CN104434788A - Preparation method of atenolol injection - Google Patents
Preparation method of atenolol injection Download PDFInfo
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- CN104434788A CN104434788A CN201410817384.6A CN201410817384A CN104434788A CN 104434788 A CN104434788 A CN 104434788A CN 201410817384 A CN201410817384 A CN 201410817384A CN 104434788 A CN104434788 A CN 104434788A
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- Prior art keywords
- atenolol
- sodium
- injection
- inj
- add
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- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 title claims abstract description 73
- 229960002274 atenolol Drugs 0.000 title claims abstract description 73
- 238000002347 injection Methods 0.000 title claims abstract description 26
- 239000007924 injection Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 23
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims abstract description 19
- 235000019799 monosodium phosphate Nutrition 0.000 claims abstract description 19
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 6
- 230000003204 osmotic effect Effects 0.000 claims abstract description 5
- 239000007853 buffer solution Substances 0.000 claims abstract description 4
- 239000003610 charcoal Substances 0.000 claims description 29
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 22
- 235000019800 disodium phosphate Nutrition 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 9
- 239000010936 titanium Substances 0.000 claims description 9
- 229910052719 titanium Inorganic materials 0.000 claims description 9
- -1 polypropylene Polymers 0.000 claims description 6
- 239000004743 Polypropylene Substances 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 230000000536 complexating effect Effects 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 5
- 238000007689 inspection Methods 0.000 claims description 5
- 229920001155 polypropylene Polymers 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 3
- 239000013618 particulate matter Substances 0.000 claims 2
- 238000004806 packaging method and process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 51
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 9
- 239000002510 pyrogen Substances 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 abstract 1
- 239000008139 complexing agent Substances 0.000 abstract 1
- 229940037001 sodium edetate Drugs 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 46
- 229940090044 injection Drugs 0.000 description 14
- 238000012360 testing method Methods 0.000 description 10
- 230000008859 change Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000035487 diastolic blood pressure Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000035488 systolic blood pressure Effects 0.000 description 5
- 206010000891 acute myocardial infarction Diseases 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 239000005388 borosilicate glass Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000013112 stability test Methods 0.000 description 3
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000003448 neutrophilic effect Effects 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000003912 basophilic leucocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940116866 metoprolol injection Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an atenolol injection. The atenolol injection is prepared from atenolol and pharmaceutically acceptable auxiliary materials, and the concentration of the atenolol injection is 0.45-0.55mg/mL according to the concentration of atenolol. The auxiliary materials comprise the following components: a composite solvent consisting of 1,2-propylene glycol and water, a buffer system consisting of sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium chloride which is taken as an osmotic pressure regulator, and sodium edetate which is taken as a metal ion complexing agent, wherein in the composite solvent, the volume percentage of 1,2-propylene glycol accounts for 10-35%. The invention also discloses a preparation method of the atenolol injection. By adopting a mode of adding carbon twice, the purpose of adsorbing pyrogen in the injection can be achieved, and a main medicine of a solution cannot be significantly adsorbed. The atenolol injection prepared by adopting the method disclosed by the invention is good in stability and safe and effective in clinical use.
Description
Technical field
The present invention relates to a kind of preparation method of atenolol inj, belong to technical field of medicine.
Background technology
Atenolol, chemistry is by name: 4-[3-[(1-Methylethyl) amino-2-hydroxyl] propoxyl group] phenyl acetamide, molecular formula: C
14h
22n
2o
3, molecular weight: 266.34, its chemical structural formula is as follows:
Atenolol is white powder, odorless or have micro-smelly, and dissolve in ethanol, slightly soluble in chloroform and water, almost insoluble in ether, fusing point is 151-155.
Atenolol (Atenolol) is that ICI Imperial Chemical Industries of Britain (ICI) developed in 1976, for a kind of new beta-blocker, large selectivity towards is had to heart β1receptor, to blood vessel and the effect of bronchus beta 2 receptor less, when heavy dose there are no suppressing the effect of myocardial contraction.Nineteen eighty-two, U.S. FDA is ratified it and is used for the treatment of hypertension, angina pectoris, early stage acute myocardial infarction, arrhythmia etc.The all loaded American Pharmacopeia of the crude drug of atenolol, tablet, injection and British Pharmacopoeia.Wherein injection is in the listing of the country such as the U.S., Britain, and loaded pharmacopeia, be used for the treatment of the early treatment of arrhythmia and acute myocardial infarction clinically.Chinese Pharmacopoeia version in 2010 has recorded atenolol raw material and tablet, and domestic do not have injection import, and for meeting domestic clinical needs, Shandong Yikang Pharmaceutical Co., Ltd. (present invention applicant) have developed atenolol inj.
But find in the atenolol inj long term test that company is produced: its related substance of the injection prepared by former process has the trend of increase, have impact on the stability of product quality; And due to the absorption of active carbon in former technique, principal agent needs to feed intake by 120% of labelled amount, adds production cost.
Summary of the invention
For the deficiency that above-mentioned prior art exists, the object of this invention is to provide that a kind of safety is high, the atenolol inj of good stability and preparation method thereof.
For achieving the above object, the present invention adopts following technical proposals:
A kind of atenolol inj, be made up of atenolol and pharmaceutically acceptable adjuvant, concentration counts 0.45mg/mL-0.55mg/mL (m/v) with atenolol;
Described adjuvant comprises: the double solvent be made up of 1,2-PD and water; The buffer system be made up of sodium dihydrogen phosphate and sodium hydrogen phosphate; By sodium chloride as osmotic pressure regulator; By edetate sodium as complexing of metal ion agent.
In described double solvent, the volume fraction of 1,2-PD is 10%-35%.
Atenolol inj prescription of the present invention is composed as follows:
| Supplementary material title | Use amount |
| Atenolol | 4.5-5.5g |
| Sodium dihydrogen phosphate | 0.12-12.0g |
| Edetate sodium | 1.0-5.0g |
| Sodium chloride | 0-90.0g |
| 0.1mol/L sodium hydrogen phosphate | 1-50mL |
| 1,2-PD | 1000-3500mL |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
The preparation method of this atenolol inj, step is as follows:
(1) water for injection of recipe quantity 60-80% (v/v) is got, add recipe quantity sodium chloride successively, sodium dihydrogen phosphate is stirred to dissolve, add 0.05-0.2% (m/v) pin charcoal, (namely every 100mL is dissolved with the amount adding pin charcoal in the solution of sodium chloride and sodium dihydrogen phosphate is 0.05-0.2 gram), stir 20-30 minute, filter with 5 μm of titanium filters, removing pin charcoal, for subsequent use;
(2) get recipe quantity propylene glycol and be heated to 55-65 DEG C, add atenolol, be stirred to dissolve; Add solution prepared by step (1), stir;
(3) pH value of determination step (2) gained solution, by 0.1mol/L sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, injects and is settled to total amount with water, stirs;
(4) in step (3) gained solution, add 0.05% (m/v) pin charcoal, (amount namely adding pin charcoal in every 100mL solution is 0.05 gram), stir 20-30 minute;
(5) step (4) gained solution is filtered with 5 μm of titanium filters, removing pin charcoal, then filter with 0.2 μm of polypropylene filter, other particulate matters that removing is less than 5 μm;
6) determination step (5) filters rear solution ph, by 0.1mol/L sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, to correct contingent pH value change in the first two step.
7) with the above-mentioned solution of 10mL low borosilicate glass ampoule bottle fill, 10mL/ bottle.
8) by above-mentioned gained injection pressure sterilizing 121 DEG C of pressure sterilizings 15 minutes.
9) lamp inspection, pack and get final product.
Preferably, in step (1), the addition of pin charcoal is 0.1% (m/v);
Inventor has carried out detailed research to the prescription of this atenolol inj and technique, discovery phosphate buffer is as pH adjusting agent, add edetate sodium as complexing of metal ion agent, a kind of steady quality, atenolol inj controlled safely can be obtained.In process modification process, find that active carbon has obvious adsorption to the principal agent in prescription simultaneously, groped by technique, finally determine that prescription adopts the mode adding pin charcoal for 2 times, first use the pyrogen in the pin charcoal stirring and adsorbing adjuvant of 0.05-0.2% (m/v), use the pyrogen in the pin charcoal adsorbent solution of solution total amount 0.05% (m/v) again, the object of pyrogen in this injection of absorption can be reached, and significantly absorption can not be produced to the principal agent of solution.Proved by accelerated stability test, Prescription quality of the present invention is stablized, and has the space of exploitation further.
Principal agent atenolol dissolubility in water is lower, therefore only can not use water as the solvent into injection, and 1,2-PD can increase the dissolubility of atenolol, thus reaches the object solving its physical stability, and 1,2-PD is applicable to injection.
Intravenous injection requires that isotonic or height oozes usually, must not be hypotonic.Sodium chloride stable in properties is conventional osmotic pressure regulator, therefore, selects sodium chloride to be osmotic pressure regulator.
Adopt edetate sodium can with metal ion in solution generation complexing, drug solution stability can be improved.
From the angle of stability, the pH value of injection is 1 ~ 6, more stable, single from pharmacology irritation test, medicine meta-acid, zest increases, hemolytic increases, and have pain during injection, general injection pH area requirement is 4 ~ 9 at pH value, consider the dissolubility of medicine, stability and organism adaptation, preferred injection pH value range is 5.5 ~ 6.5.Above-mentioned sodium dihydrogen phosphate and sodium hydrogen phosphate are as buffer system, and concentration counts 1-100mM with sodium dihydrogen phosphate, using sodium hydrogen phosphate as pH value regulator.
Beneficial effect of the present invention:
The present invention utilizes double solvent to improve the dissolubility of atenolol, solve the dissolubility of atenolol in water little, be difficult to make the technical barrier that these people of injection want solution always, with phosphate buffer as pH adjusting agent, add edetate sodium as complexing of metal ion agent, related substance obviously reduces, and can obtain a kind of steady quality, atenolol inj controlled safely.Adopt the mode adding charcoal for 2 times simultaneously, the object of pyrogen in this injection of absorption can be reached, and significantly absorption can not be produced to the principal agent of solution, without the need to feeding intake by 120% of labelled amount, decreasing the addition of principal agent, reducing production cost.The atenolol inj good stability of preparation, Clinical practice is safe and effective.
Detailed description of the invention
Below by instantiation, the present invention will be further elaborated, should be noted that following explanation is only to explain the present invention, not limiting its content.
Embodiment 1: the preparation of atenolol inj
Prescription is:
| Supplementary material title | Use amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 5.0g |
| Sodium dihydrogen phosphate | 12.0g |
| 0.1mol/l sodium hydrogen phosphate | 20ml |
| 1,2-PD | 3500ml |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
Preparation technology:
1) water for injection of recipe quantity 70% (v/v) is got, add recipe quantity sodium chloride successively, sodium dihydrogen phosphate is stirred to dissolve, the pin charcoal of 0.1% (m/v) is added in the solution after dissolving, stir 25 minutes, filter with 5 μm of titanium filters, removing pin charcoal, for subsequent use.
2) get recipe quantity 1,2-PD and be heated to 60 DEG C, add atenolol, be stirred to dissolve; Add step 1) solution prepared, stirs.
3) determination step 2) pH value of gained solution, by 0.1mol/L sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, inject and be settled to total amount with water, stir.
4) to step 3) add the pin charcoal of 0.05% (m/v) in gained solution, stir 25 minutes.
5) above-mentioned gained solution is filtered with 5 μm of titanium filters, removing pin charcoal, then filter with 0.2 μm of polypropylene filter, other particulate matters that removing is less than 5 μm.
6) determination step 5) filter after the pH value of solution, by 0.1mol/L sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, to correct contingent pH value change in the first two step.
7) with the above-mentioned solution of 10mL low borosilicate glass ampoule bottle fill, 10mL/ bottle.
8) by above-mentioned gained injection pressure sterilizing 121 DEG C of pressure sterilizings 15 minutes.
9) lamp inspection, and to get final product.
Embodiment 2: the preparation of atenolol inj
Prescription is:
| Supplementary material title | Use amount |
| Atenolol | 5.0g |
| Sodium chloride | 75g |
| Edetate sodium | 3.0g |
| Sodium dihydrogen phosphate | 6.0g |
| 0.1mol/l sodium hydrogen phosphate | 8ml |
| 1,2-PD | 2000ml |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
Preparation technology:
1) water for injection of recipe quantity 60% (v/v) is got, add recipe quantity sodium chloride successively, sodium dihydrogen phosphate is stirred to dissolve, the pin charcoal of 0.2% (m/v) is added in the solution after dissolving, stir 30 minutes, filter with 5 μm of titanium filters, removing pin charcoal, for subsequent use.
2) get recipe quantity 1,2-PD and be heated to 55 DEG C, add atenolol, be stirred to dissolve; Add step 1) solution prepared, stirs.
3) determination step 2) pH value of gained solution, regulate pH value 5.5 ~ 6.5 with 0.1mol/L sodium hydrogen phosphate, inject and be settled to total amount with water, stir.
4) to step 3) add the pin charcoal of 0.05% (m/v) in gained solution, stir 25 minutes.
5) above-mentioned gained solution is filtered with 5 μm of titanium filters, removing pin charcoal, then filter with 0.2 μm of polypropylene filter, other particulate matters that removing is less than 5 μm.
6) measure above-mentioned solution ph, regulate pH value 5.5 ~ 6.5 with 0.1mol/l sodium hydrogen phosphate, to correct contingent pH value change in the first two step.
7) with the above-mentioned solution of 10ml low borosilicate glass ampoule bottle fill, 10ml/ bottle.
8) by above-mentioned gained injection pressure sterilizing 121 DEG C of pressure sterilizings 15 minutes.
9) lamp inspection, and to get final product.
Embodiment 3: the preparation of atenolol inj
Prescription is:
| Supplementary material title | Use amount |
| Atenolol | 5.0g |
| Sodium chloride | 45g |
| Edetate sodium | 1.5g |
| Sodium dihydrogen phosphate | 1.2g |
| 0.1mol/l sodium hydrogen phosphate | 3ml |
| 1,2-PD | 2500ml |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
Preparation technology:
1) get the water for injection of recipe quantity 75% (v/v), add recipe quantity sodium chloride successively, sodium dihydrogen phosphate is stirred to dissolve, add 0.15% (m/v) pin charcoal, stir 20 minutes, filter with 5 μm of titanium filters, removing pin charcoal, for subsequent use.
2) get recipe quantity propylene glycol and be heated to 65 DEG C, add atenolol, be stirred to dissolve; Add above-mentioned stock solution, stir.
3) measure the pH value of above-mentioned gained solution, by 0.1mol/l sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, inject and be settled to total amount with water, stir.
4) in above-mentioned gained solution, add 0.05% (m/v) pin charcoal, stir 25 minutes.
5) above-mentioned gained solution is filtered with 5 μm of titanium filters, removing pin charcoal, then filter with 0.2 μm of polypropylene filter, other particulate matters that removing is less than 5 μm.
6) above-mentioned solution ph is measured, by 0.1mol/l sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, to correct contingent pH value change in the first two step.
7) with the above-mentioned solution of 10ml low borosilicate glass ampoule bottle fill, 10ml/ bottle.
8) by above-mentioned gained injection pressure sterilizing 121 DEG C of pressure sterilizings 15 minutes.
9) lamp inspection, and to get final product.
Embodiment 4: the preparation of atenolol inj
Prescription is:
| Supplementary material title | Use amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 3.0g |
| Sodium dihydrogen phosphate | 0.12g |
| 0.1mol/l sodium hydrogen phosphate | 1.2ml |
| 1,2-PD | 3000ml |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
Preparation technology, with embodiment 1, repeats no more.
Embodiment 5: the preparation of atenolol inj
Prescription is:
| Supplementary material title | Use amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 4.0g |
| Sodium dihydrogen phosphate | 8.0g |
| 0.1mol/l sodium hydrogen phosphate | 5ml |
| 1,2-PD | 2000ml |
| Water for injection | Be settled to 10L |
| Make altogether | 1000 |
Preparation technology, with embodiment 1, repeats no more.
Accelerated stability test:
The atenolol inj respectively prepared by embodiment of the present invention 1-3, and commercially available atenolol inj (manufacturer: Shandong Yikang Pharmaceutical limited company), being placed in relative humidity is 75 ± 5%, temperature is under the condition of 40 DEG C ± 2 DEG C, place 6 months, respectively at sampling in 0,1,2,3,6 month, check indices, obtain related data, as shown in table 1:
Table 1 atenolol inj accelerated test result
In accelerated stability test, atenolol inj prepared by the present invention has good stability.Be mainly reflected in drug content and the Related substances separation item of injection.Adopt this patent grown place atenolol inj stable content, related substance number and content are all lower than the product of former explained hereafter.As can be seen from Table 1, Ah 's that injection prepared according to prescription of the present invention and technique, content all meets the requirement of the atenolol inj national drug standards, and have no obvious reduction, related substance adopts high effective liquid chromatography for measuring, have no obvious rising, illustrate that duration of test sample is stablized, quality controllable.And compare with the product of former explained hereafter, impurity reduces and gathering way of impurity obviously reduces, visible: the atenolol inj quality prepared by present invention process is higher than the product of former explained hereafter, has made marked progress compared with existing product.
Clinical trial:
Safety of clinical trials effectiveness:
The atenolol inj of the present invention's development, is group leader unit by Qingdao Municipal Hospital, carries out the clinical research of II phase by the requirement of chemical drugs III kind new medicine to it.Test is multicenter, random, blind, parallel positive drug comparative study, with metoprolol injection liquid for positive control drug, investigate the Clinical efficacy and safety of atenolol inj early intervention treatment acute myocardial infarction.Result of the test is as follows:
(1), safety: the erythrocyte of test front and back laboratory checking index, basophilic leukocyte, acidophil, platelet, ALT, ALP, Cr are not affected; Significant difference is had before and after the hemoglobin of matched group, leukocyte, neutrophilic granulocyte, lymphocyte medication; Significant difference is had before and after the hemoglobin of test group, leukocyte, neutrophilic granulocyte, lymphocyte, mononuclear cell, BUN medication; Laboratory checking index between two groups compares not statistically significant.There is hypotension, felt sick in some patients, cough, vomiting, cardiopalmus, the symptom such as uncomfortable in chest, there was no significant difference through between statistical analysis two groups.Analyze normal before and after laboratory checking index treatment and abnormal conditions, the ANOMALOUS VARIATIONS of index has nothing to do with trial drug, most relevant with disease itself or merge caused by Other diseases.
(2), effectiveness: the background information of test group and matched group patient has comparability.Matched group heart rate is down to 70.52 ± 9.81 after medication from 80.11 ± 14.08 before medication, and falling heart rate amplitude is 11.97%, and comparing before and after medication has statistical significance; Systolic pressure is down to 116.01 ± 12.76 after medication from 129.84 ± 21.15 before medication, and falling systolic pressure amplitude is 10.65%, and comparing before and after medication has statistical significance; Diastolic pressure is down to 71.16 ± 9.22 after medication from 79.90 ± 12.89 before medication, and falling diastolic pressure amplitude is 10.94%, and comparing before and after medication has statistical significance; CK is down to 986.57 ± 1190.66 after medication from 1264.99 ± 1437.63 before medication, and falling CK amplitude is 22.01%, and comparing before and after medication has statistical significance; CK-MB is down to 59.92 ± 85.11 after medication from 73.32 ± 95.83 before medication, and falling CK-MB amplitude is 18.29%, compares not statistically significant before and after medication; ST-T section changes is down to 1.54 ± 1.19 after medication from 2.80 ± 2.09 before medication, and falling ST-T section change amplitude is 45.36%, and comparing before and after medication has statistical significance;
Test group heart rate is down to 72.14 ± 12.26 after medication from 81.95 ± 16.08 before medication, and falling heart rate amplitude is 11.97%, and comparing before and after medication has statistical significance; Systolic pressure is down to 115.95 ± 16.02 after medication from 128.34 ± 20.63 before medication, and falling systolic pressure amplitude is 9.65%, and comparing before and after medication has statistical significance; Diastolic pressure is down to 70.48 ± 9.98 after medication from 80.27 ± 13.18 before medication, and falling diastolic pressure amplitude is 12.20%, and comparing before and after medication has statistical significance; CK is down to 731.53 ± 929.17 after medication from 890.03 ± 1006.50 before medication, and falling CK amplitude is 17.81%, and comparing before and after medication has statistical significance; CK-MB is down to 49.29 ± 63.41 after medication from 54.65 ± 69.71 before medication, and falling CK-MB amplitude is 9.81%, and comparing before and after medication has statistical significance; ST-T section changes is down to 1.60 ± 1.59 after medication from 2.84 ± 2.25 before medication, and falling ST-T section change amplitude is 43.31%, and comparing before and after medication has statistical significance;
Heart rate between two groups, systolic pressure, diastolic pressure, CK, CK-MB, ST-T section change the comparison not statistically significant of change.
Conclusion: the clinical effectiveness of atenolol inj early intervention treatment acute myocardial infarction of the present invention is remarkable, and is safe.
Claims (9)
1. an atenolol inj, is characterized in that, be made up of atenolol and pharmaceutically acceptable adjuvant, concentration counts 0.45mg/mL-0.55mg/mL with atenolol;
Described adjuvant is: the double solvent be made up of 1,2-PD and water; The buffer system be made up of sodium dihydrogen phosphate and sodium hydrogen phosphate; By sodium chloride as osmotic pressure regulator; By edetate sodium as complexing of metal ion agent.
2. atenolol inj as claimed in claim 1, it is characterized in that, in described double solvent, the volume fraction of 1,2-PD is 10%-35%.
3. atenolol inj as claimed in claim 1, it is characterized in that, the atenolol inj of every 10mL is made up of following raw materials according:
Atenolol 4.5-5.5mg, sodium dihydrogen phosphate 0.12-12.0mg, edetate sodium 1.0-5.0mg, sodium chloride 0-90mg, 0.1mol/L sodium hydrogen phosphate 0.001-0.05mL, 1,2-PD 1-3.5mL, water for injection adds to 10mL.
4. atenolol inj as claimed in claim 3, it is characterized in that, the atenolol inj of every 10mL is made up of following raw materials according:
Atenolol 5.0mg, sodium dihydrogen phosphate 12.0mg, edetate sodium 5.0mg, sodium chloride 90mg, 0.1mol/L sodium hydrogen phosphate 0.02mL, 1,2-PD 3.5mL, water for injection adds to 10mL.
5. the atenolol inj as described in any one of Claims 1-4, is characterized in that, the pH value of this injection is 5.5-6.5.
6. the preparation method of the arbitrary described atenolol inj of claim 1 to 5, it is characterized in that, step is as follows:
(1) get the water for injection of the 60-80% of recipe quantity volume, add recipe quantity sodium chloride successively, sodium dihydrogen phosphate is stirred to dissolve, in the solution after dissolving, add the pin charcoal that quality volume fraction is 0.05-0.2%, stir, filter, removing pin charcoal, for subsequent use;
(2) get recipe quantity 1,2-PD and be heated to 55-65 DEG C, add atenolol, be stirred to dissolve; Add solution prepared by step (1), stir;
(3) pH value of determination step (2) gained solution, by sodium hydrogen phosphate adjust ph 5.5 ~ 6.5, injects and is settled to total amount with water, stirs;
(4) in step (3) gained solution, add the pin charcoal that quality volume fraction is 0.05%, stir, filter, remove pin charcoal and the particulate matter being less than 5 μm respectively;
(6) determination step (5) filters rear solution ph, by sodium hydrogen phosphate adjust ph 5.5 ~ 6.5;
(7) fill, sterilizing, lamp inspection, packaging, to obtain final product.
7. the preparation method of atenolol inj as claimed in claim 6, it is characterized in that, in step (1), the addition of pin charcoal is 0.1%.
8. the preparation method of atenolol inj as claimed in claim 6, is characterized in that, in step (1) and step (4), what remove that pin charcoal adopts is 5 μm of titanium filters.
9. the preparation method of atenolol inj as claimed in claim 6, is characterized in that, in step (4), what removing was less than that the particulate matter of 5 μm adopts is 0.2 μm of polypropylene filter.
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| CN105168122A (en) * | 2015-09-24 | 2015-12-23 | 辰欣药业股份有限公司 | Dexmedetomidine hydrochloride injection and preparation process thereof |
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| CN108888593B (en) * | 2018-06-27 | 2021-09-21 | 济南康和医药科技有限公司 | Atenolol injection and preparation method thereof |
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