CN103070824B - Ibandronate sodium containing injection - Google Patents
Ibandronate sodium containing injection Download PDFInfo
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- CN103070824B CN103070824B CN201310026921.0A CN201310026921A CN103070824B CN 103070824 B CN103070824 B CN 103070824B CN 201310026921 A CN201310026921 A CN 201310026921A CN 103070824 B CN103070824 B CN 103070824B
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Abstract
The invention relates to an ibandronate sodium containing injection. The injection is prepared by ibandronate sodium and pharmaceutically acceptable auxiliary materials; a pH value of the injection is controlled to be 3.5-4.5 by a phosphate buffer; activated carbon accounting for 0.1% of the total volume of the injection is used for removing a pyrogen; and adsorption of activated carbon to a main medicine is avoided while the pyrogen is removed. An accelerated stability test indicates that the impurity content of the injection is lower than that of the marketed injection, and the quality is stable and controllable.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of injection that contains ibandronate and preparation method thereof.
Background technology
Ibandronate (English name: being ibandronate sodium) that ibandronic acid belongs to bisphosphonate compound, can acting on specifically osseous tissue, is because diphosphonate has high affinity to the inorganic matter in skeleton to the specificity selection of skeleton.Its chemical name is [1-hydroxyl-3-(N-methyl-N-amylamine base) propylidene]-bis-phosphonic acids list sodium salt-hydrates, i.e. ibandronic acid sodium-hydrate, and its structural formula is as shown below:
Ibandronate is third generation bisphosphonate compound, belongs to amino diphosphonate.It early than 1996 in Germany and Austria with trade name Bondronat registration and for clinical.U.S. FDA approval medication every day in 2003 Boniva listing once, but because drugmaker develops again dosage more easily, so this medicine is not gone public always.Until 2005, FDA ratifies it and monthly uses seance osteoporosis, and Boniva formally goes on the market in the U.S..
Bone shift be malignant tumor late period common branch mode according to statistics, the whole world has 1,500,000 tumor patient generation bones to shift every year, wherein breast carcinoma, carcinoma of prostate and pulmonary carcinoma are the most common.The Main Function of ibandronate is to suppress bone resorption.Potent inhibitor as osteoclast, ibandronate not only can suppress osteoclast activity and maturation, and can induce osteoclast apoptosis, and then the bone resorption due to blocking-up many reasons increases, can also induce in vitro kinds of tumor cells apoptosis, inhibition tumor cell secretion produces bone matrix metalloproteases.Parathyroid hormonerelated protein and VEGF isoreactivity material also suppress its activity, suppress breast carcinoma and the adhesion of prostate gland cancer cell to sclerotin, thereby can effectively prevent the generation that bone shifts.Ibandronate is the widest Bisphosphonates of current indication.
Ibandronate is existing import and domestic marketing drugs at present, but without exception, in its injection, all adopt acetate as buffer system, as everyone knows, constituent acetic acid and the sodium acetate of acetate buffer all have corrosivity, and glacial acetic acid has zest to respiratory system, sodium acetate is owing to generating acetic acid with airborne water effect, there is equally zest, this just requires these two kinds of materials in transportation, storage, weigh, in the time of solution preparation, all need strengthen operation personnel's consciousness of self-protection, strengthen safeguard procedures, thereby the implicit costs of product have been increased.
Summary of the invention
The object of the invention is the defect existing in order to overcome above-mentioned prior art, a kind of Ibandronate of safe, good stability is provided.
We are carrying out detailed research to the prescription of this injection and technique, unexpected discovery substitutes original acetate buffer with non-stimulated phosphate buffer, can obtain a kind of steady quality, the Ibandronate that safety is controlled, avoided the use of acetic acid and sodium acetate, guaranteeing under the prerequisite of product quality, perfection has solved the problems referred to above, in process modification process, find that active carbon has adsorption to the principal agent in this prescription simultaneously, by technique, grope, final definite with the pyrogen in the activated carbon adsorption solution of overall solution volume 0.1%, can reach the object of thermal source in this injection of absorption, and can not produce significantly absorption to the principal agent in solution.By accelerated stability test, confirm that the present invention's steady quality of writing out a prescription has the space of further exploitation.
Technical scheme of the present invention is as follows:
Injection of the present invention is made by ibandronate and pharmaceutically acceptable adjuvant, and concentration is counted 1mg/ml (m/v) with ibandronic acid, it is characterized in that:
A) adopt sodium hydrogen phosphate and sodium dihydrogen phosphate as buffer system;
B) in preparation process, adopt the active carbon room temperature absorption pyrogen of overall solution volume 0.1%;
C) final solution pH is controlled at 3.5-4.5.
D) this injection also comprises sodium chloride and the pH adjusting agent as osmotic pressure regulator.
Above-mentioned sodium hydrogen phosphate and sodium dihydrogen phosphate, as buffer system concentration, are counted 1-100mM with sodium hydrogen phosphate.
Described pH adjusting agent is hydrochloric acid and sodium hydroxide.
Ibandronate prescription of the present invention is composed as follows:
Another object of the present invention is to provide the preparation method of Ibandronate, comprises the following steps:
1) get recipe quantity 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating.
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating.
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5-4.5.With water for injection, be settled to total amount, stir.
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min.
5) above-mentioned gained solution is filtered with 5um titanium filter, remove active carbon.
6) above-mentioned solution is filtered with 0.2um flat-panel filter, remove other particulate matters that are less than 5um, further increase solution clarity.
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value, to about 3.5-4.5, to correct contingent pH value in aforementioned two steps, change.
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle.
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min.
10) lamp inspection, obtains.
By following experiment, further illustrate beneficial effect of the present invention.
Accelerated stability test:
In acceleration for stabilization Journal of Sex Research, find, Ibandronate prepared by the present invention has good stability.Be mainly reflected in drug content and the related substance check item of injection.The Ibandronate drug content that adopts this patent method to produce is stable, and related substance number and content are all lower than existing standard.
6 months accelerated stability datas
By embodiment 1-3, prepare respectively Ibandronate sample.At 40 ℃ ± 2 ℃, 60% ± 5%RH storage, measures respectively relevant nature, obtains related data, as shown in the table:
As can be seen from the above data, in acceleration for stabilization Journal of Sex Research, the Ibandronate of preparing according to this patent prescription and technique, content all meets Ibandronate national drug standards WS1-(X-251) in-2003Z about the requirement of drug content, and have no obvious reduction, related substance adopts high performance liquid chromatogram to measure, have no obvious increase, explanation is at duration of test, and properties of samples is stable, quality controllable.And originally compare with the domestic Ibandronate Chinese mugwort that gone on the market, impurity obviously reduces, and gathering way of impurity obviously reduces, and will, higher than existing listing product, than existing product, have obvious progress as seen by prescription of the present invention and the prepared Ibandronate quality of technique.
In addition, experimenter, when injection injection of the present invention, also obviously feels that zest reduces, and pain reduces.
At production link, according to original prescription and technique, produce, the technical process of every batch, operator all can feel the discomfort to respiratory system, and throat all can have intense stimulus sense, and easily cause that throat is red and swollen, according to prescription of the present invention and preparation method, in technical process, eliminated the zest of glacial acetic acid to respiratory system, all apnea system is uncomfortable, is applicable to applying.
The specific embodiment
By following embodiment, prescription of the present invention and technique are described, but the present invention is not limited to following embodiment.
Embodiment 1: injection of the present invention
Preparation technology:
1) get recipe quantity 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating.
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating.
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5-4.5.With water for injection, be settled to total amount, stir.
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min.
5) above-mentioned gained solution is filtered with 5um titanium filter, remove active carbon.
6) above-mentioned solution is filtered with 0.2um flat-panel filter, remove other particulate matters that are less than 5um, further increase solution clarity.
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value, to about 3.5-4.5, to correct contingent pH value in aforementioned two steps, change.
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle.
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min.
10) lamp inspection, obtains.
Embodiment 2: injection of the present invention
Preparation technology:
1) get recipe quantity 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating.
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating.
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.54.5.With water for injection, be settled to total amount, stir.
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min.
5) above-mentioned gained solution is filtered with 5um titanium filter, remove active carbon.
6) above-mentioned solution is filtered with 0.2um flat-panel filter, remove other particulate matters that are less than 5um, further increase solution clarity.
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value, to about 3.5-4.5, to correct contingent pH value in aforementioned two steps, change.
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle.
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min.
10) lamp inspection, obtains.
Embodiment 3: injection of the present invention
Preparation technology:
1) get recipe quantity 90% water for injection, add successively recipe quantity disodium hydrogen phosphate dodecahydrate, be stirred to dissolve, without heating.2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating.
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.54.5.With water for injection, be settled to total amount, stir.
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min.
5) above-mentioned gained solution is filtered with 5um titanium filter, remove active carbon.
6) above-mentioned solution is filtered with 0.2um flat-panel filter, remove other particulate matters that are less than 5um, further increase solution clarity.
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value, to about 3.54.5, to correct contingent pH value in aforementioned two steps, change.
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle.
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min.
10) lamp inspection, obtains.
Embodiment 4: injection of the present invention
Preparation method is with embodiment 1.
Embodiment 5: injection of the present invention
Preparation method is with embodiment 1.
Claims (4)
1. an injection that contains ibandronate, is characterized in that, by following composition, is processed into:
1) get 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating,
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating,
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, with water for injection, be settled to total amount, stir,
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min,
5) above-mentioned gained solution is filtered with 5 μ m titanium filters, removes active carbon,
6) above-mentioned solution is filtered with 0.2 μ m flat-panel filter, removes other particulate matters that are less than 5 μ m, further increase solution clarity,
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, to correct pH value possible in aforementioned two steps, change,
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle,
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min,
10) lamp inspection, obtains.
2. a preparation method that contains the injection of ibandronate, step is as follows:
Preparation technology:
1) get 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating,
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating,
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, with water for injection, be settled to total amount, stir,
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min,
5) above-mentioned gained solution is filtered with 5 μ m titanium filters, removes active carbon,
6) above-mentioned solution is filtered with 0.2 μ m flat-panel filter, removes other particulate matters that are less than 5 μ m, further increase solution clarity,
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, to correct contingent pH value in aforementioned two steps, change,
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle,
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min,
10) lamp inspection, obtains.
3. a preparation method that contains the injection of ibandronate, step is as follows:
Preparation technology:
1) get 90% water for injection, add successively recipe quantity sodium chloride, disodium hydrogen phosphate dodecahydrate, is stirred to dissolve, without heating,
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating,
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, with water for injection, be settled to total amount, stir,
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min,
5) above-mentioned gained solution is filtered with 5 μ m titanium filters, removes active carbon,
6) above-mentioned solution is filtered with 0.2 μ m flat-panel filter, removes other particulate matters that are less than 5 μ m, further increase solution clarity,
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, to correct contingent pH value in aforementioned two steps, change,
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle,
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min,
10) lamp inspection, obtains.
4. a preparation method that contains the injection of ibandronate, step is as follows:
Preparation technology:
1) get 90% water for injection, add successively recipe quantity disodium hydrogen phosphate dodecahydrate, be stirred to dissolve, without heating,
2) in above-mentioned gained solution, add recipe quantity ibandronic acid sodium-hydrate, stir, make to dissolve, without heating,
3) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, with water for injection, be settled to total amount, stir,
4) in above-mentioned gained solution, add 0.1% needle-use activated carbon, stir 30min,
5) above-mentioned gained solution is filtered with 5 μ m titanium filters, removes active carbon,
6) above-mentioned solution is filtered with 0.2 μ m flat-panel filter, removes other particulate matters that are less than 5 μ m, further increase solution clarity,
7) measure above-mentioned gained pH, with 0.1M hydrochloric acid or sodium hydrate regulator solution pH value to 3.5～4.5, to correct contingent pH value in aforementioned two steps, change,
8) with the above-mentioned gained solution of the colourless low borosilicate glass ampoule bottle fill of 1ml, 1ml/ bottle,
9) by above-mentioned gained injection pressure sterilizing, 121 ℃ of temperature, time 15min,
10) lamp inspection, obtains.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310026921.0A CN103070824B (en) | 2013-01-24 | 2013-01-24 | Ibandronate sodium containing injection |
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| CN201310026921.0A CN103070824B (en) | 2013-01-24 | 2013-01-24 | Ibandronate sodium containing injection |
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| CN103070824B true CN103070824B (en) | 2014-07-16 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103239396B (en) * | 2013-05-16 | 2015-04-08 | 成都苑东药业有限公司 | Sodium ibandronate injection composition and preparation method of sodium ibandronate injection composition |
| CN106389310A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Sodium ibandronate and glucose injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1148341A (en) * | 1994-05-17 | 1997-04-23 | 麦克公司 | Oral liquid alendronate formulations |
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN102000094A (en) * | 2010-09-27 | 2011-04-06 | 天津南开允公医药科技有限公司 | Ibandronic acid-containing medicinal composition and preparation process thereof |
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- 2013-01-24 CN CN201310026921.0A patent/CN103070824B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1148341A (en) * | 1994-05-17 | 1997-04-23 | 麦克公司 | Oral liquid alendronate formulations |
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN102000094A (en) * | 2010-09-27 | 2011-04-06 | 天津南开允公医药科技有限公司 | Ibandronic acid-containing medicinal composition and preparation process thereof |
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