that has been modified to complete the written description of all macros groups used in the appended claims.

Certain embodiments, including the best mode known to the inventors for carrying out the invention, are described herein. Of course, modifications to these described embodiments will be apparent to those skilled in the art upon a reading of the above description. The inventors expect that the skilled artisan will properly employ these variations, and the inventors intend that the invention be practiced otherwise than as specifically described herein. It is, therefore, to be understood that the appended claims are intended to cover all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, any combination in all possible variations of the above described elements is contemplated, unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it should 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, and not by way of limitation, alternative embodiments may be used in accordance with the teachings herein. Accordingly, the appended claims are not to be construed as being limited to precisely shown and described embodiments.

Claims (30)

WHAT IS CLAIMED IS: 1. A pharmaceutical composition comprising zoledronic acid for the treatment of mordic altered type 1 in a human, wherein the human is experiencing pain relief for 3 months following the administration of zoledronic acid. The pharmaceutical composition according to claim 1, wherein the zoledronic acid is orally administered. 3. The pharmaceutical composition according to claim 2, wherein about 50 mg to about 600 mg of zoledronic acid is orally administered. 3. The pharmaceutical composition according to claim 2, wherein about 200 mg to about 400 mg of zoledronic acid is orally administered. 3. The pharmaceutical composition according to claim 2, wherein about 400 mg to about 500 mg of zoledronic acid is orally administered. 3. The pharmaceutical composition according to claim 2, wherein about 150 mg to about 200 mg of zoledronic acid is orally administered. 3. The pharmaceutical composition according to claim 2, wherein a dose of about 100 mg to about 200 mg of zoledronic acid is orally administered twice or three times a month. The pharmaceutical composition of claim 2, wherein about 50 mg to about 60 mg of zoledronic acid in the form of a disodium salt is administered orally every week. 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 every week for 1 month or 2 months. The pharmaceutical composition according to claim 2, wherein the zoledronic acid is orally administered every week for 6 weeks. 2. The pharmaceutical composition of claim 1, wherein the mordic change is located at C1 / 2, C2 / 3, C3 / 4, C4 / 5, C5 / 6 or C6 / 7. The method of claim 1, wherein the mocking changes are selected from the group consisting of C7 / T1, T1 / 2, T2 / 3, T3 / 4, T4 / 5, T5 / 6, T6 / 7, T7 / 8, T8 / 9, T9 / / 11 or &lt; RTI ID = 0.0 &gt; T11 / 12. &Lt; / RTI &gt; 2. The pharmaceutical composition according to claim 1, wherein the mocking alteration is located at T12 / L1, L1 / 2, L2 / 3, L3 / 4, L4 / 5 or L5 / S1. The pharmaceutical composition of claim 1, wherein a size reduction of at least about 5% of the Mordic Change Form 1 is achieved relative to a baseline prior to administration of the zoledronic acid. 2. The pharmaceutical composition according to claim 1, wherein the human has morphological variant 1 at two or more levels. The pharmaceutical composition of claim 1, wherein the zoledronic acid is orally administered to cause a 24 hour sustained plasma level factor that is at least about 2-fold greater than when 4 mg of zoledronic acid is administered intravenously. The pharmaceutical composition according to claim 1, wherein the zoledronic acid is orally administered to cause a 48-hour sustained plasma level factor that is at least twice that of the 1 mg zoledronic acid administered intravenously. The pharmaceutical composition of claim 1, wherein the zoledronic acid is orally administered to bring about a bioavailability of at least 1.1%. The pharmaceutical composition according to claim 2, wherein the zoledronic acid is orally administered to bring about a bioavailability of between 1.3% and 3%. 8. The pharmaceutical composition of claim 1, wherein the human is experiencing pain relief for at least 3 weeks. The pharmaceutical composition of claim 1, wherein the human is experiencing a reduction in pain lasting at least 3 months. 3. The pharmaceutical composition of claim 2, wherein the human is fasting for at least 2 hours prior to oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human is fasting for at least 30 minutes following oral administration of zoledronic acid. 3. The pharmaceutical composition according to claim 2, wherein the human is fasting for at least 1 hour after oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human is fasting for at least 4 hours prior to oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human is fasting for at least 8 hours prior to oral administration of zoledronic acid. 3. The pharmaceutical composition of claim 2, wherein the human is sitting upright or straight for at least 30 minutes after oral administration of zoledronic acid. 3. The pharmaceutical composition according to claim 2, wherein the mordic change 1 type is reduced in size and maintained for at least about 3 months after the oral administration of the zoledronic acid compared to the baseline before administration. 3. The pharmaceutical composition according to claim 2, wherein at about 3 months after the oral administration of zoledronic acid, the size of the mocking variant Form 1 is reduced compared to the baseline before administration.

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