CN109568316A - Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin - Google Patents
Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin Download PDFInfo
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- CN109568316A CN109568316A CN201811553617.0A CN201811553617A CN109568316A CN 109568316 A CN109568316 A CN 109568316A CN 201811553617 A CN201811553617 A CN 201811553617A CN 109568316 A CN109568316 A CN 109568316A
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- flunixin
- polyoxyethylene
- ceftiofur
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- stearate
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- 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]
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- 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
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Abstract
The invention discloses a kind of compound long-acting injection containing Ceftiofur and Flunixin, every 1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 20~300g, in a dispersed form existing Flunixin or flunixin meglumine (in terms of Flunixin) 10~200g, Flunixin or flunixin meglumine solid dispersions (in terms of Flunixin) 10~200g, 0.5~100g of macromolecule retarding agent, 0.5~100g of wetting agent, 0.2~50g of antioxidant, surplus is decentralized medium.Ceftiofur has good stability in injection of the present invention, is long placed in and is no longer layered, while having clear improvement to the wall built-up phenomenon of injection；Only inject 1 time, can press down and kill bacterial infection again and can alleviate in time heat, pain and inflammation that infection causes, treating both manifestation and root cause of disease, save the cost is time saving and energy saving, can more enhance animal compliance, reduces Animal stress, promote and improvement disease lapse to and prognosis.
Description
Technical field
The invention belongs to animal specific field of pharmaceutical preparations, are related to a kind of injection and its system containing Ceftiofur and Flunixin
Preparation Method.
Background technique
Ceftiofur (Ceftiorfur) is the third generation cephalosporin of animal specific, commonly uses its hydrochloride, sodium salt or head
Spore thiophene furan has broad-spectrum bactericidal action.To gram-positive bacteria such as staphylococcus aureus, staphylococcus epidermis, suppuration hammer
Bacterium, Arcanobacterium pyogenes, mammitis correlation streptococcus (breast, agalasisa and stop cream etc.), Gram-negative bacteria such as Pasteurella, sand
Door bacterium, Actinobacillus pleuropneumoniae, Escherichia coli etc. have stronger suppression to kill activity, and to most drug-fast bacterias for producing beta lactamase
Also there is very strong inhibitory or killing effect.This product is for oral administration not to be absorbed, and intramuscular and subcutaneous injection absorbs rapidly, widely distributed in vivo, in blood
It is high with the drug concentration in tissue, active metabolin deoxidation furoyl Ceftiofur is generated in vivo, further generation
It thanks as inactive product, is drained from urine and excrement.Horse, ox, sheep, pig, dog, chicken Half-life in vivo are respectively 3.2h, 7.1h, 2.2
~3.9h, 14.5h, 4.1h and 6.8h, it is most of interior for 24 hours by urine and excrement discharge after injection.
Ceftiofur is very widely used in veterinary clinic.In milk cattle cultivating clinic, injectable or latex dust injection administration, in
Before dry milk or lactation period drug administration preventing and controlling mastitis for milk cows, postpartum injection prevent postpartum infection, can also prevent and treat hysteritis, rotten hoof
Disease and respiratory disease is caused by Mannheimia haemolytica, pasteurella multocida and Haemophilus somnus etc.；It can also be used for controlling
Treat claw ill etc..It is clinical in pig raising, it can be used for treating pasteurella multocida, Actinobacillus pleuropneumoniae and Streptococcus suis
Etc. causing respiratory disease, the escherichia coli Huang dysentery of piglet etc..Ceftiofur can be used for the sensitive bacteria infectivity disease of sheep, horse etc.
Disease.In pet clinic, Ceftiofur treats the diseases such as a variety of sensitive bacterias infection of dog, cat, or cooperation other drugs treatment dog ephritis
Disease.Poultry farming clinic Ceftiofur is for preventing the bacteriums such as Escherichia coli, Pasteurella, the staphylococcus of chicken, duck, turkey etc.
Property disease.
Flunixin (also known as flunixin) is the non-steroidal anti-inflammatory drugs (NSAIDs) of animal specific, is commonly used in veterinary clinic
Its meglumine salt-flunixin meglumine (Flunixin Meglumine, FM), analgesic activity is suitable with routine dose morphine, but
Tolerance and dependence phenomenon without morphine；Anti-inflammatory effect is 4 times of phenylbutazone, 2 times of Ketoprofen.This product is oral, intramuscular injection and
Subcutaneous injection absorbs rapidly, and peak time is short, widely distributed, eliminate it is very fast, after drug administration by injection ox, sheep, horse, dog, pig and
Chicken intracorporal elimination half-life period is respectively 8h, 9h, 6h, 3.7h, 8.5h, 6.8h.The flunixin meglumine injection listed
Recommend dosage regimen are as follows: 1~2 times/day, can be used cooperatively with antibiotic.
On veterinary clinic, flunixin meglumine is often combined with antimicrobial, is alleviated the symptoms such as various inflammation, pain, is such as controlled
Treat founder, arthritis, hysteritis, the alleviation post-partum pain etc. of ox, treatment sow mammitis, hysteritis and agalasisa syndrome disease
Shape, the symptom of the related diseases such as treatment dog, cat peritonitis, arthritis, fever, diarrhea.Have not yet to see Flunixin and antimicrobial
Compound preparation listing, clinical disease prevention and treatment is generally required to be administered respectively, be injected respectively, time-consuming and laborious, causes dual wound to animal
Evil, exacerbation stress, increase expense lessens the curative effect again.Currently, the clinical Ceftiofur listed and Flunixin associated syringe liquid are equal
For short-acting conventional formulation, daily administration is needed 1~2 time, and a course for the treatment of needs multi-day dosing, and to make up clinical shortcomings, inventor is sent out
A kind of bright compound long-acting preparation containing Ceftiofur and Flunixin, realizes that a course for the treatment of is only administered 1~2 time, time saving and energy saving, saves
Cost reduces Animal stress simultaneously, more conducively disease lapse to and prognosis.But Ceftiofur class raw material is found during the preparation process
Stability is poor, there are stability in long-term placement process is poor, the defects of related substance is exceeded；And flunixin meglumine absorption is fast
Speed, blood concentration Wave crest and wave trough difference is obvious, and safety is difficult to control, and efficiency time is not easy the defects of guaranteeing.
Summary of the invention
Simple, easy to use, drug release is prepared slowly containing Ceftiofur and fluorine Buddhist nun the purpose of the present invention is to provide a kind of
Pungent compound long-acting injection, the Ceftiofur raw material in the long-acting injection is through micronization processes, Control granularity D90≤5 μm；
Solid dispersions slow release drug is made in Flunixin a part in the long-acting injection, and another part is directly scattered in injection
In liquid system, action faster, to obtain excellent slow release effect；Antioxidant is added in the long-acting injection, is guaranteed
The stability of Ceftiofur while being sustained effective, is realized safely controllable.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of compound long-acting injection containing Ceftiofur and Flunixin, including it is Ceftiofur, existing in a dispersed form
Flunixin and/or flunixin meglumine, Flunixin and/or flunixin meglumine solid dispersions, macromolecule retarding agent, wetting
Agent, antioxidant, decentralized medium；Every 1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 20~300g, with dispersion
Flunixin or flunixin meglumine existing for form (in terms of Flunixin) 10~200g, Flunixin or flunixin meglumine solid point
Granular media (in terms of Flunixin) 10~200g, 0.5~100g of macromolecule retarding agent, 0.5~100g of wetting agent, antioxidant 0.2~
50g, surplus are decentralized medium.
Preferably, every 1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 50~250g, depositing in a dispersed form
Flunixin or flunixin meglumine (in terms of Flunixin) 10~80g, Flunixin or flunixin meglumine solid dispersions (with
Flunixin meter) 30~150g, 1~50g of macromolecule retarding agent, 0.5~30g of wetting agent, 0.1~10g of antioxidant, surplus is point
Dispersion media.
It is further preferred that every 1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 100~150g, with point
Flunixin or flunixin meglumine (in terms of Flunixin) 10~60g, Flunixin or flunixin meglumine solid existing for the form of dissipating
Dispersion (in terms of Flunixin) 30~100g, 10~20g of macromolecule retarding agent, 8~15g of wetting agent, 0.2~2g of antioxidant,
Surplus is decentralized medium.
Diameter of particle D90≤15 μm in the compound long-acting injection containing Ceftiofur and Flunixin, should not detect
50 μm or more of particle.
The Ceftiofur is any in Ceftiofur Hydrochloride, ceftiofur sodium, the free acid crystal of Ceftiofur
It is one or more.
The Ceftiofur passes through micronization processes, particle size D90≤5 μm.Micro mist equipment is fluidized bed supersonic speed
The step of jet mill grinding machine, micronization processes are as follows: (1), by raw material pour into charger；(2), by worm propeller by material
It is sent into pulverizer, the size of material inlet provides instruction, charging motor frequency control by controller；(3), material is crushing
Chamber mutually with mutually self head-on collision of 3 Mach velocities, reaches crushing purpose；(4), granularity fineness is by grader frequency control；(5),
The direct rewinding bucket aggregation of qualified material is collected；Equipment runs major parameter are as follows: voltmeter 380V, pressure gauge 0-13kg, pulse instrument
For the interpulse period 20s that moves in circles, grader frequency control frequency 40Hz.
In the Flunixin or flunixin meglumine solid dispersions containing 20%~50% Flunixin；Flunixin or
The granularity of flunixin meglumine solid dispersions is D90≤5 μm.
The Flunixin or flunixin meglumine solid dispersions is prepared using spray drying process, comprising: is taken
Flunixin (or flunixin meglumine), ethyl cellulose, PLURONICS F87, the mass ratio of ethyl cellulose and PLURONICS F87
For (1~4): (0.05~0.5) is dissolved in 50%~70% (V/V) ethanol water, and spray drying obtains Flunixin solid
Dispersion or flunixin meglumine solid dispersions.Drying process with atomizing parameter are as follows: solution pump applied sample amount is 1.6L/h, hot air flow
Amount is 0.45m3/ min, high pressure gas gas output are 10L/min, and inlet temperature is 50 DEG C, and acquisition solid dispersions granularity is D90
≤5μm。
The macromolecule retarding agent be selected from polyvinyl alcohol, hypromellose, hyetellose, hydroxypropylcellulose,
Sodium carboxymethylcellulose, hyaluronic acid, xanthan gum, chitosan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, tristearin
Acid, aluminium distearate, aluminum stearate, rilanit special, beeswax, microwax, yellow wax, Chinese wax, polylactic acid, gathers aluminum monostearate
Poly lactic coglycolic acid (PLGA), polycaprolactone (PCL), polyoxyethylene beeswax, tristerin, polyglycereol oleic acid
Any one or more of ester, pegoxol 7 stearate.
The wetting agent is selected from lecithin, soybean lecithin, hydroxylated lecithin, polysorbas20, polysorbate40, polysorbate60, tween
80, Pluronic/Lutrol F 44, PLURONICS F87, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, span 20, span 40,
Sorbester p18, sorbester p38, sorbester p17, span 85, propylene glycol diacetate, propylene glycol monostearate, sodium lactate, stearic acid lactic acid
Sodium, four oleyl ether of polyoxyethylene (30EO) sorbierite, four stearyl ether of polyoxyethylene (60EO) sorbierite, the mountain polyoxyethylene (40EO)
Four oleic acid ether of pears alcohol, four oleate of polyoxyethylene (60EO) sorbierite, polyoxyethylene (8) stearate, polyoxyethylene (12) are hard
Resin acid ester, polyoxyethylene (24) stearate, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, polyoxy second
Alkene (100) stearate, polyoxyethylene (110) stearate, polyoxyethylene (10) rilanit special, polyoxyethylene (30) hydrogenation
Castor oil, polyoxyethylene (40) rilanit special, polyoxyethylene (50) rilanit special, polyoxyethylene (60) rilanit special,
Polyoxyethylene (10) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (60) castor oil,
The single oleic acid of polyoxyethylene (80) castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (200) castor oil, polyoxyethylene (300)
Ester, polyoxyethylene (400) monoleate, polyoxyethylene (600) monoleate, castor oil, Labraso,
Sefsol 218, propylene glycol monolaurate, Unigly GO 102S, -3 pairs of isostearates of polyglycereol, stearic acid polyoxy
Ethylene Glycol ester, lauric acid polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glyceride, three whales
Any one or more in wax stereth -4- phosphate etc..
The antioxidant be selected from alpha-tocopherol, propylgallate, ascorbyl palmitate, to hydroxy tert-butyl
Anisole (BHA), toluene di-tert-butyl phenol (BHT), gallic acid or its esters etc..
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
Acid, Ergol, isopropyl myristate, formal glycerine, glyceryl monooleate, Masine 35-1 etc. it is any one
Kind is a variety of.
It is a further object to provide the systems of the compound long-acting injection containing Ceftiofur and Flunixin
Preparation Method, comprising:
(a), decentralized medium is in 150~180 DEG C of 1~2h of high-temperature process；
(b), when the macromolecule retarding agent of use includes aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special
At least one of when, the decentralized medium for accounting for injection total volume 50~70% is taken, at 120~140 DEG C, into decentralized medium
At least one of aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special is added, maintains 1-2h, hinders macromolecule
Stagnant dose of complete gelatinization；90~70 DEG C are cooled to, is added in addition to aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special
Macromolecule retarding agent；40 DEG C are cooled to hereinafter, wetting agent, antioxidant, Ceftiofur, existing in a dispersed form is added
Flunixin or flunixin meglumine, Flunixin or flunixin meglumine solid dispersions, high-pressure homogeneous or high speed shear processing 1~
2h；
When the macromolecule retarding agent of use does not include aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special
When, the decentralized medium for accounting for injection total volume 50~70% is taken, macromolecule retarding agent is added at 70~90 DEG C of temperature；In temperature
No more than at 40 DEG C, wetting agent, antioxidant, Ceftiofur, in a dispersed form existing Flunixin or Flunixin Portugal first is added
Amine, Flunixin or flunixin meglumine solid dispersions, the processing of high-pressure homogeneous or high speed shear；
(c), the decentralized medium being cooled to room temperature is taken, scale is settled to；Detect granularity, related substance and content；After qualification
Packing to get.
Preferably, in step (b), granularity D90≤5 μm of Ceftiofur；Existing Flunixin or fluorine Buddhist nun in a dispersed form
Granularity D90≤5 μm of granularity D90≤5 μm of pungent meglumine, Flunixin or flunixin meglumine solid dispersions.
The high-pressure homogeneous pressure is 20000psi；25000 turns/the min of revolving speed of the high speed shear.
The beneficial effects of the present invention are:
(1), the compound long-acting injection preparation technology of the invention containing Ceftiofur and Flunixin is simple, repeatability between batch
It is good；
(2), Ceftiofur has good stability in the compound long-acting injection of the invention containing Ceftiofur and Flunixin, more
Safely and effectively；
(3), the compound long-acting injection of the invention containing Ceftiofur and Flunixin, is only injected 1 time, can be pressed down and be killed infection carefully
Bacterium can alleviate heat, pain and the inflammation that infection causes in time again, and treating both manifestation and root cause of disease, save the cost is time saving and energy saving, and it is suitable more to enhance animal
Ying Xing, reduce Animal stress, promote and improve disease lapse to and prognosis.
(4), the compound long-acting injection of the invention containing Ceftiofur and Flunixin, good biocompatibility, irritation is small, peace
Quan Xinggao.
(5), the compound long-acting injection of the invention containing Ceftiofur and Flunixin is long placed in latter two ingredient and is no longer layered, together
When have clear improvement to the wall built-up phenomenon of injection.
Specific embodiment
Technical solution of the present invention is described further below by specific embodiment.
Ceftiofur micronization processes obtain the particle of granularity D90≤5 μm, and micro mist equipment is fluidized bed supersonic airstream powder
The step of broken grader, micronization processes are as follows: (1), by raw material pour into charger；(2), material is sent into powder by worm propeller
Broken machine, the size of material inlet provide instruction, charging motor frequency control by controller；(3), material is mutual in crushing chamber
With mutually self head-on collision of 3 Mach velocities, reach crushing purpose；(4), granularity fineness is by grader frequency control；(5), qualified object
Expect that direct rewinding bucket aggregation is collected；Equipment runs major parameter are as follows: voltmeter 380V, pressure gauge 0-13kg, pulse instrument are circulation
Reciprocating impulse interval time 20s, grader frequency control frequency 40Hz.
Flunixin or flunixin meglumine solid dispersions are prepared using spray drying process, comprising: according to fluorine Buddhist nun
The mass ratio of pungent (or flunixin meglumine) and ethyl cellulose, PLURONICS F87 is that 1:1:0.2 weighs raw material, is dissolved in
In 50% ethanol water, spray drying obtains Flunixin solid dispersion powder or flunixin meglumine solid dispersions powder
End.Drying process with atomizing parameter are as follows: solution pump applied sample amount is 1.6L/h, hot air flow 0.45m3/ min, high pressure gas outlet
Amount is 10L/min, and inlet temperature is 50 DEG C, and acquisition solid dispersions granularity is D90≤5 μm.
Embodiment 1:
Prescription
Preparation method: taking 1000mL soybean oil, is heated to 170 DEG C, and continue 1h, is cooled to 130 DEG C later, takes out
600mL, remaining soybean oil are down to room temperature, are used for constant volume.Aluminum monostearate, hydrogen are added into 130 DEG C of 600mL temperature of soybean oil
Change castor oil, maintains 1.5h at 130 DEG C, make the complete gelatinization of aluminum monostearate, rilanit special；Let cool to 40 DEG C hereinafter, plus
Enter Tween 80, sorbester p18, lecithin, alpha-tocopherol, Ceftiofur Hydrochloride (granularity meets D90≤5 μm), flunixin meglumine
(granularity meets D90≤5 μm) and flunixin meglumine solid dispersions (granularity meets D90≤5 μm), high-pressure homogeneous (pressure is
20000psi) handle 1h；Soybean oil is added and is settled to 1000mL.Detect granularity, related substance and content；It is dispensed after qualification, i.e.,
The compound long-acting injection that Ceftiofur and Flunixin must be contained carries out external performance evaluation, including character, granularity, sedimentation to it
Volume ratio, redispersibility, syringeability are measured in relation to substance and content etc., and measurement result is shown in Table 1.
Granularity inspection: according to " Chinese veterinary pharmacopoeia " one annex 0982 of version in 2015 " granularity and determination of particle size distribution "
One method: microscopic method.Diameter of particle D90≤5 μm should not detect 50 μm or more of particle.
Sedimentation volume ratio measurement: apparatus plug graduated cylinder measures test sample 50ml, and close plug firmly shakes 1 minute, writes down suspended matter
Beginning height H0, stand, the final height H of suspended matter when writing down 3h, calculate according to the following formula: sedimentation volume ratio=H/H0。
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.
The related substance of Ceftiofur and assay: Ceftiofur Hydrochloride is infused in " veterinary medical quality standard compendium " (2011 editions)
Method under liquid item is penetrated, related substance and assay are carried out to Ceftiofur.
The related substance of Flunixin and assay: one the 188-190 pages method of " Chinese veterinary pharmacopoeia " version in 2015, to fluorine
Ni Xin carries out related substance and assay.
Embodiment 2:
Prescription
Preparation method: taking 1000mL isopropyl myristate, is heated to 160 DEG C, and continue 1h, is cooled to 130 DEG C later,
600mL is taken out, remaining isopropyl myristate is down to room temperature, is used for constant volume.Toward the myristic acid isopropyl of 130 DEG C of 600mL temperature
Aluminum monostearate is added in ester, maintains 1h at 130 DEG C, makes the complete gelatinization of aluminum monostearate；It lets cool to 40 DEG C hereinafter, being added and spits
Warm 80, sorbester p18, PLURONICS F87, lecithin, alpha-tocopherol, Ceftiofur Hydrochloride (granularity meets D90≤5 μm), Flunixin
Meglumine (granularity meets D90≤5 μm) and Flunixin solid dispersions (granularity meets D90≤5 μm), high speed shear instrument (revolving speed
1.5h is handled for 20000 turns/min)；Isopropyl myristate is added and is settled to 1000mL.It detects granularity, related substance and contains
Amount；Packing carries out external performance evaluation to it to get the compound long-acting injection containing Ceftiofur and Flunixin after qualification, wraps
Character, granularity, 3h sedimentation volume ratio are included, redispersibility, syringeability measure, external performance evaluation side in relation to substance and content etc.
Method is the same as implementation 1.
Embodiment 3:
Prescription
Preparation method: taking 1000mL soybean oil, is heated to 170 DEG C, and continue 1h, is cooled to 140 DEG C later, takes out
600mL, remaining soybean oil are down to room temperature, are used for constant volume.Aluminum monostearate, hydrogen are added into 140 DEG C of 600mL temperature of soybean oil
Change castor oil, maintains 1.5h at 140 DEG C, make the complete gelatinization of aluminum monostearate, rilanit special；Let cool to 40 DEG C hereinafter, plus
Enter PLURONICS F87, sorbester p17, lecithin, propylgallate, ceftiofur sodium (granularity meets D90≤5 μm), Flunixin
(granularity meets D90≤5 μm) and Flunixin solid dispersions (granularity meets D90≤5 μm), high-pressure homogeneous (pressure is
20000psi) handle 2h；Soybean oil is added and is settled to 1000mL.Detect granularity, in relation to substance and content；It is dispensed after qualification, i.e.,
The compound long-acting injection that Ceftiofur and Flunixin must be contained carries out external performance evaluation to it, including character, granularity, 3h sink
Volume ratio drops, and redispersibility, syringeability are measured in relation to substance and content etc., and external method of evaluating performance is the same as implementation 1.
Embodiment 4:
Prescription
Preparation method: taking 1000mL soybean oil, is heated to 170 DEG C, and continue 1h, is cooled to 130 DEG C later, takes out
600mL, remaining soybean oil are down to room temperature, are used for constant volume.Aluminum monostearate is added into the soybean oil that 600mL temperature is 130 DEG C,
1.5h is maintained at 130 DEG C, makes the complete gelatinization of aluminum stearate；Polyvinyl alcohol is added when being cooled to 90 DEG C~70 DEG C；It lets cool to 40
DEG C hereinafter, be added PLURONICS F87, sorbester p17, lecithin, alpha-tocopherol, Ceftiofur Hydrochloride (granularity meets D90≤5 μm),
Ceftiofur free acid crystal (granularity meets D90≤5 μm), Flunixin (granularity meets D90≤5 μm) and the dispersion of Flunixin solid
Body (granularity meets D90≤5 μm), high-pressure homogeneous (pressure 20000psi) handle 2h；Soybean oil is added and is settled to 1000mL.Inspection
Survey granularity, in relation to substance and content；Packing is after qualification to get the compound long-acting injection containing Ceftiofur and Flunixin, to it
Carry out external performance evaluation, including character, granularity, 3h sedimentation volume ratio, redispersibility, syringeability, in relation to substance and content etc.
Measurement, external method of evaluating performance is the same as implementation 1.
Embodiment 5:
Prescription
Preparation method: taking 1000mL ethyl oleate, is heated to 160 DEG C, and continue 1h, is cooled to 120 DEG C later, takes out
600mL, remaining ethyl oleate are down to room temperature, are used for constant volume.Hydrogenation castor is added into the ethyl oleate that 600mL temperature is 120 DEG C
Sesame oil maintains 1.5h at 120 DEG C, makes its complete gelatinization；Polyvinyl alcohol and Chinese wax is added when being cooled to 90 DEG C~70 DEG C；It lets cool
To 40 DEG C hereinafter, PLURONICS F87, sorbester p17, lecithin, toluene di-tert-butyl phenol, the free acid crystal of Ceftiofur is added
(granularity meets for (granularity meets D90≤5 μm), flunixin meglumine (granularity meets D90≤5 μm) and Flunixin solid dispersions
D90≤5 μm), high speed disperser (25000 turns/min of revolving speed) shears 2h；Ethyl oleate is added and is settled to 1000mL.Detect grain
It spends, in relation to substance and content；Packing carries out it to get the compound long-acting injection containing Ceftiofur and Flunixin after qualification
External performance evaluation, including character, granularity, 3h sedimentation volume ratio, redispersibility, syringeability are measured in relation to substance and content etc.,
External method of evaluating performance is the same as implementation 1.
Performance evaluation outside compound long-acting injecting fluid of the table 1. containing Ceftiofur and Flunixin
Note: * represents redispersibility energy, and the fewer redispersibility of * is better.+ syringeability is represented ,+to represent syringeability better more.
Study on the stability
The sample for taking 5 embodiments to prepare, respectively at high temperature (60 DEG C), Qiang Guang (4500 ± 500lx of illumination), high humidity (phase
To humidity 90% ± 5%) under the conditions of place 10 days, with 0 day compare, carry out sample stability preliminary examinations, the results are shown in Table 2.By
For table 2 as it can be seen that placing 10 days, each index meets regulation, with comparison in 0 day without significant change, shows containing Ceftiofur and Flunixin
Compound long-acting injection quality meet regulation, and preparation stabilization.
Compound long-acting injection influence factor test result of the table 2. containing Ceftiofur and Flunixin
The sustained release performance of compound long-acting injection containing Ceftiofur and Flunixin is evaluated
The sustained release performance of compound ceftiofur injection is evaluated
18 health beasle dogs 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: the 10% Ceftiofur Hydrochloride note listed by 5mg/kgB.W. dosage (in terms of Ceftiofur) single intramuscular injection
Penetrate liquid (Qilu Animal Health Products Co., Ltd.'s production)；2nd group: by 2.2mg/kgB.W. dosage (in terms of Flunixin) single flesh
Meat injects the flunixin meglumine injection (Qilu Animal Health Products Co., Ltd.'s production) listed；3rd group: by with cephalo thiophene
Furan meter dosage is 10mg/kgB.W., or dosage is answering for 5mg/kgB.W. single intramuscular injection embodiment 1 in terms of Flunixin
Square long-acting injection；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 cave, about 4mL, is placed in heparin sodium and adopts every time
In blood vessel.The blood sample of acquisition is centrifuged 10min through 4000r/min, draws upper plasma in PA tube, and after label, sealing is kept away
Light, -20 DEG C of preservations are to be measured.Using the plasma sample of HPLC measuring method detection different time points, blood concentration-time number is obtained
According to through 5.2 software of WinNonlin progress pharmacokinetic parameters analysis, pharmacokinetic parameters are shown in Table 3 and table 4.
3. Ceftiofur of table is in the test intracorporal pharmacokinetic parameter of dog (n=6)
| Parameter | Unit | 1st group | 3rd group |
| Eliminate half-life period (T1/2λz) | h | 5.05±1.13 | 15.75±3.56 |
| Peak time Tmax | h | 2.75±0.76 | 12.12±5.15 |
| Cmax Cmax | μg/mL | 36.97±2.18 | 45.52±4.09 |
| Area under the drug-time curve AUC0→t | h*μg/mL | 389.36±6.73 | 890.13±14.78 |
| Apparent volume of distribution V | mL/kg | 96.51±23.05 | 212.59±40.52 |
| Residence time MRT0→t | h | 9.35±2.87 | 14.28±2.77 |
4. Flunixin of table is in the test intracorporal pharmacokinetic parameter of dog (n=6)
By table 3 and table 4 as it can be seen that in the case where being single-dose, with regular hydrochloric acid Cefliofur injection, Flunixin
Meglumine injection is compared, and after long-acting injection of the dog intramuscular injection containing Ceftiofur and Flunixin, Ceftiofur and Flunixin are in dog
Intracorporal elimination half-life period and residence time greatly prolong, and blood concentration does not significantly rise.Show the present invention containing head
The long-acting injection of spore thiophene furan and Flunixin, slow releasing function is obvious, and does not have phenomenon of burst release, and safety is good, can be realized one
1-2 purpose is only administered in the course for the treatment of, and one course for the treatment of of regular injection liquid is avoided to need Animal stress caused by multiple dosing more advantageous
In the performance of drug effect.
Add influence of the antioxidant to cephalo stability in the long-acting injection containing Ceftiofur and Flunixin
The prescription for respectively referring to embodiment 1-5 does not add antioxidant, as a comparison case 1-5.By embodiment 1-5, comparison
The sample of example 1-5, which is placed at 60 DEG C of high temperature, to be placed 10 days, is compared the stability of Ceftiofur, be the results are shown in Table 5.
Influence of 5. antioxidant of table to suspension performance
By table 5 as it can be seen that the compound injection containing Ceftiofur and Flunixin of addition antioxidant places 10 at high temperature
After it, the related substance of Ceftiofur meets regulation, after the sample without adding antioxidant is placed at high temperature, character hair
It is raw to change, color burn, and related substance significantly increases, and exceeds normal limit, content significantly reduces.Show to add anti-oxidant
Agent can greatly increase the stability of Ceftiofur.
Claims (10)
1. a kind of compound long-acting injection containing Ceftiofur and Flunixin, it is characterised in that including Ceftiofur, to disperse shape
Flunixin and/or flunixin meglumine existing for formula, Flunixin and/or flunixin meglumine solid dispersions, macromolecule retardance
Agent, wetting agent, antioxidant, decentralized medium；Every 1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 20~
300g, in a dispersed form existing Flunixin or flunixin meglumine (in terms of Flunixin) 10~200g, Flunixin or Flunixin
Meglumine solid dispersions (in terms of Flunixin) 10~200g, 0.5~100g of macromolecule retarding agent, 0.5~100g of wetting agent, resist
0.2~50g of oxidant, surplus are decentralized medium.
2. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that every
1000mL injection contains: Ceftiofur (in terms of Ceftiofur) 50~250g, in a dispersed form existing Flunixin or fluorine Buddhist nun
10~80g of pungent meglumine (in terms of Flunixin), Flunixin or flunixin meglumine solid dispersions (in terms of Flunixin) 30~
150g, 1~50g of macromolecule retarding agent, 0.5~30g of wetting agent, 0.1~10g of antioxidant, surplus is decentralized medium.
3. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that described
Ceftiofur is selected from one of Ceftiofur Hydrochloride, ceftiofur sodium, the free acid crystal of Ceftiofur or a variety of；The head
Granularity D90≤5 μm of spore thiophene furan.
4. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that described
In Flunixin or flunixin meglumine solid dispersions containing 20%~50% Flunixin；The Flunixin or Flunixin Portugal
The granularity of methylamine solid dispersions is D90≤5 μm.
5. the compound long-acting injection according to claim 1 or 4 containing Ceftiofur and Flunixin, it is characterised in that described
Flunixin or flunixin meglumine solid dispersions be as made from following methods: take Flunixin or flunixin meglumine, second
Base cellulose, PLURONICS F87 are dissolved in 50%~70% ethanol water, and spray drying obtains the dispersion of Flunixin solid
Body or flunixin meglumine solid dispersions；Wherein, the mass ratio of ethyl cellulose and PLURONICS F87 is (1~4): (0.05
~0.5).
6. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that described
Macromolecule retarding agent be selected from polyvinyl alcohol, hypromellose, hyetellose, hydroxypropylcellulose, sodium carboxymethylcellulose,
Hyaluronic acid, xanthan gum, chitosan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, stearic acid, aluminum monostearate, two
Aluminum stearate, aluminum stearate, rilanit special, beeswax, microwax, yellow wax, Chinese wax, polylactic acid, poly lactic-co-glycolic acid copolymerization
Object, polycaprolactone, polyoxyethylene beeswax, tristerin, Unigly GO 102S, pegoxol 7 stearate it is any
It is one or more.
7. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that described
Wetting agent be selected from lecithin, soybean lecithin, hydroxylated lecithin, polysorbas20, polysorbate40, polysorbate60, Tween 80, Pluronic/Lutrol F 44,
PLURONICS F87, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, span 20, span 40, sorbester p18, sorbester p38,
Sorbester p17, span 85, propylene glycol diacetate, propylene glycol monostearate, sodium lactate, stearic acid sodium lactate, polyoxyethylene
Four oleyl ether of (30EO) sorbierite, four stearyl ether of polyoxyethylene (60EO) sorbierite, four oleic acid of polyoxyethylene (40EO) sorbierite
Ether, four oleate of polyoxyethylene (60EO) sorbierite, polyoxyethylene (8) stearate, polyoxyethylene (12) stearate, polyoxy
Ethylene (24) stearate, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, polyoxyethylene (100) are stearic
Acid esters, polyoxyethylene (110) stearate, polyoxyethylene (10) rilanit special, polyoxyethylene (30) rilanit special, polyoxy
Ethylene (40) rilanit special, polyoxyethylene (50) rilanit special, polyoxyethylene (60) rilanit special, polyoxyethylene (10)
Castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80)
Castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (200) castor oil, polyoxyethylene (300) monoleate, polyoxyethylene
(400) monoleate, polyoxyethylene (600) monoleate, castor oil, Labraso, propylene glycol Dan Xin
Acid esters, propylene glycol monolaurate, Unigly GO 102S, -3 pairs of isostearates of polyglycereol, stearic acid polyoxyethylene glyceride,
Lauric acid polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glyceride, three cetostearyl alcohols are poly-
One of ether -4- phosphate is a variety of.
8. the compound long-acting injection according to claim 1 containing Ceftiofur and Flunixin, it is characterised in that described
Antioxidant is selected from alpha-tocopherol, propylgallate, ascorbyl palmitate, tert-butyl tert-butyl ether, two tertiary fourths
Base p-cresol, gallic acid or its esters.
9. the compound long-acting injection according to claim 1 containing Ceftiofur 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
One of isopropyl myristate, formal glycerine, glyceryl monooleate, Masine 35-1 are a variety of.
10. the preparation method of the compound long-acting injection described in claim 1 containing Ceftiofur and Flunixin, it is characterised in that
Include:
(a), decentralized medium is in 150~180 DEG C of 1~2h of high-temperature process；
(b), when the macromolecule retarding agent of use include aluminum monostearate, aluminium distearate, aluminum stearate, in rilanit special
When at least one, the decentralized medium for accounting for injection total volume 50~70% is taken, at 120~140 DEG C, is added into decentralized medium
At least one of aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special maintain 1-2h, make macromolecule retarding agent
Complete gelatinization；90~70 DEG C are cooled to, the height in addition to aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special is added
Molecule retarding agent；40 DEG C are cooled to hereinafter, wetting agent, antioxidant, Ceftiofur, in a dispersed form existing fluorine Buddhist nun is added
Pungent or flunixin meglumine, Flunixin or flunixin meglumine solid dispersions, high-pressure homogeneous or high speed shear handle 1~2h；
When the macromolecule retarding agent of use does not include aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special, take
Macromolecule retarding agent is added in the decentralized medium for accounting for injection total volume 50~70% at 70~90 DEG C of temperature；Do not surpass in temperature
It crosses at 40 DEG C, wetting agent, antioxidant, Ceftiofur, in a dispersed form existing Flunixin or flunixin meglumine, fluorine is added
Buddhist nun is pungent or flunixin meglumine solid dispersions, high-pressure homogeneous or high speed shear are handled；
(c), the decentralized medium being cooled to room temperature is taken, scale is settled to.
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| CN110327294A (en) * | 2019-07-19 | 2019-10-15 | 南京农业大学 | Compound long-acting injection and preparation method thereof containing Enrofloxacin and Flunixin |
| CN112516076A (en) * | 2020-12-16 | 2021-03-19 | 郑州百瑞动物药业有限公司 | In-situ gel for ceftiofur injection and preparation method thereof |
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| CN112516076A (en) * | 2020-12-16 | 2021-03-19 | 郑州百瑞动物药业有限公司 | In-situ gel for ceftiofur injection and preparation method thereof |
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