CN108434154A - The oral administration composition of zoledronic acid or related compound for treating disease - Google Patents

Abstract

The present invention relates to the oral administration compositions of zoledronic acid or related compound for treating disease.The invention discloses can be used for treating or relieve pain or the oral of the bisphosphonate compound of associated disease such as zoledronic acid.The oral bioavailability of zoledronic acid can be improved by the zoledronic acid of application disodium salt form.

Description

The oral administration composition of zoledronic acid or related compound for treating disease

The application is the divisional application of the Chinese patent application application No. is 201480069491.3, and original application is the applying date For the National Phase in China application of the International Application Serial No. PCT/US2014/050427 on the 8th of August in 2014.

Technical field

The present invention relates to the oral administration compositions of zoledronic acid or related compound for treating disease.

Background technology

Bisphosphonate compound is the inhibitor of potent osteoclast activity, and it is relevant with bone to be used clinically for treatment Illness, for example, osteoporosis and bone osteitis deformans；And cancer related disorders, including Huppert's disease and solid tumor Bone tumour.They usually have low oral bioavailability.

Invention content

It has been found that the oral of bisphosphonate compound (such as zoledronic acid) can be used for treating or relieve pain or phase Related disorders.

Some embodiments include the configuration having suitable for specific mammalian species containing zoledronic acid (configuration) and the oral of zoledronic acid dosage, wherein zoledronic acid with oral is administered to it is specific Lead to area under the zoledronic acid blood plasma concentration curve of about 50nghr/mL to about 700nghr/mL after mammalian species (AUC) amount exists.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein zoledronic acid after oral is administered to specific mammalian species to lead to about 5ng/ The zoledronic acid C of mL to about 300ng/mL_maxAmount exist.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that applying oral to specific mammalian species causes about The zoledronic acid T of 0.4hr to about 1hr_max。

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has for specific mammalian species About 12 to about 50 12 hours sustained plasma level factors.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has for specific mammalian species About 10 to about 30 24 hours sustained plasma level factors.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has about 6 for specific mammalian species To about 20 36 hours sustained plasma level factors.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has for specific mammalian species About 5 to about 20 48 hours sustained plasma level factors.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has for specific mammalian species About 4 to about 20 72 hours sustained plasma level factors.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that specific mammalian species had about at 12 hours The zoledronic acid plasma concentration of 0.5ng/mL to about 5ng/mL.

Some embodiments include that configuration and azoles of the having containing zoledronic acid suitable for specific mammalian species carry out phosphine The oral of sour dosage, wherein oral are configured so that elimination of the zoledronic acid in specific mammalian species half The phase of declining is about 30 hours to about 100 hours.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein zoledronic acid by oral to be administered to the food in one's mouth The amount of the zoledronic acid AUC of about 50nghr/mL to about 700nghr/mL is caused to be present in oral after newborn animal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein zoledronic acid by oral to be administered to the food in one's mouth Lead to the zoledronic acid C of about 5ng/mL to about 300ng/mL after newborn animal_maxAmount be present in oral.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so as to specific lactation Animal species, which apply oral, leads to the zoledronic acid T of about 0.4hr to about 1hr_max。

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid pair With about 12 to about 50 12 hours sustained plasma level factors for mammal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid pair With about 10 to about 30 24 hours sustained plasma level factors for mammal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid pair With about 6 to about 20 36 hours sustained plasma level factors for mammal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid pair With about 5 to about 20 48 hours sustained plasma level factors for mammal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid pair With about 4 to about 20 72 hours sustained plasma level factors for mammal.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that specific lactation is dynamic Zoledronic acid plasma concentration of the object species at 12 hours with about 0.5ng/mL to about 5ng/mL.

Some embodiments include treatment and bone, the method for cancer or the relevant disease of pain or illness, including to having This mammal needed applies the oral containing zoledronic acid, and wherein oral is configured so that zoledronic acid exists Elimination half-life period in specific mammalian species is about 30 hours to about 100 hours.

Some embodiments include the method for the oral bioavailability for improving zoledronic acid, including oral administration contains two The dosage form of the zoledronic acid of sodium-salt form.

Some embodiments include the dosage form of the zoledronic acid containing disodium salt form, and the azoles of wherein disodium salt form carrys out phosphine The bioavailability of acid in mammals is more than the bioavailability of the zoledronic acid of diacid form in same dosage form.

Some embodiments include the dosage form of the zoledronic acid containing disodium salt form, wherein the disodium salt shape contained by dosage form The zoledronic acid blood plasma that the amount of the zoledronic acid of formula provides about 4ngh/mL to about 2000ngh/mL to the people of form of administration is dense Spend area under the curve.

Some embodiments include the dosage form of the zoledronic acid containing disodium salt form, and wherein disodium salt form than azoles to come When phosphonic acids is diacid form there will be the lower mole of mole exist；And wherein the zoledronic acid of disodium salt form with The zoledronic acid of diacid form is compared with the bioavailability improved, and the disodium salt for reaching more lower mol in dosage form does not drop The degree of the amount of the low zoledronic acid for being delivered to mammalian plasma.

Although the oral improved for bisphosphonate compound bioavailability can be used, wherein two banks are used The oral agent for including bisphosphonate compound (such as zoledronic acid) that the bioavailability of salt is not improved or do not improved substantially Type is alternatively effectively.

Some embodiments include mitigating the method for inflammatory pain, and this method includes that will include the oral of zoledronic acid It is administered to the mammal of this needs, wherein mammal experiences pain after form of administration and significantly alleviates more than 3 hours.

Some embodiments include the method mitigated with the relevant pain of arthritis, and this method will be including that will include zoledronic acid Oral be administered to this needs people.

Some embodiments include the method for treating complex regional pain syndrome, and this method includes that will carry out phosphine comprising azoles The oral of acid is administered to the mammal of this needs.

Some embodiments include including the oral of zoledronic acid, wherein the oral bioavailability base of zoledronic acid It is not improved in sheet.For example, in some embodiments, the oral bioavailability in dosage form is about 0.01% to about 4%.

Some embodiments include drug products, and it includes the orals as described herein of more than one unit.One In a little embodiments, the oral of per unit includes about 1mg to about 50mg zoledronic acids.

Some embodiments include mitigating the method for inflammatory pain, and this method includes that will include the oral of zoledronic acid It is administered to the mammal of this needs.

In some embodiments, mammal receives about 800mg/m²Or less zoledronic acid moon accumulated dose.

In some embodiments, the body surface area meter based on mammal, dosage form include about 10mg/m²To about 20mg/ m²。

Some embodiments include mitigating the method for inflammatory pain, and this method includes that zoledronic acid has been administered orally to this The mammal needed.

In some embodiments, the body surface area meter based on mammal monthly applies about 300mg/m²To about 600mg/m²Zoledronic acid.

In some embodiments, the body surface area meter based on mammal monthly applies about 50mg/m²To about 600mg/ m²Zoledronic acid.

Description of the drawings

Fig. 1 be use three kinds of various doses zoledronic acid when inflammatory pain rat model in pain compression threshold value figure Line.It is after indicating number of days administration, is measured at baseline (BL) and at Each point in time.

Fig. 2A is to show that the arthritis ache of the zoledronic acids of two kinds of various doses in arthritis ache rat model is inverse The figure turned.

Fig. 2 B are the figure for showing the pain threshold of the zoledronic acids of two kinds of various doses in arthritis ache rat model.

Fig. 3 is knot of the rat in complex regional pain syndrome rat model for summarizing supporting agent and zoledronic acid processing The figure of fruit.

Fig. 4 show supporting agent and zoledronic acid processing rat in complex regional pain syndrome rat model after Pawl pain threshold.

Fig. 5 shows lotus of the rat in complex regional pain syndrome rat model of supporting agent and zoledronic acid processing Weight.

Fig. 6 shows pawl of the rat in complex regional pain syndrome rat model of supporting agent and zoledronic acid processing Thickness change.

Fig. 7 shows water solubility of the zoledronate disodium tetrahydrate compared with zoledronic acid diacid form.

Fig. 8 show dog apply 150mg disodium salt forms zoledronic acid and diacid form zoledronic acid after at any time The zoledronic acid plasma concentration of passage.

Fig. 9 shows compressibility of the dosage form of the zoledronic acid containing disodium salt form compared with diacid form.

Specific implementation mode

It is described in detail

Bisphosphonate compound, such as Pamidronate or pamidronic acid, Neridronic Acid salt or Neridronic Acid, olpadronic acid Salt or olpadronic acid, Alendronate or alendronic acid, Incadronate or Incadronic Acid, ibandronate or ibandronic acid, Risedronate or Risedronic Acid, zoledronate or zoledronic acid, etidronate or Etidronic Acid, clodronate or chlorine phosphine Acid, Tiludronate or Tiludronic Acid etc., can be used for a variety for the treatment of purposes, such as treat bad conditions or diseases, including mitigate Pain.This can be realized in many cases by application oral.In general, will include diphosphonate (such as azoles come Phosphonic acids) oral through being administered orally to mammal such as people at least once, to treat disease or illness, or mitigate pain Bitterly.

Term " treatment " broadly include any kind for the treatment of activity (including diagnosis, healing, alleviation or prevent people or its The disease of his animal) or otherwise any activity of the structure or any function of influence people or other animal bodies.

The oral of diphosphonate (such as zoledronic acid) can be used for treating or mitigate any kind of pain, the pain Including but not limited to inflammatory pain, arthritis ache, complex regional pain syndrome, lumbosacral pain, musculoskeletal pain, nerve Pain, chronic ache, cancer-related pain, Acute Pain, postoperative pain etc..In some cases, pain relief can be to appease Property or pain relief it is unrelated with the improvement of disease or illness or the basic reason of disease or illness.For example, although underlying diseases It may not improve or may continue to develop, but the pain of the individual with disease can mitigate.In some embodiments, it is controlling It treats these illnesss for the moment, the biology profit of zoledronic acid can be improved by the dosage form of zoledronic acid of the application containing disodium salt form With rate.This may make the mole for the disodium salt that reduction uses compared with diacid form is by the amount used.

In some embodiments, the mammal for receiving treatment does not suffer from Bone tumour.In some embodiments, receive The mammal for the treatment of does not suffer from cancer.In some embodiments, the mammal for receiving treatment does not suffer from osteoporosis.

For example, zoledronic acid or another diphosphonate can oral administration with mitigate musculoskeletal pain, including back pain with And with following relevant pain：Rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, aggressivity Bones and joints Scorching (the packet of inflammation, seronegativity (non-rheumatoid) arthropathy, nonarticular rheumatism, periarticular disease, axis joint of vertebral column Include ankylosing spondylitis), osteitis deformans, fibrous dysplasia, SAPHO syndromes, temporary hipbone arthritis, vertebra powder Fragility fracture, osteoporosis etc..In some embodiments, these illnesss are being treated for the moment, disodium is contained by application The bioavailability of zoledronic acid can be improved in the dosage form of the zoledronic acid of salt form.This may make the amount that will be used with diacid form Compared to the mole for reducing the disodium salt used.

The diphosphonate of such as zoledronic acid can also be used for the healing for the treatment of fracture or enhancing fracture.

In some embodiments, zoledronic acid or another diphosphonate can also oral administration to mitigate nerve pain Bitterly, including diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, single radiculopathy, phantom limb pain and maincenter Property pain.The reason of other neuropathic pains include cancer-related pain, lumbar nerve roots compression, spinal cord injury, post-stroke pain, Maincenter multiple sclerosis pain, HIV related neuropathies and with radiotherapy or the relevant neuropathy of chemotherapy. In some embodiments, these illnesss are being treated for the moment, it can by the dosage form of zoledronic acid of the application containing disodium salt form Improve the bioavailability of zoledronic acid.This may make rubbing for the disodium salt that reduction is used compared with diacid form is by the amount used You measure.

In some embodiments, zoledronic acid or another diphosphonate can oral administration to mitigate inflammatory pain, packet Include musculoskeletal pain, arthritis ache and complex regional pain syndrome.In some embodiments, these illnesss are being treated For the moment, the bioavailability of zoledronic acid can be improved by the dosage form of zoledronic acid of the application containing disodium salt form.This can So that reducing the mole for the disodium salt used compared with diacid form is by the amount used.

The example of musculoskeletal pain includes back pain；And with following relevant pain：Vertebral crush fractures, fibroid Dysplasia, osteogenesis imperfecta, the osteitis deformans of bone, temporary osteoporosis and temporary hip osteoporosis.

The diphosphonate of such as zoledronic acid can also be used for treatment in bone have can be by MRI or another Medical imaging instruments The back pain of the change of device detection or other muscle skeletons or inflammatory conditions.For example, the diphosphonate of such as zoledronic acid is available In treatment and following relevant back pain：Changed using the visible Modic of magnetic resonance imaging (MRI) or terminal plate of vertebral body signal changes (VESC) change with marrow.Modic changes can be classified into multiple types, including 1 type (M1), 2 types (M2) and 3 types (M3) lesion Or change, any of which the diphosphonate of such as zoledronic acid can be used to be treated.VESC, which is found in, to be had In the patient of different types of back pain, including but not limited to spondylitis, wound, spinal arthropathy (including rigid spine It is scorching), Schmorl tubercles, fracture, tumour and spinal infarction.Lesion in ankylosing spondylitis includes osteitis and discitis, it The detection of MRI or another Medical imaging instruments can be used.

The diphosphonate of such as zoledronic acid can be used for treat knee osteoarthritis, such as with bone marrow lesion (BML) phase The knee osteoarthritis of pass, the BML include the BML that MRI or another Medical imaging instruments detections can be used.In some embodiment party In formula, the diphosphonate of such as zoledronic acid can be used for treating and bone marrow edema (BME) relevant knee osteoarthritis, described BME includes the BME that MRI or another Medical imaging instruments detections can be used.

Arthritis refers to can be with the relevant inflammatory joint disease of pain.The example of arthritis ache include with it is following relevant Pain：Osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegativity are (non- Rheumatoid) arthropathy, nonarticular rheumatism, periarticular disease, neuroarthropathy (including charcot's foot (Charcot ' s foot)), axis joint of vertebral column scorching (including ankylosing spondylitis) and SAPHO syndromes.

In some embodiments, disease or illness such as inflammatory conditions are treated by the oral of zoledronic acid Artificially about 10 years old to about 90 years old, about 20 years old to about 80 years old, about 30 years old to about 75 years old, about 40 years old to about 70 of (such as arthritis) Year, about 1 are about to about 16 years old or about 80 years old to about 95 years old.

In some embodiments, disease or illness such as inflammatory conditions are treated by the oral of zoledronic acid The people of (such as arthritis) has had suffered from arthritis at least one moon, at least two moon, at least six moon or at least 1 year.

In some embodiments, disease or illness such as inflammatory conditions (such as arthritis) influence knee, ancon, hand Finger, wrist, shoulder or hip.

In some embodiments, zoledronic acid or another diphosphonate can oral administration to mitigate complex regional pain Syndrome, for example, complex regional pain syndrome I types (CRPS-I), complex regional pain syndrome II types (CRPS-II), CRPS-NOS or another type of CRPS.CRPS is a kind of inflammatory pain.CRPS can also have neuropathy ingredient.

Complex regional pain syndrome is a kind of debilitating pain syndrome.It is characterized in that the severe pain of limbs, With edema, independence variation, motility variation and feel variation.

For using oral zoledronic acid to mitigate with for the relevant pain of inflammatory conditions, pain relief can be short-term , such as the period of a few houres and/or pain relief can be long-term after form of administration, such as after oral administration zoledronic acid It takes several days, a few weeks or even some months.In some embodiments, mammal (such as people) includes zoledronic acid in application Oral after 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, extremely It experiences pain and significantly mitigates within few about 1 week, at least about 2 weeks, at least about 3 weeks.In some embodiments, mammal (such as People) about 3 hours to about 2 weeks after application is comprising the oral of zoledronic acid, about 3 hours to about 3 weeks, about 3 hours to about 24 hours, about 6 hours to about 2 weeks or about 6 hours to about 24 hours, about 3 days to about 2 weeks, about 6 days to about 2 weeks time extremely Pain is experienced during a few part significantly to mitigate.

Treatment for any illness enumerated herein, in some embodiments, using first comprising zoledronic acid Oral simultaneously applies the second oral comprising oral zoledronic acid.The administration time of two kinds of dosage forms may make relative to One oral, the second oral relative to the first oral, the second oral are in 5 × T_maxOr longer time (example Such as, if T_maxBe 1 hour, then at 5 hours or later), at least 10 × T_maxOr longer time, at least about 15 × T_maxOr it is longer Time, at least about 20 × T_maxOr longer time, at least about 50 × T_maxLonger time or at least about 200 × T_maxOr when longer Between when apply, wherein T_maxIt is the time of the maximal plasma concentration of the first oral.

Some embodiments include treating illness enumerated herein, such as inflammatory pain, arthritis or complex regional pain Pain syndrome, wherein treatment includes：To only a kind of dosage form of mammal application to treat illness；Or apply first to mammal Then dosage form applies the second dosage form to mammal.If using two or more dosage forms, the second oral is being realized It is applied before the maximum pain relief of first oral, or the first oral is undergone in the mammal for receiving dosage form Pain relief peak value before apply.In some embodiments, the second oral is slow in the pain for realizing observable It is applied before solving effect.In some embodiments, the second dosage form is about 12 hours to about 60 days after the first dosage form of application, about 24 Hour applied to about 28 days, about 24 hours to about 7 days, about 24 hours to about 14 days or about 24 hours to about 21 days.

Some embodiments include treating illness enumerated herein, such as inflammatory pain, arthritis or complex regional pain Then pain syndrome applies the second dosage form wherein treatment includes applying the first dosage form to mammal to mammal, wherein the Two dosage forms are applied after the maximum pain relief for realizing the first oral, and the second oral is in mammal When still experiencing the pain relief of the first oral or it can be observed to apply when the pain relief of the first oral. In some embodiments, the second dosage form application the first dosage form after about 12 hours to about 60 days, about 24 hours to about 28 days, about 24 Hour applied to about 7 days, about 24 hours to about 14 days or about 24 hours to about 21 days.

Zoledronic acid or another diphosphonate can also oral administration to mitigate cancer-related pain, including with multiple marrow Tumor and the relevant pain of metastatic bone tumor.In some embodiments, zoledronic acid is for treating pain not related to cancer The pain of pain.For example, zoledronic acid can be used for treating and following incoherent pain：Huppert's disease, metastatic bone tumor, Malignant hypercalcemia, giant cell tumor of bone, leukemia or leukaemia or solid tumor or cancer.In some embodiments, this is being treated A little illnesss for the moment, the biological utilisation of zoledronic acid can be improved by the dosage form of zoledronic acid of the application containing disodium salt form Rate.This may make the mole for the disodium salt that reduction is used compared with diacid form is by the amount used.

Other than mitigating pain, oral administration zoledronic acid or another diphosphonate can be additionally used in treatment and may include or can The disease or illness of nociceptive component are not included.For example, zoledronic acid or another diphosphonate can be used for treating it is listed above Any antalgesic or implant treatment, including do not mitigate merely the pain of these illnesss treatment and with treat illness without send out The treatment that the mode of raw pain relief carries out.Any pain that can be provided or can not provide in addition to zoledronic acid or another diphosphonate Except pain is alleviated, zoledronic acid or another diphosphonate can be additionally used in such as following disease for the treatment of or illness：Metabolic disease or disease Disease；Inflammatory disease or illness, including with the incoherent inflammatory disease of pain or illness；Cancerous disease or illness；Neurological disease or Illness etc..In some embodiments, these illnesss are being treated for the moment, the zoledronic acid of disodium salt form is included by application Dosage form the bioavailability of zoledronic acid can be improved.This may make two for reducing and using compared with diacid form is by the amount used The mole of sodium salt.

In some embodiments, oral administration zoledronic acid or another diphosphonate can be additionally used in complex regional pain Scorching (including the tatanic vertebra of syndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, axis joint of vertebral column It is scorching), acute vertebral crush fractures, fibrous dysplasia, SAPHO syndromes, osteoporosis, temporary osteoporosis Or temporary hip osteoporosis.In some embodiments, these illnesss are being treated for the moment, disodium salt is contained by application The bioavailability of zoledronic acid can be improved in the dosage form of the zoledronic acid of form.This may make the amount phase that will be used with diacid form Than the mole for reducing the disodium salt used.

In some embodiments, oral administration zoledronic acid or another diphosphonate can also be used to treat hypercalcemia of malignancy Disease, Huppert's disease, metastatic bone tumor, the osteitis deformans of bone, giant cell tumor of bone, leukemia or leukaemia or solid tumor or Cancer.In some embodiments, these illnesss are being treated for the moment, is passing through zoledronic acid of the application containing disodium salt form The bioavailability of zoledronic acid can be improved in dosage form.This may make the disodium that reduction is used compared with diacid form is by the amount used The mole of salt.

In some embodiments, the diphosphonate of such as zoledronic acid can be used for treating otospongiosis.

Zoledronic acid has structure as shown below, is also referred to as zoledronic acid root (zoledronate).

Unless otherwise specified, by structure, title or any other mode, to compound herein, (such as azoles is come phosphine Acid) any refer to including pharmaceutical salt, such as disodium salt；Substitute solid form, such as polymorph, solvate, water Close object etc.；Tautomer；Or it can be converted to compound described herein rapidly under conditions of using compound as described herein Any other chemical substance.

In some embodiments, zoledronic acid is to include the dosage form of salt form (such as zoledronic acid dianion salt) Using.In some embodiments, zoledronic acid comprising the dosage form of zoledronate disodium salt form to apply.In some embodiment party In formula, zoledronic acid is applied with sodium-salt form (such as a sodium salt, disodium salt, trisodium salt etc.).In some cases, using disodium Salt can be advantageous.For example, disodium salt is readily dissolved in water much compared with diacid form.Therefore, in some techniques, disodium salt It is more easily than processing with diacid form.In addition, sodium salt compared with diacid form can have higher bioavailability and/or It can more quickly be absorbed when being orally ingested.

Some orals for containing zoledronic acid, which have, is suitable for specific mammalian species matching such as dog, cat, people It sets and zoledronic acid dosage.Such dosage form can have by zoledronic acid existing for following amount, and the amount is in the specific mammal Lead to area (AUC) under the zoledronic acid blood plasma concentration curve of expected range in species.For example, the configuration of oral and azoles come Phosphonic acids dosage can lead to following zoledronic acid AUC after applying oral to mammal：About 1nghr/mL is to about 700nghr/mL, about 3nghr/mL are to about 30nghr/mL, about 3nghr/mL to about 10nghr/mL, about 50ng Hr/mL to about 700nghr/mL, about 130nghr/mL are to about 180nghr/mL, about 300nghr/mL to about 450nghr/mL, about 300nghr/mL to about 350nghr/mL, about 300nghr/mL to about 310nghr/mL, about 340nghr/mL to about 350nghr/mL, about 370nghr/mL to about 420nghr/mL, about 380nghr/mL extremely About 390nghr/mL, about 405nghr/mL to about 415nghr/mL, about 140nghr/mL to about 160nghr/mL, About 140nghr/mL to about 150nghr/mL, about 150nghr/mL to about 160nghr/mL, about 140nghr/mL, 142nghr/mL, about 155nghr/mL, about 305nghr/mL, 304nghr/mL, about 345nghr/mL, 343nghr/mL, about 385nghr/mL, 384nghr/mL, about 410nghr/mL, or define model by any of these values Any AUC between any AUC or any of these values enclosed.

Unless otherwise specified, AUC refers to calculating the concentration (AUC measured to the end_(0-t)) and be extrapolated to infinity (AUC_(0-inf)) AUC.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid Can have by zoledronic acid existing for following amount, which causes about 0.2ng/mL to about after applying oral to mammal 300ng/mL, about 0.5ng/mL to about 5ng/mL, about 5ng/mL to about 300ng/mL, about 5ng/mL to about 50ng/mL, about 20ng/mL to about 50ng/mL, about 30ng/mL are to about 50ng/mL, about 50ng/mL to about 200ng/mL, about 50ng/mL to about 150ng/mL, about 80ng/mL to about 120ng/mL, about 90ng/mL to about 100ng/mL, about 50ng/mL to about 200ng/mL, about The zoledronic acid C of 40ng/mL, about 95ng/mL, about 97ng/mL_max, or in the range of any value in these values is defined or Any C between any value in these values_max。

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that applying oral to specific mammalian species leads to about 0.4hr to about 1hr, about 0.5hr or about The zoledronic acid T of 0.75hr_max, or in the range of any value in these values is defined or any value in these values Between any T_max。

The oral bioavailability of zoledronic acid can be improved by the zoledronic acid of oral administration disodium salt form.Example Such as, the bioavailability of zoledronic acid can be improved at least about 10%, at least about compared with the zoledronic acid of application diacid form 20%, at least about 30%, at least about 50% and/or up to about 100% or up to about 200%.

Due to the bioavailability that disodium salt improves, dosage form can include or the mammal of such as people can receive massage The zoledronic acid of your meter disodium salt form more less than the zoledronic acid of application diacid form.For example, dosage form can include or feed The amount for the zoledronic acid of diacid form that newborn animal can receive and apply such as is to realize identical zoledronic acid blood plasma level The mole of the zoledronic acid of the diacid form of application is compared, at least low about 10 moles of %, at least low about 20 moles of %, at least low The disodium salt form of about 40 moles of %, at least low about 50 moles of % and/or up to 95 moles of % of low about 90 moles of % or low.

In some embodiments, dosage form includes or mammal (such as people) application has about 0.8n by mol_dExtremely About 1.2n_dOr about 0.9n_dTo about 1.1n_dThe disodium salt form of the amount of value, wherein：

Nd=(b_a/bd)(n_a)

Wherein b_aIt is the bioavailability of diacid form, b_dIt is the bioavailability of disodium salt form, and n_aBe containing The molal quantity for the diacid that can be applied in the dosage form of the zoledronic acid of diacid form.For example, if diacid form has 0.01 life Object utilization rate (b_a) and disodium salt form have 0.015 bioavailability (b_d), and dosage form will usually rub containing 0.001 Your diacid, then n_dIt will be (0.01/0.015) (0.001) mole or about 0.00067 mole.In some embodiments, disodium salt To have about n_dValue amount application.

Oral for the zoledronate disodium salt reduced comprising mole compared with the zoledronic acid of diacid form, In some embodiments, the bioavailability of the zoledronic acid of disodium salt form is sufficiently high so that if by the medicament administration It is dynamic in lactation compared with the amount in mammalian is will be present in when the zoledronic acid of application diacid form to mammal There is zoledronic acid at least as many in object blood.

For the oral of the zoledronic acid comprising disodium salt form, in some embodiments, disodium salt shape When formula is using than zoledronic acid as diacid form there will be the lower mole of mole exist；And the azoles of disodium salt form comes Phosphonic acids has the bioavailability improved compared with the zoledronic acid of diacid form, reaches the disodium salt of more lower mol in dosage form Do not reduce the degree of the amount for the zoledronic acid for being delivered to mammalian plasma.

In some embodiments, the amount of the zoledronic acid of disodium salt form makes oral apply two every time The zoledronic acid blood plasma for providing about 4ngh/mL to about 2000ngh/mL when the zoledronic acid of sodium-salt form to mammal is dense Spend area under the curve (AUC).In some embodiments, the amount of the zoledronic acid of disodium salt form makes oral exist Using providing about 100ngh/mL to about 2000ngh/mL, about 100ngh/mL in the mammal of the oral to about The azoles of 1000ngh/mL, about 500ngh/mL to about 1000ngh/mL or about 500ngh/mL to about 700ngh/mL Carry out area under phosphonic acids blood plasma concentration curve.The amount may be adapted to apply oral every about 3 to 4 weeks.

In some embodiments, the amount of the zoledronic acid of disodium salt form makes oral apply this orally There is provided in the mammal of dosage form about 20ngh/mL to about 700ngh/mL, about 50ngh/mL to about 500ngh/mL or Area under the zoledronic acid blood plasma concentration curve of about 100ngh/mL to about 200ngh/mL.The amount may be adapted to apply once a week With oral, or 3 to 5 individual dosage are applied within the moon.Individual dosage can be given by regularly interval, first It gives in week, or is given by any other plan for providing 3 to 5 dosage in the middle of the month.

In some embodiments, the amount of the zoledronic acid of disodium salt form makes oral apply this orally About 4ngh/mL to about 100ngh/mL, about 10ngh/mL are provided in the mammal of dosage form to about 50ngh/mL or about Area under the zoledronic acid blood plasma concentration curve of 10ngh/mL to about 30ngh/mL.The amount may be adapted to the oral agent of daily administration Type.

The oral administration of the oral administration of the zoledronic acid especially zoledronic acid of disodium salt form can cause with it is such as quiet In arteries and veins or subcutaneous parenteral administration pattern compares more lasting drug blood plasma level.For example, amount of the zoledronic acid in blood plasma For the oral administration of disodium salt after application about 24 hours or 48 hours or longer when can notable higher.In some implementations In mode, oral zoledronic acid has the 24 of about 1 or higher such as about 1 to about 10, about 1 to about 5, about 3 to about 5 or about 3 to about 4 The hour sustained plasma level factor.In some embodiments, the oral administration dosage form of zoledronic acid has than intravenously applying Zoledronic acid it is higher, such as at least 1.2 times, at least about 2 times, at least about 5 times, about 1.2 times to about 20 times, about 2 times to about 15 times, about 5 times to about 10 times or about 8 to about 15 times of 24 hours sustained plasma level factors or 48 hours sustained plasma levels because Son." the sustained plasma level factor " p_fIt is determined by following formula：

p_f=1000 (C_t/C_max)

Wherein C_maxIt is the maximal plasma concentration of zoledronic acid after application, and C_tIt is zoledronic acid in the time of interest Such as 24 hours plasma concentrations.For parenteral administration, Cmax can be about C₀, or in the drug that just will entirely measure Concentration after being injected into vivo.Pass through C zoledronic acid plasma concentration being used in above formula_t, other times also can be obtained Such as 48 hours sustained plasma level factors.For example, if the maximum blood plasma level of zoledronic acid after application is 1000ng/ ML and 24 hour zoledronic acid blood plasma level is 1ng/mL, then 24 hours sustained plasma level factors are 1.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that zoledronic acid has about 12 to about 50, about 20 to about 40, about 25 for specific mammalian species To about 30, about 30 to about 35, about 35 to about 40, about 33, about 30, about 35 12 hours sustained plasma level factors, or at these Any 12 hours sustained plasma levels in the range of any value in value defines or between any value in these values The factor.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that zoledronic acid has about 10 to about 30, about 10 to about 20, about 10 for specific mammalian species To about 15, about 12 to about 15 or 16, about 15 to about 20, about 14, about 12, about 15 24 hours sustained plasma level factors, or Any 24 hours sustained plasmas in the range of any value in these values defines or between any value in these values Horizontal factor.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that zoledronic acid has for specific mammalian species about 6 to about 20, about 8 to about 15, about 9 to about 12 or 13, about 8 to about 10, about 11 to about 13, about 9, about 13 36 hours sustained plasma level factors, or appointing in these values In the range of what value defines or any 24 hours sustained plasma level factors between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that zoledronic acid has about 5 to about 20, about 6 to about 15, about 7 or 8 for specific mammalian species To about 12 or 13, about 8 to about 10, about 11 to about 13, about 8, about 12 48 hours sustained plasma level factors, or in these values Any value define in the range of or any 48 hours sustained plasma level factors between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that zoledronic acid has about 4 to about 20, about 5 to about 10, about 5 or 6 for specific mammalian species To about 10 or 11, about 5 to about 6, about 9 to about 10, about 6, about 10 72 hours sustained plasma level factors, or in these values Any 72 hours sustained plasma level factors in the range of any value defines or between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that specific mammalian species had about 0.5ng/mL to about 5ng/mL, about 1ng/mL to about at 12 hours 3ng/mL, about 1ng/mL are to about 2ng/mL, about 2ng/mL to about 3ng/mL, about 3ng/mL to about 4ng/mL, about 1.2ng/mL, about The zoledronic acid plasma concentration of 2.6ng/mL, about 3.2ng/mL, or in the range of any value in these values is defined or be situated between Any plasma concentration between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that specific mammalian species had about 0.2ng/mL to about 2ng/mL, about 0.5ng/mL extremely at 24 hours About 1.5ng/mL, about 0.5ng/mL are to about 1ng/mL, about 1ng/mL to about 1.5ng/mL, about 0.5ng/mL, about 1.0ng/mL, about The zoledronic acid plasma concentration of 1.4ng/mL, or in the range of any value in these values is defined or in these values Any plasma concentration between any value.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that specific mammalian species had about 0.1ng/mL to about 2ng/mL, about 0.2ng/mL extremely at 36 hours About 1.5ng/mL, about 0.2ng/mL to about 0.5ng/mL, about 0.5ng/mL to about 1ng/mL, about 1ng/mL to about 1.3ng/mL, The zoledronic acid plasma concentration of about 0.3ng/mL, about 0.8ng/mL, about 1.1ng/mL, or any value in these values are defined In the range of or any plasma concentration between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that specific mammalian species had about 0.1ng/mL to about 2ng/mL, about 0.2ng/mL extremely at 48 hours About 1.5ng/mL, about 0.2ng/mL are to about 0.5ng/mL, about 0.5ng/mL to about 0.9ng/mL, about 0.9ng/mL to about 1.3ng/ The zoledronic acid plasma concentration of mL, about 0.3ng/mL, about 0.7ng/mL, about 1.1ng/mL, or any value institute in these values Any plasma concentration in the range of defining or between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid It may be configured such that specific mammalian species had about 0.2ng/mL to about 1ng/mL, about 0.2ng/mL extremely at 72 hours About 1.5ng/mL, about 0.1ng/mL are to about 0.3ng/mL, about 0.3ng/mL to about 0.6ng/mL, about 0.6ng/mL to about 1ng/ The zoledronic acid plasma concentration of mL, about 0.2ng/mL, about 0.5ng/mL, about 0.9ng/mL, or any value institute in these values Any plasma concentration in the range of defining or between any value in these values.

The oral with configuration and zoledronic acid dosage suitable for specific mammalian species containing zoledronic acid May be configured such that elimination half-life period of the zoledronic acid in specific mammal be about 30 hours to about 100 hours, about 40 Hour to about 60 hours, about 40 hours to about 50 hours, about 50 hours to about 60 hours, about 42 hours, about 51 hours, it is about 59 small When, or in the range of any value in these values is defined or any half-life period between any value in these values.

As used herein, " eliminate half-life period " refer to by using Win-Nonlin carry out non-compartment analysis obtain it is apparent Level-one terminal plasma elimination half-life period.Terminal plasma elimination half-life period is that plasma concentration is reduced half institute after realizing pseudo equilibrium The time needed, rather than administration dosage is eliminated to the time needed for half.For the drug of oral administration, end blood plasma disappears eventually Except half-life period can be influenced by drug absorption and plasma clearance and distributed degrees.

In some embodiments, the zoledronic acid of disodium salt form provides raising compared with the zoledronic acid of diacid form Bioavailability, which is added to any bioavailability provided by any bioavailability reinforcing agent in dosage form In raising.In some embodiments, the zoledronic acid of disodium salt form improves biology compared with the zoledronic acid of diacid form Utilization rate, the raising are more than the raising of any bioavailability provided by any bioavailability reinforcing agent in dosage form. In some embodiments, the zoledronic acid of disodium salt form can be applied with the dosage form substantially free of bioavailability reinforcing agent With.

In some embodiments, including the dosage form of zoledronate disodium salt is solid.

In some embodiments, including the dosage form of zoledronate disodium salt is for treating inflammatory conditions.

In some embodiments, including the dosage form of zoledronate disodium salt is used for treatment of arthritis.

In some embodiments, including the dosage form of zoledronate disodium salt is for treating complex regional pain syndrome Sign.

In some embodiments, zoledronic acid is with water-soluble form, it is intended that solubility is more than 1% (w/ in water V), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 20% (w/v), about 10% (w/v) to about 15% (w/v) or About 12% (w/v) to about 13% (w/v).

The zoledronic acid of disodium salt form can more have compressibility than the zoledronic acid of diacid form.This may make dosage form It is more easy to that there is desired hardness.It, which is also possible that, is more easy to improve drugloading rate, so that can give smaller tablet and realize Given dose intensity.In some embodiments, zoledronic acid (zoledronic acid of such as diacid form or disodium salt form Zoledronic acid) solid dosage forms can with about 5kPa to about 20kPa or about 5kPa to about 14kPa hardness.

Zoledronic acid or another diphosphonate can be combined with pharmaceutical carrier, and pharmaceutical carrier is based on selected administration method and for example Remington's Pharmaceutical Sciences, the standard pharmaceutical practice described in 2005 are selected, the document Disclosure is incorporated herein in entirety by reference accordingly.It can be for example by the solubility of compound and chemical property, selected Administration method and standard pharmaceutical practice determine the relative scale of active constituent and carrier.

Zoledronic acid or another diphosphonate can be by that can lead to (a variety of) activating agent and one or more in patient body Any mode of a expectation function site contact is applied.Compound can be by can be with any routine side of Drug combination Formula is administered, as individual therapeutic agent or the combined administration of therapeutic agent.For example, they can be used as in pharmaceutical composition only One activating agent is applied or they can be used with other treatment active ingredient combination.

Zoledronic acid or another diphosphonate can be by suitable for selected administration method (such as oral, per rectum or parenteral) Diversified forms are administered to people patient.In this respect, parenteral administration includes but not limited to be administered by following approach：Lung Portion, intrathecal, intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial (including transdermal, sublingual and buccal)；Part；By blowing Enter the nasal inhalation of method；And rectum systematicness.

The effective quantity of zoledronic acid or another diphosphonate changes many factors known to attending physician, such as Seriousness, administration method, formula and the dosage form of illness to be treated, the physical characteristic of bisphosphonate compound used and each trouble Age, weight and the response of person.

The amount of zoledronic acid or another diphosphonate in therapeutic composition can be different.For example, some liquid compositions 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% be can include about to about 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 0.5% (w/v), about 1% (w/v) are extremely About 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), the zoledronic acid of about 30% (w/v) to about 40% (w/v) or about 40% (w/v) to about 50% (w/v).

Some solid composites may include at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), extremely Few about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) Extremely to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) About 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) are to about 60% (w/w), about 70% (w/w) to about 75% (w/w), about 70% (w/w) to about 80% (w/w) or about 80% (w/w) are to about The zoledronic acid of 90% (w/w).

Some include that the solid dosage forms of the diphosphonate of such as zoledronic acid can include about double phosphines of 1mg to about 5mg or 8mg Hydrochlorate, and the gross mass of dosage form can be below about 9mg, about 10mg, about 11mg or about 15mg.

Some include that the solid dosage forms of the diphosphonate of such as zoledronic acid can include about pair of 5mg to about 10mg or 15mg Phosphonate, and the gross mass of dosage form can be below about 15mg, about 17mg, about 21mg or about 29mg.

The solid dosage forms of some diphosphonates comprising such as zoledronic acid can include about 10mg to about 50mg's or 80mg Diphosphonate, and the gross mass of dosage form can be below about 77mg, about 85mg, about 110mg or about 150mg.

The solid dosage forms of some diphosphonates comprising such as zoledronic acid can include about 100mg to about 200mg or 290mg Diphosphonate, and the gross mass of dosage form can be below about 280mg, about 315mg, about 360mg, about 430mg or about 570mg.

The solid dosage forms of some diphosphonates comprising such as zoledronic acid can include about 200mg to about 300mg or 430mg Diphosphonate, and the gross mass of dosage form can be below about 430mg, about 500mg, about 570mg, about 640mg or about 710mg.

Any proper amount of zoledronic acid can be used.Some solids or liquid oral or oral unit are (herein In be referred to as " oral ") can include about 0.005mg to about 20mg, about 0.1mg to about 10mg, about 0.5mg to about 10mg, about 0.2mg to about 5mg, about 1mg to about 500mg, about 1mg to about 50mg, about 1mg to about 75mg, about 10mg to about 250mg, about 100mg to about 300mg, about 20mg are to about 200mg, about 20mg to about 150mg, about 30mg to about 100mg, about 30mg to about 150mg, about 1mg are to about 1,000mg, about 10mg to about 50mg, about 10mg to about 300mg, about 10mg to about 150mg, about 10mg To about 100mg, about 40mg to about 150mg, about 40mg to about 220mg, about 10mg to about 600mg, about 40mg to about 600mg, about 40mg to about 2000mg, about 40mg are to about 800mg, about 25mg to about 800mg, about 30mg to about 800mg, about 10mg to about 500mg, about 50mg are to about 150mg, about 50mg, about 100mg, about 50mg to about 500mg, about 100mg to about 2000mg, about 300mg to about 1500mg, about 200mg are to about 1000mg, about 100mg to the zoledronic acid of about 500mg or about 150mg or at these The zoledronic acid of any amount in the range of any value in value defines or between any value in these values.At some In embodiment, oral zoledronic acid can once a day, once a week, monthly, each two moon or three months, 1 year one It is secondary or 1 year is administered twice.

In some embodiments, oral can include about 10mg/m²To about 20mg/m², about 15mg/m²To about 20mg/ m², about 18mg/m², about 80mg/m²To about 150mg/m², about 90mg/m²To about 150mg/m², about 100mg/m²To about 150mg/m² Zoledronic acid or in the range of defined any value in these values or any between any value in these values The zoledronic acid of amount.It is all with mg/m²The dosage range or amount of expression are based on the body surface area meter of mammal.

In some embodiments, the day oral dosages of zoledronic acid are about 0.005mg to about 20mg, about 0.1mg to about In the range of 10mg, about 0.5mg are defined to any value of about 5mg or zoledronic acid in these values to about 10mg, about 0.2mg Or any amount between any value in these values.In some embodiments, the day oral dosages of zoledronic acid are less than About 35mg/m², be less than about 30mg/m², be less than about 25mg/m², about 1mg/m²To about 35mg/m², about 1mg/m²To about 30mg/m²、 About 1.5mg/m²To about 25mg/m², about 1.8mg/m²To about 20mg/m², about 10mg/m²To about 20mg/m², about 10mg/m²To about 30mg/m², about 15mg/m²To about 20mg/m², about 18mg/m²Or the range that any value of the zoledronic acid in these values is defined Any amount interior or between any value in these values.

In some embodiments, all oral dosages of zoledronic acid are about 1mg to about 1000mg, about 1mg to about 500mg, about 10mg are to about 250mg, about 100mg to about 300mg, about 10mg to about 100mg, about 10mg to about 150mg, about 10mg To about 100mg, about 10mg to about 300mg, about 20mg to about 150mg or about 30mg to about 100mg.In some embodiments, All oral dosages of zoledronic acid are less than about 250mg/m², be less than about 200mg/m², be less than about 175mg/m², about 6mg/m²To about 250mg/m², about 10mg/m²To about 210mg/m², about 10mg/m²To about 170mg/m², about 4mg/m²To about 140mg/m², about 100mg/m²To about 140mg/m², about 126mg/m²Any value of the zoledronic acid in these values it is defined in the range of or be situated between Any amount between any value in these values.All oral dosages can be given with single dose, be given in primary or all in week It individually dosed is given with 2,3,4,5,6 or 7.

In some embodiments, zoledronic acid the moon dosage or the zoledronic acid applied within one month period amount Be about 5000mg or less, about 4000mg or less, about 3000mg or less, about 2000mg or less, about 1000mg or less, About 700mg or less, about 600mg or less, about 1mg to about 4000mg, about 1mg to about 1000mg, about 10mg to about 1000mg, About 50mg to about 1000mg, about 10mg are to about 600mg, about 40mg to about 600mg, about 50mg to about 600mg or about 100mg to about 600mg, about 40mg to about 2000mg, about 40mg to about 800mg, about 50mg to about 800mg or about 100mg to about 800mg, about 40mg to about 1000mg, about 50mg are defined to about 1000mg or about 100mg to about 1000mg or any value in these values In the range of or any month dosage between any value in these values.In some embodiments, the moon of zoledronic acid Oral dosages are less than about 1000mg/m², be less than about 800mg/m², be less than about 600mg/m², about 10mg/m²To about 1000mg/m², about 50mg/m²To about 800mg/m², about 70mg/m²To about 700mg/m², about 100mg/m²To about 700mg/m², about 100mg/m²To about 600mg/m², about 50mg/m²To about 200mg/m², about 300mg/m²To about 600mg/m², about 450mg/m²To about 600mg/m², about 300mg/m²To about 1000mg/m², about 400mg/m²To about 1000mg/m², about 500mg/m²To about 1000mg/m², about 400mg/ m²To about 700mg/m², about 500mg/m²To about 600mg/m², about 540mg/m²Or any value institute of the zoledronic acid in these values Any amount in the range of defining or between any value in these values.Month dosage can be given or within the moon with single dose With two or more individually dosed applications.In some embodiments, the moon, dosage was applied with 2 or 3 weekly doses.In some realities Apply in mode, the moon dosage applied with 4 or 5 weekly doses.In some embodiments, the moon, dosage was applied with 28 to 31 daily doses With.In some embodiments, the moon dosage within the moon with 5 to 10 individually dosed applications.Month dosage can be applied only 1 month or can Repetitive administration 2 or more the moon.

In some embodiments, six weekly doses of zoledronic acid can be about 200mg to about 500mg, about 300mg to about 450mg or about 300mg.In some embodiments, six weekly doses of zoledronic acid can be applied only primary.In some embodiments In, six weekly doses of zoledronic acid can be applied by six weekly dosages, for example, each weekly dose be about 35mg to about 80mg or About 50mg to about 75mg.

Zoledronic acid or its salt that parenteral (such as intravenous) application about 0.1mg to about 10mg can be combined are oral to apply Zoledronic acid or its disodium salt.In some embodiments, combine parenteral (such as intravenous) using 1mg zoledronic acids come through Mouth application about 50mg, about 100mg or about 150mg zoledronate disodium salt.In some embodiments, the parenteral of zoledronic acid Dosage is about 0.25mg to about 25mg, about 0.25mg to about 10mg or about 0.5mg to about 7.5mg.

For oral administration zoledronic acid or another diphosphonate to treat and inflammation, arthritis, CRPS or enumerate herein The relevant pain of any other illness, if using zoledronic acid mammal or people application zoledronic acid before 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 Drink (swallowing the drink except any water needed for oral) is not fed or do not drunk to hour, then can be helpful.Such as Fruit is using the mammal or people of zoledronic acid at least about 30 minutes, at least about 1 hour after application zoledronic acid, at least about 2 Hour does not feed or does not drink drink at least about 3 hours or at least about 4 hours, then also can be helpful.In some embodiment party In formula, avoid lying down or keep standing or sitting at least after receiving the dosage form comprising zoledronic acid using the people of zoledronic acid About 30 minutes or about 1 hour.It avoids feeding or drink drink before or after oral administration zoledronic acid and zoledronic acid can be improved Bioavailability.

The oral bioavailability of zoledronic acid can be different in dosage form.Some dosage forms can have added to improve biology profit With the ingredient of rate.However, bioavailability raising is for keeping oral effective and nonessential.In some embodiments In, dosage form is substantially free of bioavailability reinforcing agent.In some embodiments, oral can be with about 0.01% to about 10%, about 0.1% to about 7%, the zoledronic acid oral bioavailability of about 0.1% to about 5% etc..Biological there is no improving In the case of the ingredient or other methods of utilization rate, zoledronic acid usually has low bioavailability in oral.One In a little embodiments, the oral bioavailability of zoledronic acid is not improved or is not improved substantially.For example, zoledronic acid is oral Bioavailability can be about 0.01% to about 5%, about 1.1% to about 4%, about 1.1% to about 3.1%, about 1.1% to about 3.5%, about 1.5% to about 4%, about 1.5% to about 3.1%, about 1.5% to about 3.5%, about 2% to about 3%, about 3% to about 4%, about 0.01% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5%, about 0.3% to about 1%, about 0.1% to about 0.5%, about 0.3% to about 0.5%, about 0.5% to about 1%, about 0.6% to about 0.7%, about 0.7% to about 0.8%, about 0.8% to about 0.9%, about 0.9%, about 1% To about 1.1%, about 1.1% to about 1.2%, about 1.2% to about 1.3%, about 1.3% to about 1.4%, about 1.4% to about 1.5%, about 1.5% to about 1.6%, about 1.6% to about 1.8% or about 1.8% to about 2%.

One embodiment is the pharmaceutical composition comprising zoledronic acid, the oral biology profit of zoledronic acid wherein in dosage form It is about 0.01% to about 10% with rate.

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

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

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

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

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

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

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

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

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

In some embodiments, oral include about 10mg to about 300mg zoledronic acids, and daily apply one It is secondary, continuous administration about 2 days to about 15 days.This scheme can be monthly repeated once, each two moon is repeated once, every three months repeats one It is repeated once within secondary, every four months, is repeated once within every five months, is repeated once, is repeated once or every two years weighs every year within every six months It is multiple primary.

In some embodiments, oral carrys out phosphine comprising about 10mg to about 150mg or about 10mg to about 100mg azoles Acid, and be administered once a day, continuous administration about 2 days to about 15 days.This scheme can be monthly repeated once, each two moon repeats one Secondary, every three months is repeated once, is repeated once within every four months, is repeated once within every five months, is repeated once, weighs every year within every six months It answers primary or is every two years repeated once.

In some embodiments, oral carrys out phosphine comprising about 10mg to about 150mg or about 10mg to about 100mg azoles Acid, and be administered once a day, continuous administration about 5 days to about 10 days.This scheme can be monthly repeated once, each two moon repeats one Secondary, every three months is repeated once, is repeated once within every four months, is repeated once within every five months, is repeated once, weighs every year within every six months It answers primary or is every two years repeated once.

In some embodiments, oral include about 40mg to about 150mg zoledronic acids, and daily apply one It is secondary, continuous administration about 5 days to about 10 days.This scheme can be monthly repeated once, each two moon is repeated once, every three months repeats one It is repeated once within secondary, every four months, is repeated once within every five months, is repeated once, is repeated once or every two years weighs every year within every six months It is multiple primary.

In some embodiments, oral zoledronic acid can about 100mg to about 2000mg one application.In some realities Apply in mode, oral zoledronic acid can about 300mg to about 1500mg one application.In some embodiments, oral azoles Come phosphonic acids can about 200mg to about 1000mg one application.The dosage of zoledronic acid can be by single dosage or separated agent Amount application.

Zoledronic acid can for example with inert diluent or edible carrier come prepare for oral administration or its can be encapsulated in In hard shell or soft shell gelatin capsules, it is pressed into tablet or is bonded directly in diet.For therapeutic oral administration, activation Object is closed to use in combination with excipient and use in the form of following：Absorbable tablet, buccal tablet, coating tablet, pastille, capsule, Elixir, dispersant, suspension, solution, slurry agent, wafer (wafer), patch etc..

Tablet, pastille, pill, capsule etc. also may include one or more following components：Adhesive, such as yellow alpine yarrow tree Glue, Arabic gum, cornstarch or gelatin；Excipient, such as Dicalcium Phosphate；Disintegrant, such as cornstarch, potato are formed sediment Powder, alginic acid etc.；Lubricant, such as magnesium stearate；Sweetener, such as sucrose, lactose or saccharin；Or flavoring agent, such as peppermint, Wintergreen or cherry flavor enhancement.When unit dosage forms are capsules, other than the material of the above-mentioned type, it may include that liquid carries Body.Various other materials can be coated offer, such as can be coated to tablet, pill or capsule with lac, sugar or both. Elixir or slurry agent may include reactive compound, the sucrose as sweetener, the methyl p-hydroxybenzoate as preservative and right Nipasol, dyestuff and flavoring agent (such as cherry or orange flavor).Material in dosage form or pharmaceutical composition can It is pure and substantially non-toxic with used amount to be advantageously pharmacy.

Some compositions or dosage form can be liquid or may include disperseing solid phase in a liquid.

Zoledronic acid can be formulated as being applied in parenteral or peritonaeum.For the work of free acid or pharmacologically acceptable salt Property compound solution can be prepared in the water for properly mixing surfactant (such as hydroxypropyl cellulose).Dispersion is also Can have be dispersed within glycerine, liquid macrogol and its mixture or among oil.Under ordinary conditions of storage and use, These preparations may include the preservative for preventing microorganism from growing.

In some embodiments, oral may include the silicified microcrystalline cellulose of such as Prosolv.For example, about 20% (wt/wt) to about 70% (wt/wt), about 10% (wt/wt) to about 20% (wt/wt), about 20% (wt/wt) to about 40% (wt/wt), about 25% (wt/wt) to about 30% (wt/wt), about 40% (wt/wt) to about 50% (wt/wt) or about 45% (wt/ Wt it) can reside in oral or oral unit to the silicified microcrystalline cellulose of about 50% (wt/wt).

In some embodiments, oral may include cross-linking polyethylene pyrrolidone, such as Crospovidone.Example Such as, about 1% (wt/wt) to about 10% (wt/wt), about 1% (wt/wt) to about 5% (wt/wt) or about 1% (wt/wt) are to about The cross-linking polyethylene pyrrolidone of 3% (wt/wt) can reside in oral or oral unit.

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

In some embodiments, oral may include magnesium stearate.For example, about 0.1% (wt/wt) to about 10% (wt/wt), about 0.1% (wt/wt) to about 1% (wt/wt) or about 0.4% (wt/wt) to about 0.6% (wt/wt) magnesium stearate It can reside in oral or oral unit.

Including the oral of zoledronic acid or another diphosphonate may be incorporated into drug products, which includes more In the oral of a unit.

It may include the oral of 28,29,30 or 31 units for the drug products comprising oral used daily It is supplied for the moon.Day supply in about 6 weeks may include the oral of 40 to 45 units.The day supply in about March can wrap Oral containing 85 to 95 units.Day supply in about six months may include the oral of 170 to 200 units.Greatly Day supply in about one year may include the oral of 350 to 380 units.

It may include the oral of 4 or 5 units for the moon for the drug products comprising oral used weekly Supply.Week supply in about 2 months may include the oral of 8 or 9 units.Week supply in about 6 weeks can include about 6 lists The oral of position.Week supply in about 3 months may include the oral of 12,13 or 14 units.About six months weeks Supply may include the oral of 22 to 30 units.Week supply in about one year may include the oral agent of 45 to 60 units Type.

Drug products may be adapted to other dosage regimens.For example, drug products may include the oral of 5 to 10 units, The oral of wherein each unit includes about 40mg to about 150mg zoledronic acids.Some drug products may include 1 to 10 list The oral of position, the wherein product include about 200mg to about 2000mg zoledronic acids.For such product, each unit Oral can take once a day, continue 1 to 10 day or 5 to 10 days in one month, such as at the beginning of the month.

Some orals comprising zoledronic acid or its salt can have enteric coating or film coating.

In the following embodiments, zoledronic acid is administered with the disodium salt form of zoledronate disodium tetrahydrate. Bioavailability reinforcing agent is not used in testing composition.

Embodiment 1

Effect of the zoledronic acid of oral administration in inflammatory pain rat model

Method：

Examine the zoledronic acid of oral administration to the effect of inflammatory pain using rat complete Freund's adjuvant (CFA) model Fruit.By being injected into sprague in the 0th day 100%CFA by 75 μ L volumes come the left back of (Sprague-Dawley) rat Inflammatory pain is induced in pawl, is then assessed at 1-3 days.At 1-3 days, the daily oral administration supporting agent (control) of animal, azoles Carry out phosphonic acids 18mg/m²(or 3mg/kg), zoledronic acid 120mg/m²(or 20mg/kg) or zoledronic acid 900mg/m²(or 150mg/ kg).By drug be dissolved in distilled water and daily fresh preparation.Animal carries out fasting before administration.About from animal It extrapolates to people under the existing FDA guides of initial dose, it is believed that with mg/m²The dosage of expression is equivalent between mammalian species 's.Thus, for example, it is believed that the 18mg/m in rat²The 18mg/m being equivalent in people², and the 3mg/kg in rat may be not equal to 3mg/kg in people.

CFA inject preceding 0th day and baseline and after processing in 1-3 days time point acquisition through supporting agent and through drug-treated Animal in inflammatory pain (mechanical hyperalgesia) value.Use Randall-Selitto digital devices (dRS；IITC Life Sciences, Woodland Hills, CA) assess pain.Animal is placed in the constraint sling of suspention animal, is protected Hind leg is held to can be used for testing.By being applied not to rear solid end plantar face with the dome-shaped tip being placed between the 3rd metatarsal and the 4th metatarsal Increased pressure of breaking carrys out measuring claw compression threshold value.Gradually apply pressure in about 10 seconds.From the sounding observed for the first time, earn It pricks or the anti-injury behavior (nocifensive behavior) of retraction measures.It is prevented to dynamic using the cutoff value of 300g The injury of object.

The reverse of inflammatory pain calculates according to the following formula：

% reverse=(baseline after-CFA after processing)/(baselines after baseline-CFA before CFA) x100.

It is one group using 9-10 animal to be tested.

As a result：

Oral administration zoledronic acid significantly improves inflammatory pain threshold value compared with supporting agent.In each time shown in Fig. 1 Carry out pain threshold measurement.After starting treatment during entire measurement in 30 minutes, 18mg/m²The pawl compression threshold value of group is higher than load Agent group.In third day, 18mg/m²Group and 900mg/m²The pawl compression threshold value of group is above supporting agent group.Observe 18mg/m²Group and 900mg/m²49% and 83% is respectively increased in the pain threshold of group from baseline.

The zoledronic acid of oral administration is in 18mg/m²The inflammatory pain that 29% is generated under dosage reverses, in 900mg/m²Dosage The reverse of lower generation 48%.This effect magnitude is equivalent to the clinic of commercially available NSAID when being tested in similar inflammatory pain model The magnitude that dosage is obtained.Under existing FDA guides, the reference body surface area of adult is 1.62m².Therefore, 18mg/m²Day agent Amount is equivalent to about 500-560mg/m²The moon dosage or about 800-900mg people's dosage.

It was unexpected that the two higher dosages caused threshold value when being a few days ago administered is lower than supporting agent.In the assessment phase Between all time points, 120mg/m²Group is approximately equal to or is inferior to supporting agent.Although 900mg/m²Group shows validity on day 3, But this result is with significant toxicity so that needs two days all euthanizing animals to the group after stopping being administered.

Embodiment 2

Effect of the zoledronic acid of oral administration in arthritis ache rat model

Method：

Examine the zoledronic acid of oral administration to joint in rat complete Freund's adjuvant (CFA) model of arthritis ache The effect of scorching pain.In this model, 100% complete Freund's adjuvant (CFA) of 75 μ L volumes is injected into left back pawl, then Arthritis ache was developed using 10-14 days time.First three day after CFA injections, animal oral administration are divided into three phases With supporting agent (control), the zoledronic acid 54mg/m of daily dose²(or 9mg/kg) or zoledronic acid 360mg/m²(or 60mg/kg).It will Drug is dissolved in distilled water and fresh preparation daily.Animal carries out fasting before administration.

Use Randall-Selitto digital devices (dRS within the 14th day after CFA injections；IITC Life Sciences, Woodland Hills, CA) assess the arthritis ache (mechanical hyperalgesia) in the animal through supporting agent and through drug-treated. Animal is placed in the constraint sling of suspention animal, hind leg is kept to can be used for testing.By with being placed on the 3rd metatarsal and the 4th plantar Dome-shaped tip between bone applies ever-increasing pressure to rear solid end plantar face and carrys out measuring claw compression threshold value.In about 10 seconds by Gradually apply pressure.It is measured from the anti-injury behavior for sounding, struggle or the retraction observed for the first time.Use the cut-off of 300g Value prevents the injury to animal.

The reverse of arthritis ache calculates according to the following formula in homonymy (injection CFA's) pawl：

Reverse=(homonymy drug threshold-homonymy supporting agent threshold value)/(offside supporting agent threshold value-homonymy supporting agent threshold value) × 100 %.

It is one group using 7-10 animal to be tested.

As a result：

Oral administration zoledronic acid significantly improves arthritis ache threshold value compared with supporting agent.As shown in Figure 2A and 2B, The zoledronic acid of oral administration generates the dose-dependant sex reversal of arthritis ache.In 54mg/m²Observed in group 33% it is inverse Turn, in 360mg/m²54% reverse is observed in group.Under existing FDA guides, the reference body surface area of adult is 1.62m²。 Therefore, the 54mg/m in rat²It is equivalent to people's dosage of the about 87mg of tacit declaration, the 360mg/m in rat²It is equivalent to the pact of tacit declaration People's dosage of 583mg.

The zoledronic acid of the oral administration of embodiment 3. treats complex regional pain syndrome

The azoles through oral administration is examined in the rat tibia fracture model of complex regional pain syndrome (CRPS) The effect of phosphonic acids.By making the right distal tibial of animal that fracture occur and inducing fracture rear solid end note type 4 weeks in rat CRPS, if Guo TZ et al. are in (Pain.2004；108:95-107) described in.This animal model is had proven to reproduce in people The stimulation wound observed in CRPS patient, Natural history of treated, symptom, symptom and pathological change (Kingery WS et al., Pain.2003；104:75–84).

Since fracture and the note type same day, animal is with 18mg/m²The dosage oral administration supporting agent in/day (3mg/kg/ days) is (right According to) or zoledronic acid, continue 28 days.Drug is dissolved in distilled water and is applied by gavage.It 4 hours and gives before administration Fasting was carried out to animal in 2 hours after medicine.In 28 days end cycles, note type part is removed, the rear solid end pain of rat was tested at second day Bitterly, edema and fever.

Pain Assessment

Pain is assessed by measuring hyperalgia and loading.

To measure hyperalgia, upper and lower Feng Fulei test examples (up-down von Frey testing have been used paradigm).Rat is placed in the transparent plastic drum with wire mesh bottom (a diameter of 20cm) and is adapted it to 15 minutes. One in Feng Fulei hairs for the use of eight hardness ranges being 0.41g to 15.14g tests pawl.Abut against rear solid end The substantially middle bottom of plantar skin applies Feng Fulei hairs, pays attention to avoiding protuberance foot pad.Feeler is pushed until its is slight curving, so After so that its light at the position is shaken 6 seconds.Stimulation is provided with the interval of several seconds.Feeler causes rear solid end retraction to be considered as positive sound It answers.Initial feeler is rendered as 2.1g, and presents feeler according to the method up and down of Dixon to generate six close to 50% threshold value Response.Stimulation is provided with the interval of several seconds.

Using biped balance pain-measuring equipment (incapacitance device) (IITC Inc.Life Science, Woodland, CA, USA) measure rear solid end loading, a kind of position effect of pain.Rat is maintained above equipment manually Upright position, wherein rear solid end rest on individual graduated metal plate, and the weight of rat body is supported by rear solid end.It measures every time Duration be 6 seconds, carrying out 10 times with 60 seconds intervals continuous measures.To eight readings (removing highest reading and minimum reading) It is averaged to calculate both sides rear solid end loading value.According to the ratio ((2R/ (R+ between right rear solid end (fracture) and left back pawl loading value L loading data are analyzed)) × 100%).

Edema is assessed

The back of the body abdominal depth degree of rear solid end is measured using laser sensor technology.Before baseline test, the third of rear solid end in both sides Line carves 2 to 3mm spot on dorsal skin above metatarsal midpoint.For laser measurement, every rat is carried out with isoflurane It is simple to anaesthetize and vertically fix so that rear solid end rests on the work top below laser.Apply at the top of to ankle-joint small Metal bar by pawl gently it is flat holding on the table.Optical triangulation is passed through using the laser for being equipped with distance measurement sensor The distance carried out mensuration distance work top and carve position top surface apart from rear crowsfooting is measured, back of the body abdomen pawl thickness is calculated using difference. Measurement range for the measurement sensor device (4381Precicura, Limab, Goteborg, Sweden) in these experiments For 200mm, resolution ratio 0.01mm.

Rear solid end temperature measures

Rear solid end temperature is measured using the filament thermocouple (Omega, Stanford, CT, USA) for being applied to pawl skin.Often A rear solid end tests six positions.Mean temperature is averagely obtained to six measured values of each rear solid end.

As a result

As shown in Figure 3, it compared with the animal handled through supporting agent, carries out processing with the zoledronic acid of oral administration and reverses Pain restores loading and prevents edema.

As shown in Figure 4, relative to offside (normal) rear solid end of the animal handled through supporting agent, Feng of right (fracture) rear solid end Not thunder pain threshold reduces by 72%.Compared with supporting agent processing, the pain that zoledronic acid salts for treating induces fracture reverses 77%.

As shown in Figure 5, compared with the group handled through zoledronic acid, loading reduction, position in the group handled through supporting agent Pain significant effect is higher.Loading on fracture hind leg is down to the 55% of normal value in the group handled through supporting agent.At supporting agent Ratio is managed, zoledronic acid salt treatment has significantly restored hind leg loading (the 86% of normal value).

As shown in Figure 6, compared with the group handled through zoledronic acid, expected increase of rear solid end thickness is being handled through supporting agent Bigger in group reflects the development of edema.Relative to supporting agent processing, rear solid end edema is reduced by 60% by zoledronic acid salt treatment.

Relative to supporting agent processing, rear solid end fever is reduced by 5% by zoledronic acid.

The daily dose of above-mentioned experiment is 18mg/m²/ day.Under existing FDA guides, the reference body surface area of adult is 1.62m².Therefore, 18mg/m²Daily dose be equivalent to about 500-560mg/m²The moon dosage or about 800-900mg people's dosage.

The solubility of 6 zoledronate disodium salt of embodiment

Measure the water solubility of zoledronic acid and zoledronate disodium tetrahydrate.One gram of test chemical combination is measured into beaker Object.Then softened water (pH 5.5) is added in a manner of incremental on a small quantity in test compound, and applies ultrasound to mixture Processing.Continue this process and is completely dissolved until realizing.When there is the clear solution without visible substance, it is determined that have reached completely Dissolving.The solubility values in terms of g/100mL are calculated using the volume for being completely dissolved required water is reached.To each compound all into This process of row.

As a result

As shown in Figure 7, the water solubility of zoledronate disodium tetrahydrate is about 50 times of zoledronic acid.With zoledronic acid Only 0.25g/100mL compare, the solubility of zoledronate disodium tetrahydrate is 12.5g/100mL.

The bioavailability of the zoledronic acid and zoledronate disodium of 7 oral administration of embodiment

Tablet of the manufacture containing pure zoledronic acid or zoledronate disodium salt (Zoledronate disodium tetrahydrate).Two types Every, the tablet of type contains 50mg zoledronic acid equivalents.Identical excipient is used for two kinds of tablet, amount is adjusted The whole molecular weight difference between consideration acid and disodium salt.

Make beasle dog oral administration zoledronate disodium (the 1st group) or the azoles containing 150mg of pure zoledronic acid (the 2nd group) form Carry out the tablet of phosphonic acids equivalent.Every animal gives the equivalent tablets of three pieces 50mg (150mg in total), and three pieces are applied together.It is inciting somebody to action Before tablet is placed on the animals tongue back side, animal oral cavity is soaked with water.Animal rear fasting before administration.Animal is 6 to 9 The moon is big, and weight is 6 to 10kg on the day of administration.Every group of three dogs.

Continuous blood sample is acquired from every animal by Each point in time venipuncture jugular vein upon administration, to measure Zoledronic acid plasma concentration.By blood specimen collection to containing K₂EDTA is as in the cooling tube of anti-coagulants.Then existed with about 3000rpm Sample is centrifuged 10 minutes to carry out blood plasma derivatization by+4 DEG C.Zoledronic acid plasma concentration is measured using LC/MS/MS methods.

As a result

The zoledronic acid mean plasma concentration of every group of dog summarizes and is shown in FIG. 8 in table 1.It is entire what is measured In 48 hours, detectable zoledronic acid blood plasma level has been observed.

Table 1

Zoledronic acid plasma concentration in beasle dog

Table 1

Zoledronic acid plasma concentration in beasle dog

Zoledronate disodium produces zoledronic acid blood plasma level significantly more higher than pure zoledronic acid, shows salt form Oral absorption improves.Use peak plasma concentrations (C_max) measurement when, disodium salt results in 119% compared with pure zoledronic acid Practical bioavailability increases and 74% bioavailability through weight adjustment increases.Use area under blood plasma concentration curve (AUC_0-inf) measurement when, respectively by it is actual and through weight adjustment based on, the bioavailability of disodium salt is higher than pure zoledronic acid 84% and 46%.The average AUC of disodium salt_0-∞For 4073ngh/mL, and the average AUC of diacid_0-∞For 2217ngh/mL. It has been found that AUC_0-infWith dose proportional.Therefore, for those of test similar beasle dog for, it is contemplated that about 3mg It will lead to the AUC of about 100ngh/mL to the disodium salt of about 4mg_0-∞, and it is expected that the disodium salt of about 7mg to about 8mg will cause The AUC of about 200ngh/mL_0-∞。

The elimination half-life period for receiving the dog of the disodium salt of 150mg acid equivalents is 20.5 ± 5.2hr.

Embodiment 8

Tablet is prepared by the zoledronic acid of free acid or disodium salt form is blended with identical excipient.For tool For the dosage form for having a greater amount of activating agents, proportional reduce to keep the weight of tablet of the amount of excipient is about 100mg.It is blended Afterwards, ingredient is compressed with different pressure, then film coating.Then Dr.Schleuniger Pharmatron 8M pieces are used Agent hardness tester tests the hardness of gained tablet.As a result it is shown in table 2 and Fig. 9.

Table 2

Following implementation is particularly contemplated：

A kind of method mitigating inflammatory pain of embodiment 1. comprising be administered to the oral comprising zoledronic acid There are this mammal needed, zoledronic acid moon body surface area meter of the accumulated dose based on mammal that wherein mammal receives It is about 800mg/m²Or it is less.

The method of 2. embodiment 1 of embodiment, wherein mammal are behaved, and the zoledronic acid moon accumulated dose received is About 30mg/m²To about 700mg/m²。

Accumulated dose is applied with 4 or 5 weekly doses for the method for 3. embodiment 2 of embodiment, the wherein moon.

Accumulated dose is applied with 28 to 31 daily doses for the method for 4. embodiment 2 of embodiment, the wherein moon.

The method of 5. embodiment 2 of embodiment, wherein the moon accumulated dose within the moon with 5 to 10 individually dosed applications.

The method of 6. embodiment 1 of embodiment, wherein mammal are behaved, and the zoledronic acid week accumulated dose received is About 10mg to about 300mg.

The method of 7. embodiment 6 of embodiment is applied weekly primary wherein all accumulated doses are single dose.

The method of 8. embodiment 6 of embodiment, wherein all accumulated doses within week with 2 to 7 individually dosed applications.

The method of 9. embodiment 1 of embodiment, wherein mammal are behaved, and the zoledronic acid week accumulated dose received is About 10mg to about 150mg.

Embodiment 10. is experienced according to the method for arbitrary aforementioned embodiments, wherein mammal after form of administration Significant pain relief is more than 3 hours.

The method of 11. embodiment 10 of embodiment, wherein mammal are about 3 hours to about 24 small after form of administration When time at least part during experience significant pain relief.

About 3 hours to about 3 weeks after form of administration of the method for 12. embodiment 10 of embodiment, wherein mammal Time at least part during experience significant pain relief.

A kind of method mitigating inflammatory pain of embodiment 13. comprising apply the oral comprising zoledronic acid To the mammal for having this to need, wherein oral includes the body surface area meter about 10mg/m based on mammal²To about 20mg/m²Zoledronic acid.

The method of 14. embodiment 13 of embodiment, wherein oral include the body surface area meter based on mammal About 15mg/m²To about 20mg/m²Zoledronic acid.

A kind of method mitigating inflammatory pain of embodiment 15. comprising monthly by the body surface area based on mammal Count about 300mg/m²To about 600mg/m²Zoledronic acid be administered orally to this needs mammal.

The method of 16. embodiment 15 of embodiment comprising monthly about by the body surface area meter based on mammal 450mg/m²To about 600mg/m²Zoledronic acid be administered orally to mammal.

Embodiment 17. does not suffer from Bone tumour according to the method for arbitrary aforementioned embodiments, wherein mammal.

Embodiment 18. does not suffer from cancer according to the method for arbitrary aforementioned embodiments, wherein mammal.

Embodiment 19. according to the method for arbitrary aforementioned embodiments, wherein zoledronic acid with zoledronic acid divalent the moon from Alite is applied.

A kind of method of mitigation and the relevant pain of arthritis of embodiment 20. comprising by the warp comprising zoledronic acid Mouth dosage form is administered to the people of this needs.

The zoledronic acid moon accumulated dose that the method for 21. embodiment 20 of embodiment, wherein people receive is about 40mg to about 2000mg。

Accumulated dose is applied with 4 or 5 weekly doses for the method for 22. embodiment 21 of embodiment, the wherein moon.

Accumulated dose is applied with 28 to 31 daily doses for the method for 23. embodiment 21 of embodiment, the wherein moon.

The method of 24. embodiment 21 of embodiment, wherein the moon accumulated dose within the moon with 5 to 10 individually dosed applications.

The zoledronic acid week accumulated dose that the method for 25. embodiment 20 of embodiment, wherein people receive is about 100mg to about 300mg。

The method of 26. embodiment 25 of embodiment is applied weekly primary wherein all accumulated doses are single dose.

The method of 27. embodiment 25 of embodiment, wherein all accumulated doses within week with 2 to 7 individually dosed applications.

The zoledronic acid week accumulated dose that the method for 28. embodiment 20 of embodiment, wherein people receive is about 10mg to about 100mg。

The method of Arbitrary Term in 29. embodiment 20 to 28 of embodiment, wherein people are experienced significantly after form of administration Pain relief be more than 3 hours.

About 3 hours to about 24 hours after form of administration of the method for 30. embodiment 29 of embodiment, wherein people when Between at least part during experience significant pain relief.

About 3 hours to the about 3 weeks time of the method for 31. embodiment 29 of embodiment, wherein people after form of administration At least part during experience significant pain relief.

The method of Arbitrary Term in 32. embodiment 20 to 31 of embodiment, wherein dosage form include the body surface area based on people Count about 10mg/m²To about 20mg/m²Zoledronic acid.

The method of 33. embodiment 32 of embodiment, wherein dosage form include the body surface area meter about 15mg/m based on people²Extremely About 20mg/m²Zoledronic acid.

The method of Arbitrary Term in 34. embodiment 20 to 33 of embodiment, wherein per body of the menstruation oral administration based on people Surface area meter about 50mg/m²To about 200mg/m²Zoledronic acid.

The method of Arbitrary Term in 35. embodiment 20 to 31 of embodiment, wherein dosage form include the body surface area based on people Count about 80mg/m²To about 150mg/m²Zoledronic acid.

The method of 36. embodiment 35 of embodiment, wherein about per body surface area meter of the menstruation oral administration based on people 300mg/m²To about 1000mg/m²Zoledronic acid.

The method of Arbitrary Term, wherein people do not suffer from Bone tumour in 37. embodiment 20 to 36 of embodiment.

The method of Arbitrary Term, wherein people do not suffer from cancer in 38. embodiment 20 to 37 of embodiment.

Embodiment 39. is disodium salt form according to the method for arbitrary aforementioned embodiments, wherein zoledronic acid.

A kind of oral including zoledronic acid of embodiment 40., the oral biology profit of zoledronic acid wherein in dosage form It is about 0.01% to about 4% with rate.

The oral of 41. embodiment 40 of embodiment, wherein oral carry out phosphine comprising about 10mg to about 300mg azoles Acid.

The oral of 42. embodiment 40 of embodiment, wherein oral carry out phosphine comprising about 10mg to about 50mg azoles Acid.

The oral of Arbitrary Term in 43. embodiment 40 to 42 of embodiment, zoledronic acid is oral wherein in dosage form Bioavailability is about 0.1% to about 2%.

A kind of 44. drug products of embodiment, it includes the orals of the embodiment 40 of more than one unit.

The drug products of 45. embodiment 44 of embodiment, wherein the oral of each unit include about 1mg to about 50mg zoledronic acids.

The drug products of 46. embodiment 45 of embodiment, it includes the oral of 28,29,30 or 31 units, with Using about 28mg in total to about 1600mg zoledronic acids in about 1 month.

The drug products of 47. embodiment 45 of embodiment, it includes the orals of 85 to 95 units, with about 3 Using about 85mg in total to about 4800mg zoledronic acids in a month.

The drug products of 48. embodiment 45 of embodiment, it includes the orals of 170 to 200 units, with about Using about 170mg in total to about 10,000mg zoledronic acids in 6 months.

The drug products of 49. embodiment 45 of embodiment, it includes the orals of 350 to 380 units, with about Using about 350mg in total to about 19,000mg zoledronic acids in 1 year.

The drug products of 50. embodiment 44 of embodiment, wherein the oral of each unit include about 10mg to about 300mg。

The drug products of 51. embodiment 50 of embodiment, it includes the orals of 4 or 5 units, at about 1 Using about 40mg in total to about 1500mg zoledronic acids in the period of the moon.

The drug products of 52. embodiment 50 of embodiment, it includes the orals of 8 or 9 units, at about 2 Using about 80mg in total to about 2700mg zoledronic acids in month.

The drug products of 53. embodiment 50 of embodiment, it includes the oral of 12,13 or 14 units, with Using about 120mg in total to about 4200mg zoledronic acids in about 3 months.

The drug products of 54. embodiment 50 of embodiment, it includes the orals of 22 to 30 units, with about 6 Using about 220mg in total to about 9000mg zoledronic acids in a month.

The drug products of 55. embodiment 50 of embodiment, it includes the orals of 45 to 60 units, with about 1 Using about 450mg in total to about 18000mg zoledronic acids in year.

The drug products of 56. embodiment 44 of embodiment, it includes the orals of 1 to 10 unit, wherein product Including about 200mg is to about 2000mg zoledronic acids.

Embodiment 57. is sodium-salt form according to the oral of arbitrary aforementioned embodiments, wherein zoledronic acid.

Embodiment 58. is water-soluble more than 1% according to the oral of arbitrary aforementioned embodiments, wherein zoledronic acid (w/v) form.

For embodiment 59. according to the oral of arbitrary aforementioned embodiments, it is about 5% that wherein zoledronic acid, which is water solubility, (w/v) to about 50% (w/v) form.

A kind of 60. oral of embodiment, it includes zoledronic acid and excipient, wherein zoledronic acid be water solubility More than the form of 1% (w/v).

It is about 5% (w/v) to about that the oral of 61. embodiment 60 of embodiment, wherein zoledronic acid, which are water solubility, The form of 50% (w/v).

A kind of method that treating complex regional pain syndrome of embodiment 62. comprising zoledronic acid will be included Oral is administered to the mammal of this needs.

The method of 63. embodiment 62 of embodiment, wherein mammal are behaved, at one month or in the less period The zoledronic acid amount of receiving is about 30mg/m²To about 700mg/m²。

The method of 64. embodiment 63 of embodiment, wherein applying 4 or 5 all agent at one month or in the less period Amount.

The method of 65. embodiment 63 of embodiment, wherein being applied for 28 to 31 day at one month or in the less period Dosage.

The method of 66. embodiment 63 of embodiment, wherein applying 5 to 10 lists at one month or during the less period Only dosage.

The method of 67. embodiment 63 of embodiment, wherein applying about 30mg/m during the only one moon²To about 700mg/ m²Zoledronic acid.

The method of 68. embodiment 63 of embodiment, wherein applying about 30mg/m at one month or in the less period²Extremely About 700mg/m²Zoledronic acid, 2 months or more the moons of sustained continuous.

The method of 69. embodiment 62 of embodiment, wherein mammal receive about 10mg/m daily²To about 30mg/m²'s Zoledronic acid.

The method of 70. embodiment 62 of embodiment, wherein mammal are behaved, the zoledronic acid week accumulated dose received It is about 10mg to about 300mg.

The method of 71. embodiment 70 of embodiment is applied weekly primary wherein all accumulated doses are single dose.

The method of 72. embodiment 70 of embodiment, wherein all accumulated doses within week with 2 to 7 individually dosed applications.

The method of Arbitrary Term in 73. embodiment 62 to 72 of embodiment, wherein complex regional pain syndrome is multiple Polygamy regional pain syndrome I types.

The method of Arbitrary Term in 74. embodiment 62 to 72 of embodiment, wherein complex regional pain syndrome is multiple Polygamy regional pain syndrome II types.

Embodiment 75. is salt form according to the method for arbitrary aforementioned embodiments, wherein zoledronic acid.

The method of Arbitrary Term in 76. embodiment 62 to 75 of embodiment, wherein dosage form include the body based on mammal Surface area meter about 10mg/m²To about 20mg/m²Zoledronic acid.

The method of 77. embodiment 76 of embodiment, wherein dosage form include the body surface area meter based on mammal about 15mg/m²To about 20mg/m²Zoledronic acid.

A kind of method that treating complex regional pain syndrome of embodiment 78. comprising be administered to pamidronic acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 79. comprising be administered to Neridronic Acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 80. comprising be administered to olpadronic acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 81. comprising be administered to Alendronic Acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 82. comprising be administered to Incadronic Acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 83. comprising be administered to ibandronic acid There is this people needed.

A kind of method that treating complex regional pain syndrome of embodiment 84. comprising be administered to Risedronic Acid There is this people needed.

A kind of method that treating pain of embodiment 85. comprising pamidronic acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 86. comprising Neridronic Acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 87. comprising olpadronic acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 88. comprising Alendronic Acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 89. comprising Incadronic Acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 90. comprising ibandronic acid is administered to the people of this needs.

A kind of method that treating pain of embodiment 91. comprising Risedronic Acid is administered to the people of this needs.

The method of 92. a kind for the treatment of of arthritis pain of embodiment comprising pamidronic acid is administered to this needs People.

The method of 93. a kind for the treatment of of arthritis pain of embodiment comprising Neridronic Acid is administered to this needs People.

The method of 94. a kind for the treatment of of arthritis pain of embodiment comprising olpadronic acid is administered to this needs People.

The method of 95. a kind for the treatment of of arthritis pain of embodiment comprising Alendronic Acid is administered to this needs People.

The method of 96. a kind for the treatment of of arthritis pain of embodiment comprising Incadronic Acid is administered to this needs People.

The method of 97. a kind for the treatment of of arthritis pain of embodiment comprising ibandronic acid is administered to this needs People.

The method of 98. a kind for the treatment of of arthritis pain of embodiment comprising Risedronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 99. comprising pamidronic acid is administered to the people of this needs.

A kind of method that treating inflammatory pain of embodiment 100. comprising Neridronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 101. comprising olpadronic acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 102. comprising Alendronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 103. comprising Incadronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 104. comprising ibandronic acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 105. comprising Risedronic Acid is administered to this needs People.

A kind of method that treating complex regional pain syndrome of embodiment 106. comprising be administered to Etidronic Acid There is this people needed.

A kind of method that treating pain of embodiment 107. comprising Etidronic Acid is administered to the people of this needs.

The method of 108. a kind for the treatment of of arthritis pain of embodiment comprising Etidronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 109. comprising Etidronic Acid is administered to this needs People.

A kind of method that treating complex regional pain syndrome of embodiment 110. comprising be administered to Clodronate This people needed.

A kind of method that treating pain of embodiment 111. comprising Clodronate is administered to the people of this needs.

The method of 112. a kind for the treatment of of arthritis pain of embodiment comprising Clodronate is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 113. comprising Clodronate is administered to the people of this needs.

A kind of method that treating complex regional pain syndrome of embodiment 114. comprising be administered to Tiludronic Acid There is this people needed.

A kind of method that treating pain of embodiment 115. comprising Tiludronic Acid is administered to the people of this needs.

The method of 116. a kind for the treatment of of arthritis pain of embodiment comprising Tiludronic Acid is administered to this needs People.

A kind of method that treating inflammatory pain of embodiment 117. comprising Tiludronic Acid is administered to this needs People.

The method of Arbitrary Term, wherein reactive compound oral administration in 118. embodiment 78 to 117 of embodiment.

The method of Arbitrary Term, wherein reactive compound parenteral administration in 119. embodiment 78 to 117 of embodiment.

A kind of method for the oral bioavailability improving zoledronic acid of embodiment 120. comprising oral administration contains The dosage form of the zoledronic acid of disodium salt form.

The method of 121. embodiment 120 of embodiment, the wherein azoles of the zoledronic acid of disodium salt form and diacid form Carry out raising of the phosphonic acids compared to offer bioavailability, it is any with being provided by any bioavailability enhancer in dosage form Bioavailability improves superposition.

The method of 122. embodiment 120 of embodiment, wherein dosage form is substantially free of bioavailability enhancer.

The method of 123. embodiment 120 of embodiment, the wherein zoledronic acid of disodium salt form are administered to by following amount Mammal, the amount provide about 4ngh/mL to about when applying the zoledronic acid of disodium salt form every time to mammal Area under the zoledronic acid blood plasma concentration curve of 2000ngh/mL.

The method of 124. embodiment 123 of embodiment, the wherein zoledronic acid of disodium salt form by following amount with about 3 to Interval application in about 4 weeks, the amount provide about 100ngh/ when applying the zoledronic acid of disodium salt form every time to mammal Area under the zoledronic acid blood plasma concentration curve of mL to about 2000ngh/mL.

The method of 125. embodiment 123 of embodiment, the wherein zoledronic acid of disodium salt form press following amount on every Mondays Secondary application or 3 to 5 applications within the moon, the amount provide about when applying the zoledronic acid of disodium salt form every time to mammal Area under the zoledronic acid blood plasma concentration curve of 20ngh/mL to about 700ngh/mL.

The method of 126. embodiment 123 of embodiment, the wherein zoledronic acid of disodium salt form are applied daily by following amount With the amount provides about 4ngh/mL to about 100ngh/ when applying the zoledronic acid of disodium salt form every time to mammal Area under the zoledronic acid blood plasma concentration curve of mL.

The method of 127. embodiment 120 of embodiment, wherein dosage form are solid.

The method of 128. embodiment 120,121,122,123,124,125,126 or 127 of embodiment, wherein azoles carry out phosphine The bioavailability of acid is compared improves at least about 20% using the zoledronic acid of diacid form.

The method of 129. embodiment 120,121,122,123,124,125,126,127 or 128 of embodiment, is also wrapped Include the zoledronic acid of the disodium salt form applied by mol than for realize that identical zoledronic acid blood plasma level can be applied two The zoledronic acid of sour form is less.

The method of 130. embodiment 129 of embodiment, wherein being applied with for the identical zoledronic acid blood plasma level of realization The amount of zoledronic acid of diacid form compare, the disodium salt form of at least few about 10 moles of % of application.

The method of 131. embodiment 129 of embodiment, wherein disodium salt form are by mol to have about 0.8n_dTo about 1.2n_dValue amount application, wherein：

n_d=(b_a/b_d)(n_a)

Wherein b_aIt is the bioavailability of diacid form, b_dIt is the bioavailability of disodium salt form, and n_aIt is to realize The molal quantity of the zoledronic acid for the diacid form that identical zoledronic acid blood plasma level can be applied.

The method of 132. embodiment 131 of embodiment, wherein disodium salt is to have about n_dValue amount application.

The method of Arbitrary Term in 133. embodiment 120 to 132 of embodiment, wherein zoledronic acid are for treating inflammatory disease Disease.

The method of 134. embodiment 133 of embodiment, wherein zoledronic acid are used for treatment of arthritis.

The method of 135. embodiment 133 of embodiment, wherein zoledronic acid are for treating complex regional pain syndrome Sign.

The method of Arbitrary Term in 136. embodiment 1 to 39,62 to 77 and 120 to 135 of embodiment, wherein：

Using the first oral；And

Using the second oral；

Wherein relative to the first oral, the second oral is with 10 × T_maxOr bigger application, wherein T_maxIt is first The time of the maximal plasma concentration of oral.

A kind of dosage form of the zoledronic acid containing disodium salt form of embodiment 137., the azoles of wherein disodium salt form carry out phosphine The bioavailability of acid in mammals is more than the bioavailability of the zoledronic acid of diacid form in same dosage form.

A kind of dosage form of the zoledronic acid containing disodium salt form of embodiment 138., wherein the disodium salt shape contained by dosage form The zoledronic acid blood plasma that the amount of the zoledronic acid of formula provides about 4ngh/mL to about 2000ngh/mL to the people of form of administration is dense Spend area under the curve.

The dosage form of 139. embodiment 138 of embodiment, the wherein amount of the zoledronic acid of the disodium salt form contained by dosage form Area under the zoledronic acid blood plasma concentration curve of about 100ngh/mL to about 2000ngh/mL is provided to the people of form of administration.

The dosage form of 140. embodiment 138 of embodiment, the wherein amount of the zoledronic acid of the disodium salt form contained by dosage form Area under the zoledronic acid blood plasma concentration curve of about 20ngh/mL to about 700ngh/mL is provided to the people of form of administration.

The dosage form of 141. embodiment 138 of embodiment, the wherein amount of the zoledronic acid of the disodium salt form contained by dosage form Area under the zoledronic acid blood plasma concentration curve of about 4ngh/mL to about 100ngh/mL is provided to the people of form of administration.

A kind of dosage form of the zoledronic acid containing disodium salt form of embodiment 142.,

When wherein disodium salt form is using than zoledronic acid as diacid form there will be the lower mole of mole exist； And

Wherein the zoledronic acid of disodium salt form has improved bioavailability compared with the zoledronic acid of diacid form, Reach more lower mol in dosage form disodium salt do not reduce the zoledronic acid for being delivered to mammalian plasma amount degree.

The dosage form of 143. embodiment 137,138,139,140,141 or 142 of embodiment, wherein dosage form are solid.

The dosage form of 144. embodiment 142 or 143 of embodiment, the wherein biological utilisation of the zoledronic acid of disodium salt form Rate improves at least about 10% compared to the bioavailability of other all identical dosage forms in addition to the zoledronic acid containing diacid form.

The dosage form of 145. embodiment 142,143 or 144 of embodiment, it includes will when being diacid form with zoledronic acid The amount of the zoledronic acid of existing diacid form compares the disodium salt form of low at least about 20 moles %.

The dosage form of 146. embodiment 142 of embodiment, wherein disodium salt form are by mol to have about 0.9nd to about The amount of the value of 1.1nd exists, wherein：

n_d=(b_a/b_d)(n_a)

Wherein b_aIt is the bioavailability of diacid form, b_dIt is the bioavailability of disodium salt form, and n_aIt is that azoles carrys out phosphine Acid be diacid form when there will be diacid form molal quantity.

The dosage form of 147. embodiment 146 of embodiment, wherein disodium salt is to have about n_dValue amount application.

The method of Arbitrary Term in 148. embodiment 1 to 39,62 to 77 and 120 to 136 of embodiment, wherein：

Only apply single oral；Or

Using the first oral, and the second oral is applied after the first oral, wherein the second oral It is applied before the maximum pain relief for realizing the first oral or the second oral is realizing observable pain It is applied before pain remission effect.

The method of 149. embodiment 148 of embodiment, wherein the second oral is realizing that observable pain is slow It is applied before solving effect.

The method of Arbitrary Term in 150. embodiment 1 to 39,62 to 77 and 120 to 132 of embodiment, wherein applying first Then dosage form applies the second dosage form, wherein the second dosage form is applied after the maximum pain relief for realizing the first oral, And the second oral is applied when being observed that the pain relief of the first oral.

The method of 151. embodiment 148,149 or 150 of embodiment, wherein the second oral is oral in application first It applies within about 24 hours to about 28 days after dosage form.

The method of Arbitrary Term in 152. embodiment 20 to 39 of embodiment, wherein about 30 years old to about 75 years old artificial.

The method of Arbitrary Term in 153. embodiment 20 to 39 of embodiment, wherein about 1 years old to about 16 years old artificial.

The method of Arbitrary Term in 154. embodiment 20 to 39 of embodiment, wherein about 80 years old to about 95 years old artificial.

The method of Arbitrary Term in 155. embodiment 20 to 39 of embodiment, wherein people have had suffered from arthritis at least two moon.

The method of Arbitrary Term in 156. embodiment 20 to 39 of embodiment, wherein arthritis influence knee, ancon, hand Finger, wrist, shoulder or hip.

The method of Arbitrary Term in 157. embodiment 1 to 44,62 to 133 and 144 to 156 of embodiment, wherein applying azoles The mammal or people for carrying out phosphonic acids do not feed or drink drink at least 1 hour before application zoledronic acid.

The method of 158. embodiment 157 of embodiment, wherein using the mammal or people of zoledronic acid using azoles Not feed or drink drink at least 2 hours before phosphonic acids.

The method of 159. embodiment 158 of embodiment, wherein using the mammal or people of zoledronic acid using azoles Not feed or drink drink at least 4 hours before phosphonic acids.

The method of 160. embodiment 159 of embodiment, wherein using the mammal or people of zoledronic acid using azoles Not feed or drink drink at least 6 hours before phosphonic acids.

The method of Arbitrary Term in 161. embodiment 157 to 160 of embodiment, wherein using the mammal of zoledronic acid Or people does not feed or drinks drink at least 30 minutes after application zoledronic acid.

The method of 162. embodiment 161 of embodiment, wherein using the mammal or people of zoledronic acid using azoles Not feed or drink drink at least 1 hour after phosphonic acids.

The method of 163. embodiment 161 of embodiment, wherein using the mammal or people of zoledronic acid using azoles Not feed or drink drink at least 2 hours after phosphonic acids.

Method, dosage form or the product of 164. arbitrary aforementioned embodiments of embodiment, the wherein azoles in oral carry out phosphine Acid has about 1 or higher 24 hour sustained plasma level factor.

Method, dosage form or the product of 165. arbitrary aforementioned embodiments of embodiment, the wherein azoles in oral carry out phosphine 24 hours sustained plasma level factors of acid are higher than the zoledronic acid intravenously applied.

Method, dosage form or the product of 166. arbitrary aforementioned embodiments of embodiment, wherein oral are with about 5kPa to the hardness of about 20kPa solid.

Method, dosage form or the product of 167. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein zoledronic acid by oral to apply With the amount presence to the zoledronic acid AUC for leading to about 50nghr/mL to about 700nghr/mL after specific mammalian species.

Method, dosage form or the product of 168. embodiment 167 of embodiment, wherein zoledronic acid by oral to apply With to causing the amount of the zoledronic acid AUC of about 130nghr/mL to about 180nghr/mL to be deposited after specific mammalian species .

Method, dosage form or the product of 169. embodiment 167 of embodiment, wherein zoledronic acid by oral to apply With to causing the amount of the zoledronic acid AUC of about 300nghr/mL to about 450nghr/mL to be deposited after specific mammalian species .

Method, dosage form or the product of 170. embodiment 167 of embodiment, wherein zoledronic acid by oral to apply With to causing the amount of the zoledronic acid AUC of about 300nghr/mL to about 350nghr/mL to be deposited after specific mammalian species .

Method, dosage form or the product of 171. embodiment 167 of embodiment, wherein zoledronic acid by oral to apply With to causing the amount of the zoledronic acid AUC of about 370nghr/mL to about 420nghr/mL to be deposited after specific mammalian species .

Method, dosage form or the product of 172. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein zoledronic acid by oral to apply With to the zoledronic acid C for leading to about 5ng/mL to about 300ng/mL after specific mammalian species_maxAmount exist.

Method, dosage form or the product of 173. embodiment 172 of embodiment, wherein zoledronic acid by oral to apply With to the zoledronic acid C for leading to about 5ng/mL to about 50ng/mL after specific mammalian species_maxAmount exist.

Method, dosage form or the product of 174. embodiment 172 of embodiment, wherein zoledronic acid by oral to apply With to the zoledronic acid C for leading to about 50ng/mL to about 200ng/mL after specific mammalian species_maxAmount exist.

Method, dosage form or the product of 175. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so as to spy Determining mammalian species leads to the zoledronic acid T of about 0.4h to about 1h using oral_max。

Method, dosage form or the product of 176. embodiment 175 of embodiment, wherein oral are configured so as to spy Determining mammalian species leads to the zoledronic acid T of about 0.5h using oral_max。

Method, dosage form or the product of 177. embodiment 175 of embodiment, wherein oral are configured so as to spy Determining mammalian species leads to the zoledronic acid T of about 0.75h using oral_max。

Method, dosage form or the product of 178. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Phosphonic acids has specific mammalian species about 12 to about 50 12 hours sustained plasma level factors.

Method, dosage form or the product of 179. embodiment 178 of embodiment, wherein oral are configured so that azoles Phosphonic acids has specific mammalian species about 20 to about 40 12 hours sustained plasma level factors.

Method, dosage form or the product of 180. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Phosphonic acids has specific mammalian species about 10 to about 30 24 hours sustained plasma level factors.

Method, dosage form or the product of 181. embodiment 180 of embodiment, wherein oral are configured so that azoles Phosphonic acids has specific mammalian species about 10 to about 20 24 hours sustained plasma level factors.

Method, dosage form or the product of 182. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Phosphonic acids has specific mammalian species about 6 to about 20 36 hours sustained plasma level factors.

Method, dosage form or the product of 183. embodiment 182 of embodiment, wherein oral are configured so that azoles Phosphonic acids has specific mammalian species about 8 to about 15 36 hours sustained plasma level factors.

Method, dosage form or the product of 184. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Phosphonic acids has specific mammalian species about 5 to about 20 48 hours sustained plasma level factors.

Method, dosage form or the product of 185. embodiment 184 of embodiment, wherein oral are configured so that azoles Phosphonic acids has specific mammalian species about 6 to about 15 48 hours sustained plasma level factors.

Method, dosage form or the product of 186. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Phosphonic acids has specific mammalian species about 4 to about 20 72 hours sustained plasma level factors.

Method, dosage form or the product of 187. embodiment 186 of embodiment, wherein oral are configured so that azoles Phosphonic acids has specific mammalian species about 5 to about 10 72 hours sustained plasma level factors.

Method, dosage form or the product of 188. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein oral is configured so that specific Zoledronic acid plasma concentration of the mammalian species at 12 hours with about 0.5ng/mL to about 5ng/mL.

Method, dosage form or the product of 189. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein oral is configured so that specific Zoledronic acid plasma concentration of the mammalian species at 24 hours with about 0.2ng/mL to about 2ng/mL.

Method, dosage form or the product of 190. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein oral is configured so that specific Zoledronic acid plasma concentration of the mammalian species at 36 hours with about 0.1ng/mL to about 2ng/mL.

Method, dosage form or the product of 191. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein oral is configured so that specific Zoledronic acid plasma concentration of the mammalian species at 48 hours with about 0.1ng/mL to about 2ng/mL.

Method, dosage form or the product of 192. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid Dosage form has configuration and zoledronic acid dosage suitable for specific mammalian species, and wherein oral is configured so that specific Zoledronic acid plasma concentration of the mammalian species at 72 hours with about 0.2ng/mL to about 1ng/mL.

Method, dosage form or the product of 193. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Elimination half-life period of the phosphonic acids in specific mammalian species is about 30 hours to about 100 hours.

Method, dosage form or the product of 194. arbitrary aforementioned embodiments of embodiment, wherein containing the oral of zoledronic acid There is dosage form the configuration for being suitable for specific mammalian species and zoledronic acid dosage, wherein oral to be configured so that azoles Elimination half-life period of the phosphonic acids in specific mammalian species is about 40 hours to about 60 hours.

A kind of configuration having suitable for specific mammalian species containing zoledronic acid of embodiment 195. and azoles carry out phosphine The oral of sour dosage, wherein zoledronic acid after oral is administered to specific mammalian species to cause about The amount of area (AUC) exists under the zoledronic acid blood plasma concentration curve of 50nghr/mL to about 700nghr/mL.

The oral of 196. embodiment 195 of embodiment, wherein zoledronic acid by oral to be administered to spy The amount of the zoledronic acid AUC of about 130nghr/mL to about 180nghr/mL is caused to exist after determining mammalian species.

The oral of 197. embodiment 195 of embodiment, wherein zoledronic acid by oral to be administered to spy The amount of the zoledronic acid AUC of about 300nghr/mL to about 450nghr/mL is caused to exist after determining mammalian species.

The oral of 198. embodiment 195 of embodiment, wherein zoledronic acid by oral to be administered to spy The amount of the zoledronic acid AUC of about 300nghr/mL to about 350nghr/mL is caused to exist after determining mammalian species.

The oral of 199. embodiment 195 of embodiment, wherein zoledronic acid by oral to be administered to spy The amount of the zoledronic acid AUC of about 370nghr/mL to about 420nghr/mL is caused to exist after determining mammalian species.

A kind of configuration having suitable for specific mammalian species containing zoledronic acid of embodiment 200. and azoles carry out phosphine The oral of sour dosage, wherein zoledronic acid after oral is administered to specific mammalian species to lead to about 5ng/ The zoledronic acid C of mL to about 300ng/mL_maxAmount exist.

The oral of 201. embodiment 200 of embodiment, wherein zoledronic acid by oral to be administered to spy Determine the zoledronic acid C for leading to about 5ng/mL to about 50ng/mL after mammalian species_maxAmount exist.

The oral of 202. embodiment 200 of embodiment, wherein zoledronic acid by oral to be administered to spy Determine the zoledronic acid C for leading to about 50ng/mL to about 200ng/mL after mammalian species_maxAmount exist.

A kind of configuration having suitable for specific mammalian species containing zoledronic acid of embodiment 203. and azoles carry out phosphine The oral of sour dosage, wherein oral are configured so that applying oral to specific mammalian species causes about The zoledronic acid T of 0.4h to about 1h_max。

The oral of 204. embodiment 203 of embodiment, wherein oral are configured so as to specific lactation Animal species, which apply oral, leads to the zoledronic acid T of about 0.5h_max。

The oral of 205. embodiment 203 of embodiment, wherein oral are configured so as to specific lactation Animal species, which apply oral, leads to the zoledronic acid T of about 0.75h_max。

A kind of configuration having suitable for specific mammalian species containing zoledronic acid of embodiment 206. and azoles carry out phosphine The oral of sour dosage, wherein oral are configured so that zoledronic acid has about 12 for specific mammalian species To about 50 12 hours sustained plasma level factors.

The oral of 207. embodiment 206 of embodiment, wherein oral are configured so that zoledronic acid pair There are about 20 to about 40 12 hours sustained plasma level factors in specific mammalian species.

The oral of 208. embodiment 206 or 207 of embodiment, wherein oral are configured so that azoles carrys out phosphine Acid has specific mammalian species about 10 to about 30 24 hours sustained plasma level factors.

The oral of Arbitrary Term in 209. embodiment 206 to 208 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 10 to about 20 24 hours sustained plasma level factors.

The oral of Arbitrary Term in 210. embodiment 206 to 209 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 6 to about 20 36 hours sustained plasma level factors.

The oral of Arbitrary Term in 211. embodiment 206 to 210 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 8 to about 15 36 hours sustained plasma level factors.

The oral of Arbitrary Term in 212. embodiment 206 to 211 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 5 to about 20 48 hours sustained plasma level factors.

The oral of Arbitrary Term in 213. embodiment 206 to 212 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 6 to about 15 48 hours sustained plasma level factors.

The oral of Arbitrary Term in 214. embodiment 206 to 213 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 4 to about 20 72 hours sustained plasma level factors.

The oral of Arbitrary Term in 215. embodiment 206 to 213 of embodiment, wherein oral are configured to make Obtaining zoledronic acid has specific mammalian species about 5 to about 10 72 hours sustained plasma level factors.

The oral of Arbitrary Term in 216. embodiment 206 to 215 of embodiment, wherein oral are configured to make Specific mammalian species are obtained at 12 hours with the zoledronic acid plasma concentration for about 0.5ng/mL to about 5ng/mL.

The oral of Arbitrary Term in 217. embodiment 206 to 216 of embodiment, wherein oral are configured to make Specific mammalian species are obtained at 24 hours with the zoledronic acid plasma concentration for about 0.2ng/mL to about 2ng/mL.

The oral of Arbitrary Term in 218. embodiment 206 to 217 of embodiment, wherein oral are configured to make Specific mammalian species are obtained at 36 hours with the zoledronic acid plasma concentration for about 0.1ng/mL to about 2ng/mL.

The oral of Arbitrary Term in 219. embodiment 206 to 218 of embodiment, wherein oral are configured to make Specific mammalian species are obtained at 48 hours with the zoledronic acid plasma concentration for about 0.1ng/mL to about 2ng/mL.

The oral of Arbitrary Term in 220. embodiment 206 to 219 of embodiment, wherein oral are configured to make Specific mammalian species are obtained at 72 hours with the zoledronic acid plasma concentration for about 0.2ng/mL to about 1ng/mL.

The oral of Arbitrary Term in 221. embodiment 206 to 220 of embodiment, wherein oral are configured to make It is about 30 hours to about 100 hours to obtain elimination half-life period of the zoledronic acid in specific mammalian species.

The oral of Arbitrary Term in 222. embodiment 206 to 221 of embodiment, wherein oral are configured to make It is about 40 hours to about 60 hours to obtain elimination half-life period of the zoledronic acid in specific mammalian species.

Unless otherwise indicated, in all cases, all expression composition quantity, the property used in description and claims The numerical value of matter (such as molecular weight) reaction condition should be understood to indicate shown exact value simultaneously and be modified by term " about ".Cause This, unless indicated to the contrary, the numerical parameter listed in specification and appended is approximation, can be according to thinking The desirable properties to be obtained and change.On minimum level, each digital parameters are not intended to the application limitation of doctrine of equivalents In protective scope of the claims, at least should according to report number significant digit and by usual rounding-off method come Understand each digital parameters.

It obviously contradicts, is otherwise described in the context of the present invention (especially unless otherwise specified herein or with context It is below in the context of claims) it should be interpreted to cover singulative and plural shape when not modified by quantifier Formula.All methods described herein can carry out in any suitable order, unless otherwise indicated herein or obviously and context Contradiction.The use of any and all examples presented herein or exemplary statements (such as " such as ") is intended only to for preferably It illustrates the present invention, rather than any the scope of the claims is limited.Language in specification, which is not necessarily to be construed that, points out to appoint The element what is not claimed is necessary the practice of the present invention.

The grouping of replacement element or embodiment disclosed herein should not be construed as restrictive.Each group of group member can be single Solely either to be referred to and be claimed with arbitrary combine of the other element in described group other group members or this paper.According to pre- Meter, for the reason of the facility and/or patentability, one or more members of group may include in a group or from the group Interior deletion.When occur it is any it is this kind of include or delete when, it is believed that specification includes rewritten group, to meet for appended power The written description of all marlcush groups in profit requirement.

This document describes the certain embodiments of the present invention, including realize the present invention most known to the present inventor Good pattern.Certainly, the modification of the embodiment of these descriptions will be recognized after those of ordinary skill in the art's reading foregoing description. Inventor, which is expected those skilled in the art, can suitably use such modification, and inventor be intended to the present invention with Text, which specifically describes different modes, to be implemented.Therefore, claim includes institute in claim under conditions of applicable law allows Refer to all modifications form and equivalents of theme.In addition, obviously contradict unless otherwise specified herein or with context, Otherwise it is also contemplated by arbitrary combination of the above-mentioned element in a manner of being possible to.

Closing, it is to be understood that embodiments disclosed herein is used merely to explain the principle of claim.Other are available to repair Change also within the scope of the invention.Therefore, non-limited way by example can utilize replacing for the present invention according to the teaching of this article For embodiment.Therefore, claim is not limited to the embodiment as shown in accurate and described.

The following contents corresponds to the original claims in parent application, is now incorporated to this as part of the specification Place：

1. a kind of method for the oral bioavailability improving zoledronic acid comprising oral administration contains disodium salt form Zoledronic acid dosage form.

2. according to the method described in item 1, wherein the zoledronic acid of the zoledronic acid and diacid form of the disodium salt form Compared to the raising for providing bioavailability, the raising is added to be carried by any bioavailability reinforcing agent in the dosage form On any bioavailability supplied improves.

3. according to the method described in item 1, moved wherein the zoledronic acid of the disodium salt form is administered to lactation by following amount Object, the amount provide about 4ngh/mL extremely in the zoledronic acid of the application disodium salt form every time to the mammal Area under the zoledronic acid blood plasma concentration curve of about 2000ngh/mL.

4. according to the method described in item 1, wherein the zoledronic acid of the disodium salt form pressed following amount with about 3 to about 4 weeks Interval application, the amount every time application the disodium salt form the zoledronic acid when to the mammal provide about Area under the zoledronic acid blood plasma concentration curve of 100ngh/mL to about 2000ngh/mL.

5. according to the method described in item 1, wherein the zoledronic acid of the disodium salt form by following amount once a week or 3 to 5 applications in month, the amount carry when every time using the zoledronic acid of the disodium salt form to the mammal For area under the zoledronic acid blood plasma concentration curve of about 20ngh/mL to about 700ngh/mL.

6. according to the method described in item 1, wherein the zoledronic acid of the disodium salt form presses following amount daily administration, it is described It measures and provides about 4ngh/mL to about to the mammal in the zoledronic acid of the application disodium salt form every time Area under the zoledronic acid blood plasma concentration curve of 100ngh/mL.

7. according to the method described in item 1, wherein the dosage form is solid.

8. according to the method described in item 1, wherein the bioavailability of the zoledronic acid compares the azoles using diacid form Come for phosphonic acids to improve at least about 20%.

Further include application by mol than to realize identical zoledronic acid blood plasma water 9. according to the method described in item 1 The zoledronic acid of the less disodium salt form of amount of zoledronic acid that is flat and applying diacid form.

10. according to the method described in item 9, wherein applying diacid form with for the identical zoledronic acid blood plasma level of realization The amount of zoledronic acid compare, the disodium salt form of at least few about 10 moles of % of application.

11. according to the method described in item 9, wherein the disodium salt form is by mol to have about 0.8nd to about 1.2nd Value amount application, wherein：

Nd=(ba/bd) (na)

Wherein ba is the bioavailability of the diacid form, and bd is the bioavailability of the disodium salt form, and Na is to realize identical zoledronic acid blood plasma level by the molal quantity of the zoledronic acid of the diacid form of application.

12. according to the method described in item 1, wherein the zoledronic acid is for treating inflammatory conditions.

13. according to the method described in item 1, wherein the zoledronic acid is comprehensive for treatment of arthritis or complex regional pain Simulator sickness.

14. according to the method described in item 1, wherein the zoledronic acid is for treating inflammatory conditions, arthritis or complexity Regional pain syndrome, and wherein：

Using the first oral；And

Using the second oral；

Wherein for first oral, second oral is with 10 × T_maxOr longer application, Middle T_maxIt is the time of the maximal plasma concentration of first oral.

15. a kind of oral of the zoledronic acid containing disodium salt form, wherein the azoles of the disodium salt form carrys out phosphine The bioavailability of acid in mammals is more than the bioavailability of the zoledronic acid of diacid form in same dosage form.

16. according to the oral described in item 15, wherein the zoledronic acid of the disodium salt form contained by the dosage form Amount to application the dosage form people provide about 100ngh/mL to about 2000ngh/mL zoledronic acid blood plasma concentration curve Lower area.

17. according to the oral described in item 15, wherein the zoledronic acid of the disodium salt form contained by the dosage form Amount to application the dosage form people provide about 20ngh/mL to about 700ngh/mL zoledronic acid blood plasma concentration curve under Area.

18. according to the oral described in item 15, wherein the zoledronic acid of the disodium salt form contained by the dosage form Amount to application the dosage form people provide about 4ngh/mL to about 100ngh/mL zoledronic acid blood plasma concentration curve under Area.

19. according to the oral described in item 15, wherein when the disodium salt form is using than zoledronic acid as diacid form There will be the lower mole of mole exist；And the zoledronic acid of the wherein described disodium salt form and the diacid form Zoledronic acid compare with the bioavailability improved, the disodium salt for reaching more lower mol in the dosage form do not drop The degree of the amount of the low zoledronic acid for being delivered to mammalian plasma.

20. according to the oral described in item 185, it includes when being diacid form with the zoledronic acid there will be two The amount of the zoledronic acid of sour form compares the disodium salt form of low at least about 20 moles %.

21. according to the oral described in item 185, wherein the disodium salt form is by mol to have about 0.9n_dExtremely About 1.1n_dValue amount exist, wherein：

n_d=(b_a/b_d)(n_a)

Wherein b_aIt is the bioavailability of the diacid form, b_dIt is the bioavailability of the disodium salt form, and n_a Be the zoledronic acid be diacid form when there will be the diacid form molal quantity.

22. according to the oral described in item 21, wherein the disodium salt is to have about n_dValue amount application.

23. according to the oral described in item 15, wherein the dosage form is solid.

24. according to the oral described in item 15, wherein the bioavailability phase of the zoledronic acid of the disodium salt form At least about 10% is improved than dosage form identical in addition to the zoledronic acid containing diacid form.

25. according to the method described in item 1, wherein the zoledronic acid is for treating inflammatory conditions, arthritis or complexity Regional pain syndrome, and wherein：

Only apply single oral；Or

Using the first oral, and the second oral is applied after first oral；

Wherein described second oral is applied before the maximum pain relief for realizing first oral, Or second oral is applied before the pain relief for realizing observable.

26. according to the method described in item 25, wherein second oral is in the pain relief for realizing observable It applies before.

27. according to the method described in item 1, wherein the zoledronic acid is for treating inflammatory conditions, arthritis or complexity Regional pain syndrome, and：

The first oral is wherein applied, the second oral is then applied；

Wherein described second oral is applied after the maximum pain relief for realizing first oral； And

Second oral is applied when the pain relief of first oral can be observed.

28. according to the method described in item 25, wherein second oral after application first oral about It applies within 24 hours to about 28 days.

29. the oral according to any one of item 15 to 28, wherein the zoledronic acid tool in the oral There is about 1 or higher 24 hour sustained plasma level factor.

30. the oral according to any one of item 15 to 28, wherein zoledronic acid in the oral The sustained plasma level factor is higher than 24 hours sustained plasma level factors of the zoledronic acid intravenously applied within 24 hours.

Claims (29)

1. purposes of the zoledronic acid of disodium salt form in preparing the arthritic drug for treating people, wherein the drug It is the oral of the zoledronic acid containing disodium salt form.

2. purposes according to claim 1, wherein the people receives about 10mg/m²To about 300mg/m²Disodium salt form Zoledronic acid total moon dosage.

3. purposes according to claim 2, wherein the total month dosage is applied with 4 or 5 weekly doses.

4. purposes according to claim 2, wherein the total month dosage is applied with 28 to 31 daily doses.

5. purposes according to claim 2, wherein the total month dosage within the moon with 5 to 10 individually dosed applications.

6. purposes according to claim 1, wherein the azoles that the people receives the disodium salt form of about 10mg to about 300mg comes Total weekly dose of phosphonic acids.

7. purposes according to claim 6 is applied weekly primary wherein total weekly dose is single dosage.

8. purposes according to claim 6, wherein total weekly dose within week with 2 to 7 individually dosed applications.

9. purposes according to claim 1, wherein the azoles that the people receives the disodium salt form of about 10mg to about 150mg comes Total weekly dose of phosphonic acids.

10. purposes according to claim 1, wherein body surface area of the oral based on the people includes about 10mg/m²To about 20mg/m²Disodium salt form zoledronic acid.

11. purposes according to claim 10, wherein body surface area of the oral based on the people includes about 15mg/m²To about 20mg/m²Disodium salt form zoledronic acid.

12. purposes according to claim 1, wherein the people receives about 100mg/m²To about 300mg/m²Disodium salt shape Total moon dosage of the zoledronic acid of formula.

13. purposes according to claim 12, wherein the body surface area based on the people is monthly applied about to the people 100mg/m²To about 200mg/m²Disodium salt form zoledronic acid.

14. purposes according to claim 1, wherein the people receives about 100mg to the disodium of about 600mg in one month The zoledronic acid of salt form.

15. purposes according to claim 1, wherein the oral bioavailability of zoledronic acid is about in the dosage form 0.1% to about 5%.

16. purposes according to claim 1, wherein the oral contains the molar equivalent of about 10mg to about 50mg The zoledronic acid of diacid form.

17. purposes according to claim 16, wherein the oral bioavailability of zoledronic acid is about in the dosage form 0.1% to about 2%.

18. purposes according to claim 16, wherein the oral was applied weekly, using 6 weeks.

19. purposes according to claim 1, wherein the people receives about 30mg/m at one month or in the less time²Extremely About 300mg/m²Diacid form zoledronic acid equivalent.

20. purposes according to claim 19, wherein applying 4 or 5 weekly doses at one month or in the less time.

21. purposes according to claim 19, wherein applying 28 to 31 daily doses at one month or in the less time.

22. purposes according to claim 19, wherein applying 5 to 10 independent agent at one month or in the less time Amount.

23. purposes according to claim 19, wherein applying about 30mg/m at one month or in the less time²To about 300mg/m²Equivalent diacid form zoledronic acid, using 2 or more the continuous moons.

24. purposes according to claim 1, wherein the people receives about 10mg/m daily²To about 30mg/m²Equivalent The zoledronic acid of diacid form.

25. purposes according to claim 1, wherein the people receives about 10mg to the diacid form of the equivalent of about 250mg Zoledronic acid total weekly dose.

26. purposes according to claim 25 is applied 1 time weekly wherein total weekly dose is single dosage.

27. purposes according to claim 25, wherein the weekly dose within week with 2 to 7 individually dosed applications.

28. purposes according to claim 25, wherein dosage form described in the body surface area based on the people includes about 10mg/m² To about 80mg/m²Disodium salt form zoledronic acid.

29. purposes according to claim 25, wherein the dosage form was applied weekly, using 6 weeks.