CN110327294A - Compound long-acting injection and preparation method thereof containing Enrofloxacin and Flunixin - Google Patents

Compound long-acting injection and preparation method thereof containing Enrofloxacin and Flunixin Download PDF

Info

Publication number
CN110327294A
CN110327294A CN201910655613.1A CN201910655613A CN110327294A CN 110327294 A CN110327294 A CN 110327294A CN 201910655613 A CN201910655613 A CN 201910655613A CN 110327294 A CN110327294 A CN 110327294A
Authority
CN
China
Prior art keywords
flunixin
polyoxyethylene
enrofloxacin
meglumine
stearate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910655613.1A
Other languages
Chinese (zh)
Other versions
CN110327294B (en
Inventor
余祖功
郭凡溪
苗晋锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Agricultural University
Original Assignee
Nanjing Agricultural University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Agricultural University filed Critical Nanjing Agricultural University
Priority to CN201910655613.1A priority Critical patent/CN110327294B/en
Publication of CN110327294A publication Critical patent/CN110327294A/en
Application granted granted Critical
Publication of CN110327294B publication Critical patent/CN110327294B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K9/0012—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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a kind of compound long-acting injection containing Enrofloxacin and Flunixin, every 1000mL injection contains: 50~300g of Enrofloxacin or/and its salt, in a dispersed form 0~200g of existing Flunixin or flunixin meglumine, 0~150g of Flunixin or flunixin meglumine inclusion compound, 5~20g of suspending agent, 5~15g of wetting agent, surplus is decentralized medium, and existing Flunixin and/or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound cannot be 0 simultaneously in a dispersed form.Injection of the present invention is only injected 1 time, can treating both manifestation and root cause of disease, can more enhance animal compliance, reduce Animal stress, promote and improve disease lapse to and prognosis.Drug microparticles remain to be uniformly dispersed after long-term placement；Injection of the present invention realizes sterilizing for sterilizing 30 minutes for 115 DEG C after need to only dispensing, each index of sterilizing front and back injection meets regulation, is suitble to industrialized production without aseptically operating.

Description

Compound long-acting injection and preparation method thereof containing Enrofloxacin and Flunixin
Technical field
The invention belongs to animal specific field of pharmaceutical preparations, are related to a kind of containing the compound long-acting of Enrofloxacin and Flunixin note Penetrate liquid and preparation method thereof.
Background technique
Enrofloxacin (Enrofloxacin) soluble,very slightly in acetone, it is almost insoluble in water, hydrochloride, sodium salt and Lactate is readily soluble in water.Enrofloxacin is animal specific fluoroquinolones, the most commonly used in veterinary clinic, has spy to mycoplasma Effect, effect is better than tylosin, colistin, and still valid to the two drug resistance mycoplasma, anti-chicken Deficiency Mycoplasma has better effect；To leather Lan Shi negative bacterium has potent；There is preferable effect to staphylococcus aureus, Actinomyces pyogenes, erysipelas bacillus, Chlamydia etc.；To copper Green pseudomonad, streptococcus effect are weaker；Anaerobic bacteria is acted on faint.Enrofloxacin has obvious antibacterial aftereffect to sensitive bacteria, Antibacterial activity is in concentration dependent.
Since listing, Enrofloxacin is widely applied in animal clinicals such as fowl, pig, ox, sheep, dog, rabbits.Pig: it uses In treatment streptococcosis, piglet yellow scour and dysentery characterized by white mucous stool, escherichia coli enterotoxemia (oedema), salmonellosis, infectiousness pleura Pneumonia, mazoitis-hysteritis-agalactia syndrome, mycoplasmal pneumonia etc..Ox, sheep: for treating coliform diarrhea, big Enterobacteria property septicemia, pleuropneumonia (Mycoplasma hyopneumoniae), brucellosis, pasteurella multocida disease, ox anthrax, Li Shi bar The diseases such as bacterium disease (including occur nervous symptoms person) and mammitis, hysteritis.Dog, cat: for treating alimentary canal, the breathing of dog Road, urinary system, reproductive organs infection, skin infection, wound are suppurated, gastroenteritis haemorrhagica caused by otitis externa and Escherichia coli Etc. diseases.
Enrofloxacin is for oral administration, intramuscular injection absorbs rapidly and relatively completely, and Binding rate of serum protein is 20%~40%, is divided in vivo Cloth is extensive, and in addition to central nervous system, Enrofloxacin concentration is all higher than blood plasma in nearly all tissue.It is metabolized by kidney and non-kidney Mode is eliminated, and about 15%~50% is discharged (filtration of tubular secretion and glomerulus) from urine with original shape.Liver metabolism master If the ethyl for sloughing 7- piperazine rings generates Ciprofloxacin, secondly combined for oxidation and glucuronic acid, major metabolite ring Third husky star still has powerful activity, lacks ethoxyresorufin O-deethylase in pig body and directly inactivates.Enrofloxacin eliminates half-life period in different genera Animal and different way of administration have larger difference, intravenous half-life period (h): pigeon 3.8, chicken 5.26~10.3, turkey 4.1, rabbit 2.2 ~2.5, dog 2.4, pig 3.45, ox 1.7~2.3, horse 4.4, camel 3.6.Intramuscular injection half-life period (h): pig 4.06, milk cow 5.9, horse 9.9, camel 6.4.Half-life period (h) for oral administration: chicken 9.14~14.2, dog 3.7~5.8, pig 6.93.
Non-steroid anti-inflammatory drug (Non-steroids anti-inflammatory drugs, NSAIDs) also known as antipyretic Antalgic anti-inflammatory agent is a kind of steroidal structure for being free of steroids cortin, moves back high fever except having, mitigates local dull pain, anti-inflammatory Effect is outer, and there are also inhibit platelet aggregation.Because fever, pain and inflammatory symptom can be effectively relieved in it, Animal stress is reduced, Increase animal compliance, is widely used in control infection either non-infectious inflammation and pain.On veterinary clinic, non-steroid Body anti-inflammatory agent is mainly used for preventing and treating or alleviating inflammation, the pain of animal etc. that various infection and non-infection cause, and such as alleviates Niu Zi The inflammatory pains such as cervicitis, mammitis, respiratory disease, founder, arthritis, it may also be used for Postpartum Analgesia；It is a variety of thin to alleviate pig Microbial respiratory disease, the inflammatory pains such as escherichia coli disease, sow mammitis, hysteritis and agalasisa syndrome Shape；Alleviate the internal organ colic pain of horse, arthralgia and myalgia, colic, muscle it is unusual caused by inflammatory pain, treatment colt diarrhea, colitis, Respiratory disease etc. is combined treatment horse pneumonia with terramycin；Prevent and treat dog, cat corruptibility peritonitis, arthritis, fever, diarrhea, The fevers such as ocular infection, inflammation, pain symptom.
Currently, the animal specific antipyretic-antalgic anti-inflammatory agent of approved listing is flunixin meglumine (Flunixin Meglumine, FM).The meglumine salt of flunixin meglumine system Flunixin, by Schering Plough company, the U.S. the 1990s It develops (trade name Banamine), is widely applied in the country such as China, the U.S., France, Switzerland, Germany, Britain.Fluorine Buddhist nun Pungent meglumine has stronger antipyretic, analgesia and anti-inflammatory effect, and analgesic activity is suitable with routine dose morphine, but resistance to without morphine By property and dependence phenomenon；Anti-inflammatory effect is 4 times of phenylbutazone, 2 times of Ketoprofen；It can be shared with antibacterials, alleviate disease Symptom.
Flunixin is the inhibitor of Cycloxygenase, by inhibiting the Cycloxygenase in arachidonic acid reaction chain, before reduction The generation of the inflammatory mediators such as column parathyrine and thromboxane, by maintaining normal arterial pressure, the damage for mitigating vascular endothelial cell, maintaining just The approach such as normal blood volume, prevent escherichia coli endotoxin that exudate in the bronchus in respiratory diseases is caused to increase, in exudate The number of ways such as neutrophil cell, albumin aggregation, are effectively relieved organism fever, inflammation and pain.Medicine effect is rapid, and one As can reduce pain in 15 minutes.
Bacterium infection is often with the inflammatory symptoms such as fever, pain, such as mastitis for milk cows, hysteritis, founder, ox breathing Tract disease (BRD), pig pleuropneumonia, bronchitis, hueppe's disease etc., dog, cat's flu etc. influence animal spirit and drink Food damages body tissue and organ, restricts prognosis of disease and prognosis.Antimicrobial can effectively clear cause of disease, antipyretic-antalgic anti-inflammatory agent Can alleviate clinical symptoms, the two combination, treating both manifestation and root cause of disease, be more advantageous to disease lapse to and prognosis.
The enrofloxacin injection and flunixin meglumine injection of clinical approved listing, are conventional aqueous agent, Recommend dosage regimen are as follows: be administered within 1 day 2 times, successive administration 3-7 days, have no that the compound preparation of Enrofloxacin and Flunixin is ratified on City.
103520098 A of Chinese patent application CN discloses a kind of long-acting Enrofloxacin oil suspension injection, by Sucrose acetoisobutyrate and rilanit special are added in hydrophobic medium (ethyl oleate, isopropyl myristate) or second is added Sour isobutyric acid sucrose ester and aluminum stearate prepare the oil suspension of Enrofloxacin.But the system of the Enrofloxacin oil suspension injection Standby process need to be carried out aseptically, and temperature of charge may not exceed 40 DEG C when grinding.Preparation process is to working condition requirement It is higher, industrialization promotion is constrained, and injection is without terminal sterilization, it is difficult to which effective guarantee is sterile, endangers animal safety.China 102697784 A of patent CN discloses a kind of Enrofloxacin injection for livestock and preparation method thereof, is related to containing Enrofloxacin and fluorine The pungent meglumine compound injection of Buddhist nun, but the injection is aqueous pharmaceutical, and recommending usage is twice a day, to be used in conjunction 2~3, is needed multiple Administration, it is time-consuming and laborious, and Animal stress is easily caused, influence drug effect performance.105213402 A of Chinese patent CN discloses a breeding stock Fowl compound enrofloxacin Meloxicam soluble powder, but need drinking water administration, is suitable for the poultry of intensive culture, but because pig, The waste of the drinking-water such as dog, cat is more, and ox, sheep, horse etc., using inconvenience, also need multiple dosing based on individual administration, time-consuming It is laborious to be unfavorable for drug effect performance again.
Summary of the invention
The purpose of the present invention is being directed to clinical demand and defect of the existing technology, provide a kind of containing Enrofloxacin and fluorine Suitable wetting agent is added in the pungent compound oil suspension of Buddhist nun in system, and it is existing to improve agglomeration of the Enrofloxacin in oil medium As increasing medicine stability, industrialized production is also more smooth, and prepared preparation is placed at 40 DEG C and placed at 6 months, 25 DEG C 24 months, preparation stability was high, and redispersibility is excellent；And it is directed to flunixin meglumine good water solubility, it absorbs rapid, it is difficult to be sustained The characteristics of, part or all of flunixin meglumine or/and Flunixin are prepared into inclusion compound after micronization processes, delay drug It discharges while reducing injection site irritation.Invention formulation quality is stable, easy to use, drug release is slow, good biocompatibility, One course for the treatment of is only administered 1~2 time, and can maintain effective blood anti-infectious while alleviating heat, pain, inflammation that infection causes Concentration 3~7 days.
The purpose of the present invention is achieved through the following technical solutions:
A kind of compound long-acting injection containing Enrofloxacin and Flunixin, including Enrofloxacin or/and its salt, to disperse shape Flunixin and/or flunixin meglumine existing for formula and at least one of Flunixin and/or flunixin meglumine inclusion compound help Suspension, wetting agent and decentralized medium；Every 1000mL injection contains: Enrofloxacin or/and its salt (in terms of Enrofloxacin) 50~ 300g, in a dispersed form existing Flunixin or flunixin meglumine (in terms of Flunixin) 0~200g, Flunixin or Flunixin Portugal Methylamine inclusion compound (in terms of Flunixin) 0~150g, 5~20g of suspending agent, 5~15g of wetting agent, surplus is decentralized medium, and to divide Flunixin existing for the form of dissipating and/or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound cannot be 0 simultaneously.
Preferably, every 1000mL injection contains: 100~200g of Enrofloxacin or/and its salt (in terms of Enrofloxacin), with Flunixin or flunixin meglumine existing for discrete form (in terms of Flunixin) 0~150g, Flunixin or flunixin meglumine packet Object (in terms of Flunixin) 0~100g, 16~20g of suspending agent, 8~12g of wetting agent are closed, surplus is decentralized medium, and to disperse shape Flunixin and/or flunixin meglumine existing for formula, Flunixin and/or flunixin meglumine inclusion compound cannot be 0 simultaneously.
The enrofloxacin salt be selected from Enrofloxacin sodium, Enrofloxacin HCL and Enrofloxacin any one or It is a variety of.
Through ultramicro crushing treatment, 90% grain diameter≤15 μm must not detect 50 μm for the Enrofloxacin or its salt Above particle.
The Flunixin existing in a dispersed form and/or flunixin meglumine are through ultramicro crushing treatment, 90% Grain partial size≤5 μm, must not detect 25 μm or more of particle.
The Flunixin and/or flunixin meglumine inclusion compound the preparation method is as follows: by Ethylated β-Cyclodextrins and Flunixin and/or flunixin meglumine are added in 60% ethanol water according to according to 1~2:1 of molar ratio, the ethyl alcohol The volume and Flunixin and/or the ratio between flunixin meglumine and ethyl beta-cyclodextrin gross mass of aqueous solution are 20~30:1 (mL/ G), 30 minutes ultrasonic at 25 DEG C after mixing, it is immediately transferred into colloid mill, booting operating 10~20 minutes adds Identical with first time additional amount 60% ethanol water remains in operation 0.5~1 hour；Using spray-drying process, it is made Flunixin and/or flunixin meglumine inclusion compound control the partial size of Flunixin and/or flunixin meglumine inclusion compound 90% Grain diameter≤15 μm must not detect 50 μm or more of particle.Wherein, spray dryer wriggling flow rate pump is 8~15mL/ Min, 120~130 DEG C of inlet temperature, 0.3~0.5MPa of atomizing pressure, 80~90 DEG C of leaving air temp.
The suspending agent is selected from polyvinyl alcohol, hypromellose, hyetellose, hydroxypropylcellulose, carboxymethyl Sodium cellulosate, hyaluronic acid, xanthan gum, chitosan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, stearic acid, list are hard Resin acid aluminium, aluminium distearate, aluminum stearate, rilanit special, beeswax, microwax, yellow wax, Chinese wax, polylactic acid, polylactic acid-glycolic Acetic acid copolymer (PLGA), polycaprolactone (PCL), polyoxyethylene beeswax, tristerin, glycerin monostearate and poly- Ethylene oxide (75) stearate mixture, Unigly GO 102S, any one or more in pegoxol 7 stearate； Preferably, the suspending agent is rilanit special, at least one in aluminum monostearate, aluminium distearate and aluminum stearate Kind and/or the combination selected from least one of polyvinyl alcohol, microwax and Chinese wax, it is total that the rilanit special accounts for suspending agent The 5~50% of amount.
The wetting agent be selected from lecithin, hydroxylated lecithin, tween (20,40,60,80), poloxamer (124,188, 237,338,407), it is sapn (20,40,60,65,80,85), propylene glycol diacetate, propylene glycol monostearate, sodium lactate, hard Resin acid sodium lactate, four oleyl ether of polyoxyethylene (30EO) sorbierite, four stearyl ether of polyoxyethylene (60EO) sorbierite, polyoxyethylene Four oleic acid ether of (40EO) sorbierite, four oleate of polyoxyethylene (60EO) sorbierite, polyoxyethylene (8,12,24,40,50,100, 110) stearate, polyoxyethylene (10,30,40,50,60) rilanit special, polyoxyethylene (10,35,40,60,80,90, 100) castor oil, polyoxyethylene (300,400,600) monoleate, castor oil, Labraso, propylene glycol Single caprylate, propylene glycol monolaurate, Unigly GO 102S, -3 pairs of isostearates of polyglycereol, stearic acid polyoxyethylene are sweet Grease, lauric acid polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glyceride, three cetearyl alcohols Any one or more in alcohol polyethers -4- phosphate, ethylene glycol stearate and diethylene glycol stearate mixture etc..It is excellent Choosing, the wetting agent be lecithin or hydroxylated lecithin and in tween, sapn and poloxamer at least two group It closes.
The decentralized medium be selected from sesame oil, peanut oil, cottonseed oil, soybean oil, olive oil, tea oil, Liquid Macrogol, Polyethylene glycol 400, ethyl lactate, propylene glycol, ethyl oleate, N,N-dimethylformamide, triacetyl glycerine, Medium chain fatty It is any in acid, Ergol, isopropyl myristate, formal glycerine, glyceryl monooleate, Masine 35-1 etc. It is one or more.
It is a further object of the present invention to provide the preparations of the compound long-acting injection containing Enrofloxacin and Flunixin Method, comprising:
(a), decentralized medium is heated to 150~180 DEG C, and continues 1~1.5h；
(b), when the suspending agent used is for rilanit special and in aluminum monostearate, aluminium distearate, aluminum stearate At least one when, into 120~140 DEG C of decentralized media for account for injection total volume 60%~70% be added rilanit special and Selected from least one of aluminum monostearate, aluminium distearate, aluminum stearate, 1~2h is maintained, the complete gelatinization of suspending agent is made；It puts It is cooled to 40~60 DEG C, adds the suspending agent in addition to rilanit special, aluminum monostearate, aluminium distearate, aluminum stearate, soaks Agent, Enrofloxacin and/or its salt, in a dispersed form existing Flunixin and/or flunixin meglumine, Flunixin and/or fluorine Buddhist nun Pungent meglumine inclusion compound, stirs evenly；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to；
When the suspending agent of use does not include aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special, takes and account for The decentralized medium of injection total volume 60%~70% is let cool to 40~60 DEG C, be added suspending agent, wetting agent, Enrofloxacin and/ Or its salt, in a dispersed form existing Flunixin and/or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound, It stirs evenly；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to；
(c), granularity, related substance and content are detected；It is dispensed after qualification, 100 DEG C~121 DEG C sterilize 10~30 minutes, i.e., The compound long-acting injection of Enrofloxacin and Flunixin must be contained.
Diameter of particle D90≤15 μm in the compound long-acting injection containing Enrofloxacin and Flunixin, should not detect 50 μm or more of particle.
The beneficial effects of the present invention are:
(1) the compound long-acting injection of the invention containing Enrofloxacin and Flunixin, preparation process is simple, repeatability between batch It is good；Without aseptically operating, only 100 DEG C~121 DEG C sterilizings sterilizing need to can be realized in 10~30 minutes after packing, While each index for the front and back injection that sterilizes has no significant change, and meets regulation, is suitble to industrialized production.
(2) the compound long-acting injection containing Enrofloxacin and antipyretic-antalgic anti-inflammatory agent of the invention, is added in system and is suitable for The wetting agents such as lecithin, tween, sapn, after long-term placement, drug microparticles remain to be uniformly dispersed, and granularity meets bound requirements, peace It is complete effective.
(3) the compound long-acting injection containing Enrofloxacin and Flunixin of the invention, Flunixin feedstock portions or all with fluorine The form of the pungent inclusion compound of Buddhist nun is added, and slow release effect is remarkably reinforced.
(4) the compound long-acting injection containing Enrofloxacin and Flunixin of the invention is only injected 1 time, can treating both manifestation and root cause of disease, section About cost, it is time saving and energy saving, can more enhance animal compliance, reduce Animal stress, promote and improve disease lapse to and prognosis.
Specific embodiment
Technical solution of the present invention is described further below by specific embodiment.
In specific embodiment:
Through ultramicro crushing treatment, 90% grain diameter≤15 μm must not detect 50 μm or more for Enrofloxacin or its salt Particle.
Existing Flunixin and flunixin meglumine are through ultramicro crushing treatment, 90% grain diameter≤5 μ in a dispersed form M must not detect 25 μm or more of particle.
The ultramicro crushing treatment process of Enrofloxacin or its salt, Flunixin, flunixin meglumine: fluidized bed supersonic speed is used Air-flow pulverizes hierarchy system, and material inlet is controlled in 60~80g.Material is in crushing chamber mutually with 2.5 Mach velocity phases Mutually self head-on collision, fast-crushing.Particle through crushing rises to grading room with air-flow, and qualified particle enters whirlwind point with air-flow From device, required product is finally obtained, tail gas enters deduster discharge.Biggish particle falls powder after rise under grader effect again Broken room, is crushed again, until obtaining qualified product.Granularity fineness is by grader frequency control.Equipment runs major parameter Are as follows: power pressure 0.8MPa sorts frequency 30Hz, and pulse instrument is the interpulse period 20s that moves in circles.
Flunixin inclusion compound, the preparation method of flunixin meglumine inclusion compound are as follows: by Ethylated β-Cyclodextrins and fluorine Buddhist nun is pungent or flunixin meglumine according to equimolar than being dissolved in 60% ethanol water, wherein the ethanol water Volume and Flunixin or flunixin meglumine and ethyl beta-cyclodextrin gross mass 20~30:1mL/g, after mixing in 25 Ultrasound 30 minutes, are immediately transferred into colloid mill at DEG C, and be switched on operating 10~20 minutes, are added later and addition for the first time 60% ethanol water of 60% ethanol water equivalent operates 0.5~1 hour.It is spraying dry using spray-drying process Dry machine wriggling flow rate pump be 8~15mL/min, 120~130 DEG C of inlet temperature, 0.3~0.5MPa of atomizing pressure, leaving air temp 80 ~90 DEG C, Flunixin or flunixin meglumine inclusion compound is made, the partial size for controlling Flunixin or flunixin meglumine inclusion compound exists 90% grain diameter≤15 μm must not detect 50 μm or more of particle.
Embodiment 1:
Prescription
Preparation method: taking ethyl oleate appropriate, is heated to 150-180 DEG C, and continue 1h；Ethyl oleate after taking heating 120-140 DEG C to be cooled to of 700mL, aluminum monostearate, rilanit special is added, 1-2h is maintained to make aluminum monostearate, hydrogenation castor The complete gelatinization of sesame oil；It is let cool later to 40-60 DEG C, microwax, Tween 80, sorbester p18, lecithin, Enrofloxacin, lactic acid is added Enrofloxacin, Flunixin inclusion compound and Flunixin, stir evenly, and are settled to the ethyl oleate for being cooled to room temperature after heat treatment 1000mL；Detect granularity and content；It is dispensed after qualification, 115 DEG C sterilize 30 minutes to get containing enrofloxacin injection and Flunixin Compound long-acting injection, carry out external performance evaluation, including character, granularity, 3h sedimentation volume ratio to it, it is redispersibility, logical The measurement such as needle, content, measurement result are shown in Table 1.
Granularity inspection: according to one annex 0982 of " Chinese veterinary pharmacopoeia " version in 2015, " granularity and determination of particle size distribution " First method: microscopic method.Diameter of particle D90≤5 μm should not detect 50 μm or more of particle.
Sedimentation volume ratio measurement: according to " Chinese veterinary pharmacopoeia " annex page 25 of version one in 2015, apparatus plug graduated cylinder, which measures, to be supplied Test product 50mL, close plug firmly shake 1 minute, write down the beginning height H of suspended matter0, stand, suspended matter is final when writing down 3h Height H is calculated: sedimentation volume ratio=H/H according to the following formula0。
Redispersibility measurement: suspension is placed in 100mL tool plug graduated cylinder, close plug rights again after being inverted graduated cylinder (one anti-one positive calculation is primary, firmly uniform when stirring), the sediment of graduated cylinder bottom should be uniformly dispersed again.With the heavy of graduated cylinder bottom It is fewer that drop object stirs number needed for being uniformly dispersed, and shows that redispersibility is better.Excellent suspension shakes again after storage, answers It can disperse again quickly, can guarantee the accuracy of the uniformity and divided dose when application.* to represent redispersibility poorer more.
Syringeability measurement: investigating the syringeability of preparation with the syringe for being connected with 9# syringe needle, and "+" represents that syringeability is good, and "+" is got over It is better to represent syringeability more；It is poor that "-" represents syringeability, and "-", and to represent syringeability poorer.
Assay: 2006~2011 editions methods of veterinary medical quality standard compendium carry out content to Enrofloxacin and Flunixin Measurement.
Embodiment 2:
Prescription
Preparation method: taking medium chain fatty acid appropriate, is heated to 150-180 DEG C, and continue 1h；Middle chain after taking heat treatment Fatty acid 600mL is cooled to 120-140 DEG C, and aluminum monostearate, rilanit special is added, and maintains 1-2h, makes its complete gelatinization； It lets cool to 40-60 DEG C, polyvinyl alcohol, Tween 80, span 85, hydroxylated lecithin, Enrofloxacin, flunixin meglumine inclusion is added Object stirs, and is settled to 1000mL with the medium chain fatty acid for being cooled to room temperature after heat treatment；Detect granularity and content； It is dispensed after qualification, 115 DEG C sterilize 30 minutes to get the compound long-acting injection containing Enrofloxacin and Flunixin, carry out body to it Outer performance evaluation, including character, granularity, 3h sedimentation volume ratio, the measurement such as redispersibility, syringeability, content.External performance evaluation For method with implementing 1, measurement result is shown in Table 1.
Embodiment 3:
Prescription
Preparation method: taking isopropyl myristate appropriate, is heated to 150-180 DEG C, and continue 1h；After taking heat treatment Isopropyl myristate 600mL is cooled to 120-140 DEG C, and aluminum monostearate, rilanit special is added, and maintains 1-2h, makes single hard The complete gelatinization of resin acid aluminium, rilanit special；It lets cool to 40-60 DEG C, Chinese wax, Tween 80, sorbester p18, lecithin, En Nuosha is added Star sodium, Flunixin inclusion compound and Flunixin, stir, fixed with the isopropyl myristate for being cooled to room temperature after heat treatment Hold to 1000mL；Detect granularity and content；It is dispensed after qualification, 115 DEG C of sterilizings 30 minutes are to get containing Enrofloxacin and Flunixin Compound long-acting injection carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio, redispersibility, cleansing pin to it Property, the measurement such as content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
Embodiment 4:
Prescription
Preparation method: taking soybean oil appropriate, is heated to 150-180 DEG C, and continue 1h；Soybean oil after taking heat treatment 600mL is cooled to 120-140 DEG C, and aluminum stearate, rilanit special is added, and maintains 1-2h, keeps aluminum stearate, rilanit special complete Full gelatinization；It lets cool to 40-60 DEG C, polyvinyl alcohol, PLURONICS F87, sorbester p17, hydroxylated lecithin, Enrofloxacin, lactic acid is added Enrofloxacin and Flunixin, stir, and are settled to 1000mL with the soybean oil for being cooled to room temperature after heat treatment；Detect grain Degree and content；Dispensed after qualification, 115 DEG C sterilizing 30 minutes to get the compound long-acting injection containing Enrofloxacin and Flunixin, it is right It carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio, the measurement such as redispersibility, syringeability, content.In vitro For method of evaluating performance with implementing 1, measurement result is shown in Table 1.
Embodiment 5:
Prescription
Preparation method: taking soybean oil appropriate, is heated to 150-180 DEG C, and continue 1h；Soybean oil after taking heat treatment 600mL is cooled to 120-140 DEG C, and aluminum stearate, rilanit special is added, and maintains 1-2h, makes aluminum stearate, rilanit special Complete gelatinization；It lets cool to 40-60 DEG C, polyvinyl alcohol, PLURONICS F87, sorbester p17, lecithin, Enrofloxacin, En Nuosha is added Star sodium, flunixin meglumine inclusion compound and Flunixin, stir, with the soybean oil constant volume for being cooled to room temperature after heat treatment To 1000mL；Detect granularity and content；Dispensed after qualification, 115 DEG C sterilizing 30 minutes to get answering containing Enrofloxacin and Flunixin Square long-acting injection, carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio to it, redispersibility, syringeability, The measurement such as content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
The external Evaluation results of table 1.
Note: * represents redispersibility energy, and the fewer redispersibility of * is better.+ syringeability is represented ,+to represent syringeability better more.
The influence of suspending agent and wetting agent to preparation performance
Referring to 1 prescription of embodiment, the given the test agent (being shown in Table 2) containing different component is prepared.Each given the test agent does 3 In parallel.Investigating that drug mixes respectively must incorporation time, character, sedimentation volume ratio (3h and for 24 hours) and redispersibility.In order to more preferable Simulation place for a long time caused by drug sedimentation redispersibility, it is as follows that redispersibility investigates method: with 1500 revs/min of revolving speed from The heart 30 minutes, identical dynamics shook centrifuge tube, and can observation medical fluid be uniformly mixed and mix again must incorporation time.When mixing Between, character, sedimentation volume ratio and redispersibility investigation the results are shown in Table 3.Seen from table 3, body can effectively be avoided after wetting agent being added It is the caking phenomenon of drug particles, preparation redispersibility is more preferable.
Seen from table 3, due to suspending agent rilanit special, aluminum monostearate, microwax and wetting agent Tween 80, sorbester p18 The incorporation time of the collocation of lecithin, 1 suspension of embodiment greatly reduces, and sedimentation and redispersibility can significantly optimize, preparation Shape is more excellent.Lack the sample of aluminum monostearate and (or) rilanit special, not only sedimentation volume ratio significantly reduces, redispersibility It is significantly damaged.Lack the sample of wetting agent, the aggregation of drug microparticles and uniting increased significantly, and influence settlement volume ultimate ratio and redisperse Property, also considerably increase preparation incorporation time.
2. given the test agent prescription component of table
3 test specimen character of table and suspension performance evaluation
Note: * represents redispersibility energy, and the fewer redispersibility of * is better.
The influence to sterilize to preparation performance
The sample for taking 5 embodiments to prepare, 115 DEG C sterilize 30 minutes, with comparison before sterilizing, the results are shown in Table 4.It can by table 4 See, 115 DEG C sterilize 30 minutes, and each index meets regulation, and shows 115 DEG C of sterilizings 30 without significant change with comparison before sterilizing Minute can be used as the terminal sterilization condition of the compound long-acting injection containing Enrofloxacin and Flunixin.
The influence test result that table 4. sterilizes to injection quality
Study on the stability
Take 5 embodiments prepare sample, be respectively placed in high temperature (60 DEG C) condition, Qiang Guang (intensity of illumination 4500 ± It under the conditions of 500lx) and under the conditions of high humidity (relative humidity 90% ± 5%), places 10 days, (quality evaluation was shown in Table with comparison in 0 day 1) sample stability investigation, is carried out, the results are shown in Table 5.By table 5 as it can be seen that placing 10 days, each index meets regulation, compares with 0 day Without significant change, show that the compound long-acting injection quality containing Enrofloxacin and Flunixin meets regulation, and preparation stabilization.
5. influence factor test result of table
The sustained release performance of compound long-acting injection containing Enrofloxacin and Flunixin is evaluated
18 health binary pigs are randomly divided into 3 groups, and every group 6,4h fasting after preceding 12h and administration is tested in weighing before being administered, 1st group by the commercially available conventional enrofloxacin injection (aqueous solution of 5mg/kg.B.W. dosage (in terms of Enrofloxacin) single intramuscular injection Agent is purchased from Bayer A.G)；2nd group: having been listed by 2.2mg/kgB.W. dosage (in terms of Flunixin) single intramuscular injection Flunixin meglumine injection (Qilu Animal Health Products Co., Ltd.'s production)；3rd group by single intramuscular injection embodiment 5 Compound long-acting injection containing Enrofloxacin and Flunixin is calculated as 20mg/kg.B.W. dosage (i.e. with Flunixin with Enrofloxacin It is calculated as the dosage of 10mg/kg).Before administration (0h) and administration after the 10th, 20,30,45min, 1,2,4,6,8,12,24, 36,48,60,72,84,96,108,120,132,144,168,192,216, the blood sampling of 240h vena cava anterior, about 4mL, is placed in every time In heparin sodium heparin tube.Acquisition blood sample is centrifuged 10min through 4000r/min, draws upper plasma in PA tube, after label, Sealing, is protected from light, -20 DEG C of preservations are to be measured.The plasma sample of different time points is detected using HPLC measuring method, obtains blood Concentration-time data carries out pharmacokinetic parameters analysis through 5.2 software of WinNonlin, and pharmacokinetic parameters are shown in Table 6 and table 7.
By table 6 and table 7 as it can be seen that after long-acting injection of the pig single-dose injection containing Enrofloxacin and Flunixin, in dosage In the case of conventional commercial enrofloxacin injection, flunixin meglumine injection, Enrofloxacin and Flunixin in pig body Up to Cmax (Cmax) have no significant raising, but peak time (Tmax) eliminate half-life period (T1/2λz) and residence time (MRT0→t) aobvious It writes and extends, safety is good, and slow releasing function is excellent.
6. Enrofloxacin of table is in the intracorporal pharmacokinetic parameter of test pig (n=6)
7. Flunixin of table is in the intracorporal pharmacokinetic parameter of test pig (n=6)

Claims (9)

1. a kind of compound long-acting injection containing Enrofloxacin and Flunixin, it is characterised in that including Enrofloxacin or/and its salt, In a dispersed form in existing Flunixin and/or flunixin meglumine and Flunixin and/or flunixin meglumine inclusion compound extremely Few one kind, suspending agent, wetting agent and decentralized medium；Every 1000mL injection contains: Enrofloxacin or/and its salt are (with En Nuosha Star meter) 50~300g, in a dispersed form existing Flunixin or flunixin meglumine (in terms of Flunixin) 0~200g, Flunixin Or flunixin meglumine inclusion compound (in terms of Flunixin) 0~150g, 5~20g of suspending agent, 5~15g of wetting agent, surplus are dispersion Medium, and existing Flunixin and/or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound in a dispersed form It cannot simultaneously be 0.
2. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that every 1000mL injection contains: 100~200g of Enrofloxacin or/and its salt (in terms of Enrofloxacin), in a dispersed form existing fluorine Buddhist nun is pungent or flunixin meglumine (in terms of Flunixin) 0~150g, Flunixin or flunixin meglumine inclusion compound (in terms of Flunixin) 0 ~100g, 16~20g of suspending agent, 8~12g of wetting agent, surplus are decentralized medium, and in a dispersed form existing Flunixin and/ Or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound cannot be 0 simultaneously.
3. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Enrofloxacin salt is selected from any one or more of Enrofloxacin sodium, Enrofloxacin HCL and Enrofloxacin.
4. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Through ultramicro crushing treatment, 90% grain diameter≤15 μm must not detect 50 μm or more of particle for Enrofloxacin or its salt；It is described Flunixin existing in a dispersed form and/or flunixin meglumine through ultramicro crushing treatment, 90% grain diameter≤5 μm, 25 μm or more of particle must not be detected.
5. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Flunixin and/or flunixin meglumine inclusion compound the preparation method is as follows: by Ethylated β-Cyclodextrins and Flunixin and/or fluorine Buddhist nun Pungent meglumine is added in 60% ethanol water according to according to 1~2:1 of molar ratio, the volume and fluorine of the ethanol water Buddhist nun is pungent and/or the ratio between flunixin meglumine and ethyl beta-cyclodextrin gross mass are 20~30:1, ultrasonic after mixing, is transferred to In colloid mill, booting operating 10~20 minutes adds identical with first time additional amount 60% ethanol water, after reforwarding Turn 0.5~1 hour；Using spray-drying process, be made Flunixin and/or flunixin meglumine inclusion compound, control Flunixin and/ Or the partial size of flunixin meglumine inclusion compound must not detect 50 μm or more of particle in 90% grain diameter≤15 μm.
6. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Suspending agent is selected from polyvinyl alcohol, hypromellose, hyetellose, hydroxypropylcellulose, sodium carboxymethylcellulose, hyalomitome Acid, xanthan gum, chitosan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, stearic acid, aluminum monostearate, distearyl acid Aluminium, aluminum stearate, rilanit special, beeswax, microwax, yellow wax, Chinese wax, polylactic acid, poly lactide-glycolide acid (PLGA), polycaprolactone (PCL), polyoxyethylene beeswax, tristerin, glycerin monostearate and polyoxyethylene (75) are hard Resin acid ester admixture, Unigly GO 102S, any one or more in pegoxol 7 stearate；Preferably, described Suspending agent is rilanit special, selected from least one of aluminum monostearate, aluminium distearate and aluminum stearate and/or selected from poly- The combination of at least one of vinyl alcohol, microwax and Chinese wax.
7. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Wetting agent is selected from lecithin, hydroxylated lecithin, polysorbas20, polysorbate40, polysorbate60, Tween 80, Pluronic/Lutrol F 44, poloxamer 188, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, span 20, span 40, sorbester p18, sorbester p38, sorbester p17, department Disk 85, propylene glycol diacetate, propylene glycol monostearate, sodium lactate, stearic acid sodium lactate, polyoxyethylene (30EO) sorbierite four Oleyl ether, four stearyl ether of polyoxyethylene (60EO) sorbierite, four oleic acid ether of polyoxyethylene (40EO) sorbierite, polyoxyethylene Four oleate of (60EO) sorbierite, polyoxyethylene (8) stearate, polyoxyethylene (12) stearate, polyoxyethylene (24) are hard Resin acid ester, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, polyoxyethylene (100) stearate, polyoxy second Alkene (110) stearate, polyoxyethylene (10) rilanit special, polyoxyethylene (30) rilanit special, polyoxyethylene (40) hydrogen Change castor oil, polyoxyethylene (50) rilanit special, polyoxyethylene (60) rilanit special, polyoxyethylene (10) castor oil, gather Ethylene oxide (35) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, gathers polyoxyethylene (40) castor oil The single oil of ethylene oxide (90) castor oil, polyoxyethylene (100) castor oil, polyoxyethylene (300) monoleate, polyoxyethylene (400) Acid esters, polyoxyethylene (600) monoleate, castor oil, Labraso, Sefsol 218, the third two Alcohol monolaurate, Unigly GO 102S, -3 pairs of isostearates of polyglycereol, stearic acid polyoxyethylene glyceride, lauric acid are poly- Ethylene oxide glyceride, oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glyceride, three ceteareth -4- phosphoric acid Any one or more in salt, ethylene glycol stearate and diethylene glycol stearate mixture.
8. the compound long-acting injection according to claim 1 containing Enrofloxacin and Flunixin, it is characterised in that described Decentralized medium is selected from sesame oil, peanut oil, cottonseed oil, soybean oil, olive oil, tea oil, Liquid Macrogol, polyethylene glycol 400, cream Acetoacetic ester, propylene glycol, ethyl oleate, N,N-dimethylformamide, triacetyl glycerine, medium chain fatty acid, Ergol, meat Isopropyl myristate, formal glycerine, glyceryl monooleate, any one or more in Masine 35-1.
9. the preparation method of the compound long-acting injection described in claim 1 containing Enrofloxacin and Flunixin, it is characterised in that Include:
(a), decentralized medium is heated to 150~180 DEG C, and continues 1~1.5h；
(b), when the suspending agent used for rilanit special and in aluminum monostearate, aluminium distearate, aluminum stearate extremely When few a kind of, rilanit special and choosing are added into 120~140 DEG C of decentralized media for account for decentralized medium total volume 60%~70% From at least one of aluminum monostearate, aluminium distearate, aluminum stearate, 1~2h is maintained, the complete gelatinization of suspending agent is made；It lets cool To 40~60 DEG C, adds the suspending agent in addition to rilanit special, aluminum monostearate, aluminium distearate, aluminum stearate, soaks Agent, Enrofloxacin and/or its salt, in a dispersed form existing Flunixin and/or flunixin meglumine, Flunixin and/or fluorine Buddhist nun Pungent meglumine inclusion compound, stirs evenly；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to；
When the suspending agent of use does not include aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special, takes and account for dispersion The decentralized medium of medium total volume 60%~70% is let cool to 40~60 DEG C, be added suspending agent, wetting agent, Enrofloxacin and/or Its salt, in a dispersed form existing Flunixin and/or flunixin meglumine, Flunixin and/or flunixin meglumine inclusion compound, are stirred It mixes uniformly；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to；
(c), 100 DEG C~121 DEG C sterilize 10~30 minutes to get the compound long-acting injection containing Enrofloxacin and Flunixin.
CN201910655613.1A 2019-07-19 2019-07-19 Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof Active CN110327294B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910655613.1A CN110327294B (en) 2019-07-19 2019-07-19 Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910655613.1A CN110327294B (en) 2019-07-19 2019-07-19 Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof

Publications (2)

Publication Number Publication Date
CN110327294A true CN110327294A (en) 2019-10-15
CN110327294B CN110327294B (en) 2023-06-13

Family

ID=68145965

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910655613.1A Active CN110327294B (en) 2019-07-19 2019-07-19 Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof

Country Status (1)

Country Link
CN (1) CN110327294B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568255A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Meloxicam
CN114404360A (en) * 2021-12-16 2022-04-29 江西傲新生物科技有限公司 Preparation method of flunixin meglumine injection
CN114533852A (en) * 2022-02-25 2022-05-27 四川恒通动保生物科技有限公司 Compound amoxicillin and colistin sulfate suspension injection and preparation method thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2315123A1 (en) * 2006-09-25 2009-03-16 Divasa-Farmavic, S.A. Stable pharmaceutical compositions of tetracyclines in solution, method for obtaining them and their uses
CN101658526A (en) * 2009-09-24 2010-03-03 陈建波 Veterinary compound enrofloxacin injection and preparation method thereof
CN101829124A (en) * 2010-05-19 2010-09-15 陈建波 Veterinary compound sulfadiazine sodium injection and preparation method thereof
CN102697784A (en) * 2012-06-14 2012-10-03 武汉回盛生物科技有限公司 Enrofloxacin injection for livestock and preparation method thereof
CN104800220A (en) * 2015-03-11 2015-07-29 四川成康动物药业有限公司 Medicine formula for eliminating in-vivo enolotoxin
CN106727567A (en) * 2016-11-25 2017-05-31 成都乾坤动物药业股份有限公司 A kind of Amoxicillin Enrofloxacin oil suspension and preparation method thereof
CN109568255A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Meloxicam
CN109568316A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2315123A1 (en) * 2006-09-25 2009-03-16 Divasa-Farmavic, S.A. Stable pharmaceutical compositions of tetracyclines in solution, method for obtaining them and their uses
CN101658526A (en) * 2009-09-24 2010-03-03 陈建波 Veterinary compound enrofloxacin injection and preparation method thereof
CN101829124A (en) * 2010-05-19 2010-09-15 陈建波 Veterinary compound sulfadiazine sodium injection and preparation method thereof
CN102697784A (en) * 2012-06-14 2012-10-03 武汉回盛生物科技有限公司 Enrofloxacin injection for livestock and preparation method thereof
CN104800220A (en) * 2015-03-11 2015-07-29 四川成康动物药业有限公司 Medicine formula for eliminating in-vivo enolotoxin
CN106727567A (en) * 2016-11-25 2017-05-31 成都乾坤动物药业股份有限公司 A kind of Amoxicillin Enrofloxacin oil suspension and preparation method thereof
CN109568255A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Meloxicam
CN109568316A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DONALD C. PLUMB主编，沈建忠 主译: "《兽药手册 第7版》", 30 June 2016, 中国农业大学出版社 *
吴清，等: "《物理药剂学》", 30 November 2018, 中国中医药出版社 *
孟胜男，等: "《药剂学》", 31 January 2016, 中国医药科技出版社 *
王建华，等: "甲基-β-环糊精-氟尼辛包合物的制备与表征", 《合成化学》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568255A (en) * 2018-12-19 2019-04-05 南京农业大学 Compound long-acting injection and preparation method thereof containing Ceftiofur and Meloxicam
CN114404360A (en) * 2021-12-16 2022-04-29 江西傲新生物科技有限公司 Preparation method of flunixin meglumine injection
CN114533852A (en) * 2022-02-25 2022-05-27 四川恒通动保生物科技有限公司 Compound amoxicillin and colistin sulfate suspension injection and preparation method thereof

Also Published As

Publication number Publication date
CN110327294B (en) 2023-06-13

Similar Documents

Publication Publication Date Title
Tiboni et al. 3D printed clotrimazole intravaginal ring for the treatment of recurrent vaginal candidiasis
CN110327294A (en) Compound long-acting injection and preparation method thereof containing Enrofloxacin and Flunixin
CN109568255A (en) Compound long-acting injection and preparation method thereof containing Ceftiofur and Meloxicam
Li et al. Solid lipid nanoparticles with enteric coating for improving stability, palatability, and oral bioavailability of enrofloxacin
JP2021169510A (en) Fulvestrant formulations and methods of their use
CN108815123A (en) A kind of curcumin solid dispersion and its preparation method and application
CN109568316A (en) Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin
CN109394727A (en) A kind of Enrofloxacin taste masking sustained-release granular formulation for animals and preparation method thereof
CN107106506A (en) The injectable particulate that super localization for therapeutic agent discharges
Chen et al. Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes
CN110327348A (en) Compound long-acting injection and preparation method thereof containing Enrofloxacin and Meloxicam
CN101982173B (en) Danofloxacin mesylate-amoxicillin suspension injection applicable to livestock and poultry as well as preparation and application thereof
CN112043693B (en) Application of ester-group-containing aromatic propionamide compound in preparation of medicine for treating xerophthalmia
CN102283842A (en) Compound mequindox florfenicol nanoemulsion antibacterial drug and preparation method thereof
RU2627429C2 (en) Compositions with controlled release and methods of their use
CN102274179A (en) Mequindox nanoemulsion antibacterial medicament and preparation method thereof
Tang et al. Preparation of a newly formulated long‐acting ceftiofur hydrochloride suspension and evaluation of its pharmacokinetics in pigs
CN110251481A (en) A kind of veterinary tilmicosin taste masking slow-releasing granules and its preparation process
CN106924189A (en) A kind of Tilmicosin enteric-coated sustained release powder and its preparation method and application
CN102397282A (en) Long-acting compound ceftiofur suspension injection and its preparation method
CN106420600A (en) In situ gel for tilmicosin injection and preparation method thereof
CN106038482A (en) Enrofloxacin uterus perfusion liquid as well as preparation method and application thereof
CN108210452B (en) Veterinary cyadox nano suspension and preparation method thereof
CN102614294A (en) Compound amoxicillin suspension injection and preparation method thereof
CN108904451A (en) Sustained release preparation

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant