CN113712912A - Terbutaline sulfate oral liquid and production method thereof - Google Patents
Terbutaline sulfate oral liquid and production method thereof Download PDFInfo
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- CN113712912A CN113712912A CN202111093926.6A CN202111093926A CN113712912A CN 113712912 A CN113712912 A CN 113712912A CN 202111093926 A CN202111093926 A CN 202111093926A CN 113712912 A CN113712912 A CN 113712912A
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- terbutaline sulfate
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- 239000007788 liquid Substances 0.000 title claims abstract description 142
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960005105 terbutaline sulfate Drugs 0.000 title claims abstract description 71
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 114
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 56
- 238000002360 preparation method Methods 0.000 claims abstract description 55
- 238000011049 filling Methods 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 33
- 238000003756 stirring Methods 0.000 claims abstract description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 27
- 239000008213 purified water Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 238000007865 diluting Methods 0.000 claims abstract description 6
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 238000006392 deoxygenation reaction Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 18
- 239000002738 chelating agent Substances 0.000 claims description 14
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 11
- 238000007872 degassing Methods 0.000 claims description 9
- 230000002209 hydrophobic effect Effects 0.000 claims description 9
- 239000000473 propyl gallate Substances 0.000 claims description 6
- 229940075579 propyl gallate Drugs 0.000 claims description 6
- 235000010388 propyl gallate Nutrition 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- 239000004695 Polyether sulfone Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 229920006393 polyether sulfone Polymers 0.000 claims description 4
- 230000001737 promoting effect Effects 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 15
- 230000003647 oxidation Effects 0.000 abstract description 8
- 238000007254 oxidation reaction Methods 0.000 abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 20
- 239000001301 oxygen Substances 0.000 description 20
- 229910052760 oxygen Inorganic materials 0.000 description 20
- 238000000034 method Methods 0.000 description 11
- 238000007599 discharging Methods 0.000 description 10
- 239000007789 gas Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 229910021645 metal ion Inorganic materials 0.000 description 6
- 230000006866 deterioration Effects 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000007975 buffered saline Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010036595 Premature delivery Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000005361 soda-lime glass Substances 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
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- 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
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
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- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
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Abstract
The invention discloses a production method of terbutaline sulfate oral liquid, which comprises the following steps: s1, adding terbutaline sulfate and auxiliary agent into a liquid preparation tank, filling nitrogen into the tank, exhausting air in the tank, performing vacuum suction, exhausting nitrogen, sucking preparation water into the liquid preparation tank by using negative pressure, and stirring for dissolving to obtain a liquid medicine; s2, adding 1-3 wt% of sodium hydroxide solution into the liquid medicine, adjusting the pH value to 4.0 +/-0.5, then adding purified water, diluting the liquid medicine to the prescribed amount, and mixing uniformly to obtain a filling liquid; and S3, filling nitrogen into the liquid preparation tank, transferring the filling liquid into a filter for filtering to obtain a filtrate, and filling the filtrate into a medicine bottle to obtain the terbutaline sulfate oral liquid. The production method can effectively reduce the oxidation of the oral liquid and reduce the impurity content of the oral liquid.
Description
Technical Field
The invention relates to the field of liquid medicine production, in particular to terbutaline sulfate oral liquid and a production method thereof.
Background
Terbutaline sulfate has antiasthmatic and expectorant effects, and can be used as beta clinically2Adrenoreceptor agonists are widely used in the treatment of bronchial asthma, asthmatic bronchitis, bronchiectasis and other conditions, and also in the prevention of premature delivery.
The chemical name of the terbutaline sulfate is alpha- [ (tertiary butylamino) methyl ] -3, 5-dihydroxyphenyl methanol sulfate, the molecule of the terbutaline sulfate contains 2 phenolic hydroxyl groups, and the terbutaline sulfate is easy to oxidize in the process of preparing oral solution, so that the content of impurities is increased, the color of the product is darkened, and the quality of the product is seriously influenced.
Disclosure of Invention
The application provides terbutaline sulfate oral liquid and a production method thereof, which can obviously reduce the oxidative deterioration of terbutaline sulfate in the preparation process of the oral liquid, thereby ensuring the quality of products.
In a first aspect, the present application provides a method for producing terbutaline sulfate oral liquid, comprising the following steps:
s1, adding terbutaline sulfate and an auxiliary agent into a liquid preparation tank, filling nitrogen into the tank, exhausting air in the tank, performing vacuum suction, exhausting nitrogen, sucking 75-85% of purified water for preparation into the liquid preparation tank by using negative pressure, and stirring and dissolving to obtain a liquid medicine;
s2, adding 1-3 wt% of sodium hydroxide solution into the liquid medicine, adjusting the pH value to 4.0 +/-0.5, adding the rest purified water for preparation, diluting the liquid medicine to the prescription amount, and mixing uniformly to obtain a filling liquid;
and S3, filling nitrogen into the liquid preparation tank, transferring the filling liquid into a filter for filtering to obtain a filtrate, and filling the filtrate into a medicine bottle to obtain the terbutaline sulfate oral liquid.
By adopting the technical scheme, before the liquid medicine is prepared, the nitrogen is filled to discharge the air in the liquid preparation tank, the air residue in the tank is further reduced through the vacuum suction effect, and the contact between the liquid medicine and oxygen in the stirring preparation process is effectively reduced, so that the oxidation of terbutaline sulfate is reduced, the impurity content is reduced, and the quality of the terbutaline sulfate is ensured.
After the materials are fully dissolved and uniformly dispersed in the liquid preparation tank, the liquid medicine needs to be conveyed to a subsequent process for filtering and filling, and the conventional method is to form negative pressure in the discharge pipeline through a water pump, then impel the liquid medicine to enter the discharge pipeline under the action of atmospheric pressure, and then enter the subsequent process under the action of a water pump impeller. The liquid medicine conveying mode obviously increases the contact between oxygen and liquid medicine in the subsequent process, and greatly increases the probability of oxidation and deterioration of terbutaline sulfate. Therefore, the nitrogen is filled in the device, the prepared liquid medicine is pushed to enter the subsequent working procedures by utilizing the nitrogen for pressurization, the content of oxygen in a production system is effectively reduced, and the product quality is favorably ensured.
Preferably, in step S3, the filter is a polyethersulfone filter, the filtration pressure is 0.07MPa to 0.11MPa, and the filtration flow rate is less than or equal to 3m3And h, circulating the filtered filling liquid through a pipeline for 5-10 min, and uniformly mixing to obtain a filtrate.
By adopting the technical scheme, the polyether sulfone filter has excellent filtering performance and reliable bacteria interception capability, can filter impurities which are not fully dissolved in liquid medicine, reduces the bacteria content, and is favorable for ensuring the quality of oral liquid.
Preferably, the liquid preparation tank comprises a tank body, the top of the tank body is communicated with a vacuum suction pipe, a first nitrogen filling pipe and a plurality of feeding pipes, the bottom of the tank body is communicated with a discharging pipe and a second nitrogen filling pipe, and a stirring assembly is arranged in the tank body.
By adopting the technical scheme, the production process can be effectively matched. All be provided with the control valve of adjusting the switching state on above-mentioned each pipeline, wherein, first nitrogen charging pipe all communicates with the required pump machine of nitrogen charging with the second nitrogen charging pipe, and the vacuum suction pipe intercommunication has the vacuum pump, and the inlet pipe also communicates power equipment. The method comprises the steps of firstly putting raw materials except water, such as terbutaline sulfate, an auxiliary agent and the like, into a liquid preparation tank through a feeding pipe, then filling nitrogen into the liquid preparation tank from bottom to top by using a second nitrogen filling pipe, discharging air in the tank from a vacuum suction pipe, then vacuumizing, pumping the nitrogen in the tank from the vacuum suction pipe, forming negative pressure in the tank, and promoting water required for preparation to enter the liquid preparation tank by using the negative pressure. And then, the stirring component is utilized to promote the raw materials to be fully dissolved to obtain the liquid medicine. Adding sodium hydroxide solution into the liquid medicine through a feeding pipe, adjusting the pH to 4.0 +/-0.5, then adding purified water, diluting the liquid medicine to the required prescription amount, and stirring and mixing uniformly again to obtain filling liquid; and finally, filling nitrogen into the tank from the top of the tank body through a first nitrogen filling pump, and gradually pressurizing to force the filling liquid to enter a filter from the discharge pipe for filtering.
Compared with the traditional pumping process, the nitrogen-filled discharge mode can obviously reduce the contact between oxygen and liquid medicine, and when nitrogen enters equipment such as a subsequent filter, the oxygen content in a system can be reduced, and the product quality can be effectively improved.
The degree of vacuum after evacuation is preferably from-0.04 MPa to-0.06 MPa. In addition, the second nitrogen filling pipe is arranged at the bottom because the density of nitrogen is less than that of air, and the second nitrogen filling pipe is arranged at the bottom and is beneficial to discharging air. The vacuum suction pipe is arranged at the top, so that the vacuum suction pipe is beneficial to being matched with the second nitrogen filling pipe to discharge air, and more importantly, the vacuum suction pipe can prevent liquid medicine from entering to cause the damage of the vacuum pump;
preferably, the tank body is internally provided with at least one deoxygenation pipe, the deoxygenation pipe comprises a cylindrical hollow support frame and a hydrophobic degassing membrane circumferentially wrapped on the support frame, one end of the deoxygenation pipe is communicated with a nitrogen source, and the other end of the deoxygenation pipe is communicated with a vacuum pump.
By adopting the technical scheme, in the liquid medicine preparation process, the deoxidation pipe can effectively reduce the dissolved oxygen content in the solution in the liquid preparation tank and reduce the probability of oxidation deterioration of terbutaline sulfate. The mechanism of action is that, firstly, the hydrophobic degassing membrane is a thin film with a surface having a structure of many micropores, and the surface is hydrophobically modified so that the micropores allow gas molecules to pass through but can block the penetration of water molecules. According to the Henry's law, the solubility of the gas in the water body is in direct proportion to the partial pressure of the gas on the water surface, and at the moment, the partial pressure of the gas on the water surface in contact with the hydrophobic degassing membrane is equal to the gas pressure in the deoxygenation tube, so that when a vacuum pump vacuumizes the interior of the deoxygenation tube and sweeps the inner cavity of the deoxygenation tube through nitrogen, the gas pressure in the deoxygenation tube is reduced, the solubility of the oxygen in the water body is reduced, the dissolved oxygen in the water body continuously penetrates through the hydrophobic degassing membrane, enters the deoxygenation tube and is discharged along with the nitrogen, the oxygen in the liquid medicine is effectively removed, the condition of oxidative deterioration of terbutaline sulfate is reduced, and the impurity content is reduced.
Preferably, the deoxidation pipe is provided with many in the circumference form, jar internal being annular outlet duct and the intake pipe of being that is of jar, deoxidation pipe one end and intake pipe intercommunication, the deoxidation pipe other end and outlet duct intercommunication, intake pipe and nitrogen gas source intercommunication, outlet duct and vacuum pump intercommunication.
Through adopting above-mentioned technical scheme, set up many deoxidation pipes, can effectively improve deoxidation efficiency, reduce dissolved oxygen content. The annular air inlet pipe is used for distributing nitrogen for purging, and the annular air outlet pipe is used for collecting the air, so that the air is convenient to exhaust.
Preferably, in step S1, the solution preparation tank is pretreated before adding terbutaline sulfate, and the pretreatment specifically comprises the following operations: adding a medicinal chelating agent and water with the volume of 75-99% of that of the liquid preparation tank into the liquid preparation tank, stirring for at least 30min, draining the aqueous solution, and washing with purified water.
By adopting the chelating agent to pretreat the liquid preparation tank, Fe in the tank can be effectively reduced3+And the content of metal ions with oxidizability, the probability of terbutaline sulfate oxidation is reduced, and the conditions of reduction of effective substance content and increase of impurity content are reduced. As described aboveThe stirring time is preferably 30-60 min, and the mass concentration of the medical grade chelating agent is preferably 0.05-0.2% in the pretreatment process.
Preferably, the pharmaceutical grade chelating agent is one or more of propyl gallate, citric acid and tartaric acid.
By adopting the technical scheme, the propyl gallate, the citric acid and the tartaric acid have good complexing effect, can complex metal ions into precipitates and discharge the precipitates, and is favorable for ensuring the quality of the terbutaline sulfate oral liquid.
In a second aspect, the application provides a terbutaline sulfate oral liquid, which is produced by any one of the production methods of the terbutaline sulfate oral liquid.
By adopting the technical scheme, the prepared terbutaline sulfate oral liquid has the advantages of obviously low impurity content, increased content of effective components and high product quality.
Preferably, the terbutaline sulfate oral liquid comprises the following components in percentage by weight:
terbutaline sulfate: 0.01 to 0.1 percent;
sodium benzoate: 0.05 percent to 0.15 percent;
citric acid: 0.1 to 1.0 percent;
sorbitol: 10% -30%;
sodium hydroxide: 0.03% -0.1%;
purifying water: and (4) the balance.
In the technical scheme, the sodium benzoate, the citric acid and the sorbitol have the antiseptic and antibacterial effects, so that the shelf life of the product is prolonged; sorbitol can also be used as sweetener to improve taste of oral liquid.
In summary, the present application has the following beneficial effects:
1. according to the method, nitrogen is filled into the liquid preparation tank before feeding and during discharging, so that on one hand, oxygen in the liquid preparation tank before feeding is emptied, and on the other hand, contact between terbutaline sulfate and oxygen during discharging is reduced; further obviously reducing the oxidation of the terbutaline sulfate, improving the content of effective components in the oral liquid and reducing the content of impurities in the oral liquid.
2. Dissolved oxygen in the solution is removed by adopting the deoxidizing pipe, so that the generation of impurities is reduced, and the quality of the oral liquid is improved.
3. The chelating agent is adopted to pretreat the liquid preparation tank, so that the influence of metal ions, especially oxidizing metal ions, on terbutaline sulfate in the preparation process of the oral liquid is effectively reduced, and the reduction of impurities in the oral liquid is facilitated.
Drawings
FIG. 1 is a schematic view of the overall structure of a liquid preparation tank in embodiment 1 of the present application;
FIG. 2 is a schematic view of the internal structure of a liquid dispensing tank in embodiment 1 of the present application;
FIG. 3 is a liquid chromatogram of example 6;
fig. 4 is a liquid chromatogram of comparative example 2.
Description of reference numerals:
1. a tank body; 2. a vacuum suction tube; 3. a first nitrogen-filled tube; 4. a feed pipe; 5. a discharge pipe; 6. a second nitrogen filled tube; 7. a stirring assembly; 71. a motor; 72. a stirring rod; 73. stirring blades; 8. a deoxygenation tube; 81. a support frame; 82. a hydrophobic degassing membrane; 83. a vacuum pump; 84. an air outlet pipe; 85. an air inlet pipe.
Detailed Description
Examples
Embodiment 1, a terbutaline sulfate oral liquid, each raw material component's selection and corresponding content are shown in table 1, and adopt following liquid preparation jar to prepare, should join in marriage the liquid preparation jar and include jar body 1, jar body 1 top intercommunication has inlet pipe 4, feed liquor pipe, vacuum suction pipe 2 and first nitrogen charging pipe 3, the manhole has still been seted up at jar body 1 top, jar body 1 bottom intercommunication has discharging pipe 5 and second nitrogen charging pipe 6, all be provided with the control valve on each pipeline, be provided with stirring subassembly 7 and a plurality of deoxidation pipes 8 in jar body 1. The stirring assembly 7 comprises a stirring rod 72, a stirring blade 73 arranged at the bottom end of the stirring rod 72, and a motor 71 for driving the stirring rod 72.
The plurality of oxygen removing pipes 8 are distributed in the tank body 1 in a circumferential manner by taking the stirring rod 72 as a center, and the length of the stirring paddle is smaller than the radius length of the circumference formed by the oxygen removing pipes 8. The deoxygenation tube 8 comprises a support frame 81 and a hydrophobic degassing membrane 82 wrapped on the surface of the support frame 81, the support frame 81 is a hollow cylinder, and filter holes are densely distributed on the side wall of the support frame 81.
An annular air outlet pipe 84 and an annular air inlet pipe 85 are sequentially arranged in the inner cavity of the tank body 1 along the vertical direction, the upper end of the deoxygenation pipe 8 is communicated with the air outlet pipe 84, and the lower end of the deoxygenation pipe 8 is communicated with the air inlet pipe 85. The gas inlet pipe 85 is communicated with a nitrogen source (nitrogen tank) outside the tank body 1 through a pipeline, and the gas outlet pipe 84 is communicated with a vacuum pump 83 outside the tank body 1 through a pipeline.
The hydrophobic degassing membrane 82 is an ultrafiltration grade hollow fiber membrane obtained from Hangzhou jiuxii membranes.
The production method comprises the following process steps:
s1, adding terbutaline sulfate and an auxiliary agent into a liquid preparation tank through a feeding pipe 4, filling nitrogen into a tank body 1 through a second nitrogen filling pipe 6, discharging air from a vacuum suction pipe 2, performing vacuum suction through the vacuum suction pipe 2, discharging the nitrogen, sucking 80% of purified water for preparation into the liquid preparation tank by utilizing negative pressure, stirring and dissolving at the rotating speed of 80rpm +/-4 rpm, and stirring for 1 h; in the stirring process, simultaneously starting a vacuum pump 83 connected with the deoxidation pipe 8, so that nitrogen enters the deoxidation pipe 8 for purging, the partial pressure in the solution is reduced, the solubility of dissolved oxygen in the solution is reduced, oxygen is promoted to penetrate through the hydrophobic degassing membrane 82, enter the deoxidation pipe 8 and is discharged along with the purged nitrogen, the effect of removing the dissolved oxygen in the solution is achieved, and the liquid medicine is obtained;
s2, adding part of purified water for preparation into sodium hydroxide to prepare a 1 wt% sodium hydroxide solution, adding the sodium hydroxide solution into the liquid medicine through a feeding pipe 4, adjusting the pH value to 4.0, then adding the rest purified water for preparation, diluting the liquid medicine to 1.075g/ml, and stirring for 15min to obtain a filling liquid;
s3, filling nitrogen into the liquid preparation tank through the first nitrogen filling pipe 3, promoting the filling liquid to be discharged from the discharge pipe 5 under the pressure of the nitrogen, transferring the filling liquid to a polyether sulfone filter for filtering, keeping the filtering pressure between 0.07MPa and 0.11MPa and the filtering flow rate at 3m3H, circulating the filtered filling liquid through a pipeline for 10min, and uniformly mixing to obtain a filtrate; will have passedFilling the filtrate into a soda-lime glass molded medicine bottle to obtain the terbutaline sulfate oral liquid.
Examples 2 to 3, a terbutaline sulfate oral liquid, is different from example 1 in that the selection of each raw material component and the corresponding content thereof are shown in table 1.
Table 1, compositions and amounts (Kg) of terbutaline sulfate oral solutions in examples 1 to 3
Example 4, a terbutaline sulfate oral liquid, differs from example 1 in that, in step S1, the vacuum pump 83 communicating with the deoxidation pipe 8 is not turned on during stirring, i.e., the removal of dissolved oxygen is not performed.
Example 5, a terbutaline sulfate oral liquid, which is different from example 4 in that in step S1, the solution preparation tank is pretreated before adding terbutaline sulfate, and the pretreatment specifically comprises the following operations: adding propyl gallate (pharmaceutical grade chelating agent) and 80% purified water to make chelating agent mass concentration reach 0.05%, stirring for 30min, draining water solution, and washing with purified water.
Example 6, a terbutaline sulfate oral liquid, which is different from example 1 in that in step S1, a solution preparation tank is pretreated before terbutaline sulfate is added, and the pretreatment specifically comprises the following operations: adding propyl gallate (pharmaceutical grade chelating agent) and 80% purified water to make chelating agent mass concentration reach 0.05%, stirring for 30min, draining water solution, and washing with purified water.
The liquid chromatogram is shown in FIG. 3, wherein impurity B is the oxidized impurity of terbutaline sulfate, corresponding to 2-impurity B in FIG. 3, and the peak-off time is 40.407 min.
Example 7, a terbutaline sulfate oral liquid, differs from example 6 in that tartaric acid is used as the pharmaceutical grade chelating agent.
Example 8, a terbutaline sulfate oral liquid, differs from example 6 in that propyl gallate and citric acid are used as pharmaceutical grade chelating agents.
Comparative example
Comparative example 1, a terbutaline sulfate oral liquid, differs from example 4 in that, in step S3, air is filled into the liquid preparation tank through the first nitrogen filling pipe during discharging to promote the transfer of the filling liquid into the filter.
Comparative example 2, a terbutaline sulfate oral liquid, differs from example 4 in that, in step S1, before terbutaline sulfate is fed, nitrogen gas is not fed through the second nitrogen-filled tube, that is, air in the liquid preparation tank is not discharged before feeding; in step S3, during discharging, air is filled into the liquid preparation tank through the first nitrogen filling pipe to promote the filling liquid to be transferred into the filter.
The liquid chromatogram is shown in FIG. 4, wherein impurity B is the oxidized impurity of terbutaline sulfate, corresponding to 2-impurity B in FIG. 4, and the peak-off time is 39.783 min.
Performance test
Test 1: the test method for measuring the content of the substances in the terbutaline sulfate oral liquid comprises the following steps: the test was carried out at normal temperature (25. + -. 2 ℃ C.) after the terbutaline sulfate oral liquid was prepared in the above examples and comparative examples according to the regulations of high performance chromatography in general regulation 0512 of Chinese pharmacopoeia, and the test results are shown in Table 2.
The measurement conditions were as follows:
a chromatographic column: ultimate XB-C18, 4.6 x 250mm, 5 μm;
mobile phase A: buffered saline solution (pH3.0) -methanol (90: 10);
mobile phase B: buffered saline solution (ph3.0) -methanol (50: 50);
buffered saline solution (ph 3.0): weighing about 3.15g of ammonium formate, dissolving in 900mL of water, adjusting the pH value to 3.0 by using formic acid, adding 5.49g of sodium hexanesulfonate, adding 100mL of water, and uniformly mixing;
flow rate: 1.0 mL/min; detection wavelength: 276 nm; column temperature: 30 ℃; sample introduction amount: 20 μ L
Control solution: precisely measuring 1ml of the test solution, placing the test solution into a 200ml measuring flask, diluting the test solution to a scale with water, and shaking up.
TABLE 2 determination of the substance content in terbutaline sulfate oral liquid
Note: "/" indicates no detection or less than 0.05%.
Test 2: according to the test method for testing the stability of the terbutaline sulfate oral liquid: (1) 100 bottles of terbutaline sulfate oral liquid prepared in the above example 1 were randomly selected, sampled at 60 ± 2 ℃ for 0 day, 5 days, 10 days and 30 days, respectively, and tested by high performance chromatography according to general regulation 0512 of Chinese pharmacopoeia, and the test results are shown in table 3.
TABLE 3. test results of stability of terbutaline sulfate oral liquid
Note: "/" indicates no detection or less than 0.05%.
(1) It can be seen from the combination of examples 1 to 8 and comparative examples 1 to 2 and the combination of table 2 that the oxidation of terbutaline sulfate in the oral liquid can be effectively reduced by exhausting air in the tank before the liquid preparation and simultaneously promoting the discharge of the oral liquid by using nitrogen after the liquid preparation is completed, thereby reducing the generation of impurities.
(2) By combining the embodiment 1 and the embodiment 4 and combining the table 2, it can be seen that the dissolved oxygen in the liquid medicine is removed by arranging the deoxygenation tube in the tank body of the liquid preparation tank, so that the oxidation of terbutaline sulfate in the oral liquid can be effectively reduced, and the generation of impurities is further reduced.
(3) By combining the embodiment 1 and the embodiments 5 to 8 and combining the table 2, it can be seen that the metal ions, especially the oxidizing metal ions, in the tank body can be effectively removed and cleaned by adopting the medicinal chelating agent to clean the inner cavity of the liquid preparation tank, so that the impurity content in the oral liquid is reduced.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (9)
1. A production method of terbutaline sulfate oral liquid is characterized by comprising the following steps:
s1, adding terbutaline sulfate and an auxiliary agent into a liquid preparation tank, filling nitrogen into the tank, exhausting air in the tank, performing vacuum suction, exhausting nitrogen, sucking 75-85% of purified water for preparation into the liquid preparation tank by using negative pressure, and stirring and dissolving to obtain a liquid medicine;
s2, adding 1-3 wt% of sodium hydroxide solution into the liquid medicine, adjusting the pH value to 4.0 +/-0.5, adding the rest purified water for preparation, diluting the liquid medicine to the prescription amount, and mixing uniformly to obtain a filling liquid;
and S3, filling nitrogen into the liquid preparation tank, promoting the filling liquid to be transferred into a filter under the pressure of the nitrogen for filtering to obtain a filtrate, and filling the filtrate into a medicine bottle to obtain the terbutaline sulfate oral liquid.
2. The method for producing terbutaline sulfate oral liquid according to claim 1, wherein in step S3, the filter is polyethersulfone filter, the filtering pressure is 0.07 MPa-0.11 MPa, and the filtering flow rate is not more than 3m3And h, circulating the filtered filling liquid through a pipeline for 5-10 min, and uniformly mixing to obtain a filtrate.
3. The production method of terbutaline sulfate oral liquid according to claim 1, characterized in that the liquid preparation tank comprises a tank body (1), the top of the tank body (1) is communicated with a vacuum suction pipe (2), a first nitrogen charging pipe (3) and a plurality of feeding pipes (4), the bottom of the tank body (1) is communicated with a discharge pipe (5) and a second nitrogen charging pipe (6), and a stirring assembly (7) is arranged in the tank body (1).
4. The production method of terbutaline sulfate oral liquid according to claim 3, wherein at least one deoxygenation tube (8) is arranged in the tank body (1), the deoxygenation tube (8) comprises a columnar hollow support frame (81) and a hydrophobic degassing membrane (82) circumferentially wrapped on the support frame (81), one end of the deoxygenation tube (8) is communicated with a nitrogen source, and the other end of the deoxygenation tube (8) is communicated with a vacuum pump (83).
5. The production method of terbutaline sulfate oral liquid according to claim 4, wherein a plurality of deoxygenation tubes (8) are arranged in a circumferential manner, an annular air outlet tube (84) and an annular air inlet tube (85) are arranged in the tank body (1), one end of each deoxygenation tube (8) is communicated with the air inlet tube (85), the other end of each deoxygenation tube (8) is communicated with the air outlet tube (84), the air inlet tube (85) is communicated with a nitrogen source, and the air outlet tube (84) is communicated with a vacuum pump (83).
6. The method for producing terbutaline sulfate oral liquid according to claim 1, wherein in step S1, the solution preparation tank is pretreated before terbutaline sulfate is added, and the pretreatment specifically comprises the following operations: adding a medicinal chelating agent and water with the volume of 75-99% of that of the liquid preparation tank into the liquid preparation tank, stirring for at least 30min, draining the aqueous solution, and washing with purified water.
7. The method for producing terbutaline sulfate oral liquid according to claim 6, wherein the pharmaceutical grade chelating agent is one or more of propyl gallate, citric acid and tartaric acid.
8. A terbutaline sulfate oral liquid, which is produced by the production method of terbutaline sulfate oral liquid of any one of claims 1 to 7.
9. The terbutaline sulfate oral liquid of claim 8, comprising the following components by weight percent:
terbutaline sulfate: 0.01 to 0.1 percent;
sodium benzoate: 0.05 percent to 0.15 percent;
citric acid: 0.1 to 1.0 percent;
sorbitol: 10% -30%;
sodium hydroxide: 0.03% -0.1%;
purifying water: and (4) the balance.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101982490A (en) * | 2010-10-29 | 2011-03-02 | 华东理工大学 | Preparation method of superhydrophobic self-cleaning material |
| CN110123745A (en) * | 2019-06-27 | 2019-08-16 | 四川汇宇制药有限公司 | A kind of Taxol injection liquid and preparation method thereof being resistant to terminal sterilization |
| CN111214995A (en) * | 2020-03-27 | 2020-06-02 | 江苏中有信科技有限公司 | Liquid preparation liquid preparation device for oral administration |
| CN111217904A (en) * | 2019-09-09 | 2020-06-02 | 润方（北京）生物医药研究院有限公司 | Preparation method of polymerized hemoglobin with low high polymer content |
| CN112816793A (en) * | 2021-01-04 | 2021-05-18 | 西安电子科技大学 | Method and system for measuring electromagnetic scattering coefficient of foil strip cloud and application |
| CN112826793A (en) * | 2021-01-25 | 2021-05-25 | 石家庄四药有限公司 | Terbutaline sulfate injection and preparation method thereof |
-
2021
- 2021-09-17 CN CN202111093926.6A patent/CN113712912A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101982490A (en) * | 2010-10-29 | 2011-03-02 | 华东理工大学 | Preparation method of superhydrophobic self-cleaning material |
| CN110123745A (en) * | 2019-06-27 | 2019-08-16 | 四川汇宇制药有限公司 | A kind of Taxol injection liquid and preparation method thereof being resistant to terminal sterilization |
| CN111217904A (en) * | 2019-09-09 | 2020-06-02 | 润方（北京）生物医药研究院有限公司 | Preparation method of polymerized hemoglobin with low high polymer content |
| CN111214995A (en) * | 2020-03-27 | 2020-06-02 | 江苏中有信科技有限公司 | Liquid preparation liquid preparation device for oral administration |
| CN112816793A (en) * | 2021-01-04 | 2021-05-18 | 西安电子科技大学 | Method and system for measuring electromagnetic scattering coefficient of foil strip cloud and application |
| CN112826793A (en) * | 2021-01-25 | 2021-05-25 | 石家庄四药有限公司 | Terbutaline sulfate injection and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| "PHARMANIAGA TERBUTALINE ORAL SOLUTION", 《CONSUMER MEDICATION INFORMATION LEAFLET (RIMUP) HTTPS://WWW.NPRA.GOV.MY/INDEX.PHP/EN/CONSUMER-MEDICATION-INFORMATION-LEAFLETS-RIMUP/ITEM/PHARMANIAGA-TERBUTALINE-ORAL-SOLUTION.HTML》, pages 1 - 3 * |
| 无: "PHARMANIAGA TERBUTALINE ORAL SOLUTION", 《CONSUMER MEDICATION INFORMATION LEAFLET (RIMUP) HTTPS://WWW.NPRA.GOV.MY/INDEX.PHP/EN/CONSUMER-MEDICATION-INFORMATION-LEAFLETS-RIMUP/ITEM/PHARMANIAGA-TERBUTALINE-ORAL-SOLUTION.HTML》, 19 October 2015 (2015-10-19), pages 1 - 3 * |
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