CN113368065A - Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof - Google Patents
Formulation of freeze-dried powder of methacholine chloride for inhalation and preparation method thereof Download PDFInfo
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- 229960002931 methacholine chloride Drugs 0.000 title claims abstract description 61
- JHPHVAVFUYTVCL-UHFFFAOYSA-M methacholine chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(C)=O JHPHVAVFUYTVCL-UHFFFAOYSA-M 0.000 title claims abstract description 61
- 239000000843 powder Substances 0.000 title claims abstract description 33
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 238000009472 formulation Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims description 19
- 238000004108 freeze drying Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000011049 filling Methods 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 230000001954 sterilising effect Effects 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 39
- 239000007788 liquid Substances 0.000 claims description 20
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 15
- 239000008215 water for injection Substances 0.000 claims description 13
- 229930182555 Penicillin Natural products 0.000 claims description 12
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 12
- 229940049954 penicillin Drugs 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008176 lyophilized powder Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 244000005700 microbiome Species 0.000 abstract description 3
- 229940041682 inhalant solution Drugs 0.000 abstract description 2
- 238000011068 loading method Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 21
- 239000002994 raw material Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000012982 microporous membrane Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000004806 packaging method and process Methods 0.000 description 8
- OWUBJZCBVVZIEG-UHFFFAOYSA-M trimethyl-[2-(2-oxopropoxy)ethyl]azanium chloride Chemical compound [Cl-].CC(=O)COCC[N+](C)(C)C OWUBJZCBVVZIEG-UHFFFAOYSA-M 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 230000036512 infertility Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 3
- 229960004266 acetylcholine chloride Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- MSIGGUSMCUUDGY-UHFFFAOYSA-M 2-methoxyethyl(trimethyl)azanium;chloride Chemical compound [Cl-].COCC[N+](C)(C)C MSIGGUSMCUUDGY-UHFFFAOYSA-M 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000004044 bronchoconstricting agent Substances 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
Classifications
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Otolaryngology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to a formulation of a freeze-dried powder of methacholine chloride for inhalation, which is characterized by comprising the following components: 0.5-40 wt% of methacholine chloride, and the balance of a solvent; the ratio of water in the solvent (volume of water/total volume of mixed solvent) is as follows: 0-30% (v/v), and the balance organic solvent. The freeze-dried powder of the methacholine chloride for inhalation provided by the invention is subjected to a freeze-drying process and is subjected to filtration sterilization, so that the aseptic level of the product is ensured, the product quality meets the requirements of Chinese pharmacopoeia on an inhalation solution, and the risk in the aspect of microorganisms is obviously reduced compared with non-aseptic products on the market abroad; meanwhile, the product is in a solution state during filling, which is beneficial to the accurate control of the product loading; in addition, because the product is in a low-temperature state in the production process, the stability can be fully ensured.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a formulation of a freeze-dried powder preparation of methacholine chloride for inhalation and a preparation method thereof.
Background
Methacholine Chloride (Methacholine Chloride) is a bronchoconstrictor and should be used only for airway hypersensitivity testing. The name of the commodity is
Developed by mathapharm Inc, approved by the FDA to be marketed in 1986. Through investigation, the existing marketed product is inhaled with methacholine chloride powder and is prepared by adopting a raw material powder subpackaging process, the methacholine chloride is very easy to absorb moisture and is easy to agglomerate and harden and adhere to equipment in the powder subpackaging process, so that the quality defects of prolonged redissolution time, inaccurate filling amount and the like exist, the humidity control on the production environment is very strict (the relative humidity of the environment is usually controlled to be less than 30 percent), and the conventional production workshop is difficult to achieve. In addition, the product needs to be re-dissolved into solution for use in clinical use, and is a sterile preparation according to the requirements of the current Chinese pharmacopoeia on solution absorption. If the powder subpackaging process is adopted for production, the raw material medicines are aseptic raw materials, the preparation adopts an aseptic powder subpackaging production line, the requirements on the aseptic guarantee level of the raw material medicines and a preparation production workshop are very strict, and fewer pharmaceutical production enterprises with the production conditions are provided. The products on the market abroad are non-sterile products due to the early time of marketing, and are used after redissolving and filter membrane sterilization filtration in the clinical use process, so the clinical use is inconvenient and the risk of high microorganism level exists.
Chinese patent CN110950767A provides a new crystal form of methacholine chloride bulk drug, the crystal form is not easy to absorb moisture and agglomerate, has uniform granularity and improved stability, is beneficial to preparation production, but still adopts powder split charging production, and does not solve the problems of sterility guarantee, longer redissolution time and the like.
Chinese patent CN111635327A provides an amorphous form of methacholine chloride bulk drug, and also does not solve the problems of preparation production and sterility assurance for improving the stability to moisture of bulk drug. Through the research of system documents, the related research disclosure of producing the methacholine chloride preparation by adopting a freeze-drying process is not found.
The invention provides a freeze-dried powder of methacholine chloride for inhalation and a preparation method thereof. The water-organic solvent for injection is selected as a solvent system, and the product is prepared through the steps of liquid preparation, filtration sterilization, filling, freeze-drying and the like, so that the problems of sterility guarantee, redissolution, filling amount and the like of the product are solved, and the preparation method has obvious technical advantages.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: a formulation of lyophilized powder of methacholine chloride for inhalation is provided.
The technical scheme for solving the technical problems is as follows:
a formulation of lyophilized powder of methacholine chloride for inhalation, comprising the following components:
0.5-40 wt% of methacholine chloride
The balance of solvent
Wherein the ratio of water in the solvent (volume of water/total volume of mixed solvent) is: 0-30% (v/v), and the balance organic solvent.
Preferably, the organic solvent is one or more of tert-butyl alcohol, ethanol, propylene glycol, acetonitrile and dimethyl sulfoxide.
Preferably, the mass percentage of the methacholine chloride in the formulation of the freeze-dried powder of the methacholine chloride for inhalation is 0.8-27%.
Furthermore, the mass percentage of the methacholine chloride in the preparation formula of the freeze-dried powder of the methacholine chloride for inhalation is 6-11%.
Preferably, the volume of the water for injection in the solvent accounts for 2-30%
Furthermore, the volume of the water for injection in the solvent accounts for 2-10%.
A second aspect of the invention provides a process for the preparation of a freeze-dried powder of methacholine chloride for inhalation comprising the steps of:
a. taking metered parts of methacholine chloride, water for injection and an organic solvent, and stirring until all the materials are dissolved to obtain a liquid medicine;
b. b, sterilizing and filtering the liquid medicine obtained in the step a through a microporous filter membrane of 0.1-0.22 microns, filling the liquid medicine into a penicillin bottle, and adding a rubber plug to obtain a liquid medicine product to be freeze-dried;
c. and c, putting the liquid medicine product obtained in the step b into a freeze dryer for freeze drying, quickly cooling to-40-45 ℃, preserving heat for 120-360 minutes, starting to vacuumize after a cold trap is cooled to-40-45 ℃, and slowly increasing the temperature to obtain the product.
Preferably, the vacuum degree of the vacuum pumping in the step c is 20-30 Pa.
Preferably, the slow temperature increase in step c is divided into three stages of temperature increases, and the specific temperature increase manner is as follows: slowly increasing the temperature of the shelf to-20 to-30 ℃, preserving heat for 9 to 20 hours, slowly increasing the temperature of the shelf to-10 to 10 ℃, preserving heat for 3 to 8 hours, finally increasing the temperature of the shelf to 25 to 50 ℃, and preserving heat for 4 to 10 hours to obtain the product.
The freeze-dried powder of the methacholine chloride for inhalation provided by the invention is subjected to a freeze-drying process and is subjected to filtration sterilization, so that the aseptic level of the product is ensured, the product quality meets the requirements of Chinese pharmacopoeia on an inhalation solution, and the risk in the aspect of microorganisms is obviously reduced compared with non-aseptic products on the market abroad; meanwhile, the product is in a solution state during filling, which is beneficial to the accurate control of the product loading; in addition, because the product is in a low-temperature state in the production process, the stability can be fully ensured.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
EXAMPLE 1 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 150mL of ethanol, and stirring until the raw material drug is completely dissolved (the mass percentage content of the methacholine chloride is about 0.8%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles, wherein the filling amount of each penicillin bottle is 15mL, adding a rubber plug in half, and freeze-drying in a freeze dryer. Sterilizing and filtering the medicinal liquid with 0.22 μm microporous membrane, filling into penicillin bottle, adding rubber plug, and freeze drying in freeze dryer. Quickly cooling the freeze dryer to-40-45 ℃ and preserving heat for 120 minutes, starting vacuumizing after the cold trap is cooled to-40-45 ℃, slowly increasing the temperature of a shelf to-20-30 ℃, preserving heat for 9 hours, slowly increasing the temperature of the shelf to-10 ℃, preserving heat for 4 hours, again increasing the temperature of the shelf to 25-30 ℃, preserving heat for 4 hours, and maintaining the vacuum degree at 20-30 Pa to prepare the methacholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
EXAMPLE 2 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 1mL of water for injection, stirring uniformly, adding propylene glycol to 50mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 2%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 5mL each bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Rapidly cooling to-40-45 ℃ by a freeze dryer, preserving heat for 240 minutes, starting vacuumizing after a cold trap is cooled to-40-45 ℃, slowly increasing the temperature of a shelf to-20-30 ℃, preserving heat for 9 hours, slowly increasing the temperature of the shelf to-10 ℃, preserving heat for 3 hours, again increasing the temperature of the shelf to 25-30 ℃, preserving heat for 4 hours, and maintaining the vacuum degree at 20-30 Pa to prepare a methacholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
Example 3 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 0.2mL of water for injection, stirring uniformly, adding tert-butyl alcohol to 10mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 11.2%). Sterilizing and filtering the liquid medicine by a 0.1 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 1mL per bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling to-45 ℃ by a freeze dryer, preserving heat for 4 hours, starting vacuumizing after a cold trap is cooled to-40 to-45 ℃, slowly (1 hour) increasing the temperature of a shelf to-25 ℃, and preserving heat for 9 hours; slowly (half an hour) raising the temperature of the shelf to-10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 0 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 30 ℃, and keeping the temperature for 4 hours; rapidly heating to 50 ℃, keeping the temperature for half an hour, and maintaining the vacuum degree at about 20Pa to obtain the methacholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
Example 4 Acetylmethylcholine chloride powder for inhalation
0.5g of self-made raw material drug of methacholine chloride is weighed, 0.2mL of water for injection is added, the mixture is stirred evenly, tert-butyl alcohol is added to 10mL, and the mixture is stirred until the mixture is completely dissolved (the mass percentage of the methacholine chloride is about 6%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 2mL each bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling to-45 ℃ by a freeze dryer, preserving heat for 3 hours, starting vacuumizing after a cold trap is cooled to-40 to-45 ℃, slowly (1 hour) increasing the temperature of a shelf to-25 ℃, and preserving heat for 9 hours; slowly (half an hour) raising the temperature of the shelf to-10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 0 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 10 ℃, and keeping the temperature for 3 hours; slowly (half an hour) raising the temperature of the shelf to 30 ℃, and keeping the temperature for 4 hours; the temperature is quickly raised to 50 ℃, and the temperature is kept for half an hour. Maintaining the vacuum degree at about 20Pa to obtain acetylcholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
EXAMPLE 5 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 0.5mL of water for injection, stirring uniformly, adding tert-butyl alcohol to 10mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 11.2%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 1mL in each bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling to-45 ℃ by a freeze dryer, preserving heat for 240 minutes, starting vacuumizing after a cold trap is cooled to-40 to-45 ℃, slowly (1 hour) increasing the temperature of a shelf to-25 ℃, and preserving heat for 9 hours; slowly (half an hour) raising the temperature of the shelf to-10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 0 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 30 ℃, and keeping the temperature for 4 hours; the temperature is quickly raised to 50 ℃, and the temperature is kept for half an hour. Maintaining the vacuum degree at about 20Pa to obtain acetylcholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
EXAMPLE 6 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 0.8mL of water for injection, stirring uniformly, adding tert-butyl alcohol to 10mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 11%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 1mL in each bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling to-45 ℃ by a freeze dryer, preserving heat for 240 minutes, starting vacuumizing after a cold trap is cooled to-40 to-45 ℃, slowly (1 hour) increasing the temperature of a shelf to-25 ℃, and preserving heat for 9 hours; slowly (half an hour) raising the temperature of the shelf to-10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 0 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 10 ℃, and keeping the temperature for 1 hour; slowly (half an hour) raising the temperature of the shelf to 30 ℃, and keeping the temperature for 4 hours; the temperature is quickly raised to 50 ℃, and the temperature is kept for half an hour. Maintaining the vacuum degree at about 20Pa to obtain acetylcholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
EXAMPLE 7 Acetylmethylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 0.5mL of water for injection, stirring uniformly, adding acetonitrile to 5mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 20%). Sterilizing and filtering the liquid medicine by a 0.1 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 0.5mL per bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling to-45 ℃ by a freeze dryer, preserving heat for 360 minutes, starting vacuumizing after a cold trap is cooled to-40 to-45 ℃, slowly (1 hour) increasing the temperature of a shelf to-30 ℃, and preserving heat for 20 hours; slowly (half an hour) raising the temperature of the shelf to-10 ℃, and keeping the temperature for 3 hours; slowly (half an hour) raising the temperature of the shelf to 0 ℃, and keeping the temperature for 3 hours; slowly (half an hour) raising the temperature of the shelf to 10 ℃, and keeping the temperature for 2 hours; slowly (half an hour) raising the temperature of the shelf to 25-30 ℃, and keeping the temperature for 10 hours. Maintaining the vacuum degree at 20-30 Pa to prepare a methacholine chloride product for inhalation; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
Example 8 Methylcholine chloride powder for inhalation
Weighing 1g of home-made raw material drug of methacholine chloride, adding 0.75mL of water for injection, stirring uniformly, adding dimethyl sulfoxide to 2.5mL, and stirring until the raw material drug is completely dissolved (the mass percentage of the methacholine chloride is about 27%). Sterilizing and filtering the liquid medicine by a 0.22 mu m microporous membrane, filling into 20mL penicillin bottles with the filling amount of 0.25mL in each bottle, adding a rubber plug in half, and freeze-drying in a freeze dryer. Quickly cooling the freeze dryer to-40 to-45 ℃ and preserving heat for 360 minutes, starting vacuumizing after the cold trap is cooled to-40 to-45 ℃, slowly increasing the temperature of a shelf to-20 to-30 ℃, preserving heat for 20 hours, slowly increasing the temperature of the shelf to-10 to 10 ℃, preserving heat for 8 hours, again increasing the temperature of the shelf to 25 to 30 ℃, preserving heat for 10 hours, and maintaining the vacuum degree at 20 to 30Pa to prepare the methacholine chloride product for suction; and after the water and organic solvent residues are measured to be qualified, backfilling nitrogen into the freeze-drying box to normal pressure, fully plugging, taking out the freeze-drying box, capping and packaging.
EXAMPLE 9 product testing of the prepared Acetylmethylcholine chloride powder for inhalation
The quality of the products prepared in the examples 1 to 8 provided by the invention is detected, and the main indexes comprise: the product properties, impurities, reconstitution time (all dissolved in 6.25mL sodium chloride injection), water content, organic solvent residue, sterility test, and the test results are shown in Table 1. From the results it can be seen that: the product prepared by the invention has short redissolution time, low impurity level, moisture and residual solvent meeting the requirements of pharmacopoeia, is an aseptic product after filtration sterilization, and has low microbial risk. Among them, the examples 3 to 6, which use tert-butanol as an organic solvent, are more advantageous in terms of reconstitution time, moisture, residual solvent, etc. than the other examples, and the most preferable example is example 4.
TABLE 1 product quality test results of the invention
Example 10 quality comparison with commercially available methacholine chloride powder
The quality of the product prepared by the preferred prescription of the product (example 4) is compared with the commercial methacholine chloride powder preparation product (trade name: Provocoline), and the result is shown in Table 2, and the self-made product has advantages in the aspects of sterility guarantee, redissolution time, impurity content and the like.
TABLE 2 comparison of quality of the self-made products with the commercial products
Note: the structural formula of the impurities 1-3 is as follows
Impurity 1:
impurity 2:
impurity 3:
the above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (10)
1. The formulation of a freeze-dried powder preparation of methacholine chloride for inhalation is characterized by comprising the following components:
0.5-40 wt% of methacholine chloride
The balance of solvent
Wherein the ratio of water in the solvent (volume of water/total volume of mixed solvent) is: 0-30% (v/v), and the balance organic solvent.
2. The formulation of lyophilized powder of methacholine chloride for inhalation of claim 1 wherein the organic solvent is one or more of t-butanol, ethanol, propylene glycol, acetonitrile and dimethyl sulfoxide.
3. The formulation of claim 1, wherein the content of the methacholine chloride in the formulation of the lyophilized powder of methacholine chloride for inhalation is 0.8-27% by mass.
4. The formulation of claim 3, wherein the content of the methacholine chloride in the formulation of the lyophilized powder for inhalation is 6-11% by weight.
5. The formulation of a lyophilized powder of methacholine chloride for inhalation according to claim 1, wherein the volume of the water for injection in the solvent is 2% to 30%.
6. The formulation of a lyophilized powder of methacholine chloride for inhalation according to claim 5, wherein the volume of the water for injection in the solvent is 2% to 10%.
7. A process for the preparation of a freeze-dried powder of methacholine chloride for inhalation, wherein the formulation of the freeze-dried powder of methacholine chloride for inhalation is according to any one of claims 1 to 6, comprising the steps of:
a. taking metered parts of methacholine chloride, water for injection and an organic solvent, and stirring until all the materials are dissolved to obtain a liquid medicine;
b. b, sterilizing and filtering the liquid medicine obtained in the step a through a microporous filter membrane of 0.1-0.22 microns, filling the liquid medicine into a penicillin bottle, and adding a rubber plug to obtain a liquid medicine product to be freeze-dried;
c. and c, putting the liquid medicine product obtained in the step b into a freeze dryer for freeze drying, quickly cooling to-40-45 ℃, preserving heat for 120-360 minutes, starting to vacuumize after a cold trap is cooled to-40-45 ℃, and slowly increasing the temperature to obtain the product.
8. The method for preparing a freeze-dried powder of methacholine chloride for inhalation according to claim 7, wherein the degree of vacuum of the vacuum pumping in step c is 20 to 30 Pa.
9. The method for preparing a freeze-dried powder of methacholine chloride for inhalation according to claim 7, wherein the slow temperature increase in step c is divided into three temperature increases.
10. A process for the preparation of a freeze-dried powder of methacholine chloride for inhalation according to claim 9, wherein the three-stage raising of the specific raising temperature is carried out in the following manner: slowly increasing the temperature of the shelf to-20 to-30 ℃, preserving heat for 9 to 20 hours, slowly increasing the temperature of the shelf to-10 to 10 ℃, preserving heat for 3 to 8 hours, finally increasing the temperature of the shelf to 25 to 50 ℃, and preserving heat for 4 to 10 hours to obtain the product.
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