CN113876705A - Urapidil hydrochloride injection and preparation method thereof - Google Patents
Urapidil hydrochloride injection and preparation method thereof Download PDFInfo
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- CN113876705A CN113876705A CN202111363419.XA CN202111363419A CN113876705A CN 113876705 A CN113876705 A CN 113876705A CN 202111363419 A CN202111363419 A CN 202111363419A CN 113876705 A CN113876705 A CN 113876705A
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- urapidil hydrochloride
- injection
- urapidil
- hydrochloride injection
- acid
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- 238000002347 injection Methods 0.000 title claims abstract description 108
- 239000007924 injection Substances 0.000 title claims abstract description 108
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 229960001130 urapidil Drugs 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 17
- 239000000872 buffer Substances 0.000 claims abstract description 14
- 230000003204 osmotic effect Effects 0.000 claims abstract description 10
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims abstract description 6
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims abstract description 4
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims abstract description 4
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- 238000001914 filtration Methods 0.000 claims description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 230000001954 sterilising effect Effects 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000004695 Polyether sulfone Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 229920006393 polyether sulfone Polymers 0.000 claims description 10
- 239000011148 porous material Substances 0.000 claims description 10
- 239000001509 sodium citrate Substances 0.000 claims description 10
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 10
- 238000004659 sterilization and disinfection Methods 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 5
- 230000006866 deterioration Effects 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 238000005286 illumination Methods 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical group C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, and particularly discloses urapidil hydrochloride injection and a preparation method thereof. In the injection, each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of osmotic pressure regulator and an acid-base buffer pair, wherein the pH value of the urapidil hydrochloride injection is 5.9-6.5. According to the invention, citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate are used as acid-base buffer pairs, the pH value of the injection is adjusted to 5.9-6.5, and the stability of the injection is obviously improved. In the preparation process of the injection, the adding and mixing sequence of the urapidil hydrochloride serving as a main drug and other auxiliary materials is adjusted, and the temperature in the preparation process is controlled to be lower than 60 ℃, so that the deterioration probability of the urapidil hydrochloride is effectively reduced, and the stability of the injection is remarkably improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to urapidil hydrochloride injection and a preparation method thereof.
Background
Urapidil hydrochloride is a phenylpiperazine substituted uracil derivative, is an effective and safe vasodilator for treating hypertension crisis, severe hypertension, controlling hypertension in an operation period and treating congestive heart failure at present, and belongs to national basic medicines. In addition, urapidil hydrochloride generally does not cause reflex tachycardia while lowering blood pressure.
At present, the pharmaceutical preparation mainly comprises injection, freeze-dried powder injection, tablets, capsules and the like, wherein the tablets and the capsules are oral preparations, and the drug effect is reduced because the first-pass effect cannot be avoided; the freeze-dried powder injection needs to be re-dissolved and then used, is inconvenient to use clinically and has the risk of cross contamination. In order to improve the curative effect, urapidil hydrochloride can be prepared into an injection, so that the first-pass effect is avoided, but the problems that urapidil hydrochloride has poor stability, is easy to decompose and deteriorate and the like in an injection solution seriously limit the wide application of the urapidil hydrochloride injection.
Disclosure of Invention
In view of the above, the invention provides urapidil hydrochloride injection and a preparation method thereof, and citric acid, sodium citrate and other acid-base buffers are adopted to adjust the pH value of the injection to 5.9-6.5, so that the injection preparation has the characteristics of high stability, difficult deterioration, more convenience for clinical application and the like.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
the invention provides urapidil hydrochloride injection in a first aspect, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of osmotic pressure regulator and acid-base buffer pairs, wherein the acid-base buffer pairs are citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate, and the pH value of the urapidil hydrochloride injection is 5.9-6.5.
Compared with the prior art, the urapidil hydrochloride injection provided by the invention has the following advantages:
the application takes citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate as an acid-base buffer pair, and adjusts the pH value of the injection to be 5.9-6.5, so that the stability of the injection is remarkably improved, and the large-scale industrial production of the urapidil hydrochloride injection is promoted.
Based on the fact that the main drug urapidil hydrochloride is sensitive to high temperature and is easy to deteriorate under the conditions of high temperature, light and the like, the selection of the auxiliary materials in the injection becomes a key condition for the stability of the injection, the applicant of the invention also tries to add other auxiliary materials in the injection, such as adding a metal ion complexing agent in the injection or adjusting the pH of a system by using sodium hydroxide-hydrochloric acid and the like, but the method cannot avoid the situation that part of products become deep in solution and the content of related substances is higher than 2.5% after an acceleration experiment.
Optionally, the pH value of the urapidil hydrochloride injection is 6.2.
Optionally, the osmotic pressure regulator is polyethylene glycol or glycerol.
Optionally, the osmotic pressure regulator is polyethylene glycol, and the acid-base buffer pair is citric acid-sodium citrate.
Optionally, each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.2-0.6 g of citric acid and 1.8-6 g of sodium citrate.
The optimal prescription amount of the urapidil hydrochloride injection obviously improves the stability of the main drug urapidil hydrochloride, so that the injection has excellent stability.
The second aspect of the application provides a preparation method of urapidil hydrochloride injection, which at least comprises the following steps:
the method comprises the following steps: weighing the components according to the raw material ratio;
step two: under the protection of inert gas, adding acid-base buffer pairs, osmotic pressure regulators and urapidil hydrochloride into part of water for injection at the temperature of 20-60 ℃, adding the rest of water for injection at the temperature of 20-60 ℃ after dissolving uniformly, adjusting the pH value to 5.9-6.5, and filtering to obtain filtrate;
and step three, filling, sterilizing and cooling the filtrate to 40-60 ℃ to obtain the urapidil hydrochloride injection.
Compared with the prior art, the preparation method of urapidil hydrochloride injection provided by the invention has the following advantages:
the injection effectively reduces the deterioration probability of urapidil hydrochloride and obviously improves the stability of the injection by adjusting the adding and mixing sequence of the main drug urapidil hydrochloride and other auxiliary materials and controlling the temperature to be lower than 60 ℃ in the preparation process.
Further optionally, the inert gas is nitrogen.
Optionally, in the second step, the filtering is a second-stage filtering in which the pore sizes are sequentially reduced, wherein the pore size of the first-stage filtering is sequentially 0.45 μm, and the pore size of the second-stage filtering is 0.2 μm.
Optionally, the filter elements for the first-stage filtration and the second-stage filtration are polyether sulfone.
According to the application, through secondary filtration with a specific aperture and a specific filter element, the polyethersulfone with the aperture of 0.45 mu m is used for filtering and removing heat sources and impurities in the injection, then the polyethersulfone with the aperture of 0.22 mu m is used for carrying out terminal filtration on the injection, the heat sources and endotoxin in the injection are removed for sterilization, and the specific main drug urapidil hydrochloride and other auxiliary materials are added and mixed in sequence, so that the deterioration probability of urapidil hydrochloride is further reduced, and the sterilization efficiency is improved.
The preparation method does not use active carbon in the preparation process, simplifies the process steps, avoids impurities introduced when the active carbon is added, and reduces the adsorption of the active carbon on the urapidil hydrochloride serving as a main drug, thereby causing a great amount of loss of the urapidil hydrochloride.
Optionally, in the second step, the water for part of the injection is 40-80% of the total volume of the preparation.
According to the method, an acid-base buffer pair, an osmotic pressure regulator and urapidil hydrochloride are added firstly, and the volume of the initially added water for injection is 40-80% based on the short solvent time and the content uniformity under the condition that the temperature of the water for injection is 20-60 ℃.
Optionally, in the third step, the sterilization temperature is 121 ℃, and the sterilization time is 7-15 min.
Further optionally, in the third step, the sterilization temperature is 121 ℃, and the sterilization time is 8 min.
The preferred sterilization conditions can significantly reduce the impurity content in the injection.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.3g of citric acid and 2.6g of sodium citrate, wherein the pH value of the urapidil hydrochloride injection is 6.2.
The preparation method of the urapidil hydrochloride injection comprises the following steps:
the method comprises the following steps: weighing the components according to the raw material ratio;
step two: cooling 60% of injection water of the prepared total volume to 50 ℃, adding urapidil hydrochloride, polyethylene glycol, citric acid and sodium citrate under the protection of nitrogen, adding the rest injection water at 50 ℃ after dissolving uniformly, adjusting the pH value to 6.2, filtering through a polyether sulfone filter core with the aperture of 0.45 mu m and a polyether sulfone filter core with the aperture of 0.2 mu m, and collecting filtrate;
and step three, filling the filtrate, sterilizing at the temperature of 121 ℃/12min, and cooling to 40 ℃ to obtain the urapidil hydrochloride injection.
Example 2
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.3g of citric acid and 3.3g of sodium citrate, wherein the pH value of the urapidil hydrochloride injection is 6.3.
The preparation method of the urapidil hydrochloride injection comprises the following steps:
the method comprises the following steps: weighing the components according to the raw material ratio;
step two: cooling injection water accounting for 80% of the total volume to 30 ℃, adding urapidil hydrochloride, polyethylene glycol, citric acid and sodium citrate under the protection of nitrogen, adding the residual injection water at the temperature of 45 ℃ after dissolving uniformly, adjusting the pH value to 6.3, filtering through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m, and collecting filtrate;
and step three, filling the filtrate, sterilizing at the temperature of 121 ℃/10min, and cooling to 45 ℃ to obtain the urapidil hydrochloride injection.
Example 3
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.3g of citric acid and 2.3g of sodium citrate, wherein the pH value of the urapidil hydrochloride injection is 6.1.
The preparation method of the urapidil hydrochloride injection comprises the following steps:
the method comprises the following steps: weighing the components according to the raw material ratio;
step two: cooling injection water accounting for 70% of the total volume to 35 ℃, adding urapidil hydrochloride, polyethylene glycol, citric acid and sodium citrate under the protection of nitrogen, adding the rest injection water at 40 ℃ after dissolving uniformly, adjusting the pH value to 6.1, filtering through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m, and collecting filtrate;
and step three, filling the filtrate, sterilizing at the temperature of 121 ℃/15min, and cooling to 40 ℃ to obtain the urapidil hydrochloride injection.
Example 4
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of glycerol, 0.3g of citric acid and 2.8g of sodium citrate, wherein the pH value of the urapidil hydrochloride injection is 6.2.
The preparation process of the urapidil hydrochloride injection is as described in example 1, and is not repeated.
Example 5
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.2g of acetic acid and 8.0g of sodium acetate, wherein the pH value of the urapidil hydrochloride injection is 6.2.
The preparation process of the urapidil hydrochloride injection is as described in example 2, and is not repeated.
Example 6
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.3g of citric acid and 0.8g of disodium hydrogen phosphate, wherein the pH value of the urapidil hydrochloride injection is 6.2.
The preparation process of the urapidil hydrochloride injection is as described in example 3, and is not repeated.
Example 7
The embodiment of the invention provides urapidil hydrochloride injection, wherein each 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 1.8g of phosphoric acid and 9.8g of sodium phosphate, wherein the pH value of the urapidil hydrochloride injection is 6.2.
The preparation process of the urapidil hydrochloride injection is as described in example 1, and is not repeated.
In order to better illustrate the characteristics of the preparation method of urapidil hydrochloride injection provided by the invention, influence factor test investigation and accelerated test research are carried out on the urapidil hydrochloride injection prepared in example 1 according to the drug stability guiding principle.
Test example 1
Influence factor test: the high temperature test was carried out at 60 ℃ and the results are shown in Table 1 below. As can be seen from Table 1, after the injection is placed at 60 ℃ for 30 days, the examined indexes of the injection have no obvious change, which indicates that the product has good stability.
TABLE 1 high temperature test results
Test example 2
Influence factor test: in the illumination test, the total illumination is more than or equal to 1.2 multiplied by 10 under the illumination condition6Lux hr, near ultraviolet energy not less than 200w hr/m2The results are shown in Table 2 below. As can be seen from Table 2, the examined indicators in the injection have no obvious change after being placed under the illumination condition for 30 days, which indicates that the product has good stability.
TABLE 2 illumination test results
Test example 3
Influence factor test: the freeze thawing test has the following specific conditions: three freeze-thaw cycles, each cycle being at-10 ℃ to-20 ℃ for 2 days and then at 40 ℃ for 2 days, the results are shown in table 3 below. As can be seen from Table 3, after 3 cycles of the freeze-thaw test, the examined indexes in the injection have no obvious change, which indicates that the product has good stability.
TABLE 3 Freeze thaw test results
Test example 4
Three batches of pilot test products are prepared by adopting the prescription amount and the preparation method of the urapidil hydrochloride injection provided by the embodiment 1, and accelerated test research is carried out on the pilot test samples; the accelerated test is carried out in a 40 ℃ stabilization box under the condition of packaging on the market, the result is shown in table 4, and the table 4 shows that all the investigation indexes in the injection have no obvious change, which indicates that the product has good stability.
TABLE 4 accelerated test results
The experimental results of the influence factor test investigation and the accelerated test research of the urapidil hydrochloride injection prepared in the examples 2-7 are consistent with those of the example 1, and both have excellent stability.
The same or corresponding technical effects in embodiment 1 of the invention can be achieved as long as the pH value, the acid-base buffer pair, the temperature of the water for injection in the preparation method and the sterilization conditions of the urapidil hydrochloride injection are within the preferable ranges of the invention.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. An urapidil hydrochloride injection is characterized in that: every 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of osmotic pressure regulator and acid-base buffer pairs, wherein the acid-base buffer pairs are citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate, and the pH value of the urapidil hydrochloride injection is 5.9-6.5.
2. The urapidil hydrochloride injection according to claim 1, characterized in that: the pH value of the urapidil hydrochloride injection is 6.2.
3. The urapidil hydrochloride injection according to claim 1, characterized in that: the osmotic pressure regulator is polyethylene glycol or glycerol.
4. The urapidil hydrochloride injection according to claim 1, characterized in that: the osmotic pressure regulator is polyethylene glycol, and the acid-base buffer pair is citric acid-sodium citrate.
5. The urapidil hydrochloride injection according to claim 4, characterized in that: every 1000mL of urapidil hydrochloride injection comprises the following raw materials: 5g of urapidil hydrochloride, 100g of polyethylene glycol, 0.2-0.6 g of citric acid and 1.8-6 g of sodium citrate.
6. A preparation method of urapidil hydrochloride injection is characterized by comprising the following steps: at least comprises the following steps:
the method comprises the following steps: weighing the components according to the raw material proportion of any one of claims 1 to 5;
step two: under the protection of inert gas, adding acid-base buffer pairs, osmotic pressure regulators and urapidil hydrochloride into part of water for injection at the temperature of 20-60 ℃, adding the rest water for injection at the temperature of 20-60 ℃ after dissolving uniformly, adjusting the pH value to 5.9-6.5, and filtering to obtain filtrate;
and step three, filling, sterilizing and cooling the filtrate to 40-60 ℃ to obtain the urapidil hydrochloride injection.
7. The method for preparing urapidil hydrochloride injection according to claim 6, characterized in that: in the second step, the filtration is a second-stage filtration with the sequentially reduced pore size, wherein the pore size of the first-stage filtration is 0.45 μm, and the pore size of the second-stage filtration is 0.2 μm.
8. The method for preparing urapidil hydrochloride injection according to claim 6, characterized in that: the filter elements of the first stage filtration and the second stage filtration are both polyether sulfone.
9. The method for preparing urapidil hydrochloride injection according to claim 6, characterized in that: in the second step, the water for partial injection accounts for 40-80% of the total volume of the preparation.
10. The method for preparing urapidil hydrochloride injection according to claim 6, characterized in that: in the third step, the sterilization temperature is 121 ℃, and the sterilization time is 7-15 min.
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| CN202111363419.XA CN113876705A (en) | 2021-11-17 | 2021-11-17 | Urapidil hydrochloride injection and preparation method thereof |
| PCT/CN2022/079888 WO2023087578A1 (en) | 2021-11-17 | 2022-03-09 | Urapidil hydrochloride injection and preparation method therefor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114344255A (en) * | 2022-02-28 | 2022-04-15 | 远大生命科学(武汉)有限公司 | Urapidil hydrochloride injection and preparation method thereof |
| CN115645360A (en) * | 2022-10-08 | 2023-01-31 | 石家庄四药有限公司 | Urapidil hydrochloride injection |
| WO2023087578A1 (en) * | 2021-11-17 | 2023-05-25 | 石家庄四药有限公司 | Urapidil hydrochloride injection and preparation method therefor |
| CN116869932A (en) * | 2023-08-25 | 2023-10-13 | 南京海科瑞医药科技有限公司 | Labetalol hydrochloride injection and preparation method thereof |
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| CN1593419A (en) * | 2004-06-24 | 2005-03-16 | 杨立新 | Urapidil large volume injection, its preparation method and application |
| CN102988281A (en) * | 2012-12-11 | 2013-03-27 | 辽宁科泰生物基因制药股份有限公司 | Injection of ambroxol hydrochloride and preparation method thereof |
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| CN101637447B (en) * | 2009-08-31 | 2011-09-21 | 武汉武药科技有限公司 | Sitafloxacin hydrate injection and preparation method thereof |
| CN102988291B (en) * | 2012-12-13 | 2014-05-14 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
| CN110418791B (en) * | 2017-04-28 | 2022-07-01 | 四川科伦博泰生物医药股份有限公司 | Injection composition comprising benzodiazepine compound and method for preparing the same |
| CN110314133A (en) * | 2019-06-28 | 2019-10-11 | 石家庄四药有限公司 | A kind of metronidazole injection and preparation method thereof |
| CN113876705A (en) * | 2021-11-17 | 2022-01-04 | 石家庄四药有限公司 | Urapidil hydrochloride injection and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1593419A (en) * | 2004-06-24 | 2005-03-16 | 杨立新 | Urapidil large volume injection, its preparation method and application |
| CN102988281A (en) * | 2012-12-11 | 2013-03-27 | 辽宁科泰生物基因制药股份有限公司 | Injection of ambroxol hydrochloride and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023087578A1 (en) * | 2021-11-17 | 2023-05-25 | 石家庄四药有限公司 | Urapidil hydrochloride injection and preparation method therefor |
| CN114344255A (en) * | 2022-02-28 | 2022-04-15 | 远大生命科学(武汉)有限公司 | Urapidil hydrochloride injection and preparation method thereof |
| CN115645360A (en) * | 2022-10-08 | 2023-01-31 | 石家庄四药有限公司 | Urapidil hydrochloride injection |
| CN116869932A (en) * | 2023-08-25 | 2023-10-13 | 南京海科瑞医药科技有限公司 | Labetalol hydrochloride injection and preparation method thereof |
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