CN113209016A - Iron dextran and palustralin suspension injection and preparation method thereof - Google Patents
Iron dextran and palustralin suspension injection and preparation method thereof Download PDFInfo
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- CN113209016A CN113209016A CN202011003233.9A CN202011003233A CN113209016A CN 113209016 A CN113209016 A CN 113209016A CN 202011003233 A CN202011003233 A CN 202011003233A CN 113209016 A CN113209016 A CN 113209016A
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- 238000002347 injection Methods 0.000 title claims abstract description 68
- 239000007924 injection Substances 0.000 title claims abstract description 68
- 239000000725 suspension Substances 0.000 title claims abstract description 56
- MVZXTUSAYBWAAM-UHFFFAOYSA-N iron;sulfuric acid Chemical compound [Fe].OS(O)(=O)=O MVZXTUSAYBWAAM-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title description 24
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 241001465754 Metazoa Species 0.000 claims abstract description 14
- 229920002545 silicone oil Polymers 0.000 claims abstract description 13
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 11
- 239000000787 lecithin Substances 0.000 claims abstract description 11
- 229940067606 lecithin Drugs 0.000 claims abstract description 11
- 235000010445 lecithin Nutrition 0.000 claims abstract description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008139 complexing agent Substances 0.000 claims abstract description 7
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 7
- 229940069328 povidone Drugs 0.000 claims abstract description 7
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 claims abstract description 5
- ZRWPUFFVAOMMNM-UHFFFAOYSA-N Patulin Chemical compound OC1OCC=C2OC(=O)C=C12 ZRWPUFFVAOMMNM-UHFFFAOYSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 11
- 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 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 8
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 8
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 8
- 229940083037 simethicone Drugs 0.000 claims description 8
- 208000003495 Coccidiosis Diseases 0.000 claims description 7
- 206010023076 Isosporiasis Diseases 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- 206010022971 Iron Deficiencies Diseases 0.000 claims description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229940008099 dimethicone Drugs 0.000 claims description 4
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 4
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 4
- 229920000570 polyether Polymers 0.000 claims description 4
- VBUNOIXRZNJNAD-UHFFFAOYSA-N ponazuril Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(S(=O)(=O)C(F)(F)F)C=C1 VBUNOIXRZNJNAD-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229960003508 ponazuril Drugs 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 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 description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- UWSAIOMORQUEHN-UHFFFAOYSA-L sodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate;iron(5+) Chemical compound [Na+].[Fe+5].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O UWSAIOMORQUEHN-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 34
- 229910052742 iron Inorganic materials 0.000 description 17
- 239000000203 mixture Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 8
- 238000004062 sedimentation Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000006260 foam Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000013589 supplement Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 239000000273 veterinary drug Substances 0.000 description 4
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(SC(F)(F)F)C=C1 OCINXEZVIIVXFU-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000003250 oocyst Anatomy 0.000 description 3
- 206010001526 Air embolism Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 229960000898 toltrazuril Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 241000224483 Coccidia Species 0.000 description 1
- 206010010264 Condition aggravated Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 241000606266 Nardostachys Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000001165 anti-coccidial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001275 dimeticone Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- -1 polysiloxane Polymers 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910021643 water for pharmaceutical use Inorganic materials 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/721—Dextrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Tropical Medicine & Parasitology (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a suspension injection containing iron dextran and patoteleph, which also comprises: pharmaceutically acceptable silicone oil, lecithin, metal ion complexing agent, n-butyl alcohol, povidone, water and optional pH regulator. The injection has good stability, good safety and high bioavailability, and can be used for preventing and treating animal coccidium infection and iron deficiency anemia.
Description
Technical Field
The invention belongs to the technical field of veterinary medicines, and particularly relates to a suspension injection containing iron dextran and potazuril and a preparation method thereof, which are suitable for simultaneously preventing and treating coccidiosis and iron deficiency anemia of animals.
Background
Coccidiosis and iron deficiency anemia, which are frequently caused by animal diseases in the modern livestock breeding industry, are frequently generated in young animals, have high morbidity and rapid disease aggravation, seriously affect the growth and development of the animals and even cause death.
The iron storage at birth (40-50 mg) and the iron obtained from breast milk during lactation (about 1mg/d) are very limited, which results in piglets being prone to iron deficiency during the first week after birth. Clinically, the method mainly adopts intramuscular injection iron supplement or indirect iron supplement for sows, and farmers mostly adopt an intramuscular injection mode to supplement iron for piglets because the iron supplement amount for the supplementary feeding of sows is limited.
As coccidiosis is also frequently occurred in the young stage, piglets are usually caught again within 2-3 days after iron supplement is completed in clinic, and the anti-coccidiosis drugs are orally taken.
The mode of treating only one disease brings huge workload to farmers, increases the drug cost, brings huge pressure to animals, influences the normal growth and development of the animals, and finally influences the economic benefit of cultivation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a suspension injection containing iron dextran and patulin and a preparation method thereof, which improve the stability of the preparation.
Specifically, the invention relates to an injection containing iron dextran and patotelepine, which also comprises:
pharmaceutically acceptable silicone oil (such as simethicone, dimethicone, polyether silicone oil), lecithin, metal ion complexing agent, n-butanol, povidone, water, and optionally a pH adjusting agent.
In certain embodiments, the pharmaceutically acceptable silicone oil in the injection of the present invention is simethicone, dimethicone, polyether silicone oil, or any combination thereof.
In certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention, wherein the pH regulator comprises one or more selected from citric acid, sodium citrate, potassium dihydrogen phosphate, sodium bicarbonate, and sodium hydroxide.
In certain embodiments, in the injection of the present invention, the metal ion complexing agent is ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof.
In certain embodiments, the pharmaceutically acceptable salt of ethylenediaminetetraacetic acid of the present invention is selected from disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, iron sodium ethylenediaminetetraacetate, or any combination thereof.
In certain embodiments, the injection of the present invention, wherein the metal ion complexing agent is disodium edetate.
In some embodiments, the injection of the present invention has a pH of 3 to 8, preferably 5 to 7.
In certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention comprises the following components:
in certain embodiments, the injection of the present invention comprises the following components:
the invention also relates to a method for preparing the injection containing the iron dextran and the patulin, which comprises the following steps:
adding iron dextran into a proper amount of water for 1-5 times, and stirring at a rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) at a temperature of 60-80 ℃ to obtain an initial solution I;
adding the disodium ethylene diamine tetraacetate and the povidone with the prescription amount into the initial solution I, stirring and dissolving to obtain a mixed solution II;
adding the n-butanol and the lecithin in the formula amount into the mixed solution II, stirring at 50-70 ℃ until the n-butanol and the lecithin are completely dissolved to obtain a suspension III, and cooling;
adding the dimeticone and the ponazuril in the formula amount into the suspension III, and stirring at the rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) to obtain a suspension IV;
and adding a pH regulator into the suspension IV to regulate the pH value of the suspension IV to be 3-8, and stirring at the rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) to obtain the final suspension V.
In some embodiments, the method for preparing an injection containing iron dextran and patulin, disclosed by the invention, comprises adding the iron dextran into a proper amount of water 2-4 times.
In some embodiments, the method for preparing the injection containing the iron dextran and the patulin, disclosed by the invention, comprises the steps of adding the dimethyl silicone oil and the patulin in the formula amount into the suspension III, stirring at 3000-6000 rpm, and controlling the temperature to be 20-30 ℃ to obtain the suspension IV.
In some embodiments, the method for preparing an injection containing iron dextran and patoril, provided by the invention, comprises the step of adding a pH regulator into the suspension IV to adjust the pH value of the suspension IV to be 5-7.
The invention also relates to application of the injection containing the iron dextran and the patulin in preparing a medicament for preventing and/or treating animal (such as pig) coccidiosis and/or iron deficiency anemia and/or iron deficiency state.
In certain embodiments, the water of the present invention is water for injection, preferably water for injection according to the specifications under the prescription of water for pharmaceutical use of the Chinese veterinary drug.
In the present invention, the unit "w/v%" represents a mass volume percentage and indicates the number of grams (g) of solute contained in 100mL of a suspension injection, and for example, "the content of patulin is 1 w/v%" indicates that 1g of patulin is contained in 100mL of a suspension injection.
The term "about" in the present invention is to be understood as within ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, ± 0.05% or ± 0.01% of the specified numerical value.
The term "pharmaceutically acceptable silicone oil" as used herein refers to a linear polysiloxane product that remains in a liquid state at room temperature and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Examples of pharmaceutically acceptable silicone oils include, but are not limited to, simethicone, dimethicone, polyether silicone oil, and the like.
The term "proper amount" in the present invention means a proper amount, which may be zero or any value except zero, for example, the content of the pH adjusting agent in the suspension injection is a proper amount, which means that the amount of the pH adjusting agent contained in the suspension injection can make the pH value of the suspension injection meet the target requirement (e.g., 3 to 8, preferably 5 to 7), and if the pH value of the suspension injection does not meet the target requirement (e.g., 3 to 8, preferably 5 to 7) without adding the pH adjusting agent, the content of the pH adjusting agent is zero.
The invention has the advantages of
Advantages of the present invention over the prior art include one or more of the following:
1) the injection containing the iron dextran and the iron patulin is a compound preparation of the iron dextran and the iron dextran, can be simultaneously suitable for preventing and treating coccidiosis and piglet iron deficiency, can prevent and treat two diseases simultaneously by only once administration, reduces the administration workload, reduces the medicinal cost, reduces the stress response of animals and improves the animal welfare.
2) The injection containing the iron dextran and the patulin provided by the invention has good stability and better viscosity-sedimentation ratio. The water solubility of the patozolli is poor, and the preparation of the patozolli is easy to generate particle sedimentation. Studies have found that the problem of settling of drug particles in a formulation is difficult to solve by merely adjusting the ratio of povidone and lecithin. The invention well solves the stability problem of the preparation by adding the n-butyl alcohol into the preparation.
3) The aqueous suspension generally needs to be shaken to a certain extent before use, so that the settled drug particles are uniformly dispersed in the system again. However, the aqueous suspension is very easy to generate foam during shaking, and especially, the trazinone compounds of the patulin class are easy to generate a large amount of foam, so that the accuracy of the administration dosage of the syringe is influenced besides the appearance, and the risk of gas embolism caused by air bubbles injected during injection is possibly caused. The injection containing the iron dextran and the patulin is not easy to generate foam in the process of shaking and shaking, is favorable for clinical use, and reduces the risk of gas embolism caused by air injection.
4) The injection containing the iron dextran and the patulin provided by the invention has low content of free iron, and avoids a series of side effects such as poisoning, allergy and the like caused by accumulation of free iron after multiple intramuscular injections of animals.
5) Compared with the traditional oral administration, the injection containing the iron dextran and the patulin provided by the invention has the advantages of quick response and high bioavailability. In addition, the administration dosage is accurate.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to specific examples.
The following examples are intended only to further illustrate the present invention and should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention.
The raw materials used in the examples of the present invention and the comparative examples are commercially available products.
Unless otherwise specified, the technical means used in the examples of the present invention are conventional means well known to those skilled in the art.
In the following examples:
the simethicone is purchased from Shanxi brocade Yang pharmaceutic adjuvant Co., Ltd., batch No. 20191011.
The lecithin was purchased from Xian jin Xiang pharmaceutic adjuvant, Inc., lot number 180602.
The patozolli used was from the scientific and technological company, CAS: 69004-04-2.
The iron dextran used was from the scientific and technological company of Longxiang pharmaceutical industry, Inc., Hubei, CAS: 9004-66-4.
The water for injection meets the water for injection specified in the Chinese veterinary drug classical pharmacy water.
Examples
Example 1 preparation of suspension injection 1 comprising patulin and iron dextran
1. The prescription composition is as follows:
2. the preparation method comprises the following steps:
s1, adding a proper amount of water for injection into a liquid preparation tank, adding the iron dextran according to the prescription amount for 2-4 times, stirring for 30min at the temperature of 60-80 ℃ by using a high-shear emulsifying machine at 4000-5000 r/min to obtain an initial solution I, and cooling for later use;
s2, adding the disodium ethylene diamine tetraacetate and the povidone with the prescription amount into the initial solution I, and fully stirring and dissolving to obtain a mixed solution II;
s3, adding the n-butanol and the lecithin in the formula amount into the mixed solution II, heating and stirring at 50-70 ℃ until the n-butanol and the lecithin are completely dissolved to obtain a suspension III, and cooling for later use;
s4, adding the simethicone and the ponazuril in the formula amount into the suspension III, stirring for 30min at 4000-5000 r/min by using a high-shear emulsifying machine, and controlling the temperature to be 20-30 ℃ to obtain a suspension IV;
and S5, adding a pH regulator (citric acid and sodium citrate) into the suspension IV to regulate the pH value of the suspension IV to be 5-7, and stirring for 30min at 4000-5000 r/min by using a high-shear emulsifying machine to obtain a final suspension V.
Example 2 preparation of suspension injection 2 comprising patulin and iron dextran
1. Prescription composition
2. The preparation method is the same as example 1.
Example 3 preparation of suspension injection 3 comprising Potocarpolli and iron dextran
1. The prescription composition is as follows:
2. the preparation method is the same as example 1.
Example 4 preparation of suspension injection 4 containing Potocarpolli and iron dextran
1. The prescription composition is as follows:
2. the preparation method is the same as example 1.
Example 5 preparation of suspension injection 5 comprising Potocarpolli and iron dextran
1. The prescription composition is as follows:
2. the preparation method is the same as example 1.
EXAMPLE 6 preparation of suspension injection 6 containing Potocarpolli and iron dextran
1. The prescription composition is as follows:
2. the preparation method is the same as example 1.
Examples of the experiments
Experimental example 1 physical and chemical Properties examination
To determine the properties of the prepared suspension injection, the viscosity, sedimentation volume ratio and particle size distribution thereof were measured. The suspension injections prepared in examples 1 to 6 were selected for the following tests:
1) and (3) viscosity detection: the viscosity of the suspension injection was measured using a rotor type rotational viscometer (digital viscometer, SNB-2), a number 1 rotor was rotated at a rotation speed set at 30rpm, and an average value was calculated in parallel 3 times as a reference;
2) and (3) detecting the sedimentation volume ratio: referring to the pharmacopoeia method, 50ml of suspension injection is measured by a measuring cylinder with a plug, the mixture is sealed, the mixture is vigorously shaken for 1 minute, and the starting height H of the suspension is recorded0Standing for 3 hours, recording the final height H of the suspension, and setting the volume ratio of H/H0And (4) calculating.
The formulation parameters measured according to the above method were as follows:
TABLE 1 determination of viscosity to sedimentation volume ratio
| Item | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Viscosity-mPas | 76.3 | 36.3 | 90.4 | 84.1 | 65.7 | 80.1 |
| Volume ratio of sedimentation | 0.99 | 0.50 | 0.99 | 0.98 | 0.96 | 0.98 |
From the experimental results, the preparation of example 2 without n-butanol has low viscosity, obvious drug sedimentation during standing, no compliance with the standard requirements of veterinary drugs, and poor stability; the formulations of examples 1, 3, 4, 5 and 6 all had drug precipitation ratios greater than 0.9 during standing, indicating good dispersibility, suggesting that the use of n-butanol can significantly improve the precipitation of patotelepril and improve formulation stability.
Experimental example 2 stability test
Referring to the requirements of 'technical specification for veterinary drug stability test', the following tests are designed:
the suspension injection products of examples 1, 4, 5 were subjected to stability acceleration tests. The test conditions are as follows: the formulation samples of the above examples were placed in an incubator at 40 + -2 deg.C/RH 75 + -5%, sampled at 1 st, 3 rd and 6 th months, observed for their properties, and measured for their contents by HPLC, and the test results are shown in Table 2 below.
The method for measuring the content of the patozeli comprises the following steps:
octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-phosphate buffer (v/v 45:55) is used as mobile phase, the detection wavelength is 254nm, and the number of theoretical plates is not less than 3000 according to the calculation of Paltoreq Lifeng.
The determination method comprises the following steps: taking a proper amount of sample, precisely weighing, adding acetonitrile for quantitative dilution to prepare a solution containing about 0.2mg in each 1ml, precisely weighing 10 mu l, injecting into a liquid chromatograph, recording a spectrogram until the retention time of a main peak is 2 times, and taking a Potiron reference substance for determination by the same method. And taking another sample, simultaneously measuring the relative density of the sample, converting the mass of the sample into milliliters, and calculating by peak area according to an external standard method to obtain the product.
TABLE 2 accelerated stability test results
From the above experimental results, the products of examples 1, 4 and 5 have no change in properties and sedimentation ratio of more than 0.9 in the accelerated stability test period, which indicates that the dispersibility is good and the content has no obvious change, and all indexes are in accordance with the requirements, indicating that the product has good stability.
Experimental example 3 detection of free iron
Refer to the examination method of free iron under the item of "iron dextran" in the 2015 edition of Chinese pharmacopoeia. 0.7ml of the injection suspensions prepared in examples 1 and 6, 1ml of the injection suspension prepared in example 2, 0.4ml of the injection suspension prepared in example 3, and 0.9ml of the injection suspension prepared in example 5 (both approximately equivalent to about 0.1g of iron dextran) were taken, placed in a 50ml Nardostachys colorimetric tube, 10ml of water was added and shaken to dissolve, 1.0ml of standard iron stock solution and 15g of potassium thiocyanate solution were added and placed in a 100ml measuring flask, and after dissolving about 50ml of water, 15ml of acetone was added, diluted to the scale with water and shaken to mix with 24ml of acetone, shaken to stand, and the color of the supernatant was observed. If color development occurs, it should not be darker (0.2%) than the control solution prepared by the same method, which is 3.0ml of the standard iron stock solution.
The colors were observed according to the above method as follows:
TABLE 3 color observations
From the above experimental results, the products of examples 1, 3, 5, and 6 showed no color change compared to the product of example 2 with a very small amount of disodium ethylenediaminetetraacetate added, showing a reddish-brown color; example 4 the level of free iron is higher due to the simultaneous increase in active iron content, but is still controlled by disodium edetate. The results show that the disodium ethylene diamine tetraacetate is used in the preparation of the invention, so that the content of free iron can be obviously reduced, and the risk of adverse reaction in the injection process can be reduced.
Experimental example 4 evaluation of bubble Performance
Appropriate amounts of the suspension injection samples prepared in examples 1 to 6 were selected, respectively, and loaded into test tubes with scales, and the test tubes were vigorously shaken for 30 seconds, respectively, and the heights of the formed foams were measured at time points of 1min, 3min, 5min, and 10min immediately after shaking, with the following results:
TABLE 4 evaluation of bubble Properties
The above experiments show that the products of examples 2, 5 and 6, which are not added or added with a very small amount of simethicone, have long dissipation time of bubbles generated in the shaking process, and are not beneficial to clinical use; the samples of examples 1, 3 and 4 can inhibit the generation of foam during the shaking process of the injection by adding simethicone, accelerate the disappearance of the foam, facilitate the clinical use and reduce the risk of injecting air.
Experimental example 5 evaluation of anticoccidial Effect
Coccidian-infected piglets of 3 days old (body weight about 3-4 kg) were selected as subjects, and 3 groups were provided, each group having 10 subjects. One group of animals orally took drinking water as a blank group, one group of animals orally took toltrazuril (Baycox 5% oral suspension, Bayer, administered once as a prescription, 20mg per kg body weight) as a control group, and the other group injected 1.5ml of the suspension injection of example 4 intramuscularly once for treatment, and the excretion of oocysts of piglets in each group was observed, and the excretion of oocysts among different groups was quantitatively evaluated by using Mann-whitney U test; piglets of the combined control group of the example were bled at different time points after administration, and the serum concentration of the drug was measured (the detection method can be found in Shen morning, Hohao Yuan, Hokking, et al. the methodology for measuring patozuril in pig plasma by HPLC method [ J ]. Chinese veterinary medicine journal, 2019). The day of administration was taken as day one and the day before as day 0. The results are shown in tables 5 and 6.
TABLE 5 percentage of oocyst excretion (%)
| Days after administration | Blank group | Control group | EXAMPLE 4 group |
| 0 | 100 | 100 | 100 |
| 1 | 100 | 80 | 73 |
| 3 | 100 | 64 | 52 |
| 5 | 100 | 32 | 20 |
| 7 | 100 | 15 | 9 |
| 9 | 65 | 7 | 0 |
| 11 | 30 | 0 | 0 |
TABLE 6 pharmacokinetic testing results
| Pharmacokinetic parameters | Control group | EXAMPLE 4 group |
| Tmax(h) | 148 | 25 |
| Cmax(mg/L) | 8.5 | 20 |
| T1/2(h) | 4 | 3.5 |
| AUCinf(Day*mg/l) | 61 | 179 |
The above results show that piglets administered the product of example 4 by injection did not detect coccidia on day 9, and that the injected administration did not metabolize the liver, had a rapid onset of action, time to peak (T) as compared to the commercial toltrazuril formulationmax) 25 hours, and the peak time (T) of the control groupmax) Was 148 hours. In addition, the product of example 4 of the invention exhibited maximum blood levels (C)max) And bioavailability (AUC)inf) All higher than the control group.
Finally, the above is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. An injection comprising iron dextran and patulin, further comprising:
pharmaceutically acceptable silicone oil (such as simethicone, dimethicone, polyether silicone oil), lecithin, metal ion complexing agent, n-butanol, povidone, water, and optionally a pH adjusting agent.
2. The injection according to claim 1, wherein the content of each component is:
3. the injection according to claim 2, wherein the content of each component is as follows:
4. the injection according to claim 3, wherein the content of each component is as follows:
5. the injection according to claim 1, wherein the content of each component is:
6. the injection according to any one of claims 1 to 5, wherein the pH regulator comprises one or more selected from citric acid, sodium citrate, potassium dihydrogen phosphate, sodium bicarbonate, and sodium hydroxide.
7. The injection according to any one of claims 1 to 6, wherein the metal ion complexing agent is ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof,
for example, the pharmaceutically acceptable salt of ethylenediaminetetraacetic acid is selected from disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, iron sodium ethylenediaminetetraacetate, or any combination thereof,
preferably, the metal ion complexing agent is disodium ethylenediaminetetraacetate.
8. The injection according to any one of claims 1 to 6, wherein the pH value of the injection is 3 to 8, preferably 5 to 7.
9. A method of preparing the injection of any one of claims 1 to 8, comprising:
adding iron dextran into a proper amount of water for 1-5 times, and stirring at a rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) at a temperature of 60-80 ℃ to obtain an initial solution I;
adding the disodium ethylene diamine tetraacetate and the povidone with the prescription amount into the initial solution I, stirring and dissolving to obtain a mixed solution II;
adding the n-butanol and the lecithin in the formula amount into the mixed solution II, stirring at 50-70 ℃ until the n-butanol and the lecithin are completely dissolved to obtain a suspension III, and cooling;
adding pharmaceutically acceptable silicone oil and patulin in a formula amount into the suspension III, and stirring at the rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) to obtain a suspension IV;
and adding a pH regulator into the suspension IV to regulate the pH value of the suspension IV to be 3-8, and stirring at the rotating speed of 3000-6000 rpm (for example, 4000-5000 rpm) to obtain the final suspension V.
10. The method according to claim 9, characterized by one or more of the following i) to iii):
i) adding iron dextran into proper amount of water for 2-4 times;
ii) adding pharmaceutically acceptable silicone oil and ponazuril in a formula amount into the suspension III, stirring at 3000-6000 rpm, and controlling the temperature to be 20-30 ℃ to obtain a suspension IV;
iii) adding a pH regulator into the suspension IV to regulate the pH value of the suspension IV to be 5-7.
11. Use of an injection according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention and/or treatment of coccidiosis and/or iron deficiency anaemia and/or iron deficiency status in an animal (e.g. pig).
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