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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- CN
- China
- Prior art keywords
- zoledronic acid
- injection
- taken
- drug solns
- finished product
- Prior art date
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960004276 zoledronic acid Drugs 0.000 title claims abstract description 67
- 238000002347 injection Methods 0.000 title claims abstract description 61
- 239000007924 injection Substances 0.000 title claims abstract description 61
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003182 parenteral nutrition solution Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims description 50
- 239000003814 drug Substances 0.000 claims description 50
- 239000000126 substance Substances 0.000 claims description 31
- 239000000843 powder Substances 0.000 claims description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 27
- 239000001632 sodium acetate Substances 0.000 claims description 26
- 235000017281 sodium acetate Nutrition 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 16
- 239000011265 semifinished product Substances 0.000 claims description 16
- 230000001954 sterilising effect Effects 0.000 claims description 16
- 235000011187 glycerol Nutrition 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 150000003851 azoles Chemical class 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 8
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 8
- 239000004411 aluminium Substances 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 239000005297 pyrex Substances 0.000 claims description 8
- 239000002510 pyrogen Substances 0.000 claims description 8
- 238000001179 sorption measurement Methods 0.000 claims description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 210000000988 bone and bone Anatomy 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- PRJKNHOMHKJCEJ-UHFFFAOYSA-N imidazol-4-ylacetic acid Chemical compound OC(=O)CC1=CN=CN1 PRJKNHOMHKJCEJ-UHFFFAOYSA-N 0.000 description 9
- 230000003204 osmotic effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940122361 Bisphosphonate Drugs 0.000 description 5
- 208000001132 Osteoporosis Diseases 0.000 description 5
- 150000004663 bisphosphonates Chemical class 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 208000010392 Bone Fractures Diseases 0.000 description 3
- 208000001164 Osteoporotic Fractures Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 208000013038 Hypocalcemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010034246 Pelvic fractures Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 208000005250 Spontaneous Fractures Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 208000015202 calcium metabolic disease Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000003010 carpal bone Anatomy 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000000705 hypocalcaemia Effects 0.000 description 1
- 210000003692 ilium Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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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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)
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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 |
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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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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 |
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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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