CN104434788B - A kind of preparation method of atenolol injection - Google Patents
A kind of preparation method of atenolol injection Download PDFInfo
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- CN104434788B CN104434788B CN201410817384.6A CN201410817384A CN104434788B CN 104434788 B CN104434788 B CN 104434788B CN 201410817384 A CN201410817384 A CN 201410817384A CN 104434788 B CN104434788 B CN 104434788B
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- atenolol
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- charcoal
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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 60
- 229960002274 atenolol Drugs 0.000 title claims abstract description 60
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000000243 solution Substances 0.000 claims abstract description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 34
- 239000003610 charcoal Substances 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 21
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims abstract description 17
- 235000019799 monosodium phosphate Nutrition 0.000 claims abstract description 17
- 239000011780 sodium chloride Substances 0.000 claims abstract description 17
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims abstract description 17
- 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 abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 235000013772 propylene glycol Nutrition 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 230000000536 complexating effect Effects 0.000 claims abstract description 6
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 6
- 230000003204 osmotic effect Effects 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 19
- 239000008215 water for injection Substances 0.000 claims description 13
- 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
- 238000001914 filtration Methods 0.000 claims description 5
- 238000007689 inspection Methods 0.000 claims description 5
- 229920001155 polypropylene Polymers 0.000 claims description 5
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 239000013618 particulate matter Substances 0.000 claims 2
- 239000003182 parenteral nutrition solution Substances 0.000 abstract description 12
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 239000002075 main ingredient Substances 0.000 abstract description 6
- 239000002510 pyrogen Substances 0.000 abstract description 5
- 239000007853 buffer solution Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 50
- 229940079593 drug Drugs 0.000 description 46
- 238000000034 method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 230000008859 change Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 6
- 230000035487 diastolic blood pressure Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000035488 systolic blood pressure Effects 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 239000005388 borosilicate glass Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 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
- 206010000891 acute myocardial infarction Diseases 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
- 238000002474 experimental method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 210000004493 neutrocyte Anatomy 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 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
- 206010061216 Infarction Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 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
- 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
- 210000001772 blood platelet Anatomy 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
- 230000007812 deficiency Effects 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
- 230000008676 import Effects 0.000 description 1
- 230000007574 infarction 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
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method 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
- 239000003826 tablet Substances 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of atenolol injection, it is made up of atenolol and pharmaceutically acceptable auxiliary material, concentration is calculated as 0.45mg/mL 0.55mg/mL with atenolol；The auxiliary material includes：The double solvent being made up of 1,2 propane diols and water；The buffer system being made up of sodium dihydrogen phosphate and disodium hydrogen phosphate；Osmotic pressure regulator is used as by sodium chloride；Complexing of metal ion agent is used as by edetate sodium.In double solvent, the volume fraction of 1,2 propane diols is 10% 35%.The invention also discloses the preparation method of the atenolol injection, by the way of 2 times plus charcoal, the purpose for adsorbing pyrogen in this parenteral solution can be reached, and obvious absorption will not be produced to the main ingredient of solution.Atenolol injection stability prepared by the present invention is good, and Clinical practice is safe and effective.
Description
Technical field
The present invention relates to a kind of preparation method of atenolol injection, belong to technical field of medicine.
Background technology
Atenolol, chemistry is entitled：4- [3- [(1- Methylethyls) amino -2- hydroxyls] propoxyl group] phenyl acetamide, molecule
Formula：C14H22N2O3, molecular weight：266.34, its chemical structural formula is as follows：
Atenolol is white powder, odorless or has micro- smelly, is dissolved in ethanol, the 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) were developed in 1976, is a kind of new
Beta-blocker, have large selectivity towards to heart β1receptor, to blood vessel and bronchus beta 2 receptor effect it is smaller, in heavy dose
When there are no suppress myocardial contractive power effect.Nineteen eighty-two, U.S. FDA, which ratifies it, to be used to treat hypertension, angina pectoris, early stage suddenly
Myocardial inyaretion, arrhythmia cordis etc..The loaded American Pharmacopeia of bulk drug, tablet, injection and British Pharmacopoeia of atenolol.
Wherein parenteral solution is listed in the country such as the U.S., Britain, and loaded pharmacopeia, clinically for treating arrhythmia cordis and the acute heart
The early treatment of flesh infarct.Chinese Pharmacopoeia version in 2010 has recorded atenolol raw material and tablet, and the country does not have parenteral solution import,
To meet domestic clinical needs, Shandong Yikang Pharmaceutical Co., Ltd. (present invention applicant) have developed atenolol injection.
But found in the atenolol injection long term test produced to company：The parenteral solution prepared by former process
Its relevant material has the trend of increase, have impact on the stability of product quality；And due to the absorption of activated carbon in former technique, it is main
Medicine needs to feed intake by the 120% of labelled amount, adds production cost.
The content of the invention
The deficiency existed for above-mentioned prior art, it is an object of the invention to provide a kind of safe, stability is good
Atenolol injection and preparation method thereof.
To achieve the above object, the present invention uses following technical proposals：
A kind of atenolol injection, is made up, concentration is with Ah Ti Lip river of atenolol and pharmaceutically acceptable auxiliary material
You are calculated as 0.45mg/mL-0.55mg/mL (m/v)；
The auxiliary material includes：The double solvent being made up of 1,2- propane diols and water；By sodium dihydrogen phosphate and disodium hydrogen phosphate
The buffer system of composition；Osmotic pressure regulator is used as by sodium chloride；Complexing of metal ion agent is used as by edetate sodium.
In the double solvent, the volume fraction of 1,2-PD is 10%-35%.
Atenolol injection composition of the present invention is as follows：
| Supplementary material title | Usage 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 disodium hydrogen phosphates | 1-50mL |
| 1,2- propane diols | 1000-3500mL |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
The preparation method of the atenolol injection, step is as follows：
(1) recipe quantity 60-80% (v/v) water for injection is taken, recipe quantity sodium chloride, sodium dihydrogen phosphate stirring is sequentially added
Make dissolving, add 0.05-0.2% (m/v) pin charcoal, (be dissolved with the solution of sodium chloride and sodium dihydrogen phosphate and add per 100mL
It is 0.05-0.2 grams to enter pin with the amount of charcoal), stir 20-30 minutes, filtered with 5 μm of titanium filters, remove pin charcoal, it is standby；
(2) take recipe quantity propane diols to be heated to 55-65 DEG C, add atenolol, be stirred to dissolve；Add step (1) system
Standby solution, stirring；
(3) pH value of determination step (2) resulting solution, pH value 5.5~6.5 is adjusted with 0.1mol/L disodium hydrogen phosphates, plus
Water for injection is settled to total amount, stirring；
(4) 0.05% (m/v) pin charcoal is added in step (3) resulting solution, (adds pin in i.e. per 100mL solution to use
The amount of charcoal is 0.05 gram), stir 20-30 minutes；
(5) step (4) resulting solution is filtered with 5 μm of titanium filters, removes pin charcoal, then with 0.2 μm of polypropylene filter
Device is filtered, and removes other particulate matters less than 5 μm；
6) solution ph after determination step (5) filtering, pH value 5.5~6.5 is adjusted with 0.1mol/L disodium hydrogen phosphates, to rectify
The pH value change that may occur just in the first two steps.
7) with the filling above-mentioned solution of the low borosilicate glass ampoule bottles of 10mL, 10mL/ bottles.
8) by above-mentioned 121 DEG C of gained injection pressure sterilizing pressure sterilizing 15 minutes.
9) lamp inspection, packaging are produced.
It is preferred that, in step (1), the addition of pin charcoal is 0.1% (m/v)；
Inventor has carried out detailed research, discovery phosphate-buffered to the prescription and technique of the atenolol injection
Liquid adds edetate sodium as complexing of metal ion agent as pH adjusting agent, can obtain a kind of steady quality, safely controllable
Atenolol injection.Find that activated carbon has obvious suction-operated to the main ingredient in prescription during process modification simultaneously,
Groped by technique, it is final to determine that prescription by the way of 2 times plus pin charcoal, is first stirred with 0.05-0.2% (m/v) pin with charcoal
The pyrogen in absorption auxiliary material is mixed, then with pyrogen of the pin in charcoal adsorbent solution of solution total amount 0.05% (m/v), absorption can be reached
The purpose of pyrogen in this parenteral solution, and obvious absorption will not be produced to the main ingredient of solution.Demonstrate,proved by accelerated stability test
Bright, Prescription quality of the invention is stable, with the space further developed.
Main ingredient atenolol solubility in water is relatively low, therefore can not be only with solvent of the water as parenteral solution, 1,2-PD
The solubility of atenolol can be increased, so that the purpose for solving its physical stability is reached, and 1,2-PD is adapted to note
Penetrate use.
Intravenous injection usually require that it is isotonic or hypertonic, must not be hypotonic.Sodium chloride property is stable, is that conventional osmotic pressure is adjusted
Agent is saved, is osmotic pressure regulator from sodium chloride therefore.
Can occur complexing with metal ion in solution using edetate sodium, drug solution stability can be improved.
From the angle of stability, the pH value of parenteral solution is more stable 1~6, and list can from pharmacology irritation test
Know, medicine meta-acid, excitant increase, hemolytic increase has pain, general injection pH area requirements are in pH value during injection
4~9, it is contemplated that solubility, stability and the organism adaptation of medicine, preferably parenteral solution pH value range are 5.5~6.5.It is above-mentioned
Sodium dihydrogen phosphate is with disodium hydrogen phosphate as buffer system, and concentration is calculated as 1-100mM with sodium dihydrogen phosphate, is made with disodium hydrogen phosphate
For pH value regulator.
Beneficial effects of the present invention：
The present invention improves the solubility of atenolol using double solvent, solves solubility of the atenolol in water
It is small, it is difficult to the technical barrier of this people of injection desired solution always is made, with phosphate buffer as pH adjusting agent, plus
Enter edetate sodium as complexing of metal ion agent, relevant material is substantially reduced, a kind of steady quality can be obtained, safely controllable
Atenolol injection.Simultaneously by the way of 2 times plus charcoal, the purpose for adsorbing pyrogen in this parenteral solution can be reached, and will not
Obvious absorption is produced to the main ingredient of solution, without being fed intake by the 120% of labelled amount, the addition of main ingredient is reduced, drops
Low production cost.The atenolol injection stability of preparation is good, and Clinical practice is safe and effective.
Embodiment
Below by instantiation, the present invention will be further elaborated, it should explanation, the description below be only for
The present invention is explained, its content is not defined.
Embodiment 1：The preparation of atenolol injection
Prescription is：
| Supplementary material title | Usage amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 5.0g |
| Sodium dihydrogen phosphate | 12.0g |
| 0.1mol/l disodium hydrogen phosphates | 20ml |
| 1,2- propane diols | 3500ml |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
Preparation technology：
1) take recipe quantity 70% (v/v) water for injection, sequentially add recipe quantity sodium chloride, sodium dihydrogen phosphate stirring make it is molten
Solution, 0.1% (m/v) pin charcoal is added into the solution after dissolving, is stirred 25 minutes, is filtered with 5 μm of titanium filters, removes pin
It is standby with charcoal.
2) take recipe quantity 1,2-PD to be heated to 60 DEG C, add atenolol, be stirred to dissolve；Add step 1) prepare
Solution, stirring.
3) determination step 2) resulting solution pH value, with 0.1mol/L disodium hydrogen phosphates adjust pH value 5.5~6.5, filling
Penetrate and total amount is settled to water, stir.
4) to step 3) 0.05% (m/v) pin charcoal is added in resulting solution, stir 25 minutes.
5) above-mentioned resulting solution is filtered with 5 μm of titanium filters, removes pin charcoal, then filter with 0.2 μm of polypropylene filter
Cross, remove other particulate matters less than 5 μm.
6) determination step 5) filtration after solution pH value, with 0.1mol/L disodium hydrogen phosphates adjust pH value 5.5~6.5, with
Correct the pH value change that may occur in the first two steps.
7) with the filling above-mentioned solution of the low borosilicate glass ampoule bottles of 10mL, 10mL/ bottles.
8) by above-mentioned 121 DEG C of gained injection pressure sterilizing pressure sterilizing 15 minutes.
9) lamp inspection, produce.
Embodiment 2：The preparation of atenolol injection
Prescription is：
| Supplementary material title | Usage amount |
| Atenolol | 5.0g |
| Sodium chloride | 75g |
| Edetate sodium | 3.0g |
| Sodium dihydrogen phosphate | 6.0g |
| 0.1mol/l disodium hydrogen phosphates | 8ml |
| 1,2- propane diols | 2000ml |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
Preparation technology：
1) take recipe quantity 60% (v/v) water for injection, sequentially add recipe quantity sodium chloride, sodium dihydrogen phosphate stirring make it is molten
Solution, 0.2% (m/v) pin charcoal is added into the solution after dissolving, is stirred 30 minutes, is filtered with 5 μm of titanium filters, removes pin
It is standby with charcoal.
2) take recipe quantity 1,2-PD to be heated to 55 DEG C, add atenolol, be stirred to dissolve；Add step 1) prepare
Solution, stirring.
3) determination step 2) resulting solution pH value, with 0.1mol/L disodium hydrogen phosphates adjust pH value 5.5~6.5, filling
Penetrate and total amount is settled to water, stir.
4) to step 3) 0.05% (m/v) pin charcoal is added in resulting solution, stir 25 minutes.
5) above-mentioned resulting solution is filtered with 5 μm of titanium filters, removes pin charcoal, then filter with 0.2 μm of polypropylene filter
Cross, remove other particulate matters less than 5 μm.
6) above-mentioned solution ph is determined, pH value 5.5~6.5 is adjusted with 0.1mol/l disodium hydrogen phosphates, to correct preceding two
The pH value change that may occur in individual step.
7) with the filling above-mentioned solution of the low borosilicate glass ampoule bottles of 10ml, 10ml/ bottles.
8) by above-mentioned 121 DEG C of gained injection pressure sterilizing pressure sterilizing 15 minutes.
9) lamp inspection, produce.
Embodiment 3:The preparation of atenolol injection
Prescription is：
| Supplementary material title | Usage amount |
| Atenolol | 5.0g |
| Sodium chloride | 45g |
| Edetate sodium | 1.5g |
| Sodium dihydrogen phosphate | 1.2g |
| 0.1mol/l disodium hydrogen phosphates | 3ml |
| 1,2- propane diols | 2500ml |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
Preparation technology：
1) take recipe quantity 75% (v/v) water for injection, sequentially add recipe quantity sodium chloride, sodium dihydrogen phosphate stirring make it is molten
Solution, adds 0.15% (m/v) pin charcoal, stirs 20 minutes, is filtered with 5 μm of titanium filters, removes pin charcoal, standby.
2) take recipe quantity propane diols to be heated to 65 DEG C, add atenolol, be stirred to dissolve；Above-mentioned stock solution is added,
Stirring.
3) pH value of above-mentioned resulting solution is determined, pH value 5.5~6.5 is adjusted with 0.1mol/l disodium hydrogen phosphates, filling is penetrated
Total amount is settled to water, is stirred.
4) 0.05% (m/v) pin charcoal is added in above-mentioned resulting solution, is stirred 25 minutes.
5) above-mentioned resulting solution is filtered with 5 μm of titanium filters, removes pin charcoal, then filter with 0.2 μm of polypropylene filter
Cross, remove other particulate matters less than 5 μm.
6) above-mentioned solution ph is determined, pH value 5.5~6.5 is adjusted with 0.1mol/l disodium hydrogen phosphates, to correct preceding two
The pH value change that may occur in individual step.
7) with the filling above-mentioned solution of the low borosilicate glass ampoule bottles of 10ml, 10ml/ bottles.
8) by above-mentioned 121 DEG C of gained injection pressure sterilizing pressure sterilizing 15 minutes.
9) lamp inspection, produce.
Embodiment 4:The preparation of atenolol injection
Prescription is：
| Supplementary material title | Usage amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 3.0g |
| Sodium dihydrogen phosphate | 0.12g |
| 0.1mol/l disodium hydrogen phosphates | 1.2ml |
| 1,2-PD | 3000ml |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
Preparation technology be the same as Example 1, is repeated no more.
Embodiment 5：The preparation of atenolol injection
Prescription is：
| Supplementary material title | Usage amount |
| Atenolol | 5.0g |
| Sodium chloride | 90g |
| Edetate sodium | 4.0g |
| Sodium dihydrogen phosphate | 8.0g |
| 0.1mol/l disodium hydrogen phosphates | 5ml |
| 1,2- propane diols | 2000ml |
| Water for injection | It is settled to 10L |
| It is made altogether | 1000 |
Preparation technology be the same as Example 1, is repeated no more.
Accelerated stability test：
The atenolol injection respectively prepared by 1-3 of the embodiment of the present invention, and commercially available atenolol injection are (raw
Produce producer：Shandong Yikang medicine company limited company), it is 75 ± 5% to be placed in relative humidity, and temperature is 40 DEG C ± 2 DEG C of condition
Under, place 6 months, sampled respectively at 0,1,2,3,6 months, check indices, obtain related data, as shown in table 1：
The atenolol injection accelerated test result of table 1
In accelerated stability test, atenolol injection prepared by the present invention has good stability.It is mainly reflected in note
Penetrate the drug content and Related substances separation of liquid.Using this patent grown place atenolol injection stable content, relevant thing
Matter number and content are below the product of former technique productions.As can be seen from Table 1, Ah the replacing prepared according to prescription of the present invention and technique
That parenteral solution, content meets the requirement of the atenolol injection national drug standards, and has no obvious reduction, and relevant material is adopted
With high effective liquid chromatography for measuring, have no significantly raised, sample is stable during illustrating experiment, quality controllable.And with former technique
The product of production compares, impurity reduction and the obvious reduction that gathers way of impurity, it is seen that：Ah Ti the Lip river prepared by present invention process
Your parenteral solution quality is higher than the product of former technique productions, is had made marked progress compared with existing product.
Clinical test：
Safety of clinical trials validity：
The atenolol injection that the present invention is developed, is group leader's unit by Qingdao Municipal Hospital, by the class of chemicals III
New drug requirement carries out the clinical research of II phase to it.Test as multicenter, random, blind, parallel positive drug comparative study, with U.S.
Tuo Luoer parenteral solutions are positive control drug, investigate the clinical efficacy that atenolol injection early intervention treats acute myocardial infarction
And security.Result of the test is as follows：
(1), security：The red blood cell of laboratory checking index before and after experiment, basocyte, acidophil, blood platelet,
ALT, ALP, Cr are not affected by influence；There is system before and after the hemoglobin of control group, leucocyte, neutrophil leucocyte, lymphocyte medication
Meter learns difference；There is system before and after the hemoglobin of test group, leucocyte, neutrophil leucocyte, lymphocyte, monocyte, BUN medications
Meter learns difference；Laboratory checking index between two groups is more not statistically significant.Some patientss occur in that low blood pressure, nausea, coughed
Cough, vomit, palpitaition, the symptom such as uncomfortable in chest, through there was no significant difference between two groups of statistical analysis.Before being treated to laboratory checking index
Normal and abnormal conditions are analyzed afterwards, and the anomalous variation of index is unrelated with trial drug, mostly relevant with disease or conjunction in itself
And caused by Other diseases.
(2), validity：Test group and the background information of control group patient have comparativity.Control group heart rate is before medication
80.11 ± 14.08 be down to after medication 70.52 ± 9.81, drop heart rate amplitude is 11.97%, and comparing before and after medication has statistics
Learn meaning；Systolic pressure be down to from 129.84 ± 21.15 before medication after medication 116.01 ± 12.76, drop systolic pressure amplitude be
10.65%, it is relatively more statistically significant before and after medication；Diastolic pressure is down to after medication from 79.90 ± 12.89 before medication
71.16 ± 9.22, drop diastolic pressure amplitude is 10.94%, and medication is front and rear relatively more statistically significant；CK is before medication
1264.99 ± 1437.63 be down to after medication 986.57 ± 1190.66, drop CK amplitudes are 22.01%, and comparing before and after medication has
Statistical significance；CK-MB be down to from 73.32 ± 95.83 before medication after medication 59.92 ± 85.11, drop CK-MB amplitudes be
18.29%, it is relatively more not statistically significant before and after medication；ST-T sections of changes are down to after medication from 2.80 ± 2.09 before medication
1.54 ± 1.19, it is 45.36% to drop ST-T sections to change amplitude, and medication is front and rear relatively more statistically significant；
Test group heart rate be down to from 81.95 ± 16.08 before medication after medication 72.14 ± 12.26, drop heart rate amplitude be
11.97%, it is relatively more statistically significant before and after medication；Systolic pressure is down to after medication from 128.34 ± 20.63 before medication
115.95 ± 16.02, drop systolic pressure amplitude is 9.65%, and medication is front and rear relatively more statistically significant；Diastolic pressure is before medication
80.27 ± 13.18 be down to after medication 70.48 ± 9.98, drop diastolic pressure amplitude is 12.20%, and comparing before and after medication has statistics
Learn meaning；CK be down to from 890.03 ± 1006.50 before medication after medication 731.53 ± 929.17, drop CK amplitudes be
17.81%, it is relatively more statistically significant before and after medication；CK-MB be down to from 54.65 ± 69.71 before medication after medication 49.29
± 63.41, drop CK-MB amplitude are 9.81%, and medication is front and rear relatively more statistically significant；ST-T sections change from 2.84 before medication
± 2.25 be down to after medication 1.60 ± 1.59, drop ST-T section change amplitudes be 43.31%, comparing before and after medication has statistics meaning
Justice；
Heart rate, systolic pressure, diastolic pressure, CK, CK-MB, ST-T sections of comparisons for changing change between two groups is not statistically significant.
Conclusion：The clinical effectiveness of the atenolol injection early intervention treatment acute myocardial infarction of the present invention is notable, and
And be safe.
Claims (4)
1. a kind of preparation method of atenolol injection, it is characterised in that by atenolol and pharmaceutically acceptable auxiliary
Material is made, and concentration is calculated as 0.45mg/mL-0.55mg/mL with atenolol；
The auxiliary material is：The double solvent being made up of 1,2- propane diols and water；It is made up of sodium dihydrogen phosphate and disodium hydrogen phosphate
Buffer system；Osmotic pressure regulator is used as by sodium chloride；Complexing of metal ion agent is used as by edetate sodium；
Preparation process is as follows：
(1) 60-80% of recipe quantity volume water for injection is taken, sequentially adding recipe quantity sodium chloride, sodium dihydrogen phosphate stirring makes
Dissolving, the pin charcoal that quality volume fraction is 0.05-0.2% is added into the solution after dissolving, is stirred, and filtration removes pin and used
Charcoal, it is standby；
(2) take recipe quantity 1,2-PD to be heated to 55-65 DEG C, add atenolol, be stirred to dissolve；Add step (1) system
Standby solution, stirring；
(3) pH value of determination step (2) resulting solution, pH value 5.5~6.5, plus water for injection constant volume are adjusted with disodium hydrogen phosphate
To total amount, stirring；
(4) the pin charcoal that quality volume fraction is 0.05% is added into step (3) resulting solution, is stirred, filtration is removed respectively
Pin charcoal and the particulate matter less than 5 μm；
(5) solution ph after determination step (4) filtering, pH value 5.5~6.5 is adjusted with disodium hydrogen phosphate；
(6) filling, sterilizing, lamp inspection, packaging is produced.
2. the preparation method of atenolol injection as claimed in claim 1, it is characterised in that in step (1), pin charcoal
Addition is 0.1%.
3. the preparation method of atenolol injection as claimed in claim 1, it is characterised in that step (1) and step (4)
In, remove pin charcoal and use 5 μm of titanium filters.
4. the preparation method of atenolol injection as claimed in claim 1, it is characterised in that in step (4), removing is less than
5 μm of particulate matter uses 0.2 μm of polypropylene filter.
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