CN117771245A - Nicotil preparation for injection - Google Patents
Nicotil preparation for injection Download PDFInfo
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- CN117771245A CN117771245A CN202311431385.2A CN202311431385A CN117771245A CN 117771245 A CN117771245 A CN 117771245A CN 202311431385 A CN202311431385 A CN 202311431385A CN 117771245 A CN117771245 A CN 117771245A
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- nicorandil
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- injection
- temperature
- sodium glutamate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims description 11
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960002497 nicorandil Drugs 0.000 claims abstract description 67
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims abstract description 38
- 235000013923 monosodium glutamate Nutrition 0.000 claims abstract description 38
- 229940073490 sodium glutamate Drugs 0.000 claims abstract description 38
- 239000004475 Arginine Substances 0.000 claims abstract description 29
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000007788 liquid Substances 0.000 claims abstract description 18
- 238000004108 freeze drying Methods 0.000 claims abstract description 17
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 5
- 229960003121 arginine Drugs 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 18
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 238000007710 freezing Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 238000000137 annealing Methods 0.000 claims description 12
- 238000005192 partition Methods 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 8
- 230000008014 freezing Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000000859 sublimation Methods 0.000 claims description 6
- 230000008022 sublimation Effects 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 20
- 239000008215 water for injection Substances 0.000 description 17
- 239000002994 raw material Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000011049 filling Methods 0.000 description 8
- 238000003825 pressing Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000005388 borosilicate glass Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005096 rolling process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000010220 ion permeability Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a stable nicorandil preparation for injection, which comprises the active ingredients of nicorandil, sodium glutamate and arginine; wherein, the weight ratio of nicorandil to sodium glutamate is 1: 1-20: 1, a step of; the weight ratio of nicorandil to arginine is 2: 1-20: 1. the preparation is prepared through a liquid preparation and a freeze drying process, and the prepared nicorandil for injection has good stability.
Description
Technical Field
The invention belongs to the field of chemical preparations, and particularly relates to a preparation method of a nicorandil stable solution for injection and a preparation method of a nicorandil freeze-dried powder injection for injection.
Background
Nicorandil (nicarandil), drug aliases, nicotinate, SIGMART, PERISALOL, the translated names in the patent are: ni Ke Deer, niguladi, chemical name N- (2-hydroxyethyl) nicotinamide nitrate, has the following structural formula:
nicotiana nitrate compounds are the first potassium channel openers for clinical ATP sensitivity. Has effects in preventing calcium ion dissociation in cells, increasing potassium ion permeability of cell membrane, dilating coronary blood vessel, increasing coronary blood flow, and inhibiting coronary artery spasm, and can not affect blood pressure, heart rate, myocardial contractility and myocardial oxygen consumption. Also has effects in inhibiting platelet aggregation and preventing thrombosis. Nicotil for injection is produced by Japanese besides-produced Kayaku Co., ltd, and has specifications of 2mg, 12mg and 48mg, and is commercially available in Japan. Is mainly used for unstable angina and acute heart failure (including acute exacerbation stage of chronic heart failure).
Physical and chemical properties of nicorandil: white crystals; can be completely dissolved in methanol, ethanol and acetic acid, and is slightly soluble in acetic anhydride and poorly soluble in water. The nicorandil is more stable in the crystalline state. But instability occurs after the nicorandil is formulated. Nicorandil has a nitrate group, and the nicorandil preparation is not as stable in aqueous solution as other medicines having a nitrate group, and thus, the preparation of nicorandil in aqueous solution causes a decomposition reaction from the hydrolysis of nitrate. The nicorandil formulation also causes polymerization when heated.
Disclosure of Invention
The invention aims to provide a preparation method of a nicorandil stable solution for injection.
The nicorandil preparation for injection comprises nicorandil, sodium glutamate and arginine, or further comprises pharmaceutically acceptable auxiliary materials. The composition can improve stability of nicorandil preparation.
Specifically, an injectable nicorandil preparation for injection, which comprises active ingredients of nicorandil sodium glutamate and arginine; wherein, the weight ratio of nicorandil to sodium glutamate is 1: 1-20: 1, a step of; the weight ratio of nicorandil to arginine is 2: 1-20: 1.
in some embodiments, the nicorandil to sodium glutamate weight ratio of 1:1 to 15:1.
in some embodiments, the nicorandil to sodium glutamate weight ratio of 2:1 to 10:1.
in some embodiments, the nicorandil to sodium glutamate weight ratio of 3:1 to 5:1.
in some embodiments, the nicorandil to arginine weight ratio is 5: 1-20: 1.
in some embodiments, the nicorandil to arginine weight ratio is 5:1 to 16:1.
in some embodiments, the nicorandil to arginine weight ratio is 10:1 to 13:1.
in some embodiments, sodium glutamate is used as the pH adjuster in the nicorandil pharmaceutical composition, and in other embodiments sodium glutamate is used as the sole pH adjuster in the nicorandil pharmaceutical composition.
In some embodiments, arginine in the nicorandil pharmaceutical composition acts as a stabilizer, and in other embodiments arginine in the nicorandil pharmaceutical composition acts as the sole stabilizer.
In some embodiments, the nicorandil pharmaceutical composition further comprises pharmaceutically acceptable excipients.
In some embodiments, the nicorandil pharmaceutical composition is a lyophilized powder for injection. Optionally, the freeze-dried powder injection further comprises excipient, such as mannitol, sorbitol, sucrose, lactose, glucose, fructose, ribose, etc., preferably mannitol.
In some embodiments, the weight ratio of nicorandil to excipient (e.g., mannitol) in the lyophilized powder for injection is (1.5-2.5): (2.5-4), e.g., 2:3.
In some embodiments, every 1000 prescriptions of the freeze-dried powder injection (the right amount of water for injection) are:
nicotil 2-48g
Mannitol 3-72g
Sodium glutamate 0.5-12g
Arginine 0.15-4.0g.
The invention relates to a nicorandil preparation for injection, which is prepared from the nicorandil pharmaceutical composition. Specifically, the freeze-dried powder injection contains nicorandil, sodium glutamate and arginine, or also contains excipient (such as mannitol), and is prepared by adopting a freeze-drying process.
The invention also provides a preparation method of the nicorandil for injection, which comprises the step of preparing liquid; wherein, in the step of preparing the liquid, the temperature of the liquid medicine is controlled at 5-15 ℃, preferably 8-12 ℃. The research shows that the liquid preparation in the temperature range can ensure that the nicorandil raw material medicine can be dissolved in water, and can avoid the fast degradation of the nicorandil raw material medicine in water.
In some embodiments, the step of dispensing comprises: adding sodium glutamate into water for injection at 5-15 ℃ (preferably 8-12 ℃) according to the formula amount, stirring until the sodium glutamate is dissolved, adding arginine or adding other medicinal auxiliary materials (such as excipients) into the water for injection, stirring until the arginine or the medicinal auxiliary materials are dissolved, adding the nikodil raw material medicine into the water for injection, stirring until the nikodil raw material medicine is completely dissolved, adding water for injection until the water for injection is quantitative, and stirring and mixing the mixture uniformly.
The preparation method of the nicorandil preparation for injection comprises the following steps of: the pH of the liquid medicine is controlled to be 5.8-7.8 by adjusting the amount of sodium glutamate.
The preparation method of the nicorandil preparation for injection comprises the following freeze-drying steps:
A. the preparation stage: controlling the temperature of the separator to be 2-8 ℃;
B. prefreezing and annealing:
1) Pre-freezing: pre-freezing at-45 ℃ and maintaining for 3-4 hours;
2) Annealing: gradually increasing the temperature of the plate layer to-10 ℃ and keeping for 1-3h, and reducing the temperature of the plate layer to below-45 ℃ and keeping for 1-3h;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 1-10 ℃ at the speed of 5-10 ℃/h when the vacuum degree reaches 10-20Pa, and preserving heat for 8-16h;
D. and (5) analysis and drying: setting the partition board to raise the temperature to 20-40 deg.c at 1-5 deg.c/hr, maintaining the temperature for 4-8 hr, maintaining the ultimate vacuum degree until the analysis and drying are completed.
In some embodiments, the method of preparing the nicorandil formulation for injection further comprises the step of lyophilizing; wherein, the method also comprises the step of pre-cooling the partition plate before pre-freezing; the temperature of the separator is controlled to be 2-5 ℃.
In some embodiments, the preparation method of the nicorandil freeze-dried powder injection comprises the following steps:
(1) Liquid preparation
a. Adding sodium glutamate into water for injection at 5-15 ℃ (preferably 8-12 ℃) according to the formula amount, stirring until the sodium glutamate is dissolved, adding arginine or adding other medicinal auxiliary materials (such as excipients) as well, stirring until the arginine or other medicinal auxiliary materials are dissolved, adding the nikodil raw material medicine, and stirring until the nikodil raw material medicine is completely dissolved;
b. adding water for injection to a certain amount, and stirring and mixing uniformly; controlling the pH value of the liquid medicine to be 5.8-7.8 by adjusting the quantity of sodium glutamate;
c. filling the liquid medicine into a medium borosilicate glass tube injection bottle, and half plugging;
(2) Freeze-drying
A. The preparation stage: controlling the temperature of the separator to be 2-8 ℃;
B. prefreezing and annealing
1) Pre-freezing: pre-freezing at-45 ℃ and maintaining for 3-4 hours;
2) Annealing: gradually raising the temperature of the plate layer to-10 ℃ (e.g. 1 ℃), maintaining for 1-3 hours, and lowering the temperature of the plate layer to below-45 ℃ again, and maintaining for 1-3 hours;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 1-10 ℃ at a speed of 5-10 ℃/h (e.g. 5 ℃) when the vacuum degree reaches 10-20Pa (e.g. 15 Pa), and preserving heat for 8-16h;
D. and (5) analysis and drying: the separator is set to heat up to 20-40 ℃ at a speed of 1-5 ℃/h (e.g. 3 ℃), and is kept at the temperature for 4-8h (e.g. 8 h), and the ultimate vacuum degree is always kept until the analysis drying is finished.
(3) And (3) pressing a plug: after the freeze-drying is finished, filling nitrogen into the freeze-drying box, and pressing the plug;
(4) And (3) capping: and rolling the aluminum-plastic combined cover.
The prescription compatibility of the invention has the beneficial effects of analysis: the nicorandil preparation for injection is not easy to degrade in the storage process, and has better stability and longer storage time compared with the existing products on the market.
Description of the embodiments
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1: nicotil for injection
Prescription composition
Prescription amount of the component (1000 pieces)
Nicotil 48g
Mannitol 72g
Sodium glutamate 12g
Arginine 4g
6000ml of water for injection
Preparation method
(1) Liquid preparation
a. Taking 4800ml of water for injection, controlling the water temperature to be 8-12 ℃ in an ice bath, adding 12g of sodium glutamate, stirring until the sodium glutamate is dissolved, adding 4g of arginine and 72g of mannitol, stirring until the sodium glutamate is dissolved, adding 48g of nikodil raw material medicine, and stirring until the sodium glutamate is completely dissolved;
b. adding water for injection to 6000ml, and stirring and mixing uniformly;
c. filling the liquid medicine into a medium borosilicate glass tube injection bottle, and half plugging at a volume of 6 ml/branch;
(2) Freeze-drying
A. The preparation stage: controlling the temperature of the separator to be 2 ℃;
B. prefreezing and annealing
1) Pre-freezing: pre-freezing at-45 ℃ and keeping for 3 hours;
2) Annealing: gradually increasing the temperature of the plate layer to 1 ℃ and keeping for 2 hours, and reducing the temperature of the plate layer to below-45 ℃ again and keeping for 2 hours;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 2 ℃ at a speed of 5 ℃ when the vacuum degree reaches 15Pa, and preserving heat for 16 hours;
D. and (5) analysis and drying: setting the partition board to raise the temperature to 30 ℃ at the speed of 3 ℃, preserving the heat for 8 hours, and always keeping the ultimate vacuum degree until the analysis and drying are finished.
(3) And (3) pressing a plug: after the freeze-drying is finished, filling nitrogen to 80MPa in the freeze-drying box, and pressing the plugs;
(4) And (3) capping: and rolling the aluminum-plastic combined cover.
Example 2: nicotil for injection
Prescription amount of the component (1000 pieces)
Nicorandil 12g
Mannitol 18g
Sodium glutamate 3g
Arginine 1g
3000ml of water for injection
Preparation method
(1) Liquid preparation
a. 2400ml of water for injection is taken, the water temperature is controlled to be 8-12 ℃ by ice bath, 3g of sodium glutamate is added, stirring is carried out until the sodium glutamate is dissolved, 1g of arginine and 18g of mannitol are added, stirring is carried out until the sodium glutamate is dissolved, then 12g of nikodil raw material medicine is added, and stirring is carried out until the sodium glutamate is completely dissolved;
b. adding water for injection to 3000ml, and stirring and mixing uniformly;
c. filling the liquid medicine into a medium borosilicate glass tube injection bottle, and half plugging with 3 ml/branch;
(2) Freeze-drying
A. The preparation stage: controlling the temperature of the separator to be 2 ℃;
B. prefreezing and annealing
1) Pre-freezing: pre-freezing at-45 ℃ and keeping for 3 hours;
2) Annealing: gradually increasing the temperature of the plate layer to 1 ℃ and keeping for 2 hours, and reducing the temperature of the plate layer to below-45 ℃ again and keeping for 2 hours;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 2 ℃ at a speed of 5 ℃ when the vacuum degree reaches 15Pa, and preserving heat for 12 hours;
D. and (5) analysis and drying: setting the partition board to raise the temperature to 30 ℃ at the speed of 3 ℃, preserving the heat for 6 hours, and always keeping the ultimate vacuum degree until the analysis and drying are finished.
(3) And (3) pressing a plug: after the freeze-drying is finished, filling nitrogen to 80MPa in the freeze-drying box, and pressing the plugs;
(4) And (3) capping: and rolling the aluminum-plastic combined cover.
Example 3: nicotil for injection
Prescription amount of the component (1000 pieces)
Nicotil 2g
Mannitol 3g
Sodium glutamate 0.5g
Arginine 0.17g
500ml of water for injection
Preparation method
(1) Liquid preparation
a. Taking 400ml of water for injection, controlling the water temperature to be 8-12 ℃ by using an ice bath, adding 0.5g of sodium glutamate, stirring until the sodium glutamate is dissolved, adding 0.17g of arginine and 3g of mannitol, stirring until the arginine and the mannitol are dissolved, adding 2g of nikodil raw material medicine, and stirring until the nikodil raw material medicine is completely dissolved;
b. adding water for injection to 500ml, and stirring and mixing uniformly;
c. filling the liquid medicine into a medium borosilicate glass tube injection bottle, and half plugging with 0.5 ml/branch;
(2) Freeze-drying
A. The preparation stage: controlling the temperature of the separator to be 2 ℃;
B. prefreezing and annealing
1) Pre-freezing: pre-freezing at-45 ℃ and keeping for 2 hours;
2) Annealing: gradually increasing the temperature of the plate layer to 1 ℃ and keeping for 1h, and reducing the temperature of the plate layer to below-45 ℃ again and keeping for 1h;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 2 ℃ at a speed of 5 ℃ when the vacuum degree reaches 15Pa, and preserving heat for 8 hours;
D. and (5) analysis and drying: setting the partition board to raise the temperature to 30 ℃ at the speed of 3 ℃, preserving the heat for 4 hours, and always keeping the ultimate vacuum degree until the analysis and drying are finished.
(3) And (3) pressing a plug: after the freeze-drying is finished, filling nitrogen to 80MPa in the freeze-drying box, and pressing the plugs;
(4) And (3) capping: and rolling the aluminum-plastic combined cover.
Test example 1: prescription composition and formulation screening data
The solutions of comparative example 1 were low in pH and the solutions of comparative example 2 and comparative example 3 were high in pH. The results of the measurements of the related substances I of comparative example 1, comparative example 2, comparative example 3 and comparative example 4 are all worse than those of example 1, and the sample of example 1 is the most stable.
Test example 2: the freeze-dried samples of examples 1-3 were subjected to stability studies and compared with corresponding reference formulations
The following table is attached:
the stability of the product prepared by the prescription composition and the preparation process adopted in the embodiment is superior to that of the reference preparation. While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (10)
1. A stable nicorandil preparation for injection, which comprises the active ingredients of nicorandil, sodium glutamate and arginine, wherein the weight ratio of nicorandil to sodium glutamate is 1: 1-20: 1, the weight ratio of nicorandil to arginine is 2: 1-20: 1.
2. the nicorandil preparation for injection according to claim 1, wherein the weight ratio of nicorandil to sodium glutamate is 2:1 to 10:1, a step of; the weight ratio of nicorandil to arginine is 5:1 to 16:1.
3. the nicorandil preparation for injection according to claim 1, wherein the weight ratio of nicorandil to sodium glutamate is 3:1 to 5:1. the weight ratio of nicorandil to arginine is 10:1 to 13:1.
4. a nicorandil preparation for injection according to any one of claims 1-3, wherein sodium glutamate is used as pH regulator; the arginine acts as a stabilizer.
5. An injectable nicorandil formulation as claimed in any one of claims 1 to 4 wherein the formulation further comprises excipients selected from mannitol, sorbitol, sucrose, lactose, glucose, fructose and ribose.
6. An injectable nicorandil formulation as claimed in any one of claims 1 to 5 wherein each 1000 formulations is formulated as:
nicotil 2-48g
Mannitol 3-72g
Sodium glutamate 0.5-12g
Arginine 0.15-4.0g.
7. The nicorandil preparation for injection according to claim 6, wherein the preparation method of the preparation comprises the steps of: the temperature of the liquid medicine is controlled to be 5-15 ℃, and the pH value of the liquid medicine is controlled to be 5.8-7.8 by adjusting the quantity of sodium glutamate.
8. The nicorandil preparation for injection as claimed in claim 6, wherein the preparation method of the preparation comprises the steps of freeze-drying:
A. the preparation stage: controlling the temperature of the separator to be 2-8 ℃;
B. prefreezing and annealing:
1) Pre-freezing: pre-freezing at-45 ℃ and maintaining for 3-4 hours;
2) Annealing: gradually increasing the temperature of the plate layer to-10 ℃ and keeping for 1-3h, and reducing the temperature of the plate layer to below-45 ℃ and keeping for 1-3h;
C. sublimation drying: starting a vacuum pump, setting a partition plate to heat up to 1-10 ℃ at the speed of 5-10 ℃/h when the vacuum degree reaches 10-20Pa, and preserving heat for 8-16h;
D. and (5) analysis and drying: setting the partition board to raise the temperature to 20-40 deg.c at 1-5 deg.c/hr, maintaining the temperature for 4-8 hr, maintaining the ultimate vacuum degree until the analysis and drying are completed.
9. The nicorandil preparation for injection according to claim 7, wherein the preparation method of the preparation comprises the steps of: controlling the temperature of the liquid medicine at 8-12 ℃.
10. The nicorandil preparation for injection according to claim 8, wherein the preparation method of the preparation comprises the steps of freeze-drying step A and preparation: the temperature of the separator is controlled to be 2-5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311431385.2A CN117771245A (en) | 2023-10-31 | 2023-10-31 | Nicotil preparation for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311431385.2A CN117771245A (en) | 2023-10-31 | 2023-10-31 | Nicotil preparation for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117771245A true CN117771245A (en) | 2024-03-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311431385.2A Pending CN117771245A (en) | 2023-10-31 | 2023-10-31 | Nicotil preparation for injection |
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| Country | Link |
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| CN (1) | CN117771245A (en) |
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2023
- 2023-10-31 CN CN202311431385.2A patent/CN117771245A/en active Pending
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