CN108261393A - A kind of medicinal composition for injections containing zoledronic acid - Google Patents
A kind of medicinal composition for injections containing zoledronic acid Download PDFInfo
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- CN108261393A CN108261393A CN201810355879.XA CN201810355879A CN108261393A CN 108261393 A CN108261393 A CN 108261393A CN 201810355879 A CN201810355879 A CN 201810355879A CN 108261393 A CN108261393 A CN 108261393A
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- zoledronic acid
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Abstract
The present patent application provides a kind of prescription and simple for process, the better medicinal composition for injections containing zoledronic acid of stability and reproducibility.And it provides preparation process and is prepared into parenteral solution.So as to achieve the purpose that significantly increase zoledronic acid injection storage stability.The preparation method of the pharmaceutical composition, method is simple, stablizes, and is easy to industrialized production.
Description
The present patent application number is 201510624755.3, and applying date 2015.09.27, entitled " one kind contains azoles
Carry out the composition for injection of phosphonic acids " patent divisional application.
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of composition for injection containing zoledronic acid and its preparation
Method and purposes.
Background technology
Malignant metastatic tumor of bone be the most commonly seen complication of late malignant tumour it, be more common in breast cancer, prostate cancer
Deng.The main mechanism of malignant metastatic tumor of bone is that red marrow blood supply is enriched, and is conducive to tumour cell and reaches part, and generates viscous
Attached molecule is combined with bone trabecula and bone matrix, is generated the activation that bone resorbing factor promotes osteoclast, is caused bone information, draw
Playing bone dependent event such as pain exacerbation, hypercalcinemia, the pathologic fracture of long bone or pelvic fracture, spinal compression causes to paralyse.
Bone tumour is also to lead to one of common cause of cancer death.Since the osteolysis of acceleration and inflammatory reaction are that bone photo closes
The key factor of event occurrence and development, therefore inhibitor of the bisphosphonates as osteoclast activity, pass through inhibition
The effect of bone mineralising or bone information plays a role, and can generate certain anti-inflammatory effect alleviating ostalgia etc..
Osteoporosis can make bone become fragile and die down, and then improve fracture, particularly vertebra as most common metabolic bone disease
Bone, ilium, carpal bone, basin bone and upper arm risk of bone fracture.Estimated by national sanitary research, in every 2 50 years old or more women
To just there be 1 people at least to meet with 1 osteoporotic fracture in its remaining years, it is even dead thus to greatly improve damage ratio, disability rate
Die rate.It is estimated that Postmenopausal Osteoporosis is in global implication to 200,000,000 people.Moreover, osteoporosis is also to influence old age
The disease occurred frequently of man's health estimates that there are about 1/5th 50 years old or more men at least to undergo 1 osteoporotic fracture, and bone
The death rate is also higher than women after folding.Although osteoporosis consequence is serious, can be given with therapies such as bisphosphonates
Thus treatment effectively reduces the risk of osteoporotic fracture.Bisphosphonates can by change osteoclast activity and
Its function and the bone resorption that inhibits improves bone mineral density, so as to pre- preventing bone rarefaction.
Either malignant metastatic tumor of bone or osteoporosis can be given using biphosphonates and treat.Bis phosphoric acid
Salt has been successfully used to the treatment of bone calcium metabolic diseases and some bone related diseases, mesh since the 1980s is by exploitation
It is preceding to develop for 3 generations, in its clinical practice, it is found that the main adverse reaction of Diphosphonate in addition to gastrointestinal symptom, can also draw
Play the extra-inhibitory of bone, cause hypocalcemia.
Zoledronic acid is the nitrogen heterocyclic ring diphosphonate of Novartis Co., Ltd of Switzerland research and development, for the 3rd generation bisphosphonates, body
Inside and outside experiment shows that zoledronic acid is the bisphosphonates that pharmacological activity is most strong so far.The drug was in 2000
Initial Public Offering in October, for treating malignant metastatic tumor of bone.In August, 2007, FDA have approved the new adaptation of zoledronic acid again
Disease, for the man's osteoporosis treated postmenopausal women He be in risk of bone fracture.
Zoledronic acid (Zoledronic acid), chemical name are 1- hydroxyls -2- (imidazoles -1-yl)-ethylidene -1,1-
Diphosphonic acid, structural formula are shown below：
Novartis Co., Ltd discloses its prescription in zoledronic acid injection product description, as follows：
The zoledronic acid injection prepared to above-mentioned prescription carries out research discovery：In process of production, it is also easy to produce degradation production
Object imidazoleacetic acid and other impurities, and with the extension of storage time, catabolite imidazoleacetic acid has again is further degraded to miaow
The phenomenon that azoles and acetic acid.Such degradation seriously affects the stability of drug, therefore should be preferably minimized level as far as possible.
Chinese patent 201310709854.2 provides a kind of zoledronic acid injection and preparation method thereof, by azoles come
Catabolite imidazoleacetic acid, the imidazoles one or two therein of zoledronic acid are added in phosphonic acids injection formula, it is steady to reach
Determine the purpose of parenteral solution.But impurity is added into parenteral solution, challenge undoubtedly is proposed to the safety of parenteral solution.
Invention content
In view of the above-mentioned defects in the prior art, inventor's process further investigation obtains a kind of prescription and simple for process, stabilization
The better composition for injection containing zoledronic acid of property and reproducibility.And it provides preparation process and is prepared into parenteral solution.From
And achieve the purpose that significantly increase zoledronic acid injection storage stability.
The preparation method of the pharmaceutical composition, method is simple, stablizes, and is easy to industrialized production.
Composition of the present invention is using zoledronic acid as main ingredient ingredient, by osmotic pressure regulator, pH adjusting agent, water for injection
Composition.Injection can be further prepared by following steps：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed, it is spare；
2) water for injection of total volume 80% is taken, dissolves pH adjusting agent, osmotic pressure regulator successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) it takes and contains drug solns 1. obtained by step 3), add and add to the full amount of water for injection, adjust pH value, obtain containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
It is characterized in that, the pH adjusting agent is sodium acetate, the pH value is 6.0-6.5.
Further, the operation of the crushing, for bulk pharmaceutical chemicals are crushed to fine powder, i.e. gained powder can all pass through 80 mesh
Sieve, and containing the powder that sieves with 100 mesh sieve no less than 95% can be led to.
The osmotic pressure regulator is glycerine, while glycerine can play the role of stabilizer, avoid storing for a long time
Visible foreign matters caused by the reasons such as Cheng Zhong, the precipitation of bulk pharmaceutical chemicals are unqualified.
Injection formula is as follows described in this patent：
Preparation method is as follows：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
The further preferred prescription of parenteral solution described in this patent is as follows：
Preparation method is as follows：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
The present invention reduces bulk pharmaceutical chemicals zoledronic acid to increase stability of the zoledronic acid injection in long-term storing process
It degrades in storing process, generates imidazoleacetic acid, imidazoleacetic acid, which is further degraded, generates imidazoles and acetic acid.By in parenteral solution
Sodium acetate is added, sodium acetate is dissociated into acetic acid and sodium ion under acid pH 6.0-6.5 environment, and free acetic acid effectively inhibits
The degradation of imidazoleacetic acid, and then inhibit the degradation of zoledronic acid.
Simultaneously as zoledronic acid water solubility is poor, after being configured to parenteral solution, in long-term storing process mistake, bulk pharmaceutical chemicals hold
It is easily precipitated, generates particulate matter, cause visible foreign matters unqualified, by applying crystallization inhibitor glycerine in parenteral solution, have
Solves the problems, such as this to effect.Glycerine also acts as the effect of osmotic pressure adjusting as small molecule simultaneously.
Gained zoledronic acid injection preparation method is simple, can be used customary preparation methods production, have easy industrialization,
Production efficiency is high, stability is good, the remarkable advantages such as quality controllable.Patent application is further illustrated the present invention by testing as follows.
Experiment one：Prescription screening
According to the design original intention of present patent application, i.e., sodium acetate is added in into zoledronic acid injection, to maintain to inject
While liquid pH value, enhance the storage stability of solution.Glycerine is added in, while solution osmotic pressure is maintained, inhibits bulk pharmaceutical chemicals
Crystallization is precipitated, and forms insoluble granule.
Glycerol concentration is set as 4.95% accordingly, to provide most osmotic pressure.Zoledronic acid and sodium acetate to
The osmotic pressure of rest part is provided, maintain solution isotonic or higher is oozed.
Bulk pharmaceutical chemicals zoledronic acid is water-soluble general simultaneously, need to increase its dissolving in aqueous solution in a manner of reducing grain size
Degree.
In order to increase the compliance of patient, under the precursor for ensureing parenteral solution stability, reduce as possible to injection site
Stimulation, while consider the buffering range of sodium acetate solution, parenteral solution pH value is set as 6.0-6.5.
Injection formula is screened by following prescription and technique：
1 zoledronic acid injection prescription screening of table
Preparation process：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to middle powder respectively, fine powder, most fine powder are spare；
2) water for injection of total volume 80% is taken, dissolves recipe quantity sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
Analysis of experimental results：
This prescription screening experiment using bulk pharmaceutical chemicals granularity and sodium acetate dosage as variable, takes middle powder, most fine powder, fine powder three respectively
Horizontal bulk pharmaceutical chemicals granularity and the sodium acetate concentration of 0.001M, 0.002M and 0.004M investigate the feasibility of prescription, are sent out in experiment
Existing, when bulk pharmaceutical chemicals granularity is fine powder and most fine powder, under identical mixing speed, dissolution time is obviously shortened, and is dissolved by middle powder
Required about 10 minutes or so, shorten to about 6 minutes and about 4 minutes, it is contemplated that by fine powder be crushed to most fine powder need expend compared with
More energy, but in terms of dissolution time, solubility increase is not obvious, therefore select bulk pharmaceutical chemicals being crushed to fine powder.Work as acetic acid
When na concn is 0.001M, 0.1M sodium acetate aqueous solutions needed for adjustment pH value are more, and when sodium acetate concentration is increased to 0.002M
Or after 0.004M, required 0.1M sodium acetate aqueous solutions are appropriate, from save material from the point of view of, therefore select 0.002M sodium acetates for
Final concentration.To sum up, selection bulk pharmaceutical chemicals are crushed to fine powder, and the prescription one that sodium acetate concentration is 0.001M is optimal prescription.
Prescription one is promoted, a concentration of 0.8mg/ml and 0.05mg/ml of bulk pharmaceutical chemicals is reduced, obtains other two specification
Parenteral solution, the prescription of three gauge hypodermic liquid is as follows：
Test two low temperature tests
It takes three gauge hypodermic liquors appropriate respectively, is placed 2 days respectively at 2~8 DEG C, then placed 2 days at 40 DEG C, so recycled
Three times, sampling detection visible foreign matters judge whether there is bulk pharmaceutical chemicals precipitation.After testing, the parenteral solution of this three specifications, by three
The low-temperature test of cycle is showed no visible foreign matters exception.
Test accelerated stability experiment in 36 months
4ml is taken respectively：4mg, 5ml：4mg, 100ml：Tri- specification zoledronic acid injections of 5mg and commercially available three gauge hypodermic liquid
Number A-F puts 40 DEG C ± 2 DEG C to six groups of samples respectively respectively, is stored 6 months under the conditions of 75% ± 5%RH, respectively at 0 month, January, and 2
Month, relevant nature is measured by sampling, obtains corresponding data June in March, it is as shown in the table：
6 three specification zoledronic acid injections of table are compared with commercially available parenteral solution accelerated stability
The three specification zoledronic acids prepared it can be seen from upper table data according to prescription of the present invention and technique are injected
Liquid, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 6 months, content, related substance is varied from, but
Be content more than 99.6%, imidazoleacetic acid content is respectively less than 0.045%, and total impurities are below 0.1%, it is seen that foreign matter closes
Lattice；It corresponds, after accelerating storage in 6 months, content, imidazoleacetic acid contains commercially available three specification zoledronic acid injections
Amount and total impurities content occur largely to change.
Based on as above analyzing, the three specification zoledronic acid injections prepared according to prescription of the present invention and technique are accelerating
Under the conditions of, the data after storing 6 months are shown, stability is obtained better than the content of commercially available parenteral solution, especially imidazoleacetic acid
Effectively control, so that the present invention has prominent substantive distinguishing features and marked improvement, and with practicability.
Specific embodiment
The advantageous effect further illustrated the present invention is tested by following.But it is not limited to following embodiments, this field
Technical staff made on the basis of the present invention, equivalent substitute or the transformation of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
1 4ml of embodiment：Preparation (the unit of 4mg specification zoledronic acid injections：g)
Prescription：
Preparation method is as follows：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
2 5ml of embodiment：Preparation (the unit of 4mg specification zoledronic acid injections：g)
Prescription：
Preparation method is as follows：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
3 100ml of embodiment：Preparation (the unit of 5mg specification zoledronic acid injections：g)
Prescription：
Preparation method is as follows：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
Claims (2)
1. a kind of medicinal composition for injections containing zoledronic acid, which is characterized in that the composition prescription composition is as follows：
A kind of 2. medicinal composition for injections containing zoledronic acid as described in claim 1, which is characterized in that the composition
Parenteral solution can be made by the steps into：
1) zoledronic acid bulk pharmaceutical chemicals are taken, are crushed to fine powder, it is spare；
2) water for injection of total volume 80% is taken, dissolves sodium acetate, glycerine successively；
3) step 2) acquired solution is taken, adds in zoledronic acid bulk pharmaceutical chemicals powder obtained by step 1), stirring makes dissolving, it is molten to obtain drug containing
Liquid is 1.；
4) take obtained by step 3) containing drug solns 1., add and add to the full amount of water for injection, with 0.1M sodium acetate aqueous solutions adjust pH value to
6.0-6.5 it obtains containing drug solns 2.；
5) it takes and contains drug solns 2. obtained by step 4), with 0.2% activated carbon adsorption pyrogen, and filter, obtain containing drug solns 3.；
6) it takes and contains drug solns 3. obtained by step 5), it is filling to jump a queue in middle Pyrex injection bottle, aluminium lid is pricked, azoles is obtained and carrys out phosphine
Acid injection semi-finished product；
7) zoledronic acid injection semi-finished product obtained by step 6) are taken, under the conditions of 121 DEG C, with flowing steam sterilization method, sterilizing makes
F0 values are more than 8.0, obtain zoledronic acid injection finished product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810355879.XA CN108261393B (en) | 2015-09-27 | 2015-09-27 | Zoledronic acid-containing pharmaceutical composition for injection |
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| CN201510624755.3A CN105232451B (en) | 2015-09-27 | 2015-09-27 | A kind of composition for injection containing zoledronic acid |
| CN201810355879.XA CN108261393B (en) | 2015-09-27 | 2015-09-27 | Zoledronic acid-containing pharmaceutical composition for injection |
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| CN109431990A (en) * | 2018-12-21 | 2019-03-08 | 江西润泽药业有限公司 | Zoledronic acid injection and preparation method thereof |
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| CN107011380A (en) * | 2016-01-28 | 2017-08-04 | 臧伟 | A kind of diphosphonic acid derivative and containing diphosphonic acid derivative composition treatment fracture application |
| CN106924269A (en) * | 2016-04-19 | 2017-07-07 | 南京大学 | The purposes of zoledronic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1852739A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | Pharmaceutical products comprising bisphosphonates |
| CN101198316A (en) * | 2005-03-17 | 2008-06-11 | 伊兰制药国际有限公司 | Nanoparticulate bisphosphonate compositions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR075721A1 (en) * | 2010-03-05 | 2011-04-20 | Eriochem Sa | PHARMACEUTICAL COMPOSITION THAT INCLUDES A ZOLEDRONIC ACID SOLUTION. |
| CN102000094B (en) * | 2010-09-27 | 2013-03-27 | 天津南开允公医药科技有限公司 | Ibandronic acid-containing medicinal composition and preparation process thereof |
| CN104721132B (en) * | 2013-12-21 | 2018-05-18 | 石药集团恩必普药业有限公司 | A kind of zoledronic acid injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1852739A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | Pharmaceutical products comprising bisphosphonates |
| CN101198316A (en) * | 2005-03-17 | 2008-06-11 | 伊兰制药国际有限公司 | Nanoparticulate bisphosphonate compositions |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109431990A (en) * | 2018-12-21 | 2019-03-08 | 江西润泽药业有限公司 | Zoledronic acid injection and preparation method thereof |
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| CN105232451A (en) | 2016-01-13 |
| CN105232451B (en) | 2019-02-05 |
| CN108261393B (en) | 2020-10-27 |
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