CN116509799A - Naloxone hydrochloride injection and preparation method thereof - Google Patents
Naloxone hydrochloride injection and preparation method thereof Download PDFInfo
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- CN116509799A CN116509799A CN202310646721.9A CN202310646721A CN116509799A CN 116509799 A CN116509799 A CN 116509799A CN 202310646721 A CN202310646721 A CN 202310646721A CN 116509799 A CN116509799 A CN 116509799A
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- injection
- naloxone hydrochloride
- regulator
- acid
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- 229960005250 naloxone hydrochloride Drugs 0.000 title claims abstract description 50
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 title claims abstract description 50
- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims description 14
- 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 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract 2
- 230000001954 sterilising effect Effects 0.000 claims description 29
- 238000004659 sterilization and disinfection Methods 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- -1 polypropylene Polymers 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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 3
- 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 3
- 239000002033 PVDF binder Substances 0.000 claims description 3
- 239000004695 Polyether sulfone Substances 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 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 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 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
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000011087 fumaric acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 229920006393 polyether sulfone Polymers 0.000 claims description 3
- 229920001155 polypropylene Polymers 0.000 claims description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 3
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 18
- 238000012360 testing method Methods 0.000 abstract description 7
- 241000289690 Xenarthra Species 0.000 abstract description 6
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 4
- 230000001133 acceleration Effects 0.000 abstract description 3
- 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 description 6
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 4
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 4
- 239000003002 pH adjusting agent Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940113960 edetate calcium Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000006467 substitution reaction 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a naloxone hydrochloride injection, which consists of the following components: naloxone hydrochloride, calcium sodium edetate and auxiliary materials for injection. According to the formula, the calcium disodium edentate is added, and after the calcium disodium edentate is sterilized at a high temperature terminal, the total impurity content can be as low as 0.11%, and even in an acceleration test, the total impurity content is also lower than 0.25%, so that the calcium disodium edentate has good thermal stability, the safety of injection is obviously improved, and long-term storage is facilitated.
Description
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to naloxone hydrochloride injection and a preparation method thereof.
Background
Naloxone hydrochloride, chemical name: 17-allyl-4, 5 a-epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate, of the formula: c (C) 19 H 21 NO 4 HCl, molecular weight 399.87. Naloxone hydrochloride is white crystal or crystalline powder, odorless, soluble in water, soluble in methanol, and hardly soluble in chloroform or diethyl ether.
Due to poor heat resistance of naloxone hydrochloride in aqueous solution, quality indexes such as clarity, color, related substances and content of injection are easy to be unqualified after high-temperature sterilization or long-term storage, and are not beneficial to high-temperature sterilization or long-term storage. In order to overcome the defect, manufacturers choose to develop non-liquid preparations such as naloxone hydrochloride powder injection at present so as to avoid the problem of heat resistance.
CN103877016a discloses a naloxone hydrochloride injection pharmaceutical composition and a preparation method thereof, wherein a certain amount of malic acid is added in the prescription to improve the stability of naloxone hydrochloride in aqueous solution, but the sterilization process is that steam sterilization is carried out for 30 minutes or 45 minutes at 100 ℃, and terminal sterilization and thermal stability research at more than 120 ℃ are not involved. The sterilization temperature is too low, and the sterilization requirement can not be met, thereby influencing the quality of the injection.
CN110269837a provides a naloxone hydrochloride injection and a preparation method thereof, which adds disodium ethylenediamine tetraacetate into the prescription, can improve the thermal stability of the injection after sterilization for 15 minutes at 121 ℃, according to the embodiment, the adding amount of disodium ethylenediamine tetraacetate is 0.001mg/mL, the pH of the solution is 4.5, and the total impurity content in the solution is the lowest after the injection is sterilized at the terminal and is 0.25%. However, after an acceleration test at 40 ℃ for 6 months, the total impurity content reaches 0.59%, and the stability is required to be enhanced.
Disclosure of Invention
The invention aims to overcome at least one defect in the prior art and provides a naloxone hydrochloride injection and a preparation method thereof.
The technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides a naloxone hydrochloride injection, which consists of the following components: naloxone hydrochloride, calcium sodium edetate and adjuvants.
In some examples, the calcium sodium edetate is present in an amount of 0.001 to 0.1mg/mL.
In some examples, the naloxone hydrochloride is present in an amount of 0.1 to 1mg/mL.
In some examples, the pH of the injection is 3 to 4.
In some examples, the adjuvants include isotonic agents, pH adjusting agents, water for injection.
In some examples, the isotonic regulator is selected from any one of sodium chloride and glucose, and the pH regulator is selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate.
In a second aspect, the invention provides a preparation method of naloxone hydrochloride injection, which comprises the following steps:
1) Dissolving an isotonic regulator and calcium sodium edetate in water for injection with a dissolved oxygen of less than 3ppm to obtain a stabilizer solution;
2) Adding naloxone hydrochloride into the stabilizer solution obtained in the step 1), stirring until the naloxone hydrochloride is completely dissolved, and then adding a pH regulator to adjust the pH value to 3-4 to obtain naloxone hydrochloride solution;
3) Filtering, filling and sterilizing the naloxone hydrochloride solution to obtain the naloxone hydrochloride injection.
In some examples, the isotonic regulator added in step 1) is at a concentration of 5 to 10mg/mL and the pH regulator added in step 2) is at a concentration of 0.01 to 1mol/L.
In some examples, the filter element filtered in step 3) is selected from any one of a polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element of 0.22 μm.
In some examples, the sterilization temperature in the step 3) is 121-126 ℃, the sterilization time is 12-15 minutes, and the standard sterilization time F0 value is more than or equal to 12 minutes.
The beneficial effects of the invention are as follows:
according to the invention, the calcium disodium edentate is added in the prescription, and after terminal sterilization at 121 ℃, the total impurity content can be as low as 0.11%, and even in an acceleration test (60 ℃ for 30 days), the total impurity content is lower than 0.25%, so that the injection has good thermal stability, improves the safety of the injection, and is favorable for long-term storage.
Detailed Description
In a first aspect, the invention provides a naloxone hydrochloride injection, which consists of the following components: naloxone hydrochloride, calcium sodium edetate and adjuvants.
In some examples, the calcium sodium edetate is present in an amount of 0.001 to 0.1mg/mL. The dosage of the naloxone hydrochloride can be correspondingly adjusted according to the amount of the naloxone hydrochloride.
In some examples, the naloxone hydrochloride is present in an amount of 0.1 to 1mg/mL.
In some examples, the pH of the injection is 3 to 4. This is more advantageous for the stabilization of the injection.
In some examples, the adjuvants include isotonic agents, pH adjusting agents, water for injection.
The isotonicity adjusting agent may be any acceptable common isotonicity adjusting agent. In some examples, the isotonicity modifier is selected from any of sodium chloride, dextrose.
The pH adjuster may be a pharmaceutically acceptable pH adjuster, in some examples, selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate.
In a second aspect, the invention provides a preparation method of naloxone hydrochloride injection, which comprises the following steps:
1) Dissolving an isotonic regulator and calcium sodium edetate in water for injection with a dissolved oxygen of less than 3ppm to obtain a stabilizer solution;
2) Adding naloxone hydrochloride into the stabilizer solution obtained in the step 1), stirring until the naloxone hydrochloride is completely dissolved, and then adding a pH regulator to adjust the pH value to 3-4 to obtain naloxone hydrochloride solution;
3) Filtering, filling and sterilizing the naloxone hydrochloride solution to obtain the naloxone hydrochloride injection.
In some examples, the isotonic regulator added in step 1) is at a concentration of 5 to 10mg/mL and the pH regulator added in step 2) is at a concentration of 0.01 to 1mol/L.
In some examples, the filter element filtered in step 3) is selected from any one of a polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element of 0.22 μm.
The sterilization may be high temperature sterilization or filtration sterilization, preferably high temperature sterilization. In some examples, the sterilization temperature in the step 3) is 121-126 ℃, the sterilization time is 12-15 minutes, and the standard sterilization time F0 value is more than or equal to 12 minutes.
The following disclosure provides many different embodiments, or examples, for implementing different aspects of the invention.
The names of edetate calcium sodium and edetate disodium are very similar and the effect is also substantially similar, but the effect is greatly different due to the presence of calcium ions in edetate calcium sodium. The invention aims to provide a novel naloxone hydrochloride injection and a preparation method thereof, and calcium sodium edetate is added in a prescription, so that the thermal stability and the safety of the injection can be greatly improved.
Example 1
1. The formulation of naloxone hydrochloride injection is shown in table 1:
TABLE 1
2. Preparation method
Adding injection water with the prescription amount of 50-95%, and introducing nitrogen into the liquid until the dissolved oxygen is less than 3ppm; sequentially adding the sodium chloride and the calcium sodium edetate with the prescription amount, and stirring until the sodium edetate and the calcium sodium edetate are completely dissolved; adding naloxone hydrochloride with a prescription amount, and stirring until the naloxone hydrochloride is completely dissolved; adjusting the pH to 3-4; adding injectable water to the prescribed dosage, and stirring to obtain naloxone hydrochloride injection.
3. The performance test results of naloxone hydrochloride injections of experimental groups 1-5 are shown in Table 2.
TABLE 2
From the above data, it is clear that in experiment group 1 without calcium disodium edentate, the total impurity content before sterilization was 0.18%, the total impurity content after terminal sterilization (121 ℃ C., 12 min) reached 0.4%, and the total impurity content after accelerated test (60 ℃ C., 30 d) was more 1.19%. However, after adding calcium disodium edentate, the total impurity content changes little before and after terminal sterilization, which are less than 0.15%, and even after accelerated test (60 ℃ C., 30 d), the total impurity content does not exceed 0.25%.
The invention is different from CN110269837A in that disodium ethylenediamine tetraacetate is added in the prescription of CN110269837A, the adding amount of disodium ethylenediamine tetraacetate is 0.001mg/mL, the pH of the solution is 4.5, the total impurity content in the solution is 0.25% at the minimum after the injection is sterilized at a terminal, and the total impurity content reaches 0.59% in an accelerated test at 40 ℃ for 6 months, which is higher than that of the experimental group 2-5 added with calcium sodium edetate in the invention.
It can be seen that the addition of calcium sodium edetate greatly improves the thermal stability of the injection, and the thermal stability is best when the addition amount is 0.075 mg/mL.
Example 2
1. The formulation of naloxone hydrochloride injection is shown in table 3:
TABLE 3 Table 3
2. Preparation method
The preparation method of this example was identical to that of example 1.
3. The performance test results of naloxone hydrochloride injections of experimental groups 6-10 are shown in Table 4.
TABLE 4 Table 4
To determine the effect of pH on the thermal stability of the injecta, the performance of the injecta after terminal sterilization at pH 3, 3.5, 4,5, 6.5 was tested by accelerated test (60 ℃ C.). From the above data, it was found that the total impurities were less than 0.2% when the pH was 3 to 4, and the reaction was accelerated for 30 days. When the pH is 5, the speed is increased for 30 days, the pH of the injection is increased to 5.5, the total impurity content is 0.49%, and the impurity content is higher, but the injection meets the requirement of internal impurity control (< 0.8%). However, the pH was accelerated for 30 days at pH 6.5, pH 6.8 and total impurities at 3.51% which was not satisfactory. The pH has a great influence on the thermal stability of the injection, and the pH is between 3 and 4, so that the injection has good stability.
The above description of the present invention is further illustrated in detail and should not be taken as limiting the practice of the present invention. It is within the scope of the present invention for those skilled in the art to make simple deductions or substitutions without departing from the concept of the present invention.
Claims (10)
1. The naloxone hydrochloride injection is characterized by comprising the following components: naloxone hydrochloride, calcium sodium edetate and adjuvants.
2. The injection according to claim 1, wherein the calcium sodium edetate is present in an amount of 0.001-0.1 mg/mL.
3. The injection according to claim 1, wherein the naloxone hydrochloride content is 0.1-1 mg/mL.
4. The injection according to claim 1, wherein the pH of the injection is 3-4.
5. The injection according to claim 1, wherein the auxiliary materials comprise an isotonic regulator, a pH regulator and water for injection.
6. The injection according to claim 5, wherein the isotonic regulator is selected from any one of sodium chloride and glucose, and the pH regulator is selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate.
7. The preparation method of naloxone hydrochloride injection as claimed in claims 1-6, comprising the steps of:
dissolving an isotonic regulator and calcium sodium edetate in water for injection with a dissolved oxygen of less than 3ppm to obtain a stabilizer solution;
adding naloxone hydrochloride into the stabilizer solution obtained in the step 1), stirring until the naloxone hydrochloride is completely dissolved, and then adding a pH regulator to adjust the pH value to 3-4 to obtain naloxone hydrochloride solution;
filtering, filling and sterilizing the naloxone hydrochloride solution to obtain the naloxone hydrochloride injection.
8. The method according to claim 7, wherein the concentration of the isotonic regulator added in the step 1) is 5 to 10mg/mL, and the concentration of the pH regulator added in the step 2) is 0.01 to 1mol/L.
9. The method according to claim 7, wherein the filter element filtered in the step 3) is selected from any one of a polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element having a particle size of 0.22 μm.
10. The method according to claim 7, wherein the sterilization temperature in the step 3) is 121-126 ℃, the sterilization time is 12-15 minutes, and the standard sterilization time F 0 The value is more than or equal to 12 minutes.
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| CN202310646721.9A CN116509799A (en) | 2023-06-02 | 2023-06-02 | Naloxone hydrochloride injection and preparation method thereof |
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