CN113750041A - Dexamethasone sodium phosphate liquid preparation and preparation method thereof - Google Patents
Dexamethasone sodium phosphate liquid preparation and preparation method thereof Download PDFInfo
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- sodium phosphate
- dexamethasone sodium
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- 229960002344 dexamethasone sodium phosphate Drugs 0.000 title claims abstract description 64
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 title claims abstract description 64
- 239000007788 liquid Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 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 claims abstract description 34
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 31
- 238000002347 injection Methods 0.000 claims abstract description 28
- 239000007924 injection Substances 0.000 claims abstract description 28
- 230000003204 osmotic effect Effects 0.000 claims abstract description 20
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 12
- 230000001954 sterilising effect Effects 0.000 claims abstract description 12
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 11
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 107
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 28
- 239000008215 water for injection Substances 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 238000011049 filling Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000012528 membrane Substances 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000012669 liquid formulation Substances 0.000 claims 2
- 239000012535 impurity Substances 0.000 abstract description 26
- 239000000463 material Substances 0.000 abstract description 16
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 235000011187 glycerol Nutrition 0.000 description 34
- 239000003814 drug Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 229960003957 dexamethasone Drugs 0.000 description 8
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 8
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- UEAVLBXLOZNDHT-UHFFFAOYSA-K calcium;sodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Ca+2].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEAVLBXLOZNDHT-UHFFFAOYSA-K 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000065 osmolyte Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention discloses a dexamethasone sodium phosphate liquid preparation and a preparation method thereof, wherein the dexamethasone sodium phosphate liquid preparation comprises dexamethasone sodium phosphate, an osmotic pressure regulator, edetate disodium and injection water, the mass and the dosage of the dexamethasone sodium phosphate, the osmotic pressure regulator and the edetate disodium are 0.1-0.6%, 0.9-4.5% and 0.005-0.04% of the mass of the injection water in sequence, and the pH value is regulated to 7.3-8.2 by a pH regulator. The dexamethasone sodium phosphate liquid preparation is not added with sulfite antioxidant, the product stability is still excellent, the antioxidant can be prevented from reacting with the main component to generate impurity I, the components are simple, the addition amount of each auxiliary material is small, and the product quality and safety are improved. Compared with the traditional high-temperature sterilization mode, the preparation process provided by the invention is an aseptic production process, can effectively reduce hydrolysis of dexamethasone sodium phosphate, reduce impurity level, improve product quality, is simple to operate, and can realize large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dexamethasone sodium phosphate liquid preparation and a preparation method thereof.
Background
Dexamethasone sodium phosphate belongs to adrenocortical hormone medicines, is white or yellowish powder, has no odor and slight bitter taste, is easy to absorb moisture, and is difficult to dissolve in chloroform, diethyl ether and acetone. The injection is prepared for administration, has the functions of resisting inflammation, allergy, rheumatism and immunosuppression, is mainly used for treating allergic and autoimmune inflammatory diseases clinically, and has wide application.
Dexamethasone sodium phosphate is poor in thermal stability and easy to hydrolyze, dexamethasone generated by hydrolysis is insoluble in water, the impurity dexamethasone is easy to exceed the standard, and dexamethasone is easy to oxidize, so that the liquid medicine is discolored. In order to solve the above problems, propylene glycol and sodium bisulfite are added as stabilizers in the market. The propylene glycol can change the environment of the solution and is beneficial to inhibiting hydrolysis, and the sodium bisulfite is an antioxidant and is beneficial to inhibiting further hydrolysis of the dexamethasone as an impurity.
However, in the existing product, the two auxiliary materials are large in dosage, adverse reaction can occur, and the safety risk is high. The sulfite is heated to react to generate a sulfonate of dexamethasone sodium phosphate, namely an impurity I in the second part of 'Chinese pharmacopoeia' 2015 edition, the limit requirement of the second part of 'Chinese pharmacopoeia' 2015 edition on the impurity I in the dexamethasone sodium phosphate injection is less than or equal to 1.0 percent, and the structure of the impurity I is as follows:
the related data show that some dexamethasone sodium phosphate injection from some manufacturers exceed the standard, wherein the impurity I is more obviously out of limit, the content measurement result does not meet the standard, see Table 1 (reference: impurity research and preparation influence factor discussion of Cao Xiao Gem. dexamethasone sodium phosphate injection [ D ]. Zhejiang industry university, 2013):
TABLE 1 examination and assay results of dexamethasone sodium phosphate injection for related substances
Therefore, the development of a novel dexamethasone sodium phosphate injection with low impurity content and high safety is of great significance.
Disclosure of Invention
The invention mainly solves the technical problem of providing a high-quality dexamethasone sodium phosphate liquid preparation which has few components and low impurity content.
In order to solve the problems, the invention provides a dexamethasone sodium phosphate liquid preparation which comprises a metal ion chelating agent and does not use an antioxidant, wherein the metal ion chelating agent is edetate disodium.
Dexamethasone sodium phosphate has hygroscopicity, is unstable to heat, and is easy to hydrolyze at high temperature and pH value change to generate dexamethasone, so that an antioxidant, a dispersing agent, a solubilizer, a pH regulator, an integrating agent and the like are usually added in a preparation formula to ensure the stability and quality of a medicine.
Further, the liquid preparation is an injection and comprises dexamethasone sodium phosphate, an osmotic pressure regulator, edetate disodium and water for injection, wherein the mass amounts of the dexamethasone sodium phosphate, the osmotic pressure regulator and the edetate disodium are 0.1-0.6%, 0.9-4.5% and 0.005-0.04% of the mass of the water for injection in sequence.
The commonly used oxidant in the injection is sulfite antioxidant, which mainly comprises sodium bisulfite, sodium metabisulfite (sodium metabisulfite), sodium sulfite, sodium formaldehyde sulfoxylate, sodium dithionite, sodium thiosulfate, etc.
The dexamethasone sodium phosphate injection disclosed by the invention is not added with an antioxidant, the product still has good stability, the generation of impurity I can be avoided, and the product quality is better.
Further, the dexamethasone sodium phosphate injection is adjusted to have a pH value of 7.3-8.2 by a pH regulator.
Further, the osmotic pressure regulator is one or more selected from glycerol, sodium chloride and glucose, and preferably glycerol.
Further, the mass amount of the glycerol is 1.8-3.0%, preferably 2.2-2.6%, and more preferably 2.2% of the mass of the water for injection.
In the invention, the relative dosage of glycerol is low, so that the stability is ensured, and the safety of clinical use is improved.
Furthermore, the mass amount of the edetate disodium is 0.005-0.02% of the mass of the water for injection.
Further, the mass amount of the dexamethasone sodium phosphate is 0.05-0.55% of the mass of the water for injection, and further 0.1-0.5%.
Further, the pH regulator is selected from one or more of phosphoric acid, hydrochloric acid, citric acid and sodium hydroxide.
In a particular embodiment of the invention, the pH adjusting agent is phosphoric acid or sodium hydroxide.
The invention also provides a preparation method of the dexamethasone sodium phosphate liquid preparation, which comprises the following steps: mixing the raw materials and the auxiliary materials, adjusting the pH value to 7.3-8.2 by using a pH regulator, and then sterilizing and filtering.
The mixing form of mixing the raw and auxiliary materials is not limited, all the raw and auxiliary materials can be directly mixed together, or all the components can be separately dissolved by part of water for injection and then mixed and subjected to volume fixing, or part of the raw and auxiliary materials can be mixed and dissolved by a little of water for injection, and the other part of the raw and auxiliary materials can be mixed and subjected to volume fixing after being dissolved by a little of water for injection, and the like.
In the specific embodiment of the invention, the following are adopted: dissolving adjuvants such as metal ion chelating agent and osmotic pressure regulator with part of water for injection, dissolving dexamethasone sodium phosphate with 5% (m/m) of water for injection, mixing dexamethasone sodium phosphate solution with adjuvant solution, and metering volume.
Further, the sterilization filtration is filtration through 0.45 μm and 0.22 μm filter membranes in sequence.
Furthermore, the temperature of the water for injection is 10-50 ℃.
Further, after degerming and filtering, filling protective gas and sealing are carried out; the protective gas is selected from nitrogen and/or inert gas, preferably nitrogen;
furthermore, the range of headspace residual oxygen in the sealed product is less than or equal to 6.0 percent.
The invention has the beneficial effects that:
(1) according to the dexamethasone sodium phosphate liquid preparation, the sulfite antioxidant is not added, the stability of the product is still excellent, the antioxidant can be prevented from reacting with the main component to generate the impurity I, and the product quality is improved.
(2) The dexamethasone sodium phosphate liquid preparation disclosed by the invention is simple in components, the addition amount of each auxiliary material is less, and the safety of the product is improved.
(3) Compared with the traditional high-temperature sterilization mode, the preparation process provided by the invention is an aseptic production process, and can effectively reduce the hydrolysis of dexamethasone sodium phosphate, reduce the impurity level and improve the product quality.
(4) The preparation of the invention has simple process operation and can realize large-scale industrial production.
Detailed Description
The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE 1 Effect of the use of antioxidants on product quality
TABLE 2
| Prescription composition | Prescription 1 | Prescription 2 |
| Dexamethasone sodium phosphate | 2.0g | 2.0g |
| Edetate disodium | 0.12g | 0.12g |
| Glycerol | 22.0g | 22.0g |
| Sodium bisulfite | / | 2.0g |
| Sodium hydroxide/phosphoric acid | Proper amount of | Proper amount of |
| Water for injection | 1000mL | 1000mL |
Taking 2 beakers, respectively adding 800mL of injection water, controlling the water temperature at 10-50 ℃, adding 0.12g of edetate disodium and 22.0g of glycerol into one beaker according to the prescription, adding 0.12g of edetate disodium, 22.0g of glycerol and 2.0g of sodium bisulfite into the other beaker, and stirring to completely dissolve the edetate disodium, the glycerol and the sodium bisulfite; weighing 2 parts of 2.0g dexamethasone sodium phosphate, dissolving the dexamethasone sodium phosphate in 50mL of injection water respectively, stirring the mixture for 5 minutes at the water temperature of 10-50 ℃, completely dissolving the dexamethasone sodium phosphate, adding the mixture into 2 parts of auxiliary material solution respectively, and performing constant volume and uniform mixing. Adjusting the pH value of the liquid medicine to be 7.3-8.2 by using sodium hydroxide or phosphoric acid, filtering the liquid medicine by using a 0.22 mu m filter membrane, filling the filtered liquid medicine into an ampoule, filling nitrogen, controlling the residual oxygen to be less than or equal to 6.0%, sealing by melting, delivering samples, and detecting related indexes. The samples were stored at 2-8 ℃.
The test results of the above 2 prescriptions are shown in table 3:
TABLE 3
Comparing the data, the fact that whether the antioxidant is added or not in the injection system has no obvious influence on the content of the product, dexamethasone in related substances, maximum single impurities and unknown total impurities can be known, but the generation of the impurity I can be effectively avoided by adding no sodium bisulfite in the formula, and the safety of the product can be effectively improved.
Example 2 Effect of Metal ion chelating agent species on product quality
TABLE 4
Taking 2 beakers, respectively adding 800mL of injection water, controlling the water temperature at 10-50 ℃, adding 0.12g of edetate disodium and 22.0g of glycerol into one beaker according to the prescription, adding 0.12g of edetate disodium and 22.0g of glycerol into the other beaker, and stirring to completely dissolve the edetate disodium and the glycerol; weighing 2 parts of 2.0g dexamethasone sodium phosphate, dissolving the dexamethasone sodium phosphate in 50mL of injection water respectively, stirring the mixture for 5 minutes at the water temperature of 10-50 ℃, completely dissolving the dexamethasone sodium phosphate, adding the mixture into 2 parts of auxiliary material solution respectively, and performing constant volume and uniform mixing. Adjusting the pH value of the liquid medicine to be 7.3-8.2 by using sodium hydroxide or phosphoric acid, filtering the liquid medicine by using a 0.22 mu m filter membrane, filling the filtered liquid medicine into an ampoule, filling nitrogen, controlling the residual oxygen to be less than or equal to 6.0%, sealing by melting, delivering samples, and detecting related indexes. The samples were stored at 2-8 ℃.
The test results of the above 2 prescriptions are shown in table 5:
TABLE 5
From the data, it can be seen that the impurity level of the sample using disodium edetate as a stabilizer is obviously lower than that of the sample using calcium sodium edetate as a stabilizer at 0 day and 25 ℃ for 3 months, which indicates that the disodium edetate has better stability to the product under the condition of the same dosage.
Example 3 Effect of disodium edetate dosage on product quality
TABLE 6
Taking 5 beakers, respectively adding 800mL of water for injection, controlling the water temperature at 10-50 ℃, adding 22.0g of glycerol into each beaker according to the prescription, respectively adding 0g, 0.02g, 0.05g, 0.2g and 0.4g of edetate disodium, and stirring to completely dissolve the edetate disodium; weighing 5 parts of 2.0g dexamethasone sodium phosphate, dissolving the dexamethasone sodium phosphate in 50mL of injection water respectively, stirring the mixture for 5 minutes at the water temperature of 10-50 ℃, completely dissolving the dexamethasone sodium phosphate, adding the mixture into 5 parts of auxiliary material solution respectively, and performing constant volume and uniform mixing. And adjusting the pH value of the liquid medicine to 7.3-8.2 by using sodium hydroxide or phosphoric acid, filling the liquid medicine filtered by a filter membrane of 0.22 mu m into an ampoule, filling nitrogen, controlling the residual oxygen to be less than or equal to 6.0%, sealing by melting, delivering samples, and detecting related indexes. Samples were stored at 2-8 ℃.
The results of the above 5 prescriptions are shown in table 7:
TABLE 7
From the data, the impurity growth of the product is faster under the conditions of no addition of the edetate disodium and 0.002% dosage, and 0.005%, 0.02% and 0.04% can all meet the product stability, which indicates that the dosage of the edetate disodium directly influences the product stability. On the premise of meeting the requirement of product stability, the smaller the dosage of the auxiliary materials, the safer the dosage is, and the dosage is preferably 0.005-0.02%.
EXAMPLE 4 Effect of osmolyte type on product quality
TABLE 8
Taking 3 beakers, respectively adding 800mL of injection water, controlling the water temperature at 10-50 ℃, adding 0.12g of edetate disodium into each beaker according to the prescription, respectively adding 22.0g of glycerol, 9.0g of sodium chloride and 45.0g of glucose into each beaker, and stirring to completely dissolve the edetate disodium; 3 parts of 2.0g dexamethasone sodium phosphate are weighed and respectively dissolved in 50mL injection water, the water temperature is 10-50 ℃, the mixture is stirred for 5 minutes and completely dissolved, and the mixture is respectively added into 3 parts of auxiliary material solution, and the volume is determined and the mixture is uniformly mixed. Adjusting the pH value of the solution to 7.3-8.2 by using sodium hydroxide or phosphoric acid, and filtering the solution through a filter membrane of 0.22 mu m. Filling the filtered liquid medicine into an ampoule, filling nitrogen, controlling the residual oxygen to be less than or equal to 6.0 percent, sealing by melting, delivering samples, and detecting related indexes. Samples were stored at 2-8 ℃.
Different osmotic pressure regulators are used in the 3 embodiments, the using modes of the osmotic pressure regulator are combined, the using amounts of the 3 osmotic pressure regulators are adjusted, so that the product can reach isotonic, and the specific data are shown in table 9:
TABLE 9
| Name (R) | Kind of osmotic pressure regulator | Traits | Dosage (m/v%) | Osmotic pressure (mosmol/kg) |
| Prescription 10 | Glycerol | Colorless clear liquid | 2.2 | 285 |
| Prescription 11 | Sodium chloride | Colorless clear liquid | 0.9 | 290 |
| Prescription 12 | Glucose | Colorless clear liquid | 4.5 | 294 |
From the data, the dosage of the osmotic pressure regulator required by the isotonic is glucose, glycerol and sodium chloride in turn, the injection administration of different parts is carried out according to different indications by combining the clinical use of the product, the dosage range is likely to be larger according to the clinical practical situation, 0.9% of sodium chloride is not suitable for specific people such as hypertension patients, and compared with glucose, the dosage of glycerol is less, and the safety is higher. Therefore, the glycerin is used as an isotonic agent, so that the irritation to patients during clinical administration can be reduced, and the glycerin is convenient for clinical use, and is finally selected as an osmotic pressure regulator of the product.
Example 5 Effect of Glycerol amount on product quality
Watch 10
| Prescription composition | Prescription 13 | Prescription 14 | Prescription 15 | Prescription 16 | Prescription 17 | Prescription 18 |
| Dexamethasone sodium phosphate | 2.0g | 2.0g | 2.0g | 2.0g | 2.0g | 2.0g |
| Edetate disodium | 0.12g | 0.12g | 0.12g | 0.12g | 0.12g | 0.12g |
| Glycerol (m/v) | 0％ | 1.8％ | 2.2％ | 2.6％ | 4.0％ | 25.0％ |
| Sodium hydroxide/phosphoric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water for injection | 1000mL | 1000mL | 1000mL | 1000mL | 1000mL | 1000mL |
Taking 6 beakers, respectively adding 800mL of water for injection, controlling the water temperature at 10-50 ℃, adding 0.12g of edetate disodium into each beaker according to a prescription, respectively adding 0g, 11.0g, 22.0g, 26.0g, 40.0g, 250.0g, 11.6g, 23.1g and 34.6g of glycerol into the beakers, and stirring to completely dissolve the edetate disodium; weighing 6 parts of 2.0g dexamethasone sodium phosphate, dissolving in 50mL of injection water respectively, stirring at 10-50 ℃ for 5 minutes until the dexamethasone sodium phosphate is completely dissolved, respectively adding into 6 parts of auxiliary material solution, fixing the volume, and uniformly mixing. Adjusting the pH value of the solution to 7.3-8.2 by using sodium hydroxide or phosphoric acid, and filtering the solution through a filter membrane of 0.22 mu m. Filling the filtered liquid medicine into an ampoule, filling nitrogen, controlling the residual oxygen to be less than or equal to 6.0 percent, sealing by melting, delivering samples, and detecting related indexes. Samples were stored at 2-8 ℃.
The results of the above 9 prescriptions are shown in tables 11 and 12:
TABLE 11 Effect of different glycerol amounts on product quality
From the above results, it can be seen that at day 0, the samples prepared from different proportions of glycerin have no obvious difference in properties, pH values, contents and related substances. And when the sample is placed for 1 month at 25 ℃, the characters and the pH values of all samples have no obvious change, related substances have a growing trend, but the increasing amplitude of all samples is close to that of all samples, and no large difference exists, which indicates that the stability of the product is not influenced by different dosages of glycerin.
TABLE 12
| Prescription | Traits | Osmotic pressure (mosmol/kg) |
| Prescription 13 | Colorless clear liquid | 28 |
| Prescription 14 | Colorless clear liquid | 260 |
| Prescription 15 | Colorless clear liquid | 285 |
| Prescription 16 | Colorless clear liquid | 350 |
| Prescription 17 | Colorless clear liquid | Is unable to detect |
| Prescription 18 | Colorless clear liquid | Is unable to detect |
The data show that different dosages of glycerol have large influence on the osmotic pressure of the sample, 1.8 percent of glycerol is slightly lower than the osmotic pressure of a human body, 2.6 percent of glycerol is slightly higher than the osmotic pressure of the human body, 2.2 percent of the dosage is optimal, and the reasonable glycerol dosage range is determined when the glycerol dosage is 1.8-2.6 percent.
EXAMPLE 6 Effect of sterilization mode on product quality
Adding 800mL of water for injection into a beaker, controlling the water temperature to be 10-50 ℃, adding 0.12g of edetate disodium and 22.0g of glycerol, and stirring to completely dissolve the edetate disodium and the glycerol; weighing 2.0g of dexamethasone sodium phosphate, dissolving in 50mL of injection water at 10-50 ℃, stirring for 5 minutes, dissolving completely, adding into the auxiliary material solution, fixing the volume, and mixing uniformly. Adjusting the pH value to 7.3-8.2 by using sodium hydroxide or phosphoric acid, filtering the liquid medicine through a filter membrane of 0.22 mu m, filling nitrogen, and sealing by melting. The dosage of each component is the same as that of the prescription 1, the sample is divided into 6 parts, the sterilization is carried out according to different modes, and the detection results are shown in a table 13:
watch 13
The results show that under different sterilization conditions, the content of the product is greatly reduced after the product is subjected to a sterilization process, and related substances are greatly increased. Therefore, the product can not endure high temperature sterilization and needs to be produced by an aseptic technique.
Example 7 stability Performance testing
TABLE 14
| Prescription composition | Prescription 19 | Prescription 20 | Prescription 21 |
| Dexamethasone sodium phosphate | 0.6kg | 1.5kg | 0.3kg |
| Edetate disodium | 36g | 36g | 36g |
| Glycerol | 6.6kg | 6.6kg | 6.6kg |
| Sodium hydroxide/phosphoric acid | Proper amount of | Proper amount of | Proper amount of |
| Water for injection | 300L | 300L | 300L |
Adding 240L of water for injection into the liquid preparation tank, controlling the water temperature at 10-50 ℃, adding 36g of edetate disodium and 6.6kg of glycerol, and stirring to completely dissolve the edetate disodium and the glycerol; respectively weighing 0.6kg, 1.5kg and 0.3kg of dexamethasone sodium phosphate, respectively dissolving the dexamethasone sodium phosphate in 15L of injection water at the temperature of 10-50 ℃, stirring for 5 minutes, completely dissolving, respectively adding the dexamethasone sodium phosphate into an auxiliary material solution, fixing the volume, uniformly mixing, adjusting the pH value to 7.3-8.2 by using sodium hydroxide or phosphoric acid, filtering the liquid medicine through a 0.45 mu m filter membrane, detecting the character, the pH value, the content and the related substances to be qualified, filtering the liquid medicine through two stages of 0.22 mu m filter membranes, filling nitrogen, and sealing by melting. The stability data for this batch of samples is shown in table 15:
watch 15
Compared with the data, the dexamethasone sodium phosphate injection has the advantages that after long-time standing, the contents of dexamethasone, maximum single impurities and total impurities in the dexamethasone sodium phosphate injection are still very low, the contents are not obviously increased compared with the initial values, and the stability is good. Comparing with table 1, it can be seen that the impurity dexamethasone level in the dexamethasone sodium phosphate injection produced by the invention is obviously lower than that of the product sold on the market, the product does not produce impurity I, the maximum single impurity and total impurity levels are also obviously lower than that of the existing product sold on the market, the impurity level is low, the product quality can be obviously improved, and the safety of the product in clinical use is ensured.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. The dexamethasone sodium phosphate liquid preparation is characterized by comprising a metal ion chelating agent, wherein an antioxidant is not used, and the metal ion chelating agent is edetate disodium.
2. The dexamethasone sodium phosphate liquid preparation according to claim 1, wherein the liquid preparation is an injection, and comprises dexamethasone sodium phosphate, an osmotic pressure regulator, edetate disodium and water for injection, and the mass amounts of the dexamethasone sodium phosphate, the osmotic pressure regulator and the edetate disodium are 0.1-0.6%, 0.9-4.5% and 0.005-0.04% of the mass of the water for injection in sequence.
3. The dexamethasone sodium phosphate liquid formulation according to claim 1 or 2, wherein the pH is adjusted to 7.3-8.2 by a pH adjusting agent.
4. The dexamethasone sodium phosphate liquid formulation according to claim 2 or 3, wherein the osmotic pressure regulator is selected from one or more of glycerol, sodium chloride and glucose, preferably glycerol;
further, the mass amount of the glycerol is 1.8-3.0%, preferably 2.2-2.6%, and more preferably 2.2% of the mass of the water for injection.
5. The dexamethasone sodium phosphate liquid preparation according to any one of claims 1 to 4, wherein the mass amount of the edetate disodium is 0.005-0.02% of the mass of the water for injection.
6. The dexamethasone sodium phosphate liquid preparation according to any one of claims 1 to 5, wherein the mass amount of the dexamethasone sodium phosphate is 0.05-0.55% of the mass of the water for injection, and further 0.1-0.5%.
7. The dexamethasone sodium phosphate liquid preparation according to any one of claims 3 to 6, wherein the pH regulator is selected from one or more of phosphoric acid, hydrochloric acid, citric acid and sodium hydroxide, preferably phosphoric acid or sodium hydroxide.
8. The method for preparing the dexamethasone sodium phosphate liquid preparation according to any one of claims 1 to 7, wherein the method comprises the following steps: mixing the raw materials, adjusting the pH value to 7.3-8.2 by using a pH regulator, and then sterilizing and filtering.
Further, the sterilization filtration is filtration through 0.45 μm and 0.22 μm filter membranes in sequence.
9. The method according to claim 8, wherein the temperature of the water for injection is 10 to 50 ℃.
10. The preparation method according to claim 8 or 9, wherein the sterilization filtration is followed by filling, filling with a protective gas, and sealing; the protective gas is selected from nitrogen and/or inert gas, preferably nitrogen;
furthermore, the range of headspace residual oxygen in the sealed product is less than or equal to 6.0 percent.
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