CN116672360A - Composition of toltrazuril and iron glucoheptonate - Google Patents
Composition of toltrazuril and iron glucoheptonate Download PDFInfo
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- CN116672360A CN116672360A CN202310788419.7A CN202310788419A CN116672360A CN 116672360 A CN116672360 A CN 116672360A CN 202310788419 A CN202310788419 A CN 202310788419A CN 116672360 A CN116672360 A CN 116672360A
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- iron
- toltrazuril
- stirring
- anhydride
- combination
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 194
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 96
- 229960000898 toltrazuril Drugs 0.000 title claims abstract description 41
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical group 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 title claims abstract description 40
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 title claims abstract description 13
- MVZXTUSAYBWAAM-UHFFFAOYSA-N iron;sulfuric acid Chemical compound [Fe].OS(O)(=O)=O MVZXTUSAYBWAAM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000009826 distribution Methods 0.000 claims abstract description 7
- 229920002307 Dextran Polymers 0.000 claims abstract description 4
- 230000000536 complexating effect Effects 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 238000002347 injection Methods 0.000 claims description 18
- 239000007924 injection Substances 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000004094 surface-active agent Substances 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- YPZMPEPLWKRVLD-PJEQPVAWSA-N D-Glycero-D-gulo-Heptose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O YPZMPEPLWKRVLD-PJEQPVAWSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 13
- 239000000084 colloidal system Substances 0.000 claims description 11
- 238000010008 shearing Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 238000000498 ball milling Methods 0.000 claims description 6
- 239000006070 nanosuspension Substances 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002518 antifoaming agent Substances 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 239000013530 defoamer Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000003801 milling Methods 0.000 claims description 2
- 238000009210 therapy by ultrasound Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 description 12
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 10
- 102000001554 Hemoglobins Human genes 0.000 description 6
- 108010054147 Hemoglobins Proteins 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- -1 oligosaccharide iron complex Chemical class 0.000 description 6
- 208000003495 Coccidiosis Diseases 0.000 description 4
- 206010023076 Isosporiasis Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001165 anti-coccidial effect Effects 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000004698 iron complex Chemical class 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 230000001502 supplementing effect Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229910002588 FeOOH Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 150000002506 iron compounds Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- CUPCBVUMRUSXIU-UHFFFAOYSA-N [Fe].OOO Chemical compound [Fe].OOO CUPCBVUMRUSXIU-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 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 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 229910021519 iron(III) oxide-hydroxide Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000003307 reticuloendothelial effect Effects 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- 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
- 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
- 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
Abstract
The invention discloses a composition of toltrazuril and iron glucoheptonate, which is characterized in that: comprises a solution of iron dextran and toltrazuril which is dispersed in the solution of iron dextran and has a molecular weight distribution range of 2000-4000 for complexing the iron dextran with the dextran acid.
Description
Technical Field
The invention relates to the technical field of veterinary medicines, in particular to a composition of toltrazuril and iron glucoheptonate.
Background
Sugar generally has the characteristic of complexing metal ions, sugar molecules are protonated and charged under alkaline conditions, and are combined with polymerized FeOOH particles through hydroxyl bridge bonds to form a hydroxyl bridge complex, and then hydroxyl groups in the hydroxyl bridge complex lose protons to become thermodynamically stable oxygen bridge complexes, so that stable sugar iron complexes are formed. The sugar iron complex has the following characteristics: (1) the chemical property is stable, the water solubility is good, no fishy smell exists, and the palatability is good; (2) because the polymer is more stable than the mononuclear complex, the chelate tends to polymerize in the placing process, and the non-sugar ligand is complexed with iron to form polynuclear iron compounds or polymers which are not easy to absorb; and the sugar iron complex forms polynuclear iron compounds which are in a polymerized state and can be effectively absorbed in the storage process; (3) the absorption is fast, the absorption rate is 1.8 times faster than ferrous sulfate, and intestinal villi has specific selectivity for the absorption of sugar-iron complex, and is superior to other iron agents such as FeSO 4 Is not limited; (4) the oligosaccharide ligand has stronger antibacterial activity, can solve the problem of drug resistance caused by using antibiotics, and especially DP 3-DP 5 can effectively inhibit harmful bacteria and promote the growth of beneficial bacteria, thereby improving the microecological balance in animals, so that the oligosaccharide iron complex can play a role in supplementing iron, effectively prevent diarrhea, promote animal growth and improve animal immunity.
The sugar iron complex is supplied to human body in molecular form and contains no Fe 2+ And Fe (Fe) 3+ And has high iron content and high bioavailability, and can be absorbed by in vivo reducing substances such as vitamin C into ferrous iron. The compound does not contain iron ions, has no corrosion and stimulation to gastrointestinal mucosa, is easy to be absorbed by small intestine mucosa cells, can regulate plasma concentration through a gastrointestinal mucosa absorption valve, and is not easy to cause poisoning. Furthermore, the polysaccharide iron can promote hematopoiesis of organisms and rapidly increase the level of hemoglobin, thereby effectively treating anemia.
Iron dextran molecular formula (FeOOH) m [ HO- (C) 6 H 10 O 5 ) x -C 7 H 13 O 7 ]n is a fourth generation iron, is a complex of polynuclear iron oxyhydroxide and glucoheptylic acidThe compound, which is soluble iron, is dissociated into iron and polysaccharide by reticuloendothelial cells (mononuclear phagocyte system) by intramuscular injection of glucoheptose anhydride; iron is transported to the main component hemoglobin of bone marrow synthesized red blood cells through transferrin, or converted into stored iron for urgent need of the body. The iron glucoheptose anhydride can supplement iron element and correct iron deficiency anemia.
The applicant finds that the iron glucoheptonate solution has colloid property, moderate viscosity and small particle size, so that the iron glucoheptonate solution is hoped to be used as a dispersion carrier for dispersing active ingredients insoluble in water to prepare a compound preparation, and can realize the effect of iron supplementing and improve the immunity while treating.
Toltrazuril triazinone compounds have broad-spectrum anticoccidial activity and are currently used for anticoccidial activity in chickens and pigs. Because the piglets are iron-deficient after birth, the iron agent can be injected in the next day after birth to prevent iron-deficiency anemia, anticoccidial is mainly prevented, and totrazuril is generally administered in a mode of being mixed in feed at present, and the medicine feeding is uneven due to the difference of pig feeding.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a composition of toltrazuril and iron glucoheptide, which can realize the preparation of injection by toltrazuril which is insoluble in water, ensures uniform administration along with the injection of iron, and reduces the labor capacity of workers by one injection.
In order to achieve the above purpose, the invention is realized by the following technical scheme: a composition of toltrazuril and iron glucoheptonate characterized in that: comprises a solution of iron dextran and toltrazuril which is dispersed in the solution of iron dextran and has a molecular weight distribution range of 2000-4000 for complexing the iron dextran with the dextran acid.
In the scheme, the method comprises the following steps: the Tf value of the molecular weight distribution of the glucoheptic anhydride is 1.15-1.30.
In the scheme, the method comprises the following steps: the composition is in the form of injection, and each 1ml of injection contains toltrazuril 30-36mg, and each 1ml of injection contains glucoheptylic anhydride iron 180+ -5 mg.
In the scheme, the method comprises the following steps: the anti-freezing agent and the defoaming agent, the pH regulator and the preservative are also included as the pharmaceutical additive.
In the scheme, the method comprises the following steps: the pharmaceutical additive may also or alternatively comprise a surfactant.
In the scheme, the method comprises the following steps: the preparation method comprises the following steps:
1) Adding a surfactant and a defoaming agent into pure water, and stirring for dissolving to obtain a component A;
2) Adding toltrazuril into an organic solvent capable of dissolving in water, and stirring and dissolving by ultrasonic to obtain a component B; the organic solvent capable of being dissolved in water is dimethyl sulfoxide;
3) Slowly dripping the component B into the component A, and simultaneously starting ultrasonic treatment and stirring to obtain a nano suspension;
4) Standing the nano suspension, precipitating, filtering, and washing to obtain micrometer-to-nanometer-level active ingredients;
5) Placing part of the required amount of the glucoheptose anhydride iron colloid solution into a container, adding the required amount of the active ingredient, stirring and mixing uniformly by ultrasonic,
6) Adding pharmaceutical additives, continuing ultrasonic stirring and uniformly mixing, and then uniformly shearing, dispersing and homogenizing for 10min;
7) Adding the rest of the glucoheptose anhydride iron, shearing or ball milling at high speed, and uniformly dispersing.
8) Water is added to the desired final concentration.
In the scheme, the method comprises the following steps: the pharmaceutical additive in step (6) further comprises a surfactant.
In the scheme, the method comprises the following steps: the preparation method comprises the following steps: 1) Milling toltrazuril to a size below D901 microns;
2) Placing part of the required amount of the glucoheptose anhydride iron colloid solution into a beaker, respectively adding the required amount of active ingredients with different particle sizes, stirring and mixing uniformly by ultrasonic waves,
3) Adding pharmaceutical additives, wherein the pharmaceutical additives are preservative, surfactant, defoamer and pH regulator, continuously stirring and mixing evenly by ultrasound, then uniformly dispersing and homogenizing for 10min by high-speed shearing,
4) Adding the rest of the glucoheptose anhydride iron, and carrying out high-speed shearing or ball milling to uniformly disperse;
5) Water is added to the desired final concentration. The PH regulator is hydrochloric acid, citric acid, methanesulfonic acid or sodium hydroxide.
Compared with the prior art, the invention has the following advantages:
the glucoheptic anhydride iron prepared by the glucoheptic anhydride with the molecular weight of 2000-4000 has moderate viscosity and small particle size, is a soluble iron colloid, is favorable for forming an injection preparation, is favorable for dispersing the water-insoluble active ingredient toltrazuril, can be stably dispersed in the glucoheptic anhydride iron colloid without adding a surfactant, can wrap the active ingredient to form a stable injection preparation, achieves the slow release effect of the medicine, and realizes that the water-insoluble medicine ingredient is prepared into the injection. The composition is injected 2 days after birth of pig, and has effects of supplementing iron and resisting coccidiosis, and can reduce work load by once injection.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
Preparation of iron glucoheptonate reference CN114249844 a preparation method: the molecular weight of the glucoheptonic acid is 2000, 3000, 4000 and 5000 respectively), and the glucoheptonic acid with the molecular weight of 2000 is marked as iron 1, the glucoheptonic acid with the molecular weight of 3000 is marked as iron 2, the glucoheptonic acid with the molecular weight of 200+/-5 mg/ml is marked as iron 3, the glucoheptonic acid with the molecular weight of 5000 is marked as iron 7, and the glucoheptonic acid with the molecular weight of 4000 is marked as iron 7, and the concentration of iron is 200+/-5 mg/ml. Free iron is less than 0.2%. The Tf values of the molecular weight distribution of the iron glucoheptonate are all 1.15-1.30.
Reference may also be made to the preparation process of US3536696, in which the molecular weight of the glucoheptonic acid is 2000, 3000, 5000, respectively), and the glucoheptonic acid having a molecular weight of 2000 is denoted as iron 4, the concentration of iron is 200.+ -.5 mg/ml, the glucoheptonic acid having a molecular weight of 3000 is denoted as iron 5, the concentration of iron is 200.+ -.5 mg/ml, and the glucoheptonic acid having a molecular weight of 5000 is denoted as iron 6, the concentration of iron is 200.+ -.5 mg/ml. Free iron is less than 0.2%. The Tf values of the molecular weight distribution of the iron glucoheptonate are all 1.15-1.30.
Example 2
Toltrazuril and glucoheptose anhydride iron 1, 1ML preparation (injection)
The preparation method comprises the following steps:
120mg of sodium dodecyl sulfate, 240mg of polyvinylpyrrolidone K30 and 200mg of simethicone are taken and added into 240ml of purified water, and 420R/min is stirred and dissolved to obtain a component A.
Taking 2.4g of toltrazuril, adding 60ml of dimethyl sulfoxide, and stirring ultrasonically to dissolve to obtain the component B.
And (3) dropwise adding the component B into the component A at 30ml/min, simultaneously starting ultrasonic and stirring at 420R/min for 30min to obtain the toltrazuril nanosuspension.
And (3) standing the nano suspension, precipitating, filtering, washing to obtain the micron-to-nano-scale active ingredient, and detecting that the D90 of the active ingredient is smaller than 1 micron.
Placing part (one third) of the required amount of the glucoheptose anhydride iron colloid solution into a beaker, adding the required amount of the active ingredient, stirring uniformly by ultrasonic wave,
adding pharmaceutical additives according to the above table, continuing ultrasonic stirring, mixing, and then uniformly dispersing and homogenizing for 10min by high-speed shearing. Adding the rest of the glucoheptose anhydride iron, shearing or ball milling at high speed, and uniformly dispersing. Water is added to the desired final concentration. Namely, the concentration of the medium iron in the iron glucoheptonate colloid solution is 180+/-5 mg/ml.
Examples 2 to 12
Otherwise, the procedure was as in example 2-1, except that the preparation method was as follows:
1) Toltrazuril was ball milled to D90 less than 1 μm, 0.5 micron, 2 micron, respectively.
2) Placing part of the required amount of the glucoheptose anhydride iron colloid solution into a beaker, respectively adding the required amount of active ingredients with different particle sizes, stirring and mixing uniformly by ultrasonic waves,
3) Adding pharmaceutical additives (including antiseptic, defoamer and PH regulator), stirring with ultrasound, homogenizing for 10min,
4) Adding the rest of the glucoheptose anhydride iron, shearing or ball milling at high speed, and uniformly dispersing.
5) Adding water to the required final concentration, namely 180+/-5 mg/ml of middle iron of the glucoheptic anhydride iron colloid solution.
Examples 2 to 13
Otherwise, the same as in examples 2 to 12, except that 2mg of surfactant T-80 was added in step 3), the mixture was dispersible and allowed to stand for 3 months without precipitation.
2. The compositions of examples 2-1 to 2-11 were subjected to stability test
The test results are shown in the following table
Examples 2-12 toltrazuril was ball milled directly to D90 2 microns and did not disperse well, below D90 microns was able to disperse initially, but settled after placement. But the addition of surfactant is dispersible and does not settle.
From the table it can be seen that: when iron 1, iron 2, iron 7, iron 4 and iron 5 are used for preparing the composition, no surfactant is required to be added, toltrazuril can be well dispersed, and when iron 6, iron 3 and dextran iron are dispersed, if no surfactant is added, a uniform system can not be obtained, and the product can be placed to generate precipitation. The iron 1, the iron 2, the iron 4, the iron 5 and the iron 7 can play a good role in dispersing under the condition of adding the surfactant. Through analysis, the surface tension of the iron 1, the iron 2, the iron 4, the iron 5 and the iron 7 is moderate, so that the toltrazuril can be dispersed conveniently, and a good dispersing effect can be achieved without adding a surfactant.
3. Biological assay
The compositions prepared in examples 2-1, 2-2, 2-5, 2-6, 2-7, 2-8, 2-9 of the present invention were used in biological assays.
For the pig farm with piglet coccidiosis, the piglets just born are divided into 8 groups, 10 heads of each group have an average weight of 1.72kg, the compositions (injection amount of 1 ml) prepared in examples 2-1, 2-2, 2-5, 2-6, 2-7, 2-8 and 2-9 of the invention are injected the next day after birth, then the iron 1 preparation (injection amount of 1 ml) prepared in the invention is independently injected in group 7, and toltrazuril is orally taken (toltrazuril is dissolved in water, 1ml,5% toltrazuril is dressed according to the existing method). Group 8 was injected with iron 1 alone and piglets were observed for abnormal status. After 6 weeks (out of the column), the average weights of the 8 groups of piglets were: 9.0, 9.2, 9.1, 9.0, 9.1, 8.9, 8.6kg (there is one head infected with coccidium, affecting body weight).
The average value of hemoglobin in each group of blood at the beginning of the experiment was 7.16gms/100ml, 7.08gms/100ml, 7.32gms/100ml, 7.21gms/100ml, 7.26gms/100ml, 7.19gms/100ml, 6.98gms/100ml, 7.30gms/100ml, respectively, and after six weeks, the average level of hemoglobin in each group was 12.3gms/100ml, 12.9gms/100ml, 12.1gms/100ml, 12.7gms/100ml, 12.4gms/100ml, 12.2gms/100ml, 12.9gms/100ml, 12.2gms/100ml.
It can be seen from the numerical values that after compounding, the iron absorption is not affected.
From samples taken at 0h, 6h, 24h, 32h, 2d, 3d, 72h, 7d, 14d, 21d, 28d after dosing, the concentration of the active substance toltrazuril in plasma was analyzed by rayleigh chromatography/tandem mass spectrometry, giving the results as shown in the table below.
It can be seen from the table that both the absence of added surfactant and the addition of surfactant have a positive effect on the pharmacokinetics.
4 into oral preparation (oral liquid 1ml preparation)
Biological assay
The compositions prepared in examples 2 '-1 to 2' -9 according to the invention were used for biological tests.
For the pig farm with piglet coccidiosis, the pig farm with the piglet coccidiosis is mainly prepared by dividing the newborn piglets into 11 groups, 10 heads of each group, the average weight of each group is 1.72kg, injecting the composition prepared in the examples 2 '-1 to 2' -9 of the invention (injection amount is 1 ml) the next day after birth, then taking the iron 1 preparation prepared by the invention (injection amount is 1 ml) singly in the 10 th group, and taking toltrazuril orally (according to the prior method, toltrazuril is dissolved in water, 1ml and 5% toltrazuril is taken orally). The presence or absence of abnormal status in piglets was observed.
The average value of hemoglobin in each group of blood at the beginning of the experiment was 7.16gms/100ml, 7.08gms/100ml, 7.32gms/100ml, 7.21gms/100ml, 7.26gms/100ml, 7.19gms/100ml, 6.98gms/100ml, 7.30gms/100ml,7.16gms/100ml, 7.08gms/100ml after six weeks, and the average level of hemoglobin in each group was 10.3gms/100ml, 10.9gms/100ml, 10.1gms/100ml, 10.7gms/100ml, 10.4gms/100ml, 10.2gms/100ml, 10.9gms/100ml, 10.2gms/100ml, 10.5gms/100ml, 10.7gms/100ml.
It can be seen from the numerical values that after compounding, the iron absorption is not affected.
From the post-dose, samples were taken at 0h, 6h, 24h, 32h, 2d, 3d, 72h, 7d, 14d, 21d, 28d and plasma was analyzed for the concentration of the active substance toltrazuril by rayleigh chromatography/tandem mass spectrometry with a limit of 25 μg/L for each analyte. PK data for each group was calculated from the samples obtained.
It can be seen from the table that the addition of iron glucoheptonate has a positive effect on the pharmacokinetics.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A composition of toltrazuril and iron glucoheptonate characterized in that: comprises a solution of iron dextran and toltrazuril which is dispersed in the solution of iron dextran and has a molecular weight distribution range of 2000-4000 for complexing the iron dextran with the dextran acid.
2. The combination of toltrazuril and iron glucoheptylase according to claim 1, characterized in that: the Tf value of the molecular weight distribution of the glucoheptic anhydride is 1.15-1.30.
3. The combination of toltrazuril and iron glucoheptoxide according to claim 1 or 2, characterized in that: the composition is in the form of injection, and each 1ml of injection contains toltrazuril 30-36mg, and each 1ml of injection contains glucoheptylic anhydride iron 180+ -5 mg.
4. The combination of toltrazuril and iron glucoheptoxide according to claim 1 or 2, characterized in that: the anti-freezing agent also comprises a pharmaceutical additive, wherein the pharmaceutical additive is an anti-freezing agent, an antifoaming agent, a pH regulator and a preservative.
5. The combination of toltrazuril and iron glucoheptylase according to claim 4, characterized in that: the pharmaceutical additive may also or alternatively comprise a surfactant.
6. The combination of toltrazuril and iron glucoheptylase according to claim 4, characterized in that: the preparation method comprises the following steps:
1) Adding a surfactant and a defoaming agent into pure water, and stirring for dissolving to obtain a component A;
2) Adding toltrazuril into an organic solvent capable of dissolving in water, and stirring and dissolving by ultrasonic to obtain a component B; the organic solvent capable of being dissolved in water is dimethyl sulfoxide;
3) Slowly dripping the component B into the component A, and simultaneously starting ultrasonic treatment and stirring to obtain a nano suspension;
4) Standing the nano suspension, precipitating, filtering, and washing to obtain micrometer-to-nanometer-level active ingredients;
5) Placing part of the required amount of the glucoheptose anhydride iron colloid solution into a container, adding the required amount of the active ingredient, stirring and mixing uniformly by ultrasonic,
6) Adding pharmaceutical additives, continuing ultrasonic stirring and uniformly mixing, and then uniformly shearing, dispersing and homogenizing for 10min;
7) Adding the rest of the glucoheptose anhydride iron, shearing or ball milling at high speed, and uniformly dispersing.
8) Water is added to the desired final concentration.
7. The combination of toltrazuril and iron glucoheptylase according to claim 6, characterized in that: the pharmaceutical additive in step (6) further comprises a surfactant.
8. The combination of toltrazuril and iron glucoheptylase according to claim 5, characterized in that: the preparation method comprises the following steps: 1) Milling toltrazuril to a size below D901 microns;
2) Placing part of the required amount of the glucoheptose anhydride iron colloid solution into a beaker, respectively adding the required amount of active ingredients with different particle sizes, stirring and mixing uniformly by ultrasonic waves,
3) Adding pharmaceutical additives, wherein the pharmaceutical additives are preservative, surfactant, defoamer and pH regulator, continuously stirring and mixing evenly by ultrasound, then uniformly dispersing and homogenizing for 10min by high-speed shearing,
4) Adding the rest of the glucoheptose anhydride iron, and carrying out high-speed shearing or ball milling to uniformly disperse;
5) Water is added to the desired final concentration.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85104452A (en) * | 1984-06-15 | 1986-12-10 | 派弗·兰根公司 | Make the method for water-soluble iron dextran |
| CN102361651A (en) * | 2009-03-25 | 2012-02-22 | 法码科思莫斯控股有限公司 | Stable iron oligosaccharide compound |
| CN112165946A (en) * | 2018-06-05 | 2021-01-01 | 拜耳动物保健有限责任公司 | Formulations containing triazineone and iron with small amounts of free iron ions |
| CN112423762A (en) * | 2018-06-05 | 2021-02-26 | 拜耳动物保健有限责任公司 | Formulation for the simultaneous treatment of coccidial infections and iron deficiency |
-
2023
- 2023-06-30 CN CN202310788419.7A patent/CN116672360A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85104452A (en) * | 1984-06-15 | 1986-12-10 | 派弗·兰根公司 | Make the method for water-soluble iron dextran |
| CN102361651A (en) * | 2009-03-25 | 2012-02-22 | 法码科思莫斯控股有限公司 | Stable iron oligosaccharide compound |
| CN112165946A (en) * | 2018-06-05 | 2021-01-01 | 拜耳动物保健有限责任公司 | Formulations containing triazineone and iron with small amounts of free iron ions |
| CN112423762A (en) * | 2018-06-05 | 2021-02-26 | 拜耳动物保健有限责任公司 | Formulation for the simultaneous treatment of coccidial infections and iron deficiency |
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