CN113143868B - Papaverine hydrochloride for injection and preparation method thereof - Google Patents
Papaverine hydrochloride for injection and preparation method thereof Download PDFInfo
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- CN113143868B CN113143868B CN202110233742.9A CN202110233742A CN113143868B CN 113143868 B CN113143868 B CN 113143868B CN 202110233742 A CN202110233742 A CN 202110233742A CN 113143868 B CN113143868 B CN 113143868B
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- papaverine hydrochloride
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- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 229960003207 papaverine hydrochloride Drugs 0.000 title claims abstract description 87
- 238000002347 injection Methods 0.000 title claims abstract description 66
- 239000007924 injection Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 53
- 239000008215 water for injection Substances 0.000 claims abstract description 40
- 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 abstract description 34
- 229930195725 Mannitol Natural products 0.000 claims abstract description 34
- 235000010355 mannitol Nutrition 0.000 claims abstract description 34
- 239000000594 mannitol Substances 0.000 claims abstract description 34
- 238000004108 freeze drying Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 39
- 239000007788 liquid Substances 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- 230000003115 biocidal effect Effects 0.000 claims description 19
- 239000011521 glass Substances 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 238000001179 sorption measurement Methods 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 230000001502 supplementing effect Effects 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 13
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 12
- 230000001954 sterilising effect Effects 0.000 claims description 12
- 238000007710 freezing Methods 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 11
- 238000005262 decarbonization Methods 0.000 claims description 10
- 238000005261 decarburization Methods 0.000 claims description 10
- 238000004140 cleaning Methods 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 7
- 229920005549 butyl rubber Polymers 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 238000007602 hot air drying Methods 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 229930008281 A03AD01 - Papaverine Natural products 0.000 claims description 2
- 229960001789 papaverine Drugs 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000011146 sterile filtration Methods 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 238000000859 sublimation Methods 0.000 abstract description 7
- 230000008022 sublimation Effects 0.000 abstract description 7
- 238000001035 drying Methods 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 6
- 230000000857 drug effect Effects 0.000 abstract description 4
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 3
- 230000002542 deteriorative effect Effects 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 17
- 229920001971 elastomer Polymers 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 206010003175 Arterial spasm Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010008132 Cerebral thrombosis Diseases 0.000 description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000018152 Cerebral disease Diseases 0.000 description 1
- 206010065420 Coronary artery dilatation Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- 210000000626 ureter Anatomy 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses papaverine hydrochloride for injection and a preparation method thereof, and provides papaverine hydrochloride for injection, which takes mannitol as a low-temperature protective agent and an excipient to protect the papaverine hydrochloride from deteriorating in a low-temperature freeze-drying environment and enhance the stability of the papaverine hydrochloride. On the other hand, the preparation method of the papaverine hydrochloride for injection is also provided, and the papaverine hydrochloride has better stability and solubility by adjusting the proper pH value and the temperature of water for injection; proper prefreezing time and temperature and proper sublimation drying method are selected, so that the papaverine hydrochloride is completely dried, the stability is improved, the solubility of the medicine is good, the product is convenient to use, the drug effect is ensured, and the use safety of the product is improved. The invention is used for solving the technical problems that the existing papaverine hydrochloride is easily degraded into the papaverol in the long-term storage process, the stability is poor, the moisture content in the medicine is more, and the medicine effect of the medicine is influenced.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to papaverine hydrochloride for injection and a preparation method thereof.
Background
Papaverine hydrochloride is an isoquinoline type alkaloid with molecular formula of C20H21NO4It is a major alkaloid in poppy, has the effect of relaxing smooth muscles of blood vessels, bronchus, gastrointestinal tract, bile duct and the like, and can reduce coronary artery dilatation, peripheral resistance and cerebrovascular resistance by relaxing the smooth muscles of the blood vessels, and is mainly used for cerebral thrombosis, pulmonary embolism, limb arterial spasm, arterial embolic pain and the like. The medicine is mainly used for relieving cerebral and peripheral vascular diseases accompanied with arterial spasm, and treating cerebral thrombosis, pulmonary embolism, limb arterial spasm, arterial embolism pain and the like; can also be used for treating spasm pain of intestinal tract, ureter and biliary tract and dysmenorrhea, and can be used as one component of compound bronchodilator spray; it can also be used for treating hypertension, angina pectoris, and arrhythmia complicated with ischemia of heart.
The papaverine hydrochloride is prepared into freeze-dried powder injection, so that the problems of oxidation and hydrolysis of the medicine in the preparation process are reduced, and the freeze-dried powder injection has faster effect and higher bioavailability than the common powder injection. The existing papaverine hydrochloride is easily degraded into the papaverol in the long-term storage process, the stability is poor, the water content in the medicine is more, and the medicine effect of the medicine is influenced. Therefore, there is an urgent need to provide papaverine hydrochloride for injection and a preparation method thereof to solve the above problems.
Disclosure of Invention
The invention provides papaverine hydrochloride for injection and a preparation method thereof, which are used for solving the technical problems that the existing papaverine hydrochloride is easily degraded into papaverol in the long-term storage process, the stability is poor, the water content in a medicine is more, and the medicine effect of the medicine is influenced.
In view of the above, the invention provides papaverine hydrochloride for injection, each thousand bottles comprise the following components in parts by weight: 30g of papaverine hydrochloride; 100g of mannitol; the volume of the water for injection is up to 2000 ml.
The invention also provides a preparation method of the papaverine hydrochloride for injection based on the papaverine hydrochloride for injection, which comprises the following steps:
(1) pretreatment of the process: cleaning an antibiotic glass bottle and a rubber plug by ultrasonic waves, and sterilizing at high temperature for later use;
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount, adding 80% water for injection in the prescription amount into a preparation tank, stirring to fully dissolve the papaverine hydrochloride and the mannitol, adjusting the pH value to 2.8-3.5 by using citric acid, supplementing the water for injection to the full amount, adding active carbon for adsorption for 30min, and then removing carbon;
(3) sterilizing and filtering;
(4) filling;
(5) and (3) freeze drying: putting the filled sample into a freeze dryer, cooling to-40 ℃, and pre-freezing for 2 hours; after pre-freezing, maintaining the sample in a vacuum environment for 10 hours, and heating the sample to 0 ℃ during the period; then continuously maintaining the sample in a vacuum environment to heat the sample to 10 ℃, and preserving the heat for 10 hours;
(6) and (5) after the freeze drying is finished, performing full-pressure plugging, taking out the bottle, capping and packaging.
Optionally, in the step (1), the antibiotic glass bottle is cleaned by ultrasonic waves, washed by purified water and water for injection again, and sterilized at a high temperature of 350 ℃ for later use; cleaning the rubber plug by ultrasonic wave, rinsing with water for injection, sterilizing at 121 deg.C for 30min, and hot air drying.
Optionally, in step (2), stirring for at least 20 min.
Optionally, adding 80% of the prescription amount of water for injection at a temperature of 9-15 ℃; the temperature for supplementing the water for injection is 4-10 ℃.
Alternatively, in the step (3), the sterilizing filtration comprises filtration twice using a cartridge filter with a 0.2 μm microporous membrane.
Optionally, in the step (4), the filling comprises filling the sample obtained in the step (3) into an antibiotic glass bottle, and inserting a rubber plug into a half of the opening of the antibiotic glass bottle.
Optionally, the plug is a pharmaceutical butyl plug.
Optionally, in the step (2), the adding amount of the activated carbon is 0.02% of the total weight of the preparation solution.
Optionally, in the step (5), the vacuum environment is an environment which is vacuumized to 15 Pa.
According to the technical scheme, the embodiment of the invention has the following advantages:
the invention provides papaverine hydrochloride for injection, which comprises the following components in parts by weight per thousand bottles: 30g of papaverine hydrochloride; 100g of mannitol; the volume of the water for injection is up to 2000 ml. Mannitol is used as cryoprotectant and excipient to protect papaverine hydrochloride from deterioration in low temperature freeze drying environment and enhance its stability.
On the other hand, the invention also provides a preparation method of the papaverine hydrochloride for injection based on the papaverine hydrochloride for injection, which is characterized in that the antibiotic glass bottle and the rubber plug are subjected to deep ultrasonic cleaning before the process, and then are subjected to high-temperature sterilization, so that the antibiotic glass bottle and the rubber plug are prevented from polluting medicines during use. The papaverine hydrochloride has better stability and solubility by adjusting the proper pH value; sublimation drying is the key stage of freeze-drying, selects suitable time and temperature of prefreezing and proper sublimation drying method for papaverine hydrochloride is dry completely, and stability improves, and the dissolubility of medicine is better, makes things convenient for the product to use, guarantees the drug effect, improves the safety in utilization of product.
The invention provides papaverine hydrochloride for injection and a preparation method thereof, which are used for solving the technical problems that the existing papaverine hydrochloride is easily degraded into papaverol in the long-term storage process, the stability is poor, the water content in a medicine is more, and the medicine effect of the medicine is influenced.
Detailed Description
In order to make those skilled in the art better understand the technical solutions of the present invention, the following embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
Example 1
The invention provides an embodiment of papaverine hydrochloride for injection and a preparation method thereof, wherein each thousand bottles of papaverine hydrochloride for injection comprise the following components in parts by weight: 30g of papaverine hydrochloride; 100g of mannitol; the volume of the water for injection is up to 2000 ml.
The preparation process comprises the following steps:
(1) pretreatment of the process: cleaning an antibiotic glass bottle and a medicinal butyl rubber plug by ultrasonic waves, and sterilizing at high temperature for later use;
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of injection water in the prescription amount into the preparation tank, and stirring to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the injection water is 9-15 ℃; adjusting the pH value to 2.8-3.5 by using citric acid, supplementing the injection water to the full amount, wherein the temperature of the supplemented injection water is 4-10 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate;
(3) taking the filtrate obtained in the step (2) for sterilization filtration, and filtering the filtrate twice through a cylindrical filter with a 0.2 mu m microporous membrane;
(4) filling: filling the sample obtained in the step (3) into an antibiotic glass bottle, and plugging a medical butyl rubber plug into a half of the opening of the antibiotic glass bottle, so as to facilitate the subsequent freeze drying step;
(5) and (3) freeze drying: putting the filled sample into a freeze dryer, cooling to-40 ℃, and pre-freezing for 2 hours; after pre-freezing, maintaining the sample in an environment of vacuumizing to 15Pa for 10 hours, and heating the sample to 0 ℃ during the period; then continuously maintaining the sample in an environment of vacuumizing to 15Pa, heating the sample to 10 ℃, and preserving the temperature for 10 hours;
(6) and (5) after the freeze drying is finished, performing full-pressure plugging, taking out the bottle, capping and packaging.
The invention provides papaverine hydrochloride for injection, which comprises the following components in parts by weight per thousand bottles: 30g of papaverine hydrochloride; 100g of mannitol; the volume of the water for injection is up to 2000 ml. Mannitol is used as cryoprotectant and excipient to protect papaverine hydrochloride from deterioration in low temperature freeze drying environment and enhance its stability. On the other hand, the preparation method of the papaverine hydrochloride for injection is provided, the water for injection is prepared by taking purified water as a water source and passing through a multi-effect distiller, and the influence of any impurity is avoided in the preparation process of the medicine; the medicinal butyl rubber plug has better intrinsic cleanliness, chemical stability, air tightness and biological performance, and can reduce the adsorption condition between the rubber plug and the medicament. The antibiotic glass bottle and the rubber plug are subjected to deep cleaning by ultrasonic waves before the process, and then are subjected to high-temperature sterilization, so that the antibiotic glass bottle and the rubber plug are prevented from polluting medicines when in use. By adjusting a proper pH value, papaverine hydrochloride has better stability and solubility, and the capacities of adsorbing pigment and removing heat source substances by activated carbon are increased; sublimation drying is the key stage of freeze-drying, selects suitable time and temperature of prefreezing and proper sublimation drying method for papaverine hydrochloride is dry completely, and stability improves, and the dissolubility of medicine is better, makes things convenient for the product to use, guarantees the drug effect, improves the safety in utilization of product.
The invention provides papaverine hydrochloride for injection and a preparation method thereof, which are used for solving the technical problems that the existing papaverine hydrochloride is easily degraded into papaverol in the long-term storage process, the stability is poor, the water content in a medicine is more, and the medicine effect of the medicine is influenced.
Example 2
As a further modification to example 1, the difference from example 1 is that:
(1) pretreatment of the process: cleaning an antibiotic glass bottle by ultrasonic waves, washing the antibiotic glass bottle by purified water and water for injection, and sterilizing the antibiotic glass bottle at the high temperature of 350 ℃ for later use; cleaning the medicinal butyl rubber plug by ultrasonic wave, rinsing with water for injection, sterilizing at 121 deg.C for 30min, and hot air drying;
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% water for injection in the prescription amount into the preparation tank, stirring for 20min to fully dissolve papaverine hydrochloride and mannitol, wherein the temperature of water for injection is 9 ℃; adjusting the pH value to 2.8 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 4 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate;
(5) and (3) freeze drying: setting the temperature of a freeze dryer to be 10 ℃, and preserving the temperature until all filled samples are transferred into a freeze drying box; after the filled samples are all put into a freeze dryer, rapidly cooling to-40 ℃, and pre-freezing for 2 hours; after pre-freezing, maintaining the sample in an environment of vacuumizing to 15Pa for 10 hours, wherein the temperature rise rate of the sample is 5 ℃/h, and keeping the temperature for 2h after the temperature rises to 0 ℃; then the sample is continuously maintained in the environment of vacuumizing to 15Pa, the temperature of the sample is increased to 10 ℃, and the temperature is kept for 10 hours.
The temperature of the freeze dryer is set to be 10 ℃, so that the quality of all the medicines is uniform and stable before freeze drying; cooling the sample to-40 deg.C within 30min for pre-freezing to quickly coagulate the water in the medicinal liquid into uniform ice crystals, so as to form water sublimation channels and quickly sublimate the free water in the medicine; the free water and crystal water in the drug are removed by sublimation drying.
Example 3
The difference between this example and example 2 is:
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, stirring for 25min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 10 ℃; adjusting the pH value to 3.0 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 5 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
Example 4
The difference between this example and example 2 is:
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring for 30min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 12 ℃; adjusting the pH value to 3.2 by using citric acid, supplementing the injection water to the full amount, wherein the temperature of the supplemented injection water is 7 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
Example 5
The difference between this example and example 2 is:
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring for 20min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 14 ℃; adjusting the pH value to 3.4 by using citric acid, supplementing the injection water to the full amount, wherein the temperature of the supplemented injection water is 8 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
Example 6
The difference between this example and example 2 is:
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring for 20min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 15 ℃; adjusting the pH value to 3.5 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 10 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
Comparative example 1
The comparative example provides papaverine hydrochloride for injection and a preparation method thereof, and the difference from the example 2 is that:
(5) and (3) freeze drying: putting the filled sample into a freeze dryer, cooling to-45 ℃, and pre-freezing for 7 hours; after pre-freezing, maintaining the sample in a vacuum environment for 10 hours, and heating the sample to 0 ℃ during the period; then the sample is continuously maintained in the environment of vacuumizing to 15Pa, the temperature of the sample is raised to 30 ℃, and the temperature is kept for 10 hours.
Comparative example 2
The comparative example provides papaverine hydrochloride for injection and a preparation method thereof, and the difference from the example 2 is that:
weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 40 ℃; adjusting the pH value to 2.8 by using citric acid, supplementing the injection water to the full amount, and controlling the temperature of the supplemented injection water to be 40 ℃; adding active carbon for adsorption for 30min, and filtering with titanium rod to remove carbon.
Comparative example 3
The comparative example provides papaverine hydrochloride for injection and a preparation method thereof, and the difference from the example 2 is that:
weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 7 ℃; adjusting the pH value to 2.8 by using citric acid, supplementing the injection water to full dose, and controlling the temperature of the supplemented injection water to be 3 ℃; adding active carbon for adsorption for 30min, and filtering with titanium rod to remove carbon.
Comparative example 4
The comparative example provides papaverine hydrochloride for injection and a preparation method thereof, and the difference from the example 2 is that:
weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring for 20min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 9 ℃; adjusting the pH value to 4.0 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 4 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
Comparative example 5
The comparative example provides papaverine hydrochloride for injection and a preparation method thereof, and the difference from the example 2 is that:
weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, and stirring for 20min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 9 ℃; adjusting the pH value to 5.0 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 4 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
In order to illustrate the advantages of the present invention, the quality test of the papaverine hydrochloride for injection prepared in the above examples and comparative examples is as follows:
1. measuring the content of the papaverine hydrochloride for injection prepared in the embodiments 2 to 6 and the comparative examples 1 to 5 according to a detection method provided in the Chinese pharmacopoeia 2015 edition; respectively placing 30mg of the prepared papaverine hydrochloride sample for injection into a Karl Fischer moisture tester for moisture detection; the papaverine hydrochloride for injection prepared by 30mg was dissolved in 5ml of water for injection at normal temperature, and the change in appearance was observed, and the results were as follows:
as can be seen from the above table, when the pH value of the solution is 2.8-3.5, the content of papaverine hydrochloride is not very different, but the content of papaverine hydrochloride in the solution tends to decrease with the gradual decrease of acidity; when the pH value is adjusted to 4.0 in the comparative example 4, the adsorption of the activated carbon on the pigment and the heat source substance in the medicine is incomplete, and the solution is light yellow, while when the pH value is adjusted to 5.0 in the comparative example 5, the incomplete adsorption is aggravated, the solubility of the medicine is reduced, the content of papaverine hydrochloride in the medicine is obviously reduced, and the papaverine hydrochloride is converted into papaverine due to the over-high pH value, so that the medicine effect is influenced. The papaverine hydrochloride for injection prepared in the comparative examples 1 to 5 has a large water content, which indicates that the water content of the injection water is increased due to the temperature of the injection water, the pH value of the solution or the change of freeze-drying conditions, and the drug effect of the drug is influenced.
2. The papaverine hydrochloride for injection prepared in examples 2 to 6 and comparative examples 1 to 5 was subjected to stability test, and the content of papaverine hydrochloride was measured at storage times of 0, 6, 12, 18 and 24 months, respectively, and the results were as follows:
as can be seen from the above table, the papaverine hydrochloride for injection prepared in examples 2 to 6 has good storage stability, while comparative examples 1 to 5 have poor storage stability at room temperature and are not suitable for long-term storage.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (2)
1. A method for preparing papaverine hydrochloride for injection comprises the following steps:
(1) pretreatment of the process: cleaning an antibiotic glass bottle by ultrasonic waves, washing the antibiotic glass bottle by purified water and water for injection, and sterilizing the antibiotic glass bottle at the high temperature of 350 ℃ for later use; cleaning the medicinal butyl rubber plug by ultrasonic wave, rinsing with water for injection, sterilizing at 121 deg.C for 30min, and hot air drying;
(2) preparing liquid: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% water for injection in the prescription amount into the preparation tank, stirring for 20min to fully dissolve papaverine hydrochloride and mannitol, wherein the temperature of water for injection is 9 ℃; adjusting the pH value to 2.8 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 4 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate;
(3) performing sterile filtration, namely performing sterile filtration on the filtrate obtained in the step (2), and filtering the filtrate twice through a cylindrical filter with a 0.2 mu m microporous membrane;
(4) filling, namely filling the sample obtained in the step (3) into an antibiotic glass bottle, and filling a medical butyl rubber plug into one half of the opening of the antibiotic glass bottle, so as to be beneficial to performing the subsequent freeze drying step;
(5) and (3) freeze drying: setting the temperature of a freeze dryer to be 10 ℃, and preserving the temperature until all filled samples are transferred into a freeze drying box; after the filled samples are all put into a freeze dryer, rapidly cooling to-40 ℃, and pre-freezing for 2 hours; after pre-freezing, maintaining the sample in an environment of vacuumizing to 15Pa for 10 hours, wherein the temperature rise rate of the sample is 5 ℃/h, and keeping the temperature for 2h after the temperature rises to 0 ℃; then continuously maintaining the sample in an environment of vacuumizing to 15Pa, heating the sample to 10 ℃, and preserving the temperature for 10 hours;
(6) and (3) after the freeze drying is finished, taking out and capping, and packaging, wherein each thousand bottles of the injection hydrochloride papaverine comprise the following components in parts by weight: 30g of papaverine hydrochloride; 100g of mannitol; the volume of the water for injection is up to 2000 ml.
2. The method for preparing papaverine hydrochloride for injection according to claim 1, wherein the solution preparation operation in the step (2) is replaced with: weighing papaverine hydrochloride and mannitol in a prescription amount into a preparation tank, adding 80% of water for injection in the prescription amount into the preparation tank, stirring for 25min to fully dissolve the papaverine hydrochloride and the mannitol, wherein the temperature of the water for injection is 10 ℃; adjusting the pH value to 3.0 by using citric acid, supplementing the injection water to the full dose, wherein the temperature of the supplemented injection water is 5 ℃; adding active carbon accounting for 0.02 percent of the total weight of the prepared solution for adsorption for 30min, and then carrying out decarburization treatment; the decarbonization treatment comprises circulating the liquid medicine for 5min through a 5 mu m titanium rod filter, and then roughly filtering the liquid medicine through a 0.45 mu m cylinder filter to obtain filtrate.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482426B1 (en) * | 1998-09-17 | 2002-11-19 | Zonagen, Inc. | Compositions for the treatment of male erectile dysfunction |
| CN1390545A (en) * | 2002-04-15 | 2003-01-15 | 高华 | Prescription and preparing process of dispamil injection |
| CN111796043A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride powder injection for injection and quality detection method thereof |
| CN111789818A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN111848512A (en) * | 2020-08-15 | 2020-10-30 | 山东北大高科华泰制药有限公司 | Powder injection pharmaceutical composition prepared from high-purity papaverine hydrochloride |
-
2021
- 2021-03-03 CN CN202110233742.9A patent/CN113143868B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482426B1 (en) * | 1998-09-17 | 2002-11-19 | Zonagen, Inc. | Compositions for the treatment of male erectile dysfunction |
| CN1390545A (en) * | 2002-04-15 | 2003-01-15 | 高华 | Prescription and preparing process of dispamil injection |
| CN111796043A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride powder injection for injection and quality detection method thereof |
| CN111789818A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN111848512A (en) * | 2020-08-15 | 2020-10-30 | 山东北大高科华泰制药有限公司 | Powder injection pharmaceutical composition prepared from high-purity papaverine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 注射用盐酸罂粟碱冻干曲线的研究;房磊等;《黑龙江医药》;20081231;第21卷(第4期);第63-64页 * |
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