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CN110327294B - Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof - Google Patents

Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof Download PDF

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CN110327294B
CN110327294B CN201910655613.1A CN201910655613A CN110327294B CN 110327294 B CN110327294 B CN 110327294B CN 201910655613 A CN201910655613 A CN 201910655613A CN 110327294 B CN110327294 B CN 110327294B
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flunixin
enrofloxacin
injection
compound
xin
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CN110327294A (en
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余祖功
郭凡溪
苗晋锋
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Nanjing Agricultural University
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Nanjing Agricultural University
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • 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
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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]
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention discloses a compound long-acting injection containing enrofloxacin and flunixin, wherein each 1000mL of the injection contains: 50-300 g of enrofloxacin or/and salt thereof, 0-200 g of flunixin or flunixin meglumine in a dispersed form, 0-150 g of flunixin or flunixin meglumine inclusion compound, 5-20 g of suspending agent, 5-15 g of wetting agent and the balance of dispersing medium, wherein the flunixin and/or flunixin meglumine in a dispersed form and the flunixin and/or flunixin meglumine inclusion compound cannot be 0 at the same time. The injection can treat both principal and secondary aspect of disease only by injecting for 1 time, can further enhance animal compliance, reduce animal stress, and promote and improve disease prognosis. After long-term placement, the medicine particles can be uniformly dispersed; the injection provided by the invention does not need to be operated under aseptic conditions, and can be sterilized only by sterilizing for 30 minutes at 115 ℃ after sub-packaging, and all indexes of the injection before and after sterilization meet the requirements, so that the injection is suitable for industrial production.

Description

Compound long-acting injection containing enrofloxacin and flunixin and preparation method thereof
Technical Field
The invention belongs to the field of special pharmaceutical preparations for animals, and relates to a compound long-acting injection containing enrofloxacin and flunixin and a preparation method thereof.
Background
Enrofloxacin (Enrofloxacin) is very slightly soluble in acetone, is almost insoluble in water, and its hydrochloride, sodium and lactate salts are readily soluble in water. Enrofloxacin is fluoroquinolone special for animals, is most commonly used in veterinary clinics, has special effects on mycoplasma, has stronger efficacy than tylosin and colistin, is still effective on both drug-resistant mycoplasma, and has good effect on resisting mycoplasma gallisepticum; has strong effect on gram-negative bacteria; has good effects on staphylococcus aureus, actinomyces suppuration, erysipelas bacillus, chlamydia and the like; the effect on pseudomonas aeruginosa and streptococcus is weak; has weak effect on anaerobic bacteria. Enrofloxacin has obvious antibacterial effect on sensitive bacteria, and the antibacterial activity is concentration-dependent.
Since the market, enrofloxacin has been widely used in the clinic of animals such as poultry, pigs, cattle, sheep, dogs, rabbits and the like. Pig: can be used for treating streptococcosis, yellow diarrhea and white diarrhea of piglets, colibacillosis, salmonella, infectious pleuropneumonia, mastitis-metritis-agalactia syndrome, mycoplasma pneumonia, etc. Cattle and sheep: can be used for treating diarrhea due to Escherichia coli, septicemia due to Escherichia coli, bovine plague (mycoplasmal pneumonia), brucellosis, pasteurellosis, bovine anthrax, and Lev bacillosis (including those with neurological symptoms), and mastitis and metritis. Dogs and cats: can be used for treating diseases such as digestive tract, respiratory tract, urinary system, genital organ infection, skin infection, wound suppuration, otitis externa, and hemorrhagic gastroenteritis caused by Escherichia coli.
The enrofloxacin is taken orally, is injected into muscles and is absorbed rapidly and completely, the serum protein binding rate is 20% -40%, the in-vivo distribution is wide, and the enrofloxacin concentration in almost all tissues except the central nervous system is higher than that of blood plasma. About 15% to 50% is excreted from the urine as is (tubular secretion and glomerular filtration) by renal and non-renal metabolic means. The liver metabolism mainly removes the ethyl of the 7-piperazine ring to generate ciprofloxacin, and then oxidation and glucuronic acid combination are carried out, and the ciprofloxacin which is a main metabolite still has strong activity, and the pig body lacks the deethylating enzyme to be directly inactivated. Enrofloxacin elimination half-life has a large difference between different species of animals and different administration routes, intravenous injection half-life (h): pigeon 3.8, chicken 5.26-10.3, turkey 4.1, rabbit 2.2-2.5, dog 2.4, pig 3.45, cow 1.7-2.3, horse 4.4 and camel 3.6. Myoinjection half-life (h): pig 4.06, cow 5.9, horse 9.9, camel 6.4. Half-life for oral administration (h): 9.14 to 14.2 portions of chickens, 3.7 to 5.8 portions of dogs and 6.93 portions of pigs.
Non-steroidal anti-inflammatory drugs (NSAIDs), also known as antipyretic analgesic anti-inflammatory drugs, are steroid structures without steroid corticoids, and have the functions of removing hyperthermia, relieving local dull pain and resisting inflammation, and inhibiting platelet aggregation. Because of their effective relief from fever, pain and inflammation symptoms, reduced animal stress, increased animal compliance, have been widely used to control inflammation and pain, whether infectious or non-infectious. Clinically, the non-steroidal anti-inflammatory drugs are mainly used for preventing and treating or relieving inflammation, pain and the like of various animals caused by infection and non-infection, such as relieving inflammation pain of cow metritis, mammitis, respiratory diseases, laminitis, arthritis and the like, and also can be used for postpartum pain relieving; relieving inflammatory pain symptoms such as respiratory diseases, colibacillosis, sow mastitis, metritis, and agalactia syndrome caused by various bacteria of pigs; relieving inflammation pain caused by visceral colic, bone and muscle pain, hernia pain and muscle abnormality of horse, treating foal diarrhea, colitis, respiratory system diseases, etc., and treating horse pneumonia in combination with terramycin; preventing and treating canine and feline putrefying peritonitis, arthritis, fever, diarrhea, eye infection, etc.
Currently, the approved animal-specific antipyretic analgesic anti-inflammatory agent is flunixin meglumine (Flunixin Meglumine, FM). The meglumine salt of flunixin, was developed by the company of pionibacterium in the united states in the 90 th century (trade name Banamine), and is now widely used in countries such as china, the united states, france, swiss, germany, and the united kingdom. The flunixin meglumine has stronger antipyretic, analgesic and anti-inflammatory effects, and the analgesic effect is equivalent to that of the conventional morphine dose, but has no morphine tolerance and dependency phenomenon; the anti-inflammatory effect is 4 times that of phenylbutazone and 2 times that of ketoprofen; can be used together with antibacterial agent to relieve disease symptoms.
Flunixin is an inhibitor of cyclooxygenase, reduces the generation of inflammatory mediators such as prostaglandin, thromboxane and the like by inhibiting the cyclooxygenase in an arachidonic acid reaction chain, and effectively relieves fever, inflammation and pain of a body by preventing various ways such as increase of endobronchial exudates in respiratory diseases, aggregation of neutrophils and albumin in exudates caused by escherichia coli endotoxin through ways such as maintaining normal blood pressure, reducing damage of vascular endothelial cells, maintaining normal blood volume and the like. The composition has rapid action and can relieve pain within 15 min.
Bacterial infection is often accompanied by inflammatory symptoms such as fever, pain and the like, such as cow mastitis, hysteritis, hoof leaf inflammation and the like, bovine Respiratory Disease (BRD), porcine pleuropneumonia, bronchitis, hemorrhagic septicemia and the like, canine and feline pneumonia and the like, which affect animal spirit and diet, damage organism tissues and organs and restrict disease prognosis. The antibacterial agent can effectively remove pathogens, and the antipyretic analgesic anti-inflammatory agent can relieve clinical symptoms, and the combination of the antipyretic analgesic anti-inflammatory agent and the antibacterial agent can treat both symptoms and root causes, thereby being more beneficial to the prognosis and the prognosis of diseases.
The enrofloxacin injection and the flunixin meglumine injection which are approved to be marketed clinically are conventional water solutions, and the recommended dosing scheme is as follows: the compound preparation of enrofloxacin and flunixin is approved for marketing after being administered for 2 times in 1 day and continuously administered for 3 to 7 days.
Chinese patent application CN 103520098A discloses a long-acting enrofloxacin oil suspension injection prepared by adding sucrose acetate isobutyrate and hydrogenated castor oil or sucrose acetate isobutyrate and aluminum stearate to a hydrophobic medium (ethyl oleate, isopropyl myristate). However, the preparation process of the enrofloxacin oil suspension injection needs to be carried out under aseptic conditions, and the temperature of the material during grinding cannot exceed 40 ℃. The preparation process has high requirements on production conditions, restricts industrialized popularization, and the injection is not sterilized by a terminal, so that sterility is difficult to be effectively ensured, and animal safety is endangered. Chinese patent CN 102697784A discloses a veterinary enrofloxacin injection and a preparation method thereof, and relates to a compound injection containing enrofloxacin and flunixin meglumine, but the injection is an aqueous solution, the recommended use is 2 times a day, and the continuous use is 2-3 days, and the injection needs multiple times of administration, is time-consuming and labor-consuming, is easy to actuate, and affects the efficacy. Chinese patent CN 105213402A discloses a compound enrofloxacin meloxicam soluble powder for livestock and poultry, which is administered by drinking water and is suitable for the poultry in intensive cultivation, but is inconvenient to use mainly for individual administration of cattle, sheep, horses and the like because of more drinking water waste of pigs, dogs, cats and the like, and also needs multiple administrations, which is time-consuming and labor-consuming and is unfavorable for the exertion of drug effect.
Disclosure of Invention
Aiming at clinical demands and defects existing in the prior art, the invention provides a compound oil suspension containing enrofloxacin and flunixin, and a proper wetting agent is added into a system to improve caking phenomenon of enrofloxacin in an oily medium, improve medicine stability and enable industrial production to be smoother, and the prepared preparation is placed at 40 ℃ for 6 months and at 25 ℃ for 24 months, and has high stability and excellent redispersibility; aiming at the characteristics of good water solubility, rapid absorption and difficult slow release of the flunixin meglumine, part or all of the flunixin meglumine or/and flunixin is/are micronized to prepare an inclusion compound, so that the release of the medicament is delayed and the irritation at the injection position is reduced. The preparation has stable quality, convenient use, slow drug release and good biocompatibility, can relieve heat, pain and inflammation caused by infection and maintain the effective blood concentration for 3-7 days when being administered for 1-2 times in one treatment course.
The aim of the invention is realized by the following technical scheme:
a compound long-acting injection containing enrofloxacin and flunixin comprises enrofloxacin or/and salt thereof, at least one of flunixin and/or flunixin meglumine in a dispersed form and flunixin and/or flunixin meglumine inclusion compound, a suspending agent, a wetting agent and a dispersion medium; each 1000mL of injection comprises: 50-300 g of enrofloxacin or/and salt thereof (calculated as enrofloxacin), 0-200 g of flunixin or flunixin meglumine (calculated as fluni Xin Ji) in a dispersed form, 0-150 g of flunixin or flunixin meglumine inclusion compound (calculated as fluni Xin Ji), 5-20 g of suspending agent, 5-15 g of wetting agent and the balance of dispersion medium, wherein the flunixin and/or flunixin meglumine, flunixin and/or flunixin meglumine inclusion compound in a dispersed form cannot be 0 at the same time.
Preferably, each 1000mL of injection contains: 100-200 g of enrofloxacin or/and salt thereof (calculated as enrofloxacin), 0-150 g of flunixin or flunixin meglumine (calculated as fluni Xin Ji) in a dispersed form, 0-100 g of flunixin or flunixin meglumine inclusion compound (calculated as fluni Xin Ji), 16-20 g of suspending agent, 8-12 g of wetting agent and the balance of dispersion medium, wherein the flunixin and/or flunixin meglumine, the flunixin and/or flunixin meglumine inclusion compound in a dispersed form cannot be 0 at the same time.
The enrofloxacin salt is selected from any one or more of enrofloxacin sodium, enrofloxacin hydrochloride and enrofloxacin lactate.
The enrofloxacin or the salt thereof is subjected to superfine grinding treatment, 90% of particles have the particle size less than or equal to 15 mu m, and particles with the particle size more than 50 mu m cannot be detected.
The flunixin and/or flunixin meglumine in a dispersed form is subjected to superfine grinding, 90% of particles have a particle size less than or equal to 5 mu m, and particles with a particle size of more than 25 mu m are not detected.
The preparation method of the flunixin and/or flunixin meglumine inclusion compound comprises the following steps: adding ethylated beta-cyclodextrin and flunixin and/or flunixin meglumine into 60% ethanol aqueous solution according to a molar ratio of 1-2:1, wherein the volume of the ethanol aqueous solution to the total mass ratio of the flunixin and/or flunixin meglumine to the ethyl beta-cyclodextrin is 20-30:1 (mL/g), uniformly mixing, performing ultrasonic treatment at 25 ℃ for 30 minutes, immediately transferring into a colloid mill, starting up for 10-20 minutes, adding 60% ethanol aqueous solution with the same amount as the first addition, and continuously operating for 0.5-1 hour; and (3) granulating by spray drying to obtain the flunixin and/or flunixin meglumine inclusion compound, wherein the particle size of the flunixin and/or flunixin meglumine inclusion compound is controlled to be less than or equal to 15 mu m in 90% of the particle size, and 50 mu m or more particles cannot be detected. Wherein the peristaltic pump flow rate of the spray dryer is 8-15 mL/min, the inlet temperature is 120-130 ℃, the atomization pressure is 0.3-0.5 MPa, and the air outlet temperature is 80-90 ℃.
The suspending agent is selected from any one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hyaluronic acid, xanthan gum, chitosan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, stearic acid, aluminum monostearate, aluminum distearate, aluminum stearate, hydrogenated castor oil, beeswax, microcrystalline wax, yellow wax, white wax, polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polyoxyethylene beeswax, glyceryl stearate, glyceryl monostearate and polyoxyethylene (75) stearate mixture, polyglycerol oleate and polyethylene glycol-7-stearate; preferably, the suspending agent is hydrogenated castor oil, at least one selected from aluminum monostearate, aluminum distearate and aluminum stearate and/or at least one selected from polyvinyl alcohol, microcrystalline wax and white wax, and the hydrogenated castor oil accounts for 5-50% of the total amount of the suspending agent.
The wetting agent is selected from lecithin, hydroxylated lecithin, tween (20, 40, 60, 80), poloxamer (124, 188, 237, 338, 407), span (20, 40, 60, 65, 80, 85), propylene glycol diethyl ester, propylene glycol monostearate, sodium lactate, sodium stearate, polyoxyethylene (30 EO) sorbitol tetraoleyl ether, polyoxyethylene (60 EO) sorbitol tetrastearyl ether, polyoxyethylene (40 EO) sorbitol tetraoleate, polyoxyethylene (60 EO) sorbitol tetraoleate, polyoxyethylene (8, 12, 24, 40, 50, 100, 110) stearate, polyoxyethylene (10, 30, 40, 50, 60) hydrogenated castor oil, polyoxyethylene (10, 35, 40, 60, 80, 90, 100) castor oil, polyoxyethylene (300, 400, 600) monooleate, castor oil, caprylic acid polyethylene glycol glyceride, propylene glycol monocaprylate, polyglycerol oleate, polyglycerol-3 diisostearate, polyoxyethylene glyceryl stearate, oleoyl polyoxyethylene glyceryl stearate, polyoxyethylene glyceryl linoleate, polyoxyethylene glyceryl triester, polyoxyethylene glycol 4-stearate, or a mixture of any one or more of these. Preferably, the wetting agent is lecithin or hydroxylated lecithin and a combination of at least two selected from tween, span and poloxamer.
The dispersion medium is selected from one or more of sesame oil, peanut oil, cotton seed oil, soybean oil, olive oil, tea oil, polyethylene glycol 300, polyethylene glycol 400, ethyl lactate, propylene glycol, ethyl oleate, N-dimethylformamide, glyceryl triacetate, medium-chain fatty acid, benzyl benzoate, isopropyl myristate, formal glycerol, glycerol monooleate, glycerol monolinoleate and the like.
The invention also aims to provide a preparation method of the compound long-acting injection containing enrofloxacin and flunixin, which comprises the following steps:
(a) Heating the dispersion medium to 150-180 ℃ for 1-1.5 h;
(b) When the suspending agent is hydrogenated castor oil and at least one selected from aluminum monostearate, aluminum distearate and aluminum stearate, adding the hydrogenated castor oil and at least one selected from aluminum monostearate, aluminum distearate and aluminum stearate into a dispersion medium of 120-140 ℃ accounting for 60-70% of the total volume of the injection, and maintaining for 1-2 hours to enable the suspending agent to be completely gelled; cooling to 40-60 deg.c, adding suspending agent, wetting agent, enrofloxacin and/or its salt, dispersed flunixin and/or flunixin meglumine and flunixin and/or flunixin meglumine clathrate, and stirring; taking a dispersion medium cooled to room temperature, and fixing the volume to 1000mL;
when the suspending agent does not comprise aluminum monostearate, aluminum distearate, aluminum stearate and hydrogenated castor oil, taking a dispersion medium accounting for 60-70% of the total volume of the injection, cooling to 40-60 ℃, adding the suspending agent, wetting agent, enrofloxacin and/or salt thereof, flunixin and/or flunixin meglumine in a dispersion form and uniformly stirring; taking a dispersion medium cooled to room temperature, and fixing the volume to 1000mL;
(c) Detecting granularity, related substances and content; and (3) packaging after the qualified product, and sterilizing for 10-30 minutes at 100-121 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin.
The particle size D90 of the particles in the enrofloxacin and flunixin-containing compound long-acting injection is less than or equal to 15 mu m, and particles with the particle size of more than 50 mu m cannot be detected.
The invention has the beneficial effects that:
(1) The compound long-acting injection containing enrofloxacin and flunixin has the advantages of simple preparation process and good batch-to-batch repeatability; the sterilization can be realized only by sterilizing for 10-30 minutes at 100-121 ℃ after sub-packaging without operating under aseptic conditions, and all indexes of the injection before and after sterilization are not obviously changed, thus meeting the regulations and being suitable for industrial production.
(2) The compound long-acting injection containing enrofloxacin and antipyretic analgesic and anti-inflammatory agent is prepared by adding proper wetting agents such as lecithin, tween, span and the like into a system, and after long-term placement, the medicine particles can be uniformly dispersed, and the granularity meets the limit requirement, so that the compound long-acting injection is safe and effective.
(3) The compound long-acting injection containing enrofloxacin and flunixin provided by the invention has the advantages that the flunixin raw material is added in the form of flunixin inclusion compound partially or completely, and the slow release effect is obviously enhanced.
(4) The compound long-acting injection containing enrofloxacin and flunixin can treat both principal and secondary aspect of disease by only injecting for 1 time, saves cost, saves time and labor, can further enhance animal compliance, reduces animal stress, and promotes and improves the prognosis and the prognosis of diseases.
Detailed Description
The technical scheme of the invention is further described by the following specific examples.
In the specific embodiment, the method comprises the following steps:
the enrofloxacin or the salt thereof is subjected to superfine grinding treatment, 90% of particles have the particle size less than or equal to 15 mu m, and particles with the particle size more than 50 mu m cannot be detected.
The flunixin and flunixin meglumine in a dispersed form are subjected to superfine grinding, 90% of particles have a particle size less than or equal to 5 mu m, and particles with a particle size more than 25 mu m cannot be detected.
The superfine grinding treatment process of enrofloxacin or salt thereof, flunixin and flunixin meglumine comprises the following steps: the supersonic airflow superfine crushing and grading system with fluidized bed is adopted, and the material entering amount is controlled at 60-80 g. The materials mutually collide with each other at Mach 2.5 speed in the crushing cavity, and are crushed rapidly. The crushed particles rise to the classifying chamber along with the air flow, the qualified particles enter the cyclone separator along with the air flow, the required product is finally obtained, and the tail gas enters the dust remover to be discharged. The larger particles fall back into the crushing chamber again under the action of the classifier and are crushed again until a qualified product is obtained. The granularity fineness is controlled by the frequency conversion of the classifier. The main parameters of the equipment operation are as follows: working medium pressure is 0.8MPa, sorting frequency is 30Hz, and pulse instrument is cycle reciprocating pulse interval time is 20s.
The preparation method of the flunixin meglumine inclusion compound of the flunixin Xin Baoge compound is as follows: dissolving ethylated beta-cyclodextrin and flunixin or flunixin meglumine in 60% ethanol water solution according to an equimolar ratio, wherein the volume of the ethanol water solution is 20-30:1 mL/g of the total mass of the flunixin or flunixin meglumine and the ethyl beta-cyclodextrin, uniformly mixing, performing ultrasonic treatment at 25 ℃ for 30 minutes, immediately transferring the mixture into a colloid mill, starting the colloid mill, operating the colloid mill for 10-20 minutes, then adding 60% ethanol water solution equivalent to the 60% ethanol water solution added for the first time, and operating the colloid mill for 0.5-1 hour. And granulating by spray drying, wherein the flow rate of a peristaltic pump of a spray dryer is 8-15 mL/min, the inlet temperature is 120-130 ℃, the atomization pressure is 0.3-0.5 MPa, the air outlet temperature is 80-90 ℃, so that the flunixin or flunixin meglumine inclusion compound is prepared, the particle size of the flunixin or flunixin meglumine inclusion compound is controlled to be less than or equal to 15 mu m, and the particle size of the flunixin or flunixin meglumine inclusion compound is controlled to be 90%, so that the particle size of the particles above 50 mu m cannot be detected.
Example 1:
prescription of prescription
Figure BDA0002136787600000061
Figure BDA0002136787600000071
The preparation method comprises the following steps: heating proper amount of ethyl oleate to 150-180deg.C for 1 hr; taking 700mL of heated ethyl oleate, cooling to 120-140 ℃, adding aluminum monostearate and hydrogenated castor oil, and maintaining for 1-2h to completely gel the aluminum monostearate and the hydrogenated castor oil; cooling to 40-60deg.C, adding microcrystalline wax, tween 80, span 60, lecithin, enrofloxacin lactate, fluni Xin Baoge and flunixin, stirring, heating, cooling to room temperature, and metering volume to 1000mL with ethyl oleate; detecting granularity and content; and (3) packaging after the qualified product, sterilizing at 115 ℃ for 30 minutes to obtain a compound long-acting injection containing enrofloxacin injection and flunixin, and evaluating in-vitro performance of the compound long-acting injection, wherein the measurement results comprise properties, granularity, 3h sedimentation volume ratio, redispersibility, needle penetrating property, content and the like, and are shown in table 1.
Granularity inspection: according to the first method of "particle size and particle size distribution determination" of appendix 0982, part 2015 of the Chinese veterinary pharmacopoeia: microscopy. The particle diameter D90 is less than or equal to 5 μm, and particles with a particle diameter of more than 50 μm should not be detected.
Determination of sedimentation volume ratio: according to the 25 pages of appendix of 2015 edition of Chinese animal pharmacopoeia, 50mL of the test sample is measured by a plug measuring cylinder, the test sample is sealed and shaken forcefully for 1 minute, and the starting height H of the suspension is recorded 0 Standing, and recording the final height H of the suspension at 3H, wherein the final height H is calculated according to the following formula: sedimentation volume ratio = H/H 0 。
Redispersibility measurement: the suspension is placed in a 100mL measuring cylinder with a plug, the measuring cylinder is sealed, the measuring cylinder is turned upside down (calculated once from the back to the front, the force is uniform during turning), and sediment at the bottom of the measuring cylinder is uniformly dispersed again. The smaller the number of turns needed to disperse the sediment uniformly with the bottom of the cylinder, the better the redispersibility. The excellent suspension is stored and then shaken, and can be quickly redispersed, so that the uniformity and the accuracy of dose distribution in application can be ensured. * The more the representation the worse the redispersibility.
Needle penetration assay: the syringe connected with a 9# needle is used for examining the needle penetrating property of the preparation, wherein "+" represents good needle penetrating property, and "+" more represents better needle penetrating property; "-" means poor needle passing ability, and "-" more means poor needle passing ability.
And (3) content measurement: veterinary medicine quality standard assembler 2006-2011 edition method, the content determination of enrofloxacin and flunixin is carried out.
Example 2:
prescription of prescription
Figure BDA0002136787600000072
Figure BDA0002136787600000081
The preparation method comprises the following steps: heating moderate medium chain fatty acid to 150-180deg.C for 1 hr; taking 600mL of medium-chain fatty acid after heat treatment, cooling to 120-140 ℃, adding aluminum monostearate and hydrogenated castor oil, and maintaining for 1-2h to enable the medium-chain fatty acid to be completely gelled; cooling to 40-60deg.C, adding polyvinyl alcohol, tween 80, span 85, hydroxylated lecithin, enrofloxacin, and flunixin meglumine clathrate, stirring, heating, cooling to room temperature, and constant volume with medium chain fatty acid to 1000mL; detecting granularity and content; and (3) packaging after the qualified product, sterilizing for 30 minutes at 115 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin, and evaluating in-vitro performances of the compound long-acting injection, wherein the performances comprise properties, granularity, 3h sedimentation volume ratio, redispersibility, needle penetrating property, content and the like. The in vitro performance evaluation method is the same as in example 1, and the measurement results are shown in Table 1.
Example 3:
prescription of prescription
Figure BDA0002136787600000082
The preparation method comprises the following steps: heating isopropyl myristate to 150-180deg.C for 1 hr; taking 600mL of isopropyl myristate after heat treatment, cooling to 120-140 ℃, adding aluminum monostearate and hydrogenated castor oil, and maintaining for 1-2h to enable the aluminum monostearate and the hydrogenated castor oil to be completely gelled; cooling to 40-60deg.C, adding Cera chinensis, tween 80, span 60, lecithin, enrofloxacin sodium, flunixin Xin Baoge and flunixin, stirring thoroughly, heating, cooling to room temperature, and fixing volume with isopropyl myristate to 1000mL; detecting granularity and content; and (3) packaging after the qualified product, sterilizing for 30 minutes at 115 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin, and evaluating in-vitro performances of the compound long-acting injection, wherein the performances comprise properties, granularity, 3h sedimentation volume ratio, redispersibility, needle penetrating property, content and the like. The in vitro performance evaluation method is the same as in example 1, and the measurement results are shown in Table 1.
Example 4:
prescription of prescription
Figure BDA0002136787600000091
The preparation method comprises the following steps: heating soybean oil to 150-180deg.C for 1 hr; cooling 600mL of the heated soybean oil to 120-140 ℃, adding aluminum stearate and hydrogenated castor oil, and maintaining for 1-2h to completely gel the aluminum stearate and the hydrogenated castor oil; cooling to 40-60deg.C, adding polyvinyl alcohol, poloxamer 188, span 80, hydroxylated lecithin, enrofloxacin lactate and flunixin, stirring, heating, and cooling to room temperature to 1000mL; detecting granularity and content; and (3) packaging after the qualified product, sterilizing for 30 minutes at 115 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin, and evaluating in-vitro performances of the compound long-acting injection, wherein the performances comprise properties, granularity, 3h sedimentation volume ratio, redispersibility, needle penetrating property, content and the like. The in vitro performance evaluation method is the same as in example 1, and the measurement results are shown in Table 1.
Example 5:
prescription of prescription
Figure BDA0002136787600000092
Figure BDA0002136787600000101
The preparation method comprises the following steps: heating soybean oil to 150-180deg.C for 1 hr; taking 600mL of the soybean oil after the heating treatment, cooling to 120-140 ℃, adding aluminum stearate and hydrogenated castor oil, and maintaining for 1-2h to enable the aluminum stearate and the hydrogenated castor oil to be completely gelled; cooling to 40-60deg.C, adding polyvinyl alcohol, poloxamer 188, span 80, lecithin, enrofloxacin sodium, flunixin meglumine clathrate and flunixin, stirring thoroughly, heating and cooling to room temperature, and fixing volume to 1000mL; detecting granularity and content; and (3) packaging after the qualified product, sterilizing for 30 minutes at 115 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin, and evaluating in-vitro performances of the compound long-acting injection, wherein the performances comprise properties, granularity, 3h sedimentation volume ratio, redispersibility, needle penetrating property, content and the like. The in vitro performance evaluation method is the same as in example 1, and the measurement results are shown in Table 1.
TABLE 1 in vitro Performance evaluation results
Figure BDA0002136787600000102
Note that: * Representing redispersibility, the less redispersible. + represents the needle penetration, and +more represents the better needle penetration.
Effects of suspending and wetting agents on formulation performance
With reference to the prescription of example 1, test samples containing different components were prepared (see table 2). Each test sample was run in 3 replicates. The mixing time, the properties, the sedimentation volume ratio (3 h and 24 h) and the redispersibility of the medicines which are uniformly mixed are respectively examined. In order to better simulate the redispersibility of drug sedimentation caused by long-term placement, the redispersibility examination method is as follows: the centrifuge tube was shaken with the same force at a rotational speed of 1500 rpm for 30 minutes to observe whether the liquid medicine could be mixed again uniformly and the mixing time was necessary. The mixing time, properties, sedimentation volume ratio and redispersibility were examined and the results are shown in Table 3. As can be seen from Table 3, the agglomeration of the drug particles in the system can be effectively avoided after the wetting agent is added, and the redispersibility of the preparation is better.
As can be seen from table 3, the mixing time of the suspension of example 1 is greatly reduced, the sedimentation and redispersion properties are significantly optimized, and the formulation properties are better due to the collocation of the suspending agent hydrogenated castor oil, aluminum monostearate, microcrystalline wax, the wetting agent tween 80 and span 60 lecithin. Samples lacking aluminum monostearate and/or hydrogenated castor oil not only have significantly reduced sedimentation volume ratios, but also have greatly impaired redispersibility. In the sample lacking the wetting agent, the aggregation and agglomeration of the drug particles are obviously increased, the sedimentation polar ratio and redispersibility are affected, and the mixing time of the preparation is greatly prolonged.
TABLE 2 prescription Components of test sample
Figure BDA0002136787600000111
TABLE 3 evaluation of test sample Properties and suspension Property
Figure BDA0002136787600000112
Note that: * Representing redispersibility, the less redispersible.
Effect of Sterilization on formulation Properties
Samples prepared in 5 examples were sterilized at 115℃for 30 minutes and compared with those before sterilization, and the results are shown in Table 4. As can be seen from Table 4, the sterilization at 115 ℃ for 30 minutes, all indexes meet the regulations, and the comparison with the sterilization before shows that the sterilization at 115 ℃ for 30 minutes can be used as the terminal sterilization condition of the compound long-acting injection containing enrofloxacin and flunixin.
TABLE 4 Effect of sterilization on injection quality test results
Figure BDA0002136787600000121
Stability investigation
Samples prepared in 5 examples were taken, placed under high temperature (60 ℃) conditions, strong light (light intensity 4500.+ -. 500 lx) conditions and high humidity (relative humidity 90%.+ -. 5%) conditions, respectively, and allowed to stand for 10 days, and compared with 0 day (quality evaluation is shown in Table 1), and subjected to sample stability investigation, and the results are shown in Table 5. As can be seen from Table 5, the compound long-acting injection containing enrofloxacin and flunixin has no obvious change compared with the 0 day after being placed for 10 days, and the quality of the compound long-acting injection is in accordance with the regulations, and the preparation is stable.
TABLE 5 influence factor test results
Figure BDA0002136787600000122
Figure BDA0002136787600000131
Sustained release performance evaluation of compound long-acting injection containing enrofloxacin and flunixin
The 18 healthy binary pigs were randomly divided into 3 groups of 6, each, weighed before dosing, fasted 12 hours before trial and 4 hours after dosing, group 1 were single intramuscular injected with a commercial conventional enrofloxacin injection (aqueous solution, purchased from bayer company germany) at a dose of 5mg/kg.b.w. (in enrofloxacin); group 2: the commercially available flunixin meglumine injection (manufactured by Qilu animal health products Co., ltd.) is injected into muscle at a dose of 2.2 mg/kg.B.W. (as fluni Xin Ji) once; group 3 compound long-acting injection containing enrofloxacin and flunixin according to single intramuscular injection example 5, wherein the dosage of enrofloxacin is 20mg/kg.B.W. (i.e. the dosage of flunixin Xin Ji is 10 mg/kg). The vena cava blood was collected before (0 h) and after (10, 20, 30, 45min,1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 192, 216, 240h, about 4mL each time, and placed in heparin sodium blood collection tubes. And (3) centrifuging the collected blood sample for 10min at 4000r/min, sucking the upper plasma layer into a polypropylene tube, marking, sealing, keeping away from light, and preserving at-20 ℃ to be detected. Plasma samples at different time points are detected by adopting an HPLC (high Performance liquid chromatography) determination method to obtain blood concentration-time data, and pharmacokinetic parameter analysis is carried out by using WinNonlin 5.2 software, and the pharmacokinetic parameters are shown in tables 6 and 7.
As can be seen from tables 6 and 7, after a single intramuscular injection of a long-acting injection containing enrofloxacin and flunixin, the peak concentrations of enrofloxacin and flunixin (C max ) No significant increase was seen, but the time to peak (T max ) Elimination half-life (T) 1/2λz ) And Residence Time (MRT) 0→t ) Obviously prolonged, good safety and excellent slow release effect.
Table 6 pharmacokinetic parameters of enrofloxacin in test pigs (n=6)
Figure BDA0002136787600000132
Table 7. Pharmacokinetic parameters of flunixin in test pigs (n=6)
Figure BDA0002136787600000133
Figure BDA0002136787600000141

Claims (3)

1. A compound long-acting injection containing enrofloxacin and flunixin is characterized by comprising enrofloxacin and lactic enrofloxacin, flunixin and fluni Xin Baoge in a dispersed form, a suspending agent, a wetting agent and a dispersing medium;
each 1000mL of injection comprises: 100.0g of enrofloxacin, 50.0g of enrofloxacin lactate calculated by enrofloxacin, 30.0g of flunixin, 70.0g of flunixin Xin Jifu Ni Xin Baoge, 12.8g of aluminum monostearate, 3.1g of hydrogenated castor oil, 0.5g of microcrystalline wax, 3.0g of tween 80, 60.0 g of span, 2.0g of lecithin and the balance of dispersion medium ethyl oleate;
the enrofloxacin or the lactic enrofloxacin is subjected to superfine grinding treatment, 90% of particles have a particle size less than or equal to 15 mu m, and particles with a particle size more than 50 mu m cannot be detected;
the preparation method of the flunixin inclusion compound comprises the following steps: adding ethylated beta-cyclodextrin and flunixin into 60% ethanol aqueous solution according to a molar ratio of 1-2:1, wherein the ratio of the volume of the ethanol aqueous solution to the total mass of the flunixin and the ethyl beta-cyclodextrin is 20-30:1, uniformly mixing, performing ultrasonic treatment, transferring into a colloid mill, starting up for 10-20 minutes, adding 60% ethanol aqueous solution with the same amount as the first addition, and continuing to operate for 0.5-1 hour; spray drying and granulating to obtain flunixin Xin Baoge, wherein the particle size of the flunixin inclusion compound is controlled to be less than or equal to 15 μm and the particle size of the flunixin inclusion compound is controlled to be 90%, and 50 μm or more particles cannot be detected.
2. The enrofloxacin and flunixin-containing compound long-acting injection according to claim 1, wherein the flunixin Xin Jingchao in a dispersed form is subjected to micro-pulverization treatment, 90% of particles have a particle size of less than or equal to 5 μm, and no particles above 25 μm are detected.
3. The method for preparing the compound long-acting injection containing enrofloxacin and flunixin according to claim 1, which is characterized by comprising the following steps:
(a) Heating the dispersion medium ethyl oleate to 150-180 ℃ and continuing for 1h;
(b) Taking 700mL of heated ethyl oleate, cooling to 120-140 ℃, adding aluminum monostearate and hydrogenated castor oil, and maintaining for 1-2h to completely gel the aluminum monostearate and the hydrogenated castor oil; cooling to 40-60deg.C, adding microcrystalline wax, tween 80, span 60, lecithin, enrofloxacin lactate, fluni Xin Baoge and flunixin, stirring, heating, cooling to room temperature, and metering volume to 1000mL with ethyl oleate;
(c) Detecting granularity and content; and (5) packaging after the qualified product, and sterilizing for 30 minutes at 115 ℃ to obtain the compound long-acting injection containing enrofloxacin and flunixin.
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