WO2022156796A1 - 一种硫酸特布他林注射液及其制备方法 - Google Patents
一种硫酸特布他林注射液及其制备方法 Download PDFInfo
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- WO2022156796A1 WO2022156796A1 PCT/CN2022/073448 CN2022073448W WO2022156796A1 WO 2022156796 A1 WO2022156796 A1 WO 2022156796A1 CN 2022073448 W CN2022073448 W CN 2022073448W WO 2022156796 A1 WO2022156796 A1 WO 2022156796A1
- Authority
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- WIPO (PCT)
- Prior art keywords
- injection
- terbutaline sulfate
- preparation
- water
- solution
- Prior art date
Links
- 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 112
- 229960005105 terbutaline sulfate Drugs 0.000 title claims abstract description 112
- 238000002360 preparation method Methods 0.000 title claims abstract description 93
- 238000002347 injection Methods 0.000 title claims abstract description 75
- 239000007924 injection Substances 0.000 title claims abstract description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 68
- 239000008215 water for injection Substances 0.000 claims abstract description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 31
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000001301 oxygen Substances 0.000 claims abstract description 27
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003708 ampul Substances 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims description 83
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 37
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 230000001954 sterilising effect Effects 0.000 claims description 15
- 238000004659 sterilization and disinfection Methods 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 6
- 230000002572 peristaltic effect Effects 0.000 claims description 5
- REJPDMLLCDXIOV-UHFFFAOYSA-N but-2-ynal Chemical compound CC#CC=O REJPDMLLCDXIOV-UHFFFAOYSA-N 0.000 claims description 2
- 238000010926 purge Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 241000894006 Bacteria Species 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 claims 1
- 150000004985 diamines Chemical class 0.000 claims 1
- 230000002262 irrigation Effects 0.000 claims 1
- 238000003973 irrigation Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910021645 metal ion Inorganic materials 0.000 abstract description 11
- 239000003963 antioxidant agent Substances 0.000 abstract description 6
- 239000008139 complexing agent Substances 0.000 abstract description 6
- 238000010668 complexation reaction Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 abstract description 4
- 239000003381 stabilizer Substances 0.000 abstract description 3
- 230000003078 antioxidant effect Effects 0.000 abstract description 2
- 238000011010 flushing procedure Methods 0.000 abstract 1
- 239000012266 salt solution Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 26
- 239000013558 reference substance Substances 0.000 description 19
- HAQLHRYUDBKTJG-UHFFFAOYSA-N 3,5-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=CC(C=O)=C1 HAQLHRYUDBKTJG-UHFFFAOYSA-N 0.000 description 13
- 230000008569 process Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 6
- 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 4
- 239000003814 drug Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012088 reference solution Substances 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000005388 borosilicate glass Substances 0.000 description 3
- 229960001305 cysteine hydrochloride Drugs 0.000 description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinyl group Chemical group C1(O)=CC(O)=CC=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005429 filling process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- -1 (±)α-[(tert-butylamino)methyl]-3,5-dihydroxybenzyl Chemical group 0.000 description 1
- 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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000003859 hyphenated technique Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 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
- 150000003462 sulfoxides Chemical class 0.000 description 1
- NEUOBESLMIKJSB-UHFFFAOYSA-J tetrasodium;tetraacetate Chemical compound [Na+].[Na+].[Na+].[Na+].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O NEUOBESLMIKJSB-UHFFFAOYSA-J 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000005303 weighing Methods 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
Definitions
- the application relates to the technical field of pharmaceutical preparations, in particular to a terbutaline sulfate injection and a preparation method thereof.
- Terbutaline sulfate the English name is Terbutaline Sulfate, the chemical name is ( ⁇ ) ⁇ -[(tert-butylamino)methyl]-3,5-dihydroxybenzyl alcohol sulfate (2:1), and the structural formula is as follows:
- Terbutaline sulfate is an adrenergic agonist that selectively activates ⁇ 2 receptors, relaxes bronchial smooth muscle, inhibits the release of endogenous spasmodic substances and edema caused by endogenous mediators, and improves bronchial mucociliary epithelial clearance It also relaxes uterine smooth muscle and is mainly used for short-term treatment of bronchiectasis and preterm labor.
- Terbutaline sulfate contains resorcinol group, and under the influence of light, oxygen, metal ions and temperature, resorcinol will not only make the content and color of the product unstable, but also make unknown impurities in the product. content increased.
- the conventional process is mainly by adding metal ion complexing agents (such as disodium EDTA) and antioxidants (such as sulfoxide) to terbutaline sulfate injection sodium bisulfate and cysteine hydrochloride) to reduce the effects of metal ions and oxygen.
- metal ion complexing agents such as disodium EDTA
- antioxidants such as sulfoxide
- disodium EDTA can combine with calcium ions in blood to form a soluble complex, resulting in a decrease in blood calcium content, which may cause severe voluntary muscle and smooth muscle spasm.
- Sodium bisulfite and cysteine hydrochloride can interact with cytochromes, oxidase, and disulfide bonds (-S-S-) in human proteins and amino acids in the human body, affecting the oxidation process of cells and causing cell hypoxia.
- activated carbon is generally used in the current storage process of terbutaline sulfate injection, which not only introduces metal ions, but also other impurities such as sulfides, and the activated carbon after use can also cause environmental pollution.
- the present application provides a terbutaline sulfate injection and a preparation method thereof.
- a preparation method of terbutaline sulfate injection comprising the steps:
- step a the sodium ethylenediaminetetraacetate solution is circulated and sprayed into the preparation tank, and the spraying time is not less than 30min, and then the preparation tank is rinsed with water for injection until the pH is 5.0-7.0, and the electrical conductivity is less than 0.5, and the pretreatment preparation is required.
- the spraying time is not less than 30min, and then the preparation tank is rinsed with water for injection until the pH is 5.0-7.0, and the electrical conductivity is less than 0.5, and the pretreatment preparation is required.
- step b nitrogen is charged into the pretreatment preparation tank, the air in it is drained, and then the water for injection of 60-80% of the total volume of the preparation is added, and nitrogen is charged into the water for injection to keep the dissolved oxygen in the water for injection less than 100ppb, then add the terbutaline sulfate of the recipe quantity to the water for injection, after stirring and dissolving, obtain the first dissolving solution;
- the first dissolving solution add the sodium chloride of the recipe quantity, stirring and dissolving, obtain the second dissolving solution;
- Step c fill the ampoule with nitrogen to discharge the air therein, fill the terbutaline sulfate liquid, fill with nitrogen after filling, so that the headspace residual oxygen in the ampoule (the Residual oxygen content) is less than 2%, sterilized to obtain Terbutaline Sulfate Injection.
- the inventor found that the terbutaline sulfate injection prepared according to the preparation method of conventional injections, even if metal ion complexing agents (such as disodium EDTA) and antioxidants (such as Sodium bisulfite and cysteine hydrochloride) to reduce the influence of metal ions and oxygen, but there will still be an unknown impurity that increases significantly during the placement process.
- the relative retention time (RRT) of the unknown impurity is 0.3.
- the hyphenated technique gas chromatography-mass spectrometry (GC-MS) technique
- GC-MS gas chromatography-mass spectrometry
- the specific steps of step a are: adding water for injection with a volume of more than 1/3 of the volume of the preparation tank to the water for injection, adding sodium EDTA to the water for injection, and mixing evenly to obtain EDTA Sodium acetate solution, turn on the peristaltic pump, and spray the sodium ethylenediaminetetraacetate solution into the preparation tank through the circulation pipeline and the spray device at the top of the preparation tank, and the spraying time is not less than 30min.
- the sodium tetraacetate solution is discharged, and the preparation tank is rinsed with water for injection until the pH is 5.0-7.0, and the electrical conductivity is less than 0.5, and the pretreatment preparation tank is obtained.
- step a 1/3-2/3 of the volume of water for injection is added to the preparation tank for preparing the sodium EDTA solution.
- the concentration of the sodium EDTA solution is 0.05-0.15 mol/L.
- step a the spraying time is 30-60 min.
- step a the sodium EDTA solution is discharged through the filling port on the preparation tank, and the discharge time is at least 30 minutes.
- the complexation treatment of the preparation tank with sodium EDTA solution can effectively reduce the content of metal ions in the preparation tank, thereby avoiding the influence of metal ions on the stability of terbutaline sulfate injection.
- step b the method for purging the air in the pretreatment preparation tank is: filling the pretreatment preparation tank with water for injection, and then using nitrogen to pressurize the injection in the pretreatment preparation tank Fill the pretreatment formulation tank with nitrogen using water.
- the preferred method of discharging the air in the pretreatment preparation tank can completely remove the air in the pretreatment preparation tank, which is beneficial to control the dissolved oxygen content in the water for injection for preparation to be less than 100ppb in the later stage, thereby effectively reducing the effect of dissolved oxygen on sulfuric acid. Influence of the stability of butaline injection.
- step b 0.1-0.5mol/L hydrochloric acid solution is used to adjust the pH to 3.5-4.0.
- step b 0.1-0.5 mol/L hydrochloric acid solution is used to adjust the pH to 3.8, and the dosage of the hydrochloric acid solution is set according to the required pH adjustment.
- step c the headspace residual oxygen content in the ampoule is controlled to be less than 1.5%.
- the sterilization method is constant temperature sterilization at 121° C. for 8 minutes.
- the traditional terbutaline sulfate injection generally adopts the method of adding activated carbon to filter and sterilize.
- This application realizes the terminal sterilization process (terminal sterilization process) through strict control of the process and parameters in the terbutaline sulfate injection (on the basis of controlling the amount of microbial contamination, after the medicine is potted, sterilized by moist heat sterilization), and the constant temperature sterilization process at 121 ° C for 8 minutes is adopted, which greatly improves the sterilization level and sterilization efficiency of the product.
- the embodiment of the present application also provides a terbutaline sulfate injection, which is prepared by the preparation method of any one of the above-mentioned terbutaline sulfate injections.
- the terbutaline sulfate injection is composed of terbutaline sulfate, sodium chloride, hydrochloric acid and water for injection, wherein every 1 mL of terbutaline sulfate injection contains terbutaline sulfate 0.25-1.0mg, sodium chloride 8.0-9.0mg, pH of Terbutaline Sulfate Injection is 3.5-4.0.
- each 1 mL of terbutaline sulfate injection contains 0.5 mg of terbutaline sulfate and 8.9 mg of sodium chloride.
- the formulation amount mentioned in this application refers to the amount of each component in the formulation of the formulation.
- the total volume of preparation mentioned in this application refers to the total volume of the prepared terbutaline sulfate injection, and the water for injection with 60-80% of the total volume of the preparation refers to the amount of water for injection that is terbutaline sulfate. 60-80% of the total volume of the injection solution.
- excipients for injections especially for intravenous injections, is: on the premise of ensuring the stability of the injection, try not to use excipients; species and number of ionic species to minimize irritation or allergy problems.
- the preparation method of Terbutaline Sulfate Injection provided by the application, by using EDTA sodium solution to carry out complexation treatment on the preparation tank, to reduce the content of metal ions in the preparation tank, complexation treatment is carried out.
- the preparation tank can be used for the preparation of terbutaline sulfate injection; during the preparation process, nitrogen is filled into the water for injection to control The dissolved oxygen in the water for injection is lower than 100ppb, and then terbutaline sulfate is added, and nitrogen is introduced during the filling process to control the residual oxygen in the headspace of the ampoule to be less than 2%, which effectively avoids the effect of oxygen on terbutaline sulfate. Lin's influence.
- the present application effectively improves the stability of Terbutaline Sulfate Injection by simply complexing the preparation tank and strictly controls the dissolved oxygen content during the preparation and filling process, and reduces the amount of impurities in the storage process. Increase, especially effectively reduce the increase in the content of impurities (RRT0.3), which helps to improve the efficacy of terbutaline sulfate injection; and through strict control of the preparation process and parameters, to achieve terbutaline sulfate injection.
- RRT0.3 impurities
- the purpose of not adding other excipients except sodium chloride in the liquid avoids the adverse effects of the excipients on the injection, and also avoids the problem of medication safety caused by the excipients.
- the preparation method of terbutaline sulfate injection provided by the application has reasonable process, simple operation and high work efficiency, and the product does not contain any complexing agent, antioxidant, stabilizer and other auxiliary materials, and only contains sodium chloride.
- the auxiliary material reduces the adverse effects of the auxiliary material, has good long-term stability, and adopts the method of terminal sterilization, and does not use activated carbon in the preparation process, which greatly improves the safety of the product for clinical use.
- the terbutaline sulfate injection provided by this application is simple in prescription, and only by adding sodium chloride, a sodium chloride isotonic system with good biocompatibility is established, without the introduction of antioxidants, complexing agents, stabilizers, etc.
- the stability of terbutaline sulfate injection is significantly improved, thereby improving the safety of clinical application of terbutaline sulfate injection, and has broad application prospects.
- Figure 1 is the mass spectrum of the impurity (RRT0.3);
- Fig. 2 is the high-performance liquid chromatogram of mixed impurity reference substance solution and 3,5-dihydroxybenzaldehyde reference substance solution, in the high-performance liquid chromatogram, abscissa represents time, unit min, ordinate represents response value, unit AU; Among them, (a) 3,5-dihydroxybenzaldehyde reference substance solution, (b) mixed impurity reference substance solution;
- Fig. 3 is the high-performance liquid chromatogram of Terbutaline Sulfate Injection prepared in Example 1.
- the abscissa represents time, and the unit is min, and the ordinate represents the response value, and the unit is AU.
- the present embodiment provides a kind of terbutaline sulfate injection, and the recipe quantity is shown in the following table:
- Step a adding more than 1/3 of its volume water for injection to the preparation tank, turning on stirring, adding sodium EDTA to the water for injection, and mixing evenly to obtain sodium EDTA with a concentration of 0.1 mol/L solution, turn on the peristaltic pump, so that the sodium EDTA solution is circulated and sprayed into the preparation tank through the circulation pipeline and the spray device at the top of the preparation tank for 40 minutes, and then the sodium EDTA solution is discharged , the discharge time is 30min, after the discharge is completed, rinse the preparation tank with water for injection until the pH is 5.0-7.0, and the conductivity is less than 0.5, and the pretreatment preparation tank is obtained;
- the pretreatment preparation tank is first filled with water for injection, and then the water for injection in the pretreatment preparation tank is drained by means of nitrogen pressure, so that the pretreatment preparation tank is filled with nitrogen;
- the water for injection of 70L is filled with nitrogen to keep dissolved oxygen in the water for injection less than 100ppb, then the terbutaline sulfate of the recipe quantity is added to the water for injection, after stirring and dissolving, the first dissolving solution is obtained; to the first dissolving solution Add the sodium chloride of the recipe amount, stir and dissolve to obtain the second dissolving solution; add water for injection to the second dissolving solution to prepare a total volume of 100L, adjust the pH to 3.8 with 0.1mol/L hydrochloric acid solution, and stir for 10min Mixing the medicinal solution evenly to obtain a terbutaline sulfate medicinal solution, testing the terbutaline sulfate content and pH value in the terbutaline sulfate medicinal solution to be qualified, and the dissolved oxygen
- Step c Fill a 1mL neutral borosilicate glass ampoule bottle with nitrogen to discharge the air therein, fill the terbutaline sulfate liquid into it, and fill with nitrogen after filling, so that the headspace in the ampoule bottle is left with residual gas.
- Oxygen content is less than 1.5%, constant temperature sterilization at 121 °C for 8 min, and terbutaline sulfate injection is obtained.
- the present embodiment provides a kind of terbutaline sulfate injection, and the recipe quantity is shown in the following table:
- Step a adding more than 1/3 of its volume of water for injection to the preparation tank, turning on stirring, adding sodium EDTA to the water for injection, and mixing evenly to obtain sodium EDTA with a concentration of 0.05mol/L solution, turn on the peristaltic pump, so that the sodium EDTA solution is circulated and sprayed into the preparation tank through the circulation pipeline and the spray device at the top of the preparation tank for 30 minutes, and then the sodium EDTA solution is discharged , the discharge time is 50min, after the discharge is completed, rinse the preparation tank with water for injection until the pH is 5.0-7.0, and the conductivity is less than 0.5, and the pretreatment preparation tank is obtained;
- the pretreatment preparation tank is first filled with water for injection, and then the water for injection in the pretreatment preparation tank is drained by means of nitrogen pressure, so that the pretreatment preparation tank is filled with nitrogen;
- the water for injection of 80L is filled with nitrogen to keep dissolved oxygen in the water for injection less than 100ppb, then the terbutaline sulfate of the recipe quantity is added to the water for injection, after stirring and dissolving, the first dissolving solution is obtained; to the first dissolving solution Add the sodium chloride of the recipe amount, stir and dissolve to obtain the second dissolving solution; add water for injection to the second dissolving solution to prepare a total volume of 100L, adjust the pH to 3.5 with 0.5mol/L hydrochloric acid solution, and stir for 10min Mixing the medicinal solution evenly to obtain a terbutaline sulfate medicinal solution, testing the terbutaline sulfate content and pH value in the terbutaline sulfate medicinal solution to be qualified, and the dissolved oxygen
- Step c Fill a 1mL neutral borosilicate glass ampoule bottle with nitrogen to discharge the air therein, fill the terbutaline sulfate liquid into it, and fill with nitrogen after filling, so that the headspace in the ampoule bottle is left with residual gas.
- Oxygen content is less than 2%, constant temperature sterilization at 121 °C for 8 min, to obtain terbutaline sulfate injection.
- the present embodiment provides a kind of terbutaline sulfate injection, and the recipe quantity is shown in the following table:
- Step a add more than 1/3 of its volume of water for injection to the preparation tank, start stirring, add sodium EDTA to the water for injection, and mix well to obtain sodium EDTA with a concentration of 0.15mol/L solution, turn on the peristaltic pump, so that the sodium EDTA solution is circulated and sprayed into the preparation tank through the circulation pipeline and the spray device at the top of the preparation tank for 60 minutes, and then the sodium EDTA solution is discharged , the discharge time is 40min, after the discharge is completed, rinse the preparation tank with water for injection until the pH is 5.0-7.0, and the conductivity is less than 0.5, and the pretreatment preparation tank is obtained;
- the pretreatment preparation tank is first filled with water for injection, and then the water for injection in the pretreatment preparation tank is drained by means of nitrogen pressure, so that the pretreatment preparation tank is filled with nitrogen;
- the water for injection of 60L is filled with nitrogen to keep dissolved oxygen in the water for injection lower than 100ppb, then the terbutaline sulfate of the recipe quantity is added to the water for injection, after stirring and dissolving, the first dissolving solution is obtained; to the first dissolving solution Add the sodium chloride in the recipe amount, stir and dissolve to obtain the second dissolving solution; add water for injection to the second dissolving solution to prepare a total volume of 100L, adjust the pH to 4.0 with 0.3mol/L hydrochloric acid solution, and stir for 10min Mixing the medicinal solution evenly to obtain a terbutaline sulfate medicinal solution, testing the terbutaline sulfate content and pH value in the terbutaline sulfate medicinal solution to be qualified, and the dissolved oxygen
- Step c Fill a 1mL neutral borosilicate glass ampoule bottle with nitrogen to discharge the air therein, fill the terbutaline sulfate liquid into it, and fill with nitrogen after filling, so that the headspace in the ampoule bottle is left with residual gas.
- Oxygen content is less than 1.8%, constant temperature sterilization at 121 °C for 8 min, to obtain Terbutaline Sulfate Injection.
- the impurity (RRT0.3) was confirmed to be 3,5-dihydroxybenzaldehyde by GC and the structural formula is as follows:
- total impurities refers to the total amount of impurities.
- Example 2 and Example 3 of the present application can achieve basically equivalent effects to Example 1.
- HPLC high performance liquid chromatography
- Injection volume 20 ⁇ L
- Test solution take the terbutaline sulfate injection prepared in the embodiment as the test solution.
- Control solution Precisely measure 1mL of the test solution, place it in a 50mL volumetric flask, dilute it to 50mL with mobile phase, shake well, precisely measure 1mL of the diluted solution, place it in a 10mL volumetric flask, and dilute it with mobile phase To the mark 10mL, shake well, as a control solution.
- the precise measurement refers to the measurement of the volume should be accurate to one thousandth of the volume.
- Mixed impurity reference substance solution take appropriate amount of impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance and terbutaline sulfate reference substance, accurately weigh, add mobile phase to dissolve and quantitatively dilute to make a mixture
- the solution, impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance and terbutaline sulfate reference substance in each 1mL mixed solution contain about 1 ⁇ g, and the mixed solution is used as the mixed impurity reference substance solution.
- precision weighing means that the weight taken should be accurate to one thousandth of the taken weight.
- 3,5-dihydroxybenzaldehyde reference substance solution take an appropriate amount of 3,5-dihydroxybenzaldehyde reference substance, accurately weigh, add mobile phase to dissolve and quantitatively dilute to make 3,5-dihydroxybenzaldehyde reference substance solution, Each 1mL 3,5-dihydroxybenzaldehyde reference solution contains about 1 ⁇ g of 3,5-dihydroxybenzaldehyde.
- the high performance liquid chromatograms of the mixed impurity reference solution and the 3,5-dihydroxybenzaldehyde reference solution are shown in Figure 2, wherein (a) 3,5-dihydroxybenzaldehyde, (b) mixed impurities
- A, B, C, and D in the figure represent impurity A, impurity B, impurity C, and impurity D, respectively.
- the high performance liquid chromatogram of terbutaline sulfate injection test solution is shown in Figure 3, wherein, the peak time of terbutaline sulfate is 12.190min, and the peak time of 3,5-dihydroxybenzaldehyde is 3.493min, and the peak time of impurity B is 8.024min.
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Abstract
一种硫酸特布他林注射液及其制备方法。使用乙二胺四乙酸钠溶液对配制罐进行络合处理，络合完成后，再用注射用水冲洗pH至5.0-7.0且电阻率小于0.5时，将配制罐用于注射液的配制。在配制过程中向注射用水中充入氮气，控制注射用水中溶解氧低于100 ppb后再加入硫酸特布他林，并配合灌装过程中通入氮气，控制安瓿瓶内的顶空残氧量小于2％，避免氧气和金属离子对硫酸特布他林的影响。本申请的硫酸特布他林注射液不引入抗氧剂或络合剂、稳定剂等其他辅料，提高了稳定性。
Description
本专利申请要求于2021年01月25日提交的中国专利申请No.CN202110098851.4的优先权。在先申请的公开内容通过整体引用并入本申请。
本申请涉及药物制剂技术领域，尤其涉及一种硫酸特布他林注射液及其制备方法。
硫酸特布他林，英文名为Terbutaline Sulfate，化学名称为(±)α-[(叔丁胺基)甲基]-3,5-二羟基苯甲醇硫酸盐(2:1)，结构式如下：
硫酸特布他林是一种肾上腺素能激动剂，可选择性激动β2受体，舒张支气管平滑肌、抑制内源性致痉挛物质的释放及内源性介质引起的水肿，提高支气管粘膜纤毛上皮廓清能力，也可舒张子宫平滑肌，主要用于支气管扩张和早产的短期治疗。
硫酸特布他林中含有间苯二酚基团，而间苯二酚在光、氧气、金属离子及温度的影响下，不仅会使产品的含量和颜色不稳定，还会使产品中未知杂质含量升高。为了提高硫酸特布他林注射液的稳定性，常规工艺主要是通过在硫酸特布他林注射液中加入金属离子络合剂（如乙二胺四乙酸二钠）和抗氧剂（如亚硫酸氢钠和盐酸半胱氨酸），来降低金属离子和氧气的影响。但是，乙二胺四乙酸二钠可以与血液中的钙离子结合成可溶的络合物而导致血钙含量下降，可能引发严重的随意肌及平滑肌痉挛。亚硫酸氢钠和盐酸半胱氨酸可与人体内细胞色素、氧化酶及人体蛋白、氨基酸中的二硫键(-S-S-)作用，影响细胞的氧化过程，造成细胞缺氧。而且，目前硫酸特布他林注射液的贮备工艺中一般均使用活性炭，不仅会引入金属离子，还会引入其他如硫化物一类的杂质，且使用后的活性碳还会造成环境污染。因此，研发一种新的可提高硫酸特布他林注射液稳定性，且不需要加入抗氧剂和金属离子络合剂等辅料的制备方法，对提高硫酸特布他林注射液的用药安全具有十分重要的意义。
针对现有的硫酸特布他林注射液存在的稳定性较差以及含有较多辅料的问题，本申请提供一种硫酸特布他林注射液及其制备方法。
为解决上述技术问题，本申请提供的技术方案是：
一种硫酸特布他林注射液的制备方法，包括如下步骤：
步骤a，向配制罐中循环喷淋乙二胺四乙酸钠溶液，喷淋时间不少于30min，然后用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐；
步骤b，向所述预处理配制罐内充入氮气，排净其中的空气，然后加入配制总体积量60-80%的注射用水，向注射用水中充入氮气保持注射用水中溶解氧低于100ppb，然后向注射用水中加入处方量的硫酸特布他林，搅拌溶解后，得第一溶解液；向第一溶解液中加入处方量的氯化钠，搅拌溶解，得第二溶解液；向第二溶解液中补加注射用水至配制总体积量，调节pH至3.5-4.0，搅拌混匀，得硫酸特布他林药液；
步骤c，向安瓿瓶中充入氮气排出其中的空气，灌装所述硫酸特布他林药液，灌装结束后充入氮气，使安瓿瓶内的顶空残氧量（顶部气体中的残氧量）小于2%，灭菌，得硫酸特布他林注射液。
在研发过程中，发明人发现按照常规注射液的制备方法制备得到的硫酸特布他林注射液，即便加入了金属离子络合剂（如乙二胺四乙酸二钠）和抗氧剂（如亚硫酸氢钠和盐酸半胱氨酸），来降低金属离子和氧气的影响，但是，在放置过程中还是会有一个未知杂质明显增加，未知杂质的相对保留时间（RRT）为0.3，经气质联用技术（气相色谱-质谱联用（GC-MS）技术）研究表明，该未知杂质（RRT0.3）为3,5-二羟基苯甲醛。该杂质会严重降低硫酸特布他林自身的疗效，使患者用药周期或被治愈的周期增长，也可能会导致其他副作用的发生。为了控制该杂质的增加，并减少辅料可能带来的副作用，发明人研发了一种新的硫酸特布他林注射液的制备方法。
在其中一个实施例中，步骤a的具体步骤为：向配制罐中加入配制罐体积1/3以上的注射用水，向注射用水中加入乙二胺四乙酸钠，混合均匀，得乙二胺四乙酸钠溶液，开启蠕动泵，将乙二胺四乙酸钠溶液经循环管路和配制罐顶部的喷淋装置，循环喷淋至配制罐中，喷淋时间不少于30min，然后将乙二胺四乙酸钠溶液排出，用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐。
在其中一个实施例中，步骤a中，向配制罐中加入其体积1/3-2/3的注射用水，用于配制乙二胺四乙酸钠溶液。
在其中一个实施例中，步骤a中，所述乙二胺四乙酸钠溶液的浓度为0.05-0.15mol/L。
在其中一个实施例中，步骤a中，所述喷淋时间为30-60min。
在其中一个实施例中，步骤a中，采用配制罐上的灌装口将乙二胺四乙酸钠溶液排出，排出时间至少为30min。
使用乙二胺四乙酸钠溶液对配制罐进行络合处理，可以有效降低配制罐中金属离子的含量，从而避免金属离子对硫酸特布他林注射液稳定性的影响。
在其中一个实施例中，步骤b中，排净预处理配制灌中空气的方法为：向预处理配制罐中加满注射用水，然后使用氮气加压的方式排净预处理配制罐中的注射用水，使预处理配制罐中充满氮气。
优选的排出预处理配制罐中空气的方法，可以彻底排净预处理配制罐中的空气，有利于后期将配制用注射用水中的溶解氧含量控制在100ppb以下，从而有效降低溶解氧对硫酸特布他林注射液稳定性的影响。
在其中一个实施例中，步骤b中，采用0.1-0.5mol/L的盐酸溶液调节pH至3.5-4.0。
进一步优选的，步骤b中，采用0.1-0.5mol/L的盐酸溶液调节pH至3.8，盐酸溶液的用量根据所需调节pH进行设定。
在其中一个实施例中，步骤c中，控制安瓿瓶内的顶空残氧量小于1.5%。
在其中一个实施例中，步骤c中，所述灭菌的方式为121℃恒温灭菌8min。
为了避免高温灭菌过程中温度对硫酸特布他林的影响，传统硫酸特布他林注射液一般采用加入活性炭过滤除菌的方法。本申请通过对硫酸特布他林注射液中工艺及参数的严格控制，实现了终端灭菌工艺（terminal sterilization process）（在控制微生物污染量的基础上，在药品灌封后，通过湿热灭菌方式除菌），并且采用121℃ 8min恒温灭菌工艺，大大提高了产品的无菌水平和灭菌效率。
本申请实施例还提供一种硫酸特布他林注射液，由上述任一项所述的硫酸特布他林注射液的制备方法制备得到。
在其中一个实施例中，所述硫酸特布他林注射液由硫酸特布他林、氯化钠、盐酸和注射用水组成，其中每1mL硫酸特布他林注射液中含有硫酸特布他林0.25-1.0mg，氯化钠8.0-9.0mg，硫酸特布他林注射液的pH为3.5-4.0。
进一步优选的，每1mL硫酸特布他林注射液中含有硫酸特布他林0.5mg，氯化钠8.9mg。
本申请中所述处方量是指制剂处方中各组分的量。
本申请中所述配制总体积量是指配制的硫酸特布他林注射液的总体积量，所述配制总体积量60-80%的注射用水是指注射用水的量是硫酸特布他林注射液的总体积量的60-80%。
注射液特别是静脉注射液的辅料使用原则是：在保证注射液稳定性的前提下，能尽量不使用辅料，若能使用一种辅料时尽量不使用二种辅料，以减少注射液中物质的种类及离子种类数量，尽量减少刺激或过敏问题的出现。
相对于现有技术，本申请提供的硫酸特布他林注射液的制备方法，通过使用乙二胺四乙酸钠溶液对配制罐进行络合处理，以降低配制罐中金属离子的含量，络合完成后，再用注射用水冲洗pH至5.0-7.0且电阻率小于0.5时，才可将配制罐用于硫酸特布他林注射液的配制；在配制过程中向注射用水中充入氮气，控制注射用水中溶解氧低于100ppb后再加入硫酸特布他林，并配合灌装过程中通入氮气，控制安瓿瓶内的顶空残氧量小于2%，有效避免了氧气对硫酸特布他林的影响。本申请仅通过对配制罐进行简单的络合处理，以及在配制和灌装过程中严格控制溶解氧含量，有效提高了硫酸特布他林注射液的稳定性，降低了存储过程中杂质含量的增加，尤其是有效降低了杂质（RRT0.3）含量的增加，从而有助于提高硫酸特布他林注射液的疗效；且通过严格控制制备工艺及参数，实现了在硫酸特布他林注射液中除氯化钠之外不加入其他辅料的目的，避免了辅料对注射液造成的不利影响，也避免了辅料带来的用药安全的问题。
本申请提供的硫酸特布他林注射液的制备方法工艺合理，操作简单，工作效率高，且产品中不含有任何络合剂和抗氧剂、稳定剂等辅料，只含有氯化钠一种辅料，降低了辅料带来的不利影响，长期稳定性良好，且采用终端灭菌的方法，制备过程中不采用活性炭，大大提高了产品临床用药的安全性。
本申请提供的硫酸特布他林注射液处方简单，只通过加入氯化钠，建立了生物相容性好的氯化钠等渗体系，在不引入抗氧剂或络合剂、稳定剂等其他辅料的前提下，显著提高了硫酸特布他林注射液的稳定性，从而提高了硫酸特布他林注射液的临床应用安全性，具有广阔的应用前景。
图1为杂质（RRT0.3）的质谱图；
图2为混合杂质对照品溶液及3，5-二羟基苯甲醛对照品溶液的高效液相色谱图，高效液相色谱图中横坐标代表时间，单位min，纵坐标代表响应值，单位AU；其中，（a）3，5-二羟基苯甲醛对照品溶液，（b）混合杂质对照品溶液；
图3为实施例1制备的硫酸特布他林注射液的高效液相色谱图，高效液相色谱图中横坐标代表时间，单位min，纵坐标代表响应值，单位AU。
本申请的实施方式
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合实施例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本申请，并不用于限定本申请。
为了更好的说明本申请，下面通过实施例做进一步的举例说明。
实施例1
本实施例提供一种硫酸特布他林注射液，处方量如下表所示：
硫酸特布他林
50g
氯化钠 890g
0.1mol/L盐酸溶液适量
注射用水至100L。
上述硫酸特布他林注射液的制备方法如下：
步骤a，向配制罐中加入其体积1/3以上的注射用水，开启搅拌，向注射用水中加入乙二胺四乙酸钠，混合均匀，得浓度为0.1mol/L的乙二胺四乙酸钠溶液，开启蠕动泵，使乙二胺四乙酸钠溶液经循环管路和配制罐顶部的喷淋装置，循环喷淋至配制罐中，循环喷淋40min，然后将乙二胺四乙酸钠溶液排出，排放时间为30min，排放完成后用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐；
步骤b，先向预处理配制罐中加满注射用水，然后使用氮气加压的方式排净预处理配制罐中的注射用水，使预处理配制罐中充满氮气；然后向预处理配制罐中加入70L的注射用水，向其中充入氮气保持注射用水中溶解氧低于100ppb，然后向注射用水中加入处方量的硫酸特布他林，搅拌溶解后，得第一溶解液；向第一溶解液中加入处方量的氯化钠，搅拌溶解，得第二溶解液；向第二溶解液中补加注射用水至配制总体积量100L，用0.1mol/L的盐酸溶液调节pH至3.8，搅拌10min使药液混合均匀，得硫酸特布他林药液，检测硫酸特布他林药液中硫酸特布他林含量、pH值合格，且硫酸特布他林药液中溶解氧小于100ppb；
步骤c，向1mL中性硼硅玻璃安瓿瓶中充入氮气排出其中的空气，将硫酸特布他林药液灌装至其中，灌装结束后充入氮气，使安瓿瓶内的顶空残氧量小于1.5%，121℃恒温灭菌8min，得硫酸特布他林注射液。
实施例2
本实施例提供一种硫酸特布他林注射液，处方量如下表所示：
硫酸特布他林
25g
氯化钠 800g
0.1mol/L盐酸溶液适量
注射用水至100L。
上述硫酸特布他林注射液的制备方法如下：
步骤a，向配制罐中加入其体积1/3以上的注射用水，开启搅拌，向注射用水中加入乙二胺四乙酸钠，混合均匀，得浓度为0.05mol/L的乙二胺四乙酸钠溶液，开启蠕动泵，使乙二胺四乙酸钠溶液经循环管路和配制罐顶部的喷淋装置，循环喷淋至配制罐中，循环喷淋30min，然后将乙二胺四乙酸钠溶液排出，排放时间为50min，排放完成后用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐；
步骤b，先向预处理配制罐中加满注射用水，然后使用氮气加压的方式排净预处理配制罐中的注射用水，使预处理配制罐中充满氮气；然后向预处理配制罐中加入80L的注射用水，向其中充入氮气保持注射用水中溶解氧低于100ppb，然后向注射用水中加入处方量的硫酸特布他林，搅拌溶解后，得第一溶解液；向第一溶解液中加入处方量的氯化钠，搅拌溶解，得第二溶解液；向第二溶解液中补加注射用水至配制总体积量100L，用0.5mol/L的盐酸溶液调节pH至3.5，搅拌10min使药液混合均匀，得硫酸特布他林药液，检测硫酸特布他林药液中硫酸特布他林含量、pH值合格，且硫酸特布他林药液中溶解氧小于100ppb；
步骤c，向1mL中性硼硅玻璃安瓿瓶中充入氮气排出其中的空气，将硫酸特布他林药液灌装至其中，灌装结束后充入氮气，使安瓿瓶内的顶空残氧量小于2%，121℃恒温灭菌8min，得硫酸特布他林注射液。
实施例3
本实施例提供一种硫酸特布他林注射液，处方量如下表所示：
硫酸特布他林
100g
氯化钠 900g
0.1mol/L盐酸溶液适量
注射用水至100L。
上述硫酸特布他林注射液的制备方法如下：
步骤a，向配制罐中加入其体积1/3以上的注射用水，开启搅拌，向注射用水中加入乙二胺四乙酸钠，混合均匀，得浓度为0.15mol/L的乙二胺四乙酸钠溶液，开启蠕动泵，使乙二胺四乙酸钠溶液经循环管路和配制罐顶部的喷淋装置，循环喷淋至配制罐中，循环喷淋60min，然后将乙二胺四乙酸钠溶液排出，排放时间为40min，排放完成后用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐；
步骤b，先向预处理配制罐中加满注射用水，然后使用氮气加压的方式排净预处理配制罐中的注射用水，使预处理配制罐中充满氮气；然后向预处理配制罐中加入60L的注射用水，向其中充入氮气保持注射用水中溶解氧低于100ppb，然后向注射用水中加入处方量的硫酸特布他林，搅拌溶解后，得第一溶解液；向第一溶解液中加入处方量的氯化钠，搅拌溶解，得第二溶解液；向第二溶解液中补加注射用水至配制总体积量100L，用0.3mol/L的盐酸溶液调节pH至4.0，搅拌10min使药液混合均匀，得硫酸特布他林药液，检测硫酸特布他林药液中硫酸特布他林含量、pH值合格，且硫酸特布他林药液中溶解氧小于100ppb；
步骤c，向1mL中性硼硅玻璃安瓿瓶中充入氮气排出其中的空气，将硫酸特布他林药液灌装至其中，灌装结束后充入氮气，使安瓿瓶内的顶空残氧量小于1.8%，121℃恒温灭菌8min，得硫酸特布他林注射液。
杂质（RRT0.3）的确定
通过气质联通确认杂质（RRT0.3）为3,5-二羟基苯甲醛，结构式如下：
3,5-二羟基苯甲醛的质谱图如图1所示，质谱结果如表1所示。
表1
稳定性
从实施例1制备的硫酸特布他林注射液中随机抽取1000支，分别置于60℃±2℃高温条件下，分别于0天、5天、15天和30天取样检测，结果如表2所示。
表2 高温影响因素试验结果
其中，总杂指的是杂质总量。
从实施例1制备的硫酸特布他林注射液中随机抽取1000支，分别置于40℃、相对湿度RH 25%条件下，分别于0天、1个月、2个月、3个月和6个月取样检测，结果如表3所示。
表3 加速试验结果
本申请实施例2和实施例3均可取得与实施例1基本相当的效果。
高温影响因素试验和加速试验中有关物质的检测方法为高效液相色谱法（HPLC），其中实验参数如下：
色谱柱：十八烷基硅烷键合硅胶为填充剂（Agilent ZORBAX SB-C18色谱柱，4.6×150mm，5μm）；
流动相：甲醇：缓冲盐溶液（取甲酸铵3.15g，加水980mL溶解，甲酸调节溶液pH至3.0，用水稀释至1000mL，取稀释后的溶液770mL，加己烷磺酸钠7.94g）=23：77；
检测波长：276nm；
进样量：20µL；
流速：1.0mL/min；
柱温：30℃；
供试品溶液：取实施例中制备的硫酸特布他林注射液，作为供试品溶液。
对照溶液：精密量取供试品溶液1mL，置于50mL量瓶中，用流动相稀释至刻度50mL，摇匀，精密量取稀释后的溶液1mL，置于10mL量瓶中，用流动相稀释至刻度10mL，摇匀，作为对照溶液。其中，精密量取指量取体积应准确至所量取体积的千分之一。
混合杂质对照品溶液：取杂质A对照品、杂质B对照品、杂质C对照品、杂质D对照品以及硫酸特布他林对照品适量，精密称定，加流动相溶解并定量稀释制成混合溶液，每1mL混合溶液中杂质A对照品、杂质B对照品、杂质C对照品、杂质D对照品以及硫酸特布他林对照品均约含1μg，该混合溶液作为混合杂质对照品溶液。其中，精密称定指称取重量应准确至所取重量的千分之一。
3,5-二羟基苯甲醛对照品溶液：取3,5-二羟基苯甲醛对照品适量，精密称定，加流动相溶解并定量稀释制成3,5-二羟基苯甲醛对照品溶液，每1mL3,5-二羟基苯甲醛对照品溶液中约含1μg的3,5-二羟基苯甲醛。
其中，混合杂质对照品溶液和3,5-二羟基苯甲醛对照品溶液的高效液相色谱图如图2所示，其中，（a）3，5-二羟基苯甲醛，（b）混合杂质对照品溶液，图中A、B、C、D分别代表杂质A、杂质B、杂质C和杂质D。硫酸特布他林注射液供试品溶液的高效液相色谱图如图3所示，其中，硫酸特布他林的出峰时间为12.190min，3,5-二羟基苯甲醛的出峰时间为3.493min，杂质B的出峰时间为8.024min。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本申请的保护范围之内。
Claims (10)
- 一种硫酸特布他林注射液的制备方法，其特征在于，包括如下步骤：步骤a，向配制罐中循环喷淋乙二胺四乙酸钠溶液，喷淋时间不少于30min，然后用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐；步骤b，向所述预处理配制罐内充入氮气，排净其中的空气，然后加入配制总体积量60-80%的注射用水，向注射用水中充入氮气保持注射用水中溶解氧低于100ppb，然后向注射用水中加入处方量的硫酸特布他林，搅拌溶解后，得第一溶解液；向第一溶解液中加入处方量的氯化钠，搅拌溶解，得第二溶解液；向第二溶解液中补加注射用水至配制总体积量，调节pH至3.5-4.0，搅拌混匀，得硫酸特布他林药液；步骤c，向安瓿瓶中充入氮气排出其中的空气，灌装所述硫酸特布他林药液，灌装结束后充入氮气，使安瓿瓶内的顶空残氧量小于2%，灭菌，得硫酸特布他林注射液。
- 如权利要求1所述的硫酸特布他林注射液的制备方法，其特征在于，步骤a的具体步骤为：向配制罐中加入其体积1/3以上的注射用水，向注射用水中加入乙二胺四乙酸钠，混合均匀，得乙二胺四乙酸钠溶液，开启蠕动泵，将乙二胺四乙酸钠溶液经循环管路和配制罐顶部的喷淋装置，循环喷淋至配制罐中，喷淋时间不少于30min，然后将乙二胺四乙酸钠溶液排出，用注射用水冲洗配制罐至pH为5.0-7.0，且电导率小于0.5，得预处理配制罐。
- 如权利要求1或2所述的硫酸特布他林注射液的制备方法，其特征在于，步骤a中，所述乙二胺四乙酸钠溶液的浓度为0.05-0.15mol/L。
- 如权利要求1或2所述的硫酸特布他林注射液的制备方法，其特征在于，步骤a中，所述喷淋时间为30-60min。
- 如权利要求1所述的硫酸特布他林注射液的制备方法，其特征在于，步骤b中，排净预处理配制灌中空气的方法为：向预处理配制罐中加满注射用水，然后使用氮气加压的方式排净预处理配制罐中的注射用水，使预处理配制罐中充满氮气。
- 如权利要求1所述的硫酸特布他林注射液的制备方法，其特征在于，步骤b中，采用0.1-0.5mol/L的盐酸溶液调节pH至3.5-4.0。
- 如权利要求1所述的硫酸特布他林注射液的制备方法，其特征在于，步骤c中，所述灭菌的方式为121℃恒温灭菌8min。
- 一种硫酸特布他林注射液，其特征在于，由权利要求1-7任一项所述的硫酸特布他林注射液的制备方法制备得到。
- 如权利要求8所述的硫酸特布他林注射液，其特征在于，所述硫酸特布他林注射液由硫酸特布他林、氯化钠、盐酸和注射用水组成，其中每1mL硫酸特布他林注射液中含有硫酸特布他林0.25-1.0mg，氯化钠8.0-9.0mg，硫酸特布他林注射液的pH为3.5-4.0。
- 如权利要求9所述的硫酸特布他林注射液，其特征在于，每1mL硫酸特布他林注射液中含有硫酸特布他林0.5mg，氯化钠8.9mg。
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